# Patent

## Title
Process for the preparation of substituted cycloserines

## Abstract

The present invention relates to processes for the preparation of substituted cycloserine compounds of formula (I) wherein R1 is C1-C8alkyl, C1-C8haloalkyl, C3-C6cycloalkyl, aryl or aryl substituted by one to five R11, or aryl-C1-C4alkylene or aryl-C1-C4alkylene substituted by one to five R11; and each R11 is independently C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, cyano or halogen; The invention also relates to intermediates produced by the processes. Compounds of formula (I) are useful intermediates for the production of compounds in the agricultural and pharmaceutical fields.

## Background
RELATED APPLICATION INFORMATION
This application is a 371 of International Application No. PCT/EP2015/059612, filed 30 Apr. 2015, which claims priority to EP Patent Application No. 14166654.5, filed 30 Apr. 2014, the contents of which are incorporated by reference herein.
The present invention relates to novel methods of producing 2-substituted cycloserines (4-amino-isoxazolidin-3-one) and intermediates useful in the preparation of 2-substituted cycloserines.
2-substituted cycloserines are useful intermediates in the preparation of certain insecticidally active compounds, for example those described in WO2011/067272 and WO2012/163959. Some cycloserines are also used as broad spectrum antibiotics.
2-substituted cycloserines are prepared in WO2011/067272 according to the method described in Chem. Pharm. Bull. 2002, 50(4) 554-557, which involves alkylation of the parent cycloserine or cycloserine derivative such as a tert-butyloxycarbonyl. Similar procedures are described in Tet. Lett. 2012, 2564-2567.
The main drawbacks of the known methods of alkylating cycloserines include the formation of isomeric by-products arising from O-alkylation instead of the desired N-alkylation, and possible epimerisation of the cycloserine stereo-centre, particularly when strongly basic conditions are employed. There are also limitations imposed by the low reactivity and accessibility of the corresponding alkylation reagents.
It has been found that the insecticides described in WO2011/067272 and WO2012/163959 are more efficacious when the cycloserine moiety is present in the molecule with the D stereo-configuration, making it particularly desirable to find methods of derivatising cycloserine that reduce epimerisation.
Although regioselective derivatisation of cycloserine has been described in Tet. Lett. 2012, 2564-2567, special equipment was needed and this method is not appropriate for commercial scale production.
Methods of derivatising cycloserines have now surprisingly been found that allow preparation of 2-substituted cycloserines without requiring cycloserine starting material. These methods also provide further advantages by avoiding the need for protecting groups and allowing preparation of 2-substituted cycloserines with a defined stereo configuration.
In an aspect the invention provides a process for the preparation of a compound of formula (I)




wherein

R1 is C1-C8alkyl, C1-C8haloalkyl, aryl or aryl substituted by one to five R11, or aryl-C1-C4alkylene or aryl-C1-C4alkylene substituted by one to five R11; and

each R11 is independently C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, cyano or halogen;

comprising

a. reacting a compound of formula (II) or a salt thereof





wherein R1 is as defined for the compound of formula (I)

with a compound of formula (III)





wherein R2 is a leaving group, for example halogen, C1-C8alkylsulfonyloxy, C1-C8haloalkylsulfonyloxy, C1-C8arylsulfonyloxy or C1-C8arylsulfonyloxy substituted by one to five R11, or a phosphonate ester; and each R11 is as defined for the compound of formula (I) in the presence of a base.

Examples of suitable and preferred bases for performing the step a. are given below.
In an aspect the invention provides a process for the preparation of a compound of formula (I)




wherein

R1 is C1-C8alkyl, C1-C8haloalkyl, aryl or aryl substituted by one to five R11, or aryl-C1-C4alkylene or aryl-C1-C4alkylene substituted by one to five R11; and

each R11 is independently C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, cyano or halogen;

comprising

a-1. reacting the compound of formula (II) with the compound of formula (III) to produce the compound of formula (IV) or a salt thereof





wherein R1 and R2 are as defined for the compound of formula (I) and formula (III) in the presence of a suitable acid; and

a-2. converting the compound of formula (IV) to the compound of formula (I) in the presence of a suitable base.

Examples of suitable acids used in the step a-1 and preferred acids used in the step a-1 are given below.
Examples of suitable bases used in the step a-2 and preferred bases used in the step a-2 are given below.
In a further aspect the invention provides a process for the preparation of a compound of formula (IV) comprising performing step a-1 as defined above. In a further aspect the invention provides a process for the preparation of a compound of formula (I)




wherein

R1 is C1-C8alkyl, C1-C8haloalkyl, aryl or aryl substituted by one to five R11, or aryl-C1-C4alkylene or aryl-C1-C4alkylene substituted by one to five R11; and

each R11 is independently C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, cyano or halogen;

comprising the step a-2

a-2. converting the compound of formula (IV)





wherein

R1 is C1-C8alkyl, C1-C8haloalkyl, aryl or aryl substituted by one to five R11, or aryl-C1-C4alkylene or aryl-C1-C4alkylene substituted by one to five R11;

R2 is C1-C8alkylsulfonyloxy, C1-C8haloalkylsulfonyloxy, C1-C8arylsulfonyloxy or C1-C8arylsulfonyloxy substituted by one to five R11, or a phosphonate ester; and

each R11 is independently C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, cyano or halogen; to the compound of formula (I) in the presence of a suitable base.

In a further aspect the invention provides a process for the preparation of a compound of formula (I) comprising performing step a-2. as defined above. In a further aspect the invention provides a process for the preparation of a compound of formula (IV)




wherein R1 and R2 are as defined for the compound of formula (I) and formula (III) comprising reacting according to the step a-1. the compound of formula (II) with the compound of formula (III) to produce the compound of formula (IV)

In one aspect the present invention relates to a process for the preparation of a compound of formula (I)




wherein

R1 is C1-C8alkyl, C1-C8haloalkyl, aryl or aryl substituted by one to five R11, or aryl-C1-C4alkylene or aryl-C1-C4alkylene substituted by one to five R11; and

each R11 is independently C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, cyano or halogen;

comprising

reacting a compound of formula (II) or a salt thereof





wherein R1 is as defined for the compound of formula (I);

with a compound of formula (III)





in the presence of a base

wherein

R2 is a leaving group selected from halogen, C1-C8alkylsulfonyloxy, C1-C8haloalkylsulfonyloxy, C1-C8arylsulfonyloxy or C1-C8arylsulfonyloxy substituted by one to five R11, or a phosphonate ester; and

each R11 is independently C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, cyano or halogen.

In one aspect the present invention relates to a process for the preparation of a compound of formula (I)




wherein

R1 is C1-C8alkyl, C1-C8haloalkyl, aryl or aryl substituted by one to five R11, or aryl-C1-C4alkylene or aryl-C1-C4alkylene substituted by one to five R11; and

each R11 is independently C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, cyano or halogen;

comprising

a-1. reacting the compound of formula (II)





with the compound of formula (III)





in the presence of a suitable acid

wherein

R2 is a leaving group selected from halogen, C1-C8alkylsulfonyloxy, C1-C8haloalkylsulfonyloxy, C1-C8arylsulfonyloxy or C1-C8arylsulfonyloxy substituted by one to five R11, or a phosphonate ester; and

each R11 is independently C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, cyano or halogen;

to produce the compound of formula (IV) or a salt thereof





wherein R1 and R2 are as defined for the compound of formula (I) and formula (III)

and

a-2. converting the compound of formula (IV) to the compound of formula (I) in the presence of a suitable base.

In one aspect the present invention relates to a process for the preparation of a compound of formula (IV)




comprising

a-1. reacting the compound of formula (II)





with the compound of formula (III)





in the presence of a suitable acid

wherein

R1 is C1-C8alkyl, C1-C8haloalkyl, aryl or aryl substituted by one to five R11, or aryl-C1-C4alkylene or aryl-C1-C4alkylene substituted by one to five R11;

R2 is a leaving group selected from halogen, C1-C8alkylsulfonyloxy, C1-C8haloalkylsulfonyloxy, C1-C8arylsulfonyloxy or C1-C8arylsulfonyloxy substituted by one to five R11, or a phosphonate ester; each R11 is independently C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, cyano or halogen.

In one aspect the present invention relates to a process for the preparation of a compound of formula (I)




comprising the step a-2

a-2. converting the compound of formula (IV)





to the compound of formula (I) in the presence of a suitable base

wherein

R1 is C1-C8alkyl, C1-C8haloalkyl, aryl or aryl substituted by one to five R11, or aryl-C1-C4alkylene or aryl-C1-C4alkylene substituted by one to five R11;

R2 is C1-C8alkylsulfonyloxy, C1-C8haloalkylsulfonyloxy, C1-C8arylsulfonyloxy or C1-C8arylsulfonyloxy substituted by one to five R11, or a phosphonate ester; and

each R11 is independently C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, cyano or halogen.

In one aspect the present invention relates to a compound of formula (IV)




wherein

R1 is C1-C8alkyl, C1-C8haloalkyl, aryl or aryl substituted by one to five R11, or aryl-C1-C4alkylene or aryl-C1-C4alkylene substituted by one to five R11;

R2 is C1-C8alkylsulfonyloxy, C1-C8haloalkylsulfonyloxy, C1-C8arylsulfonyloxy or C1-C8arylsulfonyloxy substituted by one to five R11, or a phosphonate ester; and

each R11 is independently C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, cyano or halogen;

or a salt or N-oxide thereof.

In one aspect the present invention relates to a process for the preparation of a compound of formula (I)




comprising

i. reacting a compound of formula (II) or a salt thereof





with a compound of formula (V)





in the presence of a suitable base to produce a compound of formula (VI)





and

ii. converting the compound of formula (VI) to a compound of formula (I) by treatment of the compound of formula (VI) with an aqueous base

wherein

R1 is C1-C8alkyl, C1-C8haloalkyl, C3-C6 cycloalkyl, aryl or aryl substituted by one to five R11, or aryl-C1-C4alkylene or aryl-C1-C4alkylene substituted by one to five R11; and

each R11 is independently C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, cyano or halogen;

R7 is hydroxy or halogen or OM where M is Na, K, Li.

In one aspect the present invention relates to a compound of formula (V)




wherein R7 is is OM where M is Na, K, Li.

A compound of formula (VI)




wherein

R1 is C1-C8alkyl, C1-C8haloalkyl, C3-C6 cycloalkyl, aryl or aryl substituted by one to five R11, or aryl-C1-C4alkylene or aryl-C1-C4alkylene substituted by one to five R11;

each R11 is independently C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, cyano or halogen;

or a salt or N-oxide thereof.

In one aspect the present invention relates to a compound of formula (I)




wherein R1 is aryl or aryl substituted by one to five R11;

each R11 is independently C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, cyano or halogen

A process for the preparation of a compound of formula (V)




wherein R7 is OM where M is Na, K, Li.

comprising the reaction of a compound (XV)





where R12 is C1-C4 alkyl

with an alkali metal salt MOH wherein M is Na, K, Li.

In one aspect the present invention relates to a process for the preparation of a compound of formula (V)




wherein R7 is OM where M is Na, K, Li.

comprising the reaction of a compound (XVI)





R13 is C1-C4 alkyl, benzyl or phenyl

with an alkali metal salt MOH wherein M is Na, K, Li.

In the processes above the compounds of formula (I), (III) and (IV) are preferably compounds of formula (I*), (III*) and (IV*) or enriched mixtures thereof




wherein R1 is as defined for the compound of formula (I) and R2 is a leaving group, or a salt or N-oxide thereof.

In a further aspect the invention provides a compound of formula (IV)




wherein R1 is as defined for the compound of formula (I) and R2 is a leaving group as defined below, or a salt or N-oxide thereof.

Preferably the compound of formula (IV) is a compound of formula (IV*).
In a further aspect the invention provides a process for the preparation of a compound of formula (I)




wherein

R1 is C1-C8alkyl, C1-C8haloalkyl, C3-C6 cycloalkyl, aryl or aryl substituted by one to five R11, or aryl-C1-C4alkylene or aryl-C1-C4alkylene substituted by one to five R11; and

each R11 is independently C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, cyano or halogen;

comprising

i. reacting a compound of formula (II) or a salt thereof





wherein R1 is as defined for the compound of formula (I)

with a compound of formula (V)





wherein R7 is hydroxy or halogen or OM where M is Na, K, Li.

in the presence of a suitable base to produce a compound of formula (VI)





wherein R1 as defined for the compound of formula (I); and

ii. converting the compound of formula (VI) to a compound of formula (I) by treatment of the compound of formula (VI) with an aqueous base.

Examples of suitable bases used in the step i and in the step ii and preferred bases used in the step i and in the step ii. are given below.
Preferably R1 is C1-C8alkyl, C1-C8haloalkyl, aryl or aryl substituted by one to five R11, or aryl-C1-C4alkylene or aryl-C1-C4alkylene substituted by one to five R11; and
each R11 is independently C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, cyano or halogen;
Preferably R7 is hydroxy or halogen.
Equally preferred R1 is C3-C6 cycloalkyl; and R7 is OM where M is Na, K, Li.
In a further aspect the invention provides a process for the preparation of a compound of formula (VI) as defined in above, comprising performing step i. as defined above. In a further aspect the invention provides a process for the preparation of a compound of formula (I) as defined above, comprising performing step ii. as defined above.
In the processes above the compounds of formula (I), (V) and (VI) are preferably compounds of formula (I*), (V*) and (VI*) or enriched mixtures thereof:




wherein R1 is as defined for the compound of formula (I) and R7 is as defined for the compound of formula (V).

In a further aspect the invention provides a compound of formula (VI)




wherein R1 is as defined for the compound of formula (I) or a salt of N-oxide thereof. Preferably the compound of formula (VI) is a compound of formula (VI*).

In a further aspect the invention provides a compound of formula (V)




wherein R7 is OLi, ONa or OK

In a further aspect the invention provides a compound of formula (I)




wherein R1 is aryl or aryl substituted by one to five R11.

each R11 is independently C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, cyano or halogen

All aspects of the invention may also include further processing of the compound of formula (I). In particular, the process may include reacting the compound of formula (I) with a second compound, wherein the second compound comprises a carboxylic acid, acid halide, ester or thioester functional group, and the reaction comprises reacting the amine functional group of the compound of formula (I) with the carboxylic acid, acid halide, ester or thioester functional group of the second compound such that the compound of formula (I) is coupled to the second compound via an amide functional group, or wherein the second compound comprises a dicarbonate group, and the reaction comprises reacting the amine functional group of the compound of formula (I) with the dicarbonate group of the second compound, such that the compound of formula (I) is coupled to the second compound via a carbamate functional group.
In one embodiment the second compound is a compound of formula (XII)




wherein

X is a leaving group, cyano, formyl, acetyl, C(O)CH═C(R3)R4, C(O)CH2C(OH)(R3)R4 or group A





—B1—B—B3— is —C═N—O—, —C═N—CH2—, —C═CH—O— or —N—CH2—CH2—;

A1, A2, A3 and A4 are independently of one another C—H, C—R5, or nitrogen;

R3 is C1-C8haloalkyl;

R4 is aryl or aryl substituted by one to three R6, or R4 is heterocyclyl or heterocyclyl substituted by one to three R6;

each R5 is independently halogen, cyano, nitro, C1-C8alkyl, C3-C8cycloalkyl, C1-C8haloalkyl, C2-C8alkenyl, C2-C8haloalkenyl, C2-C8alkynyl, C2-C8haloalkynyl, C1-C8alkoxy, C1-C8haloalkoxy, C1-C8alkoxycarbonyl-, or two R5 on adjacent carbon atoms together form a —CH═CH—CH═CH— bridge or a —N═CH—CH═CH— bridge;

each R6 is independently halogen, cyano, nitro, C1-C8alkyl, C1-C8haloalkyl, C1-C8alkoxy, or C1-C8haloalkoxy;

R8 is hydroxy, C1-C6alkoxy or chloro, fluoro, bromo, or SRx wherein Rx is H, C1-C6alkyl, imidazole or pyrrole; and

each R11 is independently C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, cyano or halogen;

and the process results in a compound of formula (VIII)





wherein A1, A2, A3, A4 and X are as defined for the compound of formula (XII) and R1 is as defined for the compound of formula (I).

In another embodiment the second compound is a compound of formula (XIII)




wherein R9 is hydrogen, C1-C8alkyl or C1-C8haloalkyl and R8 is as defined for compounds of formula (XII);

and the process results in a compound of formula (IX)





wherein R1 is as defined for the compound of formula (I) and R9 is as defined for the compound of formula (XIII).

In another embodiment the second compound is a compound of formula (XIVa) or (XIVb)




wherein each R10 is independently C1-C8alkyl, C1-C8haloalkyl, aryl-C1-C4alkylene- or aryl-C1-C4alkylene-substituted by one to five R11, wherein each R11 is independently C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, cyano or halogen;

and the process results in a compound of formula X





wherein R1 is as defined for the compound of formula (I) and R10 is as defined for the compound of formula (XIVa) and XIVb.

In a further aspect the invention provides a process wherein the compound of formula (I) is reacted with a second compound, wherein the second compound comprises a carboxylic acid, acid halide, ester or thioester functional group, and the reaction comprises reacting the amine functional group of the compound of formula (I) with the carboxylic acid, acid halide, ester or thioester functional group of the second compound such that the compound of formula (I) is coupled to the second compound via an amide functional group, or wherein the second compound comprises a dicarbonate group, and the reaction comprises reacting the amine functional group of the compound of formula (I) with the dicarbonate group of the second compound, such that the compound of formula (I) is coupled to the second compound via a carbamate functional group. Preferably in the process wherein the compound of formula (I) is reacted with a second compound
wherein
the second compound is a compound of formula (XII)




and the process results in a compound of formula (VIII)





wherein

X is a leaving group selected from halogen, C1-C8alkylsulfonyloxy, C1-C8haloalkylsulfonyloxy, C1-C8arylsulfonyloxy or C1-C8arylsulfonyloxy substituted by one to five R11, or a phosphonate ester, cyano, formyl, acetyl, C(O)CH═C(R3)R4, C(O)CH2C(OH)(R3)R4 or group A





—B1—B2—B3— is —C═N—O—, —C═N—CH2—, —C═CH2—O— or —N—CH2—CH2—;

A1, A2, A3 and A4 are independently of one another C—H, C—R5, or nitrogen;

R3 is C1-C8haloalkyl;

R4 is aryl or aryl substituted by one to three R6, or R4 is heterocyclyl or heterocyclyl substituted by one to three R6;

each R5 is independently halogen, cyano, nitro, C1-C8alkyl, C3-C8cycloalkyl, C1-C8haloalkyl, C2-C8alkenyl, C2-C8haloalkenyl, C2-C8alkynyl, C2-C8haloalkynyl, C1-C8alkoxy, C1-C8haloalkoxy, C1-C8alkoxycarbonyl-, or two R5 on adjacent carbon atoms together form a —CH═CH—CH═CH— bridge or a —N═CH—CH═CH— bridge;

each R6 is independently halogen, cyano, nitro, C1-C8alkyl, C1-C8haloalkyl, C1-C8alkoxy, or C1-C8haloalkoxy;

R8 is hydroxy, C1-C6alkoxy, fluoro, chloro, bromo, or SRx wherein Rx is H, C1-C6alkyl, imidazole or pyrrole; and

each R11 is independently C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, cyano or halogen;

R1 is C1-C8alkyl, C1-C8haloalkyl, aryl or aryl substituted by one to five R11, or aryl-C1-C4alkylene or aryl-C1-C4alkylene substituted by one to five R11; and

each R11 is independently C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, cyano or halogen;

or

the second compound is a compound of formula (XIII)





wherein and the process results in a compound of formula (IX)





wherein

R1 is C1-C8alkyl, C1-C8haloalkyl, aryl or aryl substituted by one to five R11, or aryl-C1-C4alkylene or aryl-C1-C4alkylene substituted by one to five R11; and

R9 is hydrogen, C1-C8alkyl or C1-C8haloalkyl and R8 is as defined for compound of formula (XII);

each R11 is independently C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, cyano or halogen;

or

the second compound is a compound of formula (XIVa) or (XIVb)





and the process results in a compound of formula X





wherein

R1 is C1-C8alkyl, C1-C8haloalkyl, aryl or aryl substituted by one to five R11, or aryl-C1-C4alkylene or aryl-C1-C4alkylene substituted by one to five R11;

each R10 is independently C1-C8alkyl, C1-C8haloalkyl, aryl-C1-C4alkylene- or aryl-C1-C4alkylene-substituted by one to five R11;

each R11 is independently C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, cyano or halogen;

In a further aspect the invention provides a process for the preparation of a compound of formula (VIII) or a salt or N-oxide thereof




comprising the preparation of a compound of formula (I)





according to the process any one of claims 1 or 2 or 3 or 4 or 6, and reacting the compound of formula (I) with compound of formula (XII)





wherein

X is a leaving group selected from halogen, C1-C8alkylsulfonyloxy, C1-C8haloalkylsulfonyloxy, C1-C8arylsulfonyloxy or C1-C8arylsulfonyloxy substituted by one to five R11, or a phosphonate ester, cyano, formyl, acetyl, C(O)CH═C(R3)R4, C(O)CH2C(OH)(R3)R4 or group A





—B1—B2—B3— is —C═N—O—, —C═N—CH2—, —C═CH2—O— or —N—CH2—CH2—;

A1, A2, A3 and A4 are independently of one another C—H, C—R5, or nitrogen;

R3 is C1-C8haloalkyl;

R4 is aryl or aryl substituted by one to three R6, or R4 is heterocyclyl or heterocyclyl substituted by one to three R6;

each R5 is independently halogen, cyano, nitro, C1-C8alkyl, C3-C8cycloalkyl, C1-C8haloalkyl, C2-C8alkenyl, C2-C8haloalkenyl, C2-C8alkynyl, C2-C8haloalkynyl, C1-C8alkoxy, C1-C8haloalkoxy, C1-C8alkoxycarbonyl-, or two R5 on adjacent carbon atoms together form a —CH═CH—CH═CH— bridge or a —N═CH—CH═CH— bridge;

each R6 is independently halogen, cyano, nitro, C1-C8alkyl, C1-C8haloalkyl, C1-C8alkoxy, or C1-C8haloalkoxy;

R8 is hydroxy, C1-C6alkoxy, chloro, cluoro, bromo, or SRx wherein Rx is H, C1-C6alkyl, imidazole or pyrrole;

R1 is C1-C8alkyl, C1-C8haloalkyl, aryl or aryl substituted by one to five R11, or aryl-C1-C4alkylene or aryl-C1-C4alkylene substituted by one to five R11; and

each R11 is independently C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, cyano or halogen.

The compounds of the invention may exist in different geometric or optical isomers or tautomeric forms. In particular, the compounds of the invention may contain one or more asymmetric carbon atoms and may exist as enantiomers (or as pairs of diastereoisomers) or as mixtures of such. This invention covers all such isomers and tautomers and mixtures thereof in all proportions as well as isotopic forms such as deuterated compounds. The compounds and processes of the invention include N-oxides and salts where possible.
Alkyl groups (either alone or as part of a larger group, such as alkoxy-, alkylthio-, alkylsulfinyl-, alkylsulfonyl-, alkylcarbonyl- or alkoxycarbonyl-) can be in the form of a straight or branched chain and are, for example, methyl, ethyl, propyl, prop-2-yl, butyl, but-2-yl, 2-methyl-prop-1-yl or 2-methyl-prop-2-yl. The alkyl groups are preferably C1-C6, more preferably C1-C4, most preferably C1-C3 alkyl groups. Where an alkyl moiety is said to be substituted, the alkyl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents.
Alkylene groups can be in the form of a straight or branched chain and are, for example, —CH2—, —CH2—CH2—, —CH(CH3)—, —CH2—CH2—CH2—, —CH(CH3)—CH2—, or —CH(CH2CH3)—. The alkylene groups are preferably C1-C3, more preferably C1-C2, most preferably C1 alkylene groups. Where an alkylene moiety is said to be substituted, the alkyl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents.
Alkenyl groups can be in the form of straight or branched chains, and can be, where appropriate, of either the (E)- or (Z)-configuration. Examples are vinyl and allyl. The alkenyl groups are preferably C2-C6, more preferably C2-C4, most preferably C2-C3 alkenyl groups. Where an alkenyl moiety is said to be substituted, the alkyl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents.
Alkynyl groups can be in the form of straight or branched chains. Examples are ethynyl and propargyl. The alkynyl groups are preferably C2-C6, more preferably C2-C4, most preferably C2-C3 alkynyl groups. Where an alkynyl moiety is said to be substituted, the alkyl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents.
Halogen is fluorine, chlorine, bromine or iodine.
Haloalkyl groups (either alone or as part of a larger group, such as haloalkoxy-, haloalkylthio-, haloalkylsulfinyl- or haloalkylsulfonyl-) are alkyl groups which are substituted by one or more of the same or different halogen atoms and are, for example, difluoromethyl, trifluoromethyl, chlorodifluoromethyl or 2,2,2-trifluoro-ethyl.
Haloalkenyl groups are alkenyl groups which are substituted by one or more of the same or different halogen atoms and are, for example, 2,2-difluoro-vinyl or 1,2-dichloro-2-fluoro-vinyl.
Haloalkynyl groups are alkynyl groups which are substituted by one or more of the same or different halogen atoms and are, for example, 1-chloro-prop-2-ynyl.
Cycloalkyl groups or carbocyclic rings can be in mono- or bi-cyclic form and are, for example, cyclopropyl, cyclobutyl, cyclohexyl and bicyclo[2.2.1]heptan-2-yl. The cycloalkyl groups are preferably C3-C8, more preferably C3-C6 cycloalkyl groups. Where a cycloalkyl moiety is said to be substituted, the cycloalkyl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents.
Aryl groups (either alone or as part of a larger group, such as aryl-alkylene-) are aromatic ring systems which can be in mono-, bi- or tricyclic form. Examples of such rings include phenyl, naphthyl, anthracenyl, indenyl or phenanthrenyl. Preferred aryl groups are phenyl and naphthyl, phenyl being most preferred. Where an aryl moiety is said to be substituted, the aryl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents.
Heteroaryl groups (either alone or as part of a larger group, such as heteroaryl-alkylene-) are aromatic ring systems containing at least one heteroatom and consisting either of a single ring or of two or more fused rings. Preferably, single rings will contain up to three heteroatoms and bicyclic systems up to four heteroatoms which will preferably be chosen from nitrogen, oxygen and sulfur. Examples of monocyclic groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl (e.g. 1.2.4 triazoyl), furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, tetrazolyl and thiadiazolyl. Examples of bicyclic groups include purinyl, quinolinyl, cinnolinyl, quinoxalinyl, indolyl, indazolyl, benzimidazolyl, benzothiophenyl and benzothiazolyl. Monocyclic heteroaryl groups are preferred, pyridyl being most preferred. Where a heteroaryl moiety is said to be substituted, the heteroaryl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents.
Heterocyclyl groups or heterocyclic rings (either alone or as part of a larger group, such as heterocyclyl-alkylene-) are defined to include heteroaryl groups and in addition their unsaturated or partially unsaturated analogues. Examples of monocyclic groups include isoxazolyl, thietanyl, pyrrolidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, dihydrothiophene, [1,3]dioxolanyl, piperidinyl, piperazinyl, [1,4]dioxanyl, morpholinyl, thiophene, oxetanyl, tetrahydropyranyl, 3-oxo-isoxazolidinyl-, 2,5-dioxo-1-pyrrolidinyl-, 2-oxo-1-pyrrolidinyl-, 4-oxo-1,3-oxazinanyl, 1-oxa-3,4-diazolyl, including their oxidised versions such as 1-oxo-thietanyl and 1,1-dioxo-thietanyl, thiophene 1-oxide, thiophene 1,1-dioxide, dihydrothiophene, dihydrothiophene 1-oxide, or dihydrothiophene 1,1-dioxide. Examples of bicyclic groups include 2,3-dihydro-benzofuranyl, benzo[1,4]dioxolanyl, benzo[1,3]dioxolanyl, chromenyl, and 2,3-dihydro-benzo[1,4]dioxinyl. Where a heterocyclyl moiety is said to be substituted, the heterocyclyl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents. Heterocyclyl groups (and heteroaryl groups) according to the present invention do not contain adjacent oxygen atoms, adjacent sulphur atoms, or adjacent sulphur and oxygen atoms. Preferred heterocyclyl groups are thiophene, thiophene 1-oxide, thiophene 1,1-dioxide, dihydrothiophene, dihydrothiophene 1-oxide, dihydrothiophene 1,1-dioxide, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, and tetrazoyl,
Leaving groups according to the invention include halogen, C1-C8alkylsulfonyloxy, C1-C8haloalkylsulfonyloxy, C1-C8arylsulfonyloxy or C1-C8arylsulfonyloxy substituted by one to five R11, wherein each R11 is independently C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, cyano or halogen (aryl is preferably phenyl), and phosphonate esters (e.g. —OP(O)(OR)2, wherein R is methyl or ethyl). A preferred leaving group is halogen, in particular chloro or bromo.
Preferred definitions are, in any combination, as set out below.
Preferably A1 is C—R5.
Preferably A2, A3, A4 are each CH.
Preferably —B1—B2—B3— is —C═N—O—.
Preferably R1 is C1-C8alkyl, C1-C8haloalkyl, more preferably ethyl or trifluoroethyl, even more preferably ethyl or 2,2,2-trifluoroethyl.
Preferably R2 is chloro or bromo, more preferably chloro.
Preferably R3 is trifluoromethyl, difluoromethyl or chlorodifluoromethyl, most preferably trifluoromethyl.
Preferably R4 is group (B)




wherein X2 is C—X4 or nitrogen (preferably C—X4); X1, X3 and X4 are independently hydrogen, halogen or trihalomethyl, e.g. wherein at least two of X1, X3 and X4 are not hydrogen.

Preferably R4 is 3,5-dichlorophenyl, 3-chloro-4-fluorophenyl, 3-fluoro-4-chlorophenyl, 3,4-dichlorophenyl, 3-chloro-4-bromophenyl, 3,5-dichloro-4-fluorophenyl, 3,4,5-trichlorophenyl, 3,5-dichloro-4-iodophenyl, 3,4,5-trifluorophenyl, 3-chloro-5-bromophenyl, 3-chloro-5-fluorophenyl, 3-chloro-5-(trifluoromethyl)phenyl, 3-bromo-5-(trifluoromethyl)phenyl, 3,4-dichloro-5-(trifluoromethyl)phenyl, 3,5-bis(trifluoromethyl)phenyl, 4-chloro-3,5-bis(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 2,6-dichloro-4-pyridyl, 2,6-bis(trifluoromethyl)-4-pyridyl, 2-chloro-4-pyridyl-, 2-trifluoromethyl-4-pyridyl, more preferably 3,5-dichloro-phenyl, 3-chloro-5-bromophenyl, 3-chloro-5-(trifluoromethyl)phenyl, 3,5-dichloro-4-fluorophenyl, 3,4,5-trichlorophenyl, 3,5-bis(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 2,6-dichloro-4-pyridyl, 2,6-bis(trifluoromethyl)-4-pyridyl, 3,5-dichloro-4-bromophenyl, 3-bromo-5-(trifluoromethyl)phenyl, 3,5-dibromophenyl, or 3,4-dichlorophenyl, 2-chloro-4-pyridyl-, 2-trifluoromethyl-4-pyridyl, even more preferably 3,5-dichloro-phenyl, 3,5-dichloro-4-fluorophenyl, 3,4,5-trichlorophenyl, 3-(trifluoromethyl)phenyl, 3,5-bis(trifluoromethyl)phenyl, most preferably 3,5-dichloro-phenyl, 3,5-dichloro-4-fluorophenyl, or 3,4,5-trichlorophenyl-. In one group of compounds R4 is 3,5-dichloro-phenyl. In one group of compounds R4 is 3,5-dichloro-4-fluorophenyl-. In one group of compounds R4 is 3,4,5-trichlorophenyl-. In one group of compounds R4 is 3,5-bis(trifluoromethyl)phenyl.
Preferably each R5 is independently halogen, cyano, methyl, halomethyl, methoxy or halomethoxy, more preferably chloro, fluoro, cyano or methyl.
Preferably each R6 is independently halogen, C1-C8alkyl, C1-C8haloalkyl, C1-C8alkoxy, C1-C8haloalkoxy, C1-C8alkylthio, or C1-C8haloalkylthio, more preferably bromo, chloro, fluoro, trifluoromethyl, methoxy, or methylthio, most preferably trifluoromethyl, fluoro or chloro.
Preferably R7 is hydroxy, ONa, OLi, OK, chloro or bromo, more preferably, ONa, OLi or chloro.
Preferably R8 is hydroxy, chloro or bromo, more preferably chloro.
Preferably R9 is hydrogen or C1-C6alkyl, more preferably methyl.
Preferably each R10 is independently C1-C6alkyl, more preferably C1-C4alkyl, most preferably t-butyl.
In one preferred embodiment the compounds of formula (I), (II) and (III) and (IV) are compounds wherein R1 is ethyl or trifluoroethyl (preferably 2,2,2-trifluoroethyl) and R2 is chloro or bromo, preferably chloro.
In a further preferred embodiment the compound of formula (IV) is a compound wherein R1 is ethyl or trifluoroethyl (preferably 2,2,2-trifluoroethyl) and R2 is chloro or bromo, preferably chloro.
In a further preferred embodiment the compounds of formula (I), (II), (V) and (VI) are compounds wherein R1 is ethyl or trifluoroethyl (preferably 2,2,2-trifluoroethyl) and R7 is hydroxy, ONa, OLi or chloro.
In a further preferred embodiment the compounds of formula (I), (II) and (VI) are compounds wherein R1 is ethyl, trifluoroethyl or phenyl.
In a further preferred embodiment the compounds of formula (VI) is a compound wherein R1 is ethyl or trifluoroethyl (preferably 2,2,2-trifluoroethyl)
In a further preferred embodiment the compounds of formula (VIII) and (XII) are compounds wherein
A1 is C—R5;
A2, A3, A4 are each CH;
R3 is trifluoromethyl, difluoromethyl or chlorodifluoromethyl;
X is chloro, bromo, cyano, formyl, acetyl, C(O)CH═C(R3)R4, C(O)CH2C(OH)(R3)R4 or group (A) as defined above;
R4 is group (B) as defined above;
X2 is C—X4 or nitrogen (preferably C—X4); X1, X3 and X4 are independently hydrogen, halogen or trihalomethyl;
each R5 is independently halogen, cyano, methyl, halomethyl, methoxy or halomethoxy, more preferably chloro, fluoro, cyano or methyl.
In a further preferred embodiment the compounds of formula (VIII) and (XII) are compounds wherein
X is acetyl, C(O)CH═C(R3)R4, C(O)CH2C(OH)(R3)R4 or group (A);
A1 is C—R5;
A2, A3, A4 are each CH;
X is group (A)




—B1—B2—B3— is —C═N—O—, —C═N—CH2—, —C═CH—O— or —N—CH2—CH2—, preferably —C═N—O—; R1 is C1-C8alkyl, C1-C8haloalkyl, aryl or aryl substituted by one to five R11, or aryl-C1-C4alkylene or aryl-C1-C4alkylene substituted by one to five R11;
R3 is trifluoromethyl, difluoromethyl or chlorodifluoromethyl;
R4 is group (B)




wherein X2 is C—X4 or nitrogen, X1, X3 and X4 are independently hydrogen, halogen or trihalomethyl,

R5 is halogen, cyano, methyl, halomethyl, methoxy or halomethoxy;
each R11 is independently C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, cyano or halogen.
In one preferred embodiment the compounds of formula (IX) and (XIII) are compounds wherein R9 is C1-C6alkyl.
In one preferred embodiment the compounds of formula (X) and (XIV) are compounds wherein each R10 is C1-C6alkyl, preferably t-butyl.
In enriched mixtures of the invention, the molar proportion of the compound of formula (I*), (III*), (IV*), (V*), and/or (VI*) in the mixture is for example greater than 50%, e.g. at least 60, 70, 80, 90 or at least 95% of the total molar amount of the pair of enantiomers.
The following schemes describe the reactions of the invention in more detail. The substituent definitions are the same as defined above.




Step a

Compounds of formula (I) can be prepared by reacting a compound of formula (III) with a compound of formula (II) or salt thereof. Suitable salts of compounds of formula (II) include, but are not limited to halides, organic acids, and sulphur based salts, e.g. chloride, oxalate, sulfate, trifluoroacetate, mesylate and bromide.
The reactions of compounds of formula (III) and II are preferably carried out in the presence of a suitable base. Suitable bases include, but are not limited to nitrogen-based organic bases such as amines, pyridines and derivatives thereof, e.g. triethylamine, tri-n-propylamine, pyridine and diisopropylethylamine.
The reactions of compounds of III and II are preferably carried out in the presence of a solvent. Suitable solvents include, but are not limited to organic solvents, e.g. halogenated organic solvents or alcohols such as chloroform, dichloromethane, dichloroethane, monochlorobenzene, dichlorobenzene, trichlorobenzene, 4-fluorotoluene, methanol, ethanol, isopropanol, t-butanol, cyclohexanol, heptanol, octanol, or longer chain alcohols, and diethyleneglycol, preferably chloroform, dichloromethane, isopropyl alcohol and ethanol. It is also possible to conduct the reaction in a mixture of an organic solvent and water.
The reaction can be carried out at a temperature from −20° C. to 100° C., preferably from 0° C. to 30° C. (e.g. no lower than −20° C., preferably no lower than 0° C., e.g. no more than 100° C., preferably no more than 30° C.).
The reactions of compounds of formula (III) and II are preferably carried out in the presence of a catalyst. Suitable catalysts include, but are not limited to nucleophilic catalysts capable of promoting acyl transfer reactions such as 4-dialkylaminopyridines, N-alkylimidazoles, phosphines, imidazolylidene carbenes, 1,2-diamines, bicyclic amidines, isothioureas and guanidines, triazoles, suitable alcohols, iodide and cyanide salts, preferably 4-dimethylaminopyridine.
Step a-1
Compounds of formula (IV) can be prepared by reacting a compound of formula (III) with a compound of formula (II) or salt thereof as described under step a.
The reaction is preferably carried out in the presence of a solvent. Suitable solvents include, but are not limited to polar organic solvents, e.g. acetic acid, propanoic acid or longer chain carboxylic acids, trifluoroacetic acid, methanol, ethanol, isopropanol, t-butanol, cyclohenxanol, heptanol, octanol, or longer chain alcohols, trifluoroethanol, ethyleneglycol, acetonitrile and propionitrile, preferably acetic acid. It is also possible to conduct the reaction in a mixture of organic solvents or in a mixture of organic solvents and water.
The reaction is preferably carried out in the presence of a suitable acid. Suitable acids include, but are not limited to organic acids, e.g acetic acid, propanoic acid or longer chain carboxylic acids, trifluoroacetic acid. A preferred acid is acetic acid.
The reaction can be carried out at a temperature from −20° C. to 100° C., preferably from 0° C. to 30° C. (e.g. no lower than −20° C., preferably no lower than 0° C., e.g. no more than 100° C., preferably no more than 30° C.).
Depending on the conditions used, it may be advantageous to isolate compound IV as the corresponding salt. The salt may be formed with an acid already present in the reaction mixture or formed by adding an additional acid to the reaction mixture. Suitable acids include mineral acids and organic acids such as HCl, HBr, H2SO4, acetic acid and trifluoroacetic acid.
Step a-2
Compounds of formula (I) can be prepared by treating a compound of formula (IV) or a salt thereof as described under step a-1 with a base. Suitable bases include carbonates, hydroxides, nitrogen-based organic bases such as amines, pyridines and derivatives thereof, e.g. Na2CO3, K2CO3, NaHCO3, NaOH, triethylamine, pyridine and diisopropylethylamine.
The reaction is preferably carried out in the presence of a solvent. Suitable solvents include, but are not limited to organic solvents such as diethylether, 1,2-dimethoxyethane, diethoxymethane, diglyme, t-butyl methyl ether, THF, 2-methyl-THF, dioxane; halogenated solvents such as chloroform, dichloromethane, dichloroethane, monochlorobenzene, dichlorobenzene, trichlorobenzene, 4-fluorotoluene; esters and ketones such as ethyl acetate, acetone 2-butanone, methylisobutylketone; ethers such as anisole, polar aprotic solvents such as acetonitrile, dimethylsulfoxide, dimethylformamide, N-methylpyrrolidone, dimethylacetamide; and alcohols, such as methanol, ethanol, isopropanol, t-BuOH, cyclohexanol, heptanol, octanol, or longer chain alcohols, and diethyleneglycol. Preferred organic solvents include tetrahydrofuran, dioxane and acetonitrile.
The reaction can be carried out at a temperature from −20° C. to 100° C., preferably from 0° C. to 30° C.
Compounds of formula (I) can be isolated in a free form or as salts formed by adding an acid to compounds of formula (I) in a free base form. Suitable acids include mineral acids and organic acids such as HCl, HBr, H2SO4, acetic acid and trifluoroacetic acid.
When compounds of formula (II) and formula (III) are reacted under acidic conditions as described for step a-1 a compound of formula (IV) is isolated. Treating the compound of formula (IV) in a compound under basic conditions as described for step a-2 a compound of formula (I) is formed.
When compounds of formula (II) and formula (III) are reacted under basic conditions as described for step a intermediate compound of formula (IV) cannot be isolated and compound of formula (I) is formed directly.
Steps 1-1, 1-2 and 1-3
This is described under scheme 3 below. Steps a and 1-1, 1-2 and 1-3 can be conducted in the same reaction vessel (one-pot reaction) without isolation of the compound of formula (I), e.g. when the solvent is chloroform. In other words, compounds of formula (VIII), (IX) and (X) can be prepared from the compound of formula (III) without isolation of the compound of formula (I) or (IV). Alternatively, steps a-2 and 1-1, 1-2 and 1-3 can be conducted in the same reaction vessel (one-pot reaction) without isolation of the compound of formula (I).




Step i-a

Compounds of formula (Va) can be prepared from compounds of formula (XI) by treatment with by phosgene or a derivative thereof e.g. diphosgene, triphosgene, ethyl chloroformate, benzylchloroformate, in the presence of aqueous base following the similar procedure described in Synthetic Comm. 1993, 23, 2839, which is incorporated herein by reference.
Step i
Compounds of formula (VI) can be prepared by reacting a compound of formula (Va) with a compound of formula (II). Preferably the reaction includes preparing the corresponding acid halide (preferably acid chloride) of the compound of formula (Va), compound (Vb), wherein R7 is halogen, to facilitate the conversion to the compound of formula (VI). The acid halide, compound (Vb), wherein R7 is halogen, can be prepared from the compound of formula (Va) under conditions well known to the person skilled in the art, such as by treatment with thionyl chloride, oxalyl chloride, phosgene, diphosgene or triphosgene.
Alternatively compound (Vb), wherein R7 is halogen, can be prepared from an alkali metal (Li, Na, K) salt of compound of formula (Va), compound (Vc), by treatment with oxalyl chloride, thionyl chloride, phosgene, diphosgene or triphosgene in the presence of a phase transfer catalyst. Suitable phase transfer catalysts include, but are not limited to tetrabutylammonium chloride, tetrabutylammonium bromide, triethylbenzylammonium chloride, Aliquat® 336 and (1-hexadecyl)trimethylammonium bromide




Alkali metal salts of compound of formula (V) where M is Li, Na or K, compounds Vc, can be prepared as shown in Scheme 2a.
Step iii and iv
Compounds of formula (Vc) where M is Li, Na or K can be prepared either by treating compounds of formula (XV) where R12 is C1-C4 alkyl with LiOH, NaOH or KOH or by treating compounds of formula (XVI) where R13 is C1-C4 alkyl, benzyl or phenyl with LiOH, NaOH or KOH. Suitable solvents include but are not limited to alcohols such as ethanol, methanol and isopropanol; polar organic solvents such as acetonitrile, dioxane, THF, 2-methyl-THF as well as water. Preferred solvents are ethanol and acetonitrile.
The reaction of the acid halide of compound of formula (V), compound (Vb), wherein R7 is halogen, with compounds of formula (II) are preferably carried out in the presence of a base. Suitable bases include, but are not limited to carbonates, hydroxides, nitrogen-based organic bases such as amines, pyridines and derivatives thereof, e.g. triethylamine, tri-n-propylamine, pyridine, diisopropylethylamine, Na2CO3, NaHCO3, NaOH and N-methyl morpholine.
The reaction of the acid halide of compound of formula (V), compound Vb, wherein R7 is halogen, with compounds of formula (II) are optionally carried out in the presence of a nucleophilic catalyst. Suitable catalysts include, but are not limited to nucleophilic catalysts such as 4-dimethylaminopyridine.
Suitable solvents include, but are not limited to ethers, such as diethylether, 1,2-dimethoxyethane, diethoxymethane, diglyme, t-butyl methyl ether, THF, 2-methyl-THF, dioxane; halogenated solvents such as chloroform, dichloromethane, dichloroethane, monochlorobenzene, dichlorobenzene, trichlorobenzene, 4-fluorotoluene; esters and ketones such as ethyl acetate, acetone, 2-butanone, methylisobutylketone; anisole, polar aprotic solvents such as acetonitrile, dimethylsulfoxide, dimethylformamide, N-methylpyrrolidone and dimethylacetamide; or water/biphasic systems (as is known in the so-called Schotten-Baumann conditions) as well as hydrocarbons, such as toluene and xylenes both as pure isomers and a mixture of isomers.
Compounds of formula (II) can be used as such or in the form of their salts with acids, for example HCl, HBr, trifluoroacetic acid, oxalic acid, sulfuric acids and methanesulfonic acid.
The reaction can be carried out at a temperature from −20° C. to 100° C., preferably from −10° C. to 30° C., in particular between −5° C. to +10° C.; More preferably the reaction can be carried out at a temperature from 0° C. to +10° C.
Alternatively, it is possible to conduct the reaction in a biphasic system comprising an organic solvent, preferably ethyl acetate, 2-methyltetrahydrofuran, or dichloromethane, and an aqueous solvent, preferably a solution of sodium hydrogen carbonate or sodium carbonate or organic amine such as triethylamine or diisopropylethylamine.
Alternatively the reaction of the compound of formula (V) with the compound of formula (II) can be carried out in the presence of a coupling reagent, such as N,N′-dicyclohexylcarbodiimide (“DCC”), 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (“EDC”) or bis(2-oxo-3-oxazolidinyl)phosphonic chloride (“BOP-Cl”), in the presence of a base, and optionally in the presence of a nucleophilic catalyst, such as hydroxybenzotriazole (“HOBT”).
Suitable bases include carbonates, hydroxides, nitrogen-based organic bases such as amines, pyridines and derivatives thereof, e.g. Na2CO3, K2CO3, NaHCO3, NaOH, triethylamine, pyridine, N-methyl morpholine and diisopropylethylamine.
Examples of suitable solvents include ethers, such as diethylether, 1,2-dimethoxyethane, diethoxymethane, diglyme, t-butyl methyl ether, THF, 2-methyl-THF, dioxane; halogenated solvents such as chloroform, dichloromethane, dichloroethane, monochlorobenzene, dichlorobenzene, trichlorobenzene, 4-fluorotoluene; esters and ketones such as ethyl acetate, acetone, 2-butanone, methylisobutylketone; anisole, polar aprotic solvents such as acetonitrile, dimethylsulfoxide, dimethylformamide, N-methylpyrrolidone, dimethylacetamide, hydrocarbons such as toluene and xylenes both as pure isomers and as a mixture of isomers. Preferred solvents are dichloromethane, dichloroethane, ethyl acetate, THF, 2-methyl-THF or dioxane.
The reaction can be carried out at a temperature from −20° C. to 100° C., preferably from −10° C. to 30° C., in particular from −5° C. to +5° C., more preferably from 0° C. to +5° C.
Step ii
Compounds of formula (I) can be prepared by treating compounds of formula (VI) with a base. Suitable bases include carbonates, hydroxides, nitrogen-based organic bases such as amines, pyridines and derivatives thereof, e.g. Na2CO3, K2CO3, NaHCO3, NaOH, triethylamine, pyridine, N-methyl morpholine and diisopropylethylamine.
It is possible to conduct the reaction in a mixture of an organic solvent with water or in water alone. Preferably the reaction includes the presence of water.
Examples of organic solvents include ethers, such as diethylether, 1,2-dimethoxyethane, diethoxymethane, diglyme, t-butyl methyl ether, THF, 2-methyl-THF, dioxane; halogenated solvents such as chloroform, dichloromethane, dichloroethane, monochlorobenzene, dichlorobenzene, trichlorobenzene, 4-fluorotoluene; esters and ketones such as ethyl acetate, acetone 2-butanone, methylisobutylketone; anisole, polar aprotic solvents such as acetonitrile, dimethylsulfoxide, dimethylformamide, N-methylpyrrolidone, dimethylacetamide; and alcohols, such as methanol, ethanol, isopropanol, t-BuOH, cyclohenxanol, heptanol, octanol, or longer chain alcohols, and diethyleneglycol; and aromatic hydrocarbons such as toluene and xylenes both as pure isomers and as a mixture of isomers. Preferred organic solvents include tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, acetonitrile, DMF.
Alternatively it is possible to conduct the reaction in a biphasic system comprising an organic solvent as described above under step ii that are immiscible with water, preferably ethyl acetate, 2-methyl tetrahydrofuran or dichloromethane, and an aqueous solvent, preferably a solution of sodium hydrogen carbonate or sodium carbonate or an organic amine such as triethylamine or diisopropylethylamine. It can also be possible to conduct the reaction in aqueous solvent without addition of base.
The reaction can be carried out at a temperature from 0° C. to 100° C., preferably from 20° C. to 70° C., in particular at 50° C. (e.g. no lower than 0° C., preferably no lower than 20° C., e.g. no more than 100° C., preferably no more than 70° C.). A temperature no lower than 20° C. is preferred to reduce reaction times.
Compounds of formula (I) can be isolated in a free form or as salts formed by adding an acid to compounds of formula (I) in a free base form. Suitable acids include mineral acids and organic acids such as HCl, HBr, H2SO4, acetic acid, methanesulfonic acids, p-methylphenylsulfonic acids, oxalic acid and trifluoroacetic acid.
Steps 1-1, 1-2 and 1-3
This is described under Scheme 3 below. Steps i, ii and 1-1, 1-2 and 1-3 can be conducted in the same reaction vessel (one-pot reaction) without isolation of the compound of formula (I). In other words, compound of formula (VIII), (IX) and (X) can be prepared from the compound of formula (V) without isolation of the compound of formula (VI) or (I).




Step 1-1

Compounds of formula (VIII) can be prepared by reacting a compound of formula (I) with a compound of formula (XII) wherein the substituents are defined as herein disclosed. When R8 is hydroxy such reactions are usually carried out in the presence of a coupling reagent, such as N,N′-dicyclohexylcarbodiimide (“DCC”), 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (“EDC”) or bis(2-oxo-3-oxazolidinyl)phosphonic chloride (“BOP-Cl”), in the presence of a base, and optionally in the presence of a nucleophilic catalyst, such as hydroxybenzotriazole (“HOBT”).
Suitable bases include carbonates, hydroxides, nitrogen-based organic bases such as amines, pyridines and derivatives thereof, e.g. Na2CO3, K2CO3, NaHCO3, NaOH, triethylamine, pyridine, N-methyl morpholine and diisopropylethylamine.
Suitable solvents include, but are not limited to polar organic solvents, e.g. halogenated organic solvents or ethers such as chloroform, dichloromethane, dichloroethane, monochlorobenzene, dichlorobenzene, trichlorobenzene, 4-fluorotoluene, THF, 2-methyl THF, dioxane, dimethoxyethane, toluene, acetonitrile and xylenes preferably chloroform, dichloromethane or THF.
When R8 is chloro such reactions are usually carried out in the presence of a base, and optionally in the presence of a nucleophilic catalyst such as 4-dimethylamino pyridine (“DMAP”).
Suitable bases include carbonates, hydroxides, nitrogen-based organic bases such as amines, pyridines and derivatives thereof, e.g. Na2CO3, K2CO3, NaHCO3, NaOH, triethylamine, pyridine, N-methyl morpholine and diisopropylethylamine.
Examples of solvents include ethers, such as diethylether, 1,2-dimethoxyethane, diethoxymethane, diglyme, t-butyl methyl ether, THF, 2-methyl-THF, dioxane; halogenated solvents such as chloroform, dichloromethane, dichloroethane, monochlorobenzene, dichlorobenzene, trichlorobenzene, 4-fluorotoluene; esters and ketones such as ethyl acetate, acetone 2-butanone, methylisobutylketone; anisole, polar aprotic solvents such as acetonitrile, dimethylsulfoxide, dimethylformamide, N-methylpyrrolidone and dimethylacetamide, aromatic hydrocarbons such as toluene and xylenes both as pure isomers and as a mixture of isomers. Preferred solvents are dichloromethane, dichloroethane, ethyl acetate, THF, 2-methyl tetrahydrofuran or dioxane.
Alternatively, it is possible to conduct the reaction in a biphasic system comprising an organic solvent, preferably ethyl acetate, toluene, xylenes as single isomers or as a mixture of isomers or dichloromethane, and an aqueous solvent, preferably a solution of sodium hydrogen carbonate or sodium carbonate or an organic amine such as triethylamine or diisopropylethyl amine.
The reaction can be carried out at a temperature from 0° C. to 100° C., preferably from 15° C. to 30° C., in particular at ambient temperature (e.g. no lower than 0° C., preferably no lower than 15° C., e.g. no more than 100° C., preferably no more than 30° C.).
Step 1-2
Compounds of formula (IX), wherein R9 is as defined above, can be prepared under the conditions as described under 1-1 by reacting a compound of formula (I) with a compound of formula (XIII) wherein the substituents are defined as herein disclosed.
Step 1-3
Compounds of formula X can be prepared by reacting compounds of formula (I) with a compound according to formula (XIVa) or (XIVb). An example of a compound according to formula (XIVa) di-tert-butyl dicarbonate in a presence of base. Suitable bases include carbonates, hydroxides, nitrogen-based organic bases such as amines, pyridines and derivatives thereof, e.g. Na2CO3, K2CO3, NaHCO3, NaOH, triethylamine, pyridine, N-methyl morpholine and diisopropylethylamine.
Examples of solvents include ethers, such as diethylether, 1,2-dimethoxyethane, diethoxymethane, diglyme, t-butyl methyl ether, THF, 2-methyl-THF, dioxane; halogenated solvents such as chloroform, dichloromethane, dichloroethane, monochlorobenzene, dichlorobenzene, trichlorobenzene, 4-fluorotoluene; esters and ketones such as ethyl acetate, acetone 2-butanone, methylisobutylketone; anisole, polar aprotic solvents such as acetonitrile, dimethylsulfoxide, dimethylformamide, N-methylpyrrolidone, dimethylacetamide; and alcohols, such as methanol, ethanol, isopropanol, t-BuOH, cyclohenxanol, heptanol, octanol, or longer chain alcohols, and diethyleneglycol; aromatic hydrocarbons such as toluene and xylenes both as pure isomers and as a mixture of isomers. Preferred solvents are dichloromethane, dichloroethane, ethyl acetate, THF, or dioxane. Alternatively it is possible to conduct the reaction in the mixture of these solvents and water.
Alternatively it is possible to conduct the reaction in a biphasic system comprising an organic solvent as described above under 1-3, preferably ethyl acetate, toluene, xylene or dichloromethane, and an aqueous base, preferably a solution of sodium hydrogen carbonate or sodium carbonate.
The reaction can be carried out at a temperature from −20° C. to 100° C., preferably from 0° C. to 40° C., in particular at ambient temperature (e.g. no lower than −20° C., preferably no lower than 0° C., e.g. no more than 100° C., preferably no more than 40° C.).




Scheme 4 illustrates how compounds of formula (VIII) may be reacted to produce insecticidally active compounds as described in WO2011/067272 and WO2013/069731, with reaction conditions described therein. Other methods of arriving at compounds of formula (VIIIc) using the present invention will be apparent to the person skilled in the art, and are also described in WO2011/067272. Possible combinations of substituents are shown in Table 1.


















TABLE 1






X1
X4
X3
R5
R1

X1
X4
X3
R5
R1


























1
Br
H
H
CH3
CH2CF3
397
Br
H
H
CH3
CH2CH3


2
Cl
H
H
CH3
CH2CF3
398
Cl
H
H
CH3
CH2CH3


3
F
H
H
CH3
CH2CF3
399
F
H
H
CH3
CH2CH3


4
CF3
H
H
CH3
CH2CF3
400
CF3
H
H
CH3
CH2CH3


5
H
Br
H
CH3
CH2CF3
401
H
Br
H
CH3
CH2CH3


6
Br
Br
H
CH3
CH2CF3
402
Br
Br
H
CH3
CH2CH3


7
Cl
Br
H
CH3
CH2CF3
403
Cl
Br
H
CH3
CH2CH3


8
F
Br
H
CH3
CH2CF3
404
F
Br
H
CH3
CH2CH3


9
CF3
Br
H
CH3
CH2CF3
405
CF3
Br
H
CH3
CH2CH3


10
H
Cl
H
CH3
CH2CF3
406
H
Cl
H
CH3
CH2CH3


11
Br
Cl
H
CH3
CH2CF3
407
Br
Cl
H
CH3
CH2CH3


12
Cl
Cl
H
CH3
CH2CF3
408
Cl
Cl
H
CH3
CH2CH3


13
F
Cl
H
CH3
CH2CF3
409
F
Cl
H
CH3
CH2CH3


14
CF3
Cl
H
CH3
CH2CF3
410
CF3
Cl
H
CH3
CH2CH3


15
H
F
H
CH3
CH2CF3
411
H
F
H
CH3
CH2CH3


16
Br
F
H
CH3
CH2CF3
412
Br
F
H
CH3
CH2CH3


17
Cl
F
H
CH3
CH2CF3
413
Cl
F
H
CH3
CH2CH3


18
F
F
H
CH3
CH2CF3
414
F
F
H
CH3
CH2CH3


19
CF3
F
H
CH3
CH2CF3
415
CF3
F
H
CH3
CH2CH3


20
H
H
Br
CH3
CH2CF3
416
H
H
Br
CH3
CH2CH3


21
Br
H
Br
CH3
CH2CF3
417
Br
H
Br
CH3
CH2CH3


22
Cl
H
Br
CH3
CH2CF3
418
Cl
H
Br
CH3
CH2CH3


23
F
H
Br
CH3
CH2CF3
419
F
H
Br
CH3
CH2CH3


24
CF3
H
Br
CH3
CH2CF3
420
CF3
H
Br
CH3
CH2CH3


25
H
Br
Br
CH3
CH2CF3
421
H
Br
Br
CH3
CH2CH3


26
Br
Br
Br
CH3
CH2CF3
422
Br
Br
Br
CH3
CH2CH3


27
Cl
Br
Br
CH3
CH2CF3
423
Cl
Br
Br
CH3
CH2CH3


28
F
Br
Br
CH3
CH2CF3
424
F
Br
Br
CH3
CH2CH3


29
CF3
Br
Br
CH3
CH2CF3
425
CF3
Br
Br
CH3
CH2CH3


30
H
Cl
Br
CH3
CH2CF3
426
H
Cl
Br
CH3
CH2CH3


31
Br
Cl
Br
CH3
CH2CF3
427
Br
Cl
Br
CH3
CH2CH3


32
Cl
Cl
Br
CH3
CH2CF3
428
Cl
Cl
Br
CH3
CH2CH3


33
F
Cl
Br
CH3
CH2CF3
429
F
Cl
Br
CH3
CH2CH3


34
CF3
Cl
Br
CH3
CH2CF3
430
CF3
Cl
Br
CH3
CH2CH3


35
H
F
Br
CH3
CH2CF3
431
H
F
Br
CH3
CH2CH3


36
Br
F
Br
CH3
CH2CF3
432
Br
F
Br
CH3
CH2CH3


37
Cl
F
Br
CH3
CH2CF3
433
Cl
F
Br
CH3
CH2CH3


38
F
F
Br
CH3
CH2CF3
434
F
F
Br
CH3
CH2CH3


39
CF3
F
Br
CH3
CH2CF3
435
CF3
F
Br
CH3
CH2CH3


40
H
H
Cl
CH3
CH2CF3
436
H
H
Cl
CH3
CH2CH3


41
Br
H
Cl
CH3
CH2CF3
437
Br
H
Cl
CH3
CH2CH3


42
Cl
H
Cl
CH3
CH2CF3
438
Cl
H
Cl
CH3
CH2CH3


43
F
H
Cl
CH3
CH2CF3
439
F
H
Cl
CH3
CH2CH3


44
CF3
H
Cl
CH3
CH2CF3
440
CF3
H
Cl
CH3
CH2CH3


45
H
Br
Cl
CH3
CH2CF3
441
H
Br
Cl
CH3
CH2CH3


46
Br
Br
Cl
CH3
CH2CF3
442
Br
Br
Cl
CH3
CH2CH3


47
Cl
Br
Cl
CH3
CH2CF3
443
Cl
Br
Cl
CH3
CH2CH3


48
F
Br
Cl
CH3
CH2CF3
444
F
Br
Cl
CH3
CH2CH3


49
CF3
Br
Cl
CH3
CH2CF3
445
CF3
Br
Cl
CH3
CH2CH3


50
H
Cl
Cl
CH3
CH2CF3
446
H
Cl
Cl
CH3
CH2CH3


51
Br
Cl
Cl
CH3
CH2CF3
447
Br
Cl
Cl
CH3
CH2CH3


52
Cl
Cl
Cl
CH3
CH2CF3
448
Cl
Cl
Cl
CH3
CH2CH3


53
F
Cl
Cl
CH3
CH2CF3
449
F
Cl
Cl
CH3
CH2CH3


54
CF3
Cl
Cl
CH3
CH2CF3
450
CF3
Cl
Cl
CH3
CH2CH3


55
H
F
Cl
CH3
CH2CF3
451
H
F
Cl
CH3
CH2CH3


56
Br
F
Cl
CH3
CH2CF3
452
Br
F
Cl
CH3
CH2CH3


57
Cl
F
Cl
CH3
CH2CF3
453
Cl
F
Cl
CH3
CH2CH3


58
F
F
Cl
CH3
CH2CF3
454
F
F
Cl
CH3
CH2CH3


59
CF3
F
Cl
CH3
CH2CF3
455
CF3
F
Cl
CH3
CH2CH3


60
H
H
F
CH3
CH2CF3
456
H
H
F
CH3
CH2CH3


61
Br
H
F
CH3
CH2CF3
457
Br
H
F
CH3
CH2CH3


62
Cl
H
F
CH3
CH2CF3
458
Cl
H
F
CH3
CH2CH3


63
F
H
F
CH3
CH2CF3
459
F
H
F
CH3
CH2CH3


64
CF3
H
F
CH3
CH2CF3
460
CF3
H
F
CH3
CH2CH3


65
H
Br
F
CH3
CH2CF3
461
H
Br
F
CH3
CH2CH3


66
Br
Br
F
CH3
CH2CF3
462
Br
Br
F
CH3
CH2CH3


67
Cl
Br
F
CH3
CH2CF3
463
Cl
Br
F
CH3
CH2CH3


68
F
Br
F
CH3
CH2CF3
464
F
Br
F
CH3
CH2CH3


69
CF3
Br
F
CH3
CH2CF3
465
CF3
Br
F
CH3
CH2CH3


70
H
Cl
F
CH3
CH2CF3
466
H
Cl
F
CH3
CH2CH3


71
Br
Cl
F
CH3
CH2CF3
467
Br
Cl
F
CH3
CH2CH3


72
Cl
Cl
F
CH3
CH2CF3
468
Cl
Cl
F
CH3
CH2CH3


73
F
Cl
F
CH3
CH2CF3
469
F
Cl
F
CH3
CH2CH3


74
CF3
Cl
F
CH3
CH2CF3
470
CF3
Cl
F
CH3
CH2CH3


75
H
F
F
CH3
CH2CF3
471
H
F
F
CH3
CH2CH3


76
Br
F
F
CH3
CH2CF3
472
Br
F
F
CH3
CH2CH3


77
Cl
F
F
CH3
CH2CF3
473
Cl
F
F
CH3
CH2CH3


78
F
F
F
CH3
CH2CF3
474
F
F
F
CH3
CH2CH3


79
CF3
F
F
CH3
CH2CF3
475
CF3
F
F
CH3
CH2CH3


80
H
H
CF3
CH3
CH2CF3
476
H
H
CF3
CH3
CH2CH3


81
Br
H
CF3
CH3
CH2CF3
477
Br
H
CF3
CH3
CH2CH3


82
Cl
H
CF3
CH3
CH2CF3
478
Cl
H
CF3
CH3
CH2CH3


83
F
H
CF3
CH3
CH2CF3
479
F
H
CF3
CH3
CH2CH3


84
CF3
H
CF3
CH3
CH2CF3
480
CF3
H
CF3
CH3
CH2CH3


85
H
Br
CF3
CH3
CH2CF3
481
H
Br
CF3
CH3
CH2CH3


86
Br
Br
CF3
CH3
CH2CF3
482
Br
Br
CF3
CH3
CH2CH3


87
Cl
Br
CF3
CH3
CH2CF3
483
Cl
Br
CF3
CH3
CH2CH3


88
F
Br
CF3
CH3
CH2CF3
484
F
Br
CF3
CH3
CH2CH3


89
CF3
Br
CF3
CH3
CH2CF3
485
CF3
Br
CF3
CH3
CH2CH3


90
H
Cl
CF3
CH3
CH2CF3
486
H
Cl
CF3
CH3
CH2CH3


91
Br
Cl
CF3
CH3
CH2CF3
487
Br
Cl
CF3
CH3
CH2CH3


92
Cl
Cl
CF3
CH3
CH2CF3
488
Cl
Cl
CF3
CH3
CH2CH3


93
F
Cl
CF3
CH3
CH2CF3
489
F
Cl
CF3
CH3
CH2CH3


94
CF3
Cl
CF3
CH3
CH2CF3
490
CF3
Cl
CF3
CH3
CH2CH3


95
H
F
CF3
CH3
CH2CF3
491
H
F
CF3
CH3
CH2CH3


96
Br
F
CF3
CH3
CH2CF3
492
Br
F
CF3
CH3
CH2CH3


97
Cl
F
CF3
CH3
CH2CF3
493
Cl
F
CF3
CH3
CH2CH3


98
F
F
CF3
CH3
CH2CF3
494
F
F
CF3
CH3
CH2CH3


99
CF3
F
CF3
CH3
CH2CF3
495
CF3
F
CF3
CH3
CH2CH3


100
Br
H
H
Br
CH2CF3
496
Br
H
H
Br
CH2CH3


101
Cl
H
H
Br
CH2CF3
497
Cl
H
H
Br
CH2CH3


102
F
H
H
Br
CH2CF3
498
F
H
H
Br
CH2CH3


103
CF3
H
H
Br
CH2CF3
499
CF3
H
H
Br
CH2CH3


104
H
Br
H
Br
CH2CF3
500
H
Br
H
Br
CH2CH3


105
Br
Br
H
Br
CH2CF3
501
Br
Br
H
Br
CH2CH3


106
Cl
Br
H
Br
CH2CF3
502
Cl
Br
H
Br
CH2CH3


107
F
Br
H
Br
CH2CF3
503
F
Br
H
Br
CH2CH3


108
CF3
Br
H
Br
CH2CF3
504
CF3
Br
H
Br
CH2CH3


109
H
Cl
H
Br
CH2CF3
505
H
Cl
H
Br
CH2CH3


110
Br
Cl
H
Br
CH2CF3
506
Br
Cl
H
Br
CH2CH3


111
Cl
Cl
H
Br
CH2CF3
507
Cl
Cl
H
Br
CH2CH3


112
F
Cl
H
Br
CH2CF3
508
F
Cl
H
Br
CH2CH3


113
CF3
Cl
H
Br
CH2CF3
509
CF3
Cl
H
Br
CH2CH3


114
H
F
H
Br
CH2CF3
510
H
F
H
Br
CH2CH3


115
Br
F
H
Br
CH2CF3
511
Br
F
H
Br
CH2CH3


116
Cl
F
H
Br
CH2CF3
512
Cl
F
H
Br
CH2CH3


117
F
F
H
Br
CH2CF3
513
F
F
H
Br
CH2CH3


118
CF3
F
H
Br
CH2CF3
514
CF3
F
H
Br
CH2CH3


119
H
H
Br
Br
CH2CF3
515
H
H
Br
Br
CH2CH3


120
Br
H
Br
Br
CH2CF3
516
Br
H
Br
Br
CH2CH3


121
Cl
H
Br
Br
CH2CF3
517
Cl
H
Br
Br
CH2CH3


122
F
H
Br
Br
CH2CF3
518
F
H
Br
Br
CH2CH3


123
CF3
H
Br
Br
CH2CF3
519
CF3
H
Br
Br
CH2CH3


124
H
Br
Br
Br
CH2CF3
520
H
Br
Br
Br
CH2CH3


125
Br
Br
Br
Br
CH2CF3
521
Br
Br
Br
Br
CH2CH3


126
Cl
Br
Br
Br
CH2CF3
522
Cl
Br
Br
Br
CH2CH3


127
F
Br
Br
Br
CH2CF3
523
F
Br
Br
Br
CH2CH3


128
CF3
Br
Br
Br
CH2CF3
524
CF3
Br
Br
Br
CH2CH3


129
H
Cl
Br
Br
CH2CF3
525
H
Cl
Br
Br
CH2CH3


130
Br
Cl
Br
Br
CH2CF3
526
Br
Cl
Br
Br
CH2CH3


131
Cl
Cl
Br
Br
CH2CF3
527
Cl
Cl
Br
Br
CH2CH3


132
F
Cl
Br
Br
CH2CF3
528
F
Cl
Br
Br
CH2CH3


133
CF3
Cl
Br
Br
CH2CF3
529
CF3
Cl
Br
Br
CH2CH3


134
H
F
Br
Br
CH2CF3
530
H
F
Br
Br
CH2CH3


135
Br
F
Br
Br
CH2CF3
531
Br
F
Br
Br
CH2CH3


136
Cl
F
Br
Br
CH2CF3
532
Cl
F
Br
Br
CH2CH3


137
F
F
Br
Br
CH2CF3
533
F
F
Br
Br
CH2CH3


138
CF3
F
Br
Br
CH2CF3
534
CF3
F
Br
Br
CH2CH3


139
H
H
Cl
Br
CH2CF3
535
H
H
Cl
Br
CH2CH3


140
Br
H
Cl
Br
CH2CF3
536
Br
H
Cl
Br
CH2CH3


141
Cl
H
Cl
Br
CH2CF3
537
Cl
H
Cl
Br
CH2CH3


142
F
H
Cl
Br
CH2CF3
538
F
H
Cl
Br
CH2CH3


143
CF3
H
Cl
Br
CH2CF3
539
CF3
H
Cl
Br
CH2CH3


144
H
Br
Cl
Br
CH2CF3
540
H
Br
Cl
Br
CH2CH3


145
Br
Br
Cl
Br
CH2CF3
541
Br
Br
Cl
Br
CH2CH3


146
Cl
Br
Cl
Br
CH2CF3
542
Cl
Br
Cl
Br
CH2CH3


147
F
Br
Cl
Br
CH2CF3
543
F
Br
Cl
Br
CH2CH3


148
CF3
Br
Cl
Br
CH2CF3
544
CF3
Br
Cl
Br
CH2CH3


149
H
Cl
Cl
Br
CH2CF3
545
H
Cl
Cl
Br
CH2CH3


150
Br
Cl
Cl
Br
CH2CF3
546
Br
Cl
Cl
Br
CH2CH3


151
Cl
Cl
Cl
Br
CH2CF3
547
Cl
Cl
Cl
Br
CH2CH3


152
F
Cl
Cl
Br
CH2CF3
548
F
Cl
Cl
Br
CH2CH3


153
CF3
Cl
Cl
Br
CH2CF3
549
CF3
Cl
Cl
Br
CH2CH3


154
H
F
Cl
Br
CH2CF3
550
H
F
Cl
Br
CH2CH3


155
Br
F
Cl
Br
CH2CF3
551
Br
F
Cl
Br
CH2CH3


156
Cl
F
Cl
Br
CH2CF3
552
Cl
F
Cl
Br
CH2CH3


157
F
F
Cl
Br
CH2CF3
553
F
F
Cl
Br
CH2CH3


158
CF3
F
Cl
Br
CH2CF3
554
CF3
F
Cl
Br
CH2CH3


159
H
H
F
Br
CH2CF3
555
H
H
F
Br
CH2CH3


160
Br
H
F
Br
CH2CF3
556
Br
H
F
Br
CH2CH3


161
Cl
H
F
Br
CH2CF3
557
Cl
H
F
Br
CH2CH3


162
F
H
F
Br
CH2CF3
558
F
H
F
Br
CH2CH3


163
CF3
H
F
Br
CH2CF3
559
CF3
H
F
Br
CH2CH3


164
H
Br
F
Br
CH2CF3
560
H
Br
F
Br
CH2CH3


165
Br
Br
F
Br
CH2CF3
561
Br
Br
F
Br
CH2CH3


166
Cl
Br
F
Br
CH2CF3
562
Cl
Br
F
Br
CH2CH3


167
F
Br
F
Br
CH2CF3
563
F
Br
F
Br
CH2CH3


168
CF3
Br
F
Br
CH2CF3
564
CF3
Br
F
Br
CH2CH3


169
H
Cl
F
Br
CH2CF3
565
H
Cl
F
Br
CH2CH3


170
Br
Cl
F
Br
CH2CF3
566
Br
Cl
F
Br
CH2CH3


171
Cl
Cl
F
Br
CH2CF3
567
Cl
Cl
F
Br
CH2CH3


172
F
Cl
F
Br
CH2CF3
568
F
Cl
F
Br
CH2CH3


173
CF3
Cl
F
Br
CH2CF3
569
CF3
Cl
F
Br
CH2CH3


174
H
F
F
Br
CH2CF3
570
H
F
F
Br
CH2CH3


175
Br
F
F
Br
CH2CF3
571
Br
F
F
Br
CH2CH3


176
Cl
F
F
Br
CH2CF3
572
Cl
F
F
Br
CH2CH3


177
F
F
F
Br
CH2CF3
573
F
F
F
Br
CH2CH3


178
CF3
F
F
Br
CH2CF3
574
CF3
F
F
Br
CH2CH3


179
H
H
CF3
Br
CH2CF3
575
H
H
CF3
Br
CH2CH3


180
Br
H
CF3
Br
CH2CF3
576
Br
H
CF3
Br
CH2CH3


181
Cl
H
CF3
Br
CH2CF3
577
Cl
H
CF3
Br
CH2CH3


182
F
H
CF3
Br
CH2CF3
578
F
H
CF3
Br
CH2CH3


183
CF3
H
CF3
Br
CH2CF3
579
CF3
H
CF3
Br
CH2CH3


184
H
Br
CF3
Br
CH2CF3
580
H
Br
CF3
Br
CH2CH3


185
Br
Br
CF3
Br
CH2CF3
581
Br
Br
CF3
Br
CH2CH3


186
Cl
Br
CF3
Br
CH2CF3
582
Cl
Br
CF3
Br
CH2CH3


187
F
Br
CF3
Br
CH2CF3
583
F
Br
CF3
Br
CH2CH3


188
CF3
Br
CF3
Br
CH2CF3
584
CF3
Br
CF3
Br
CH2CH3


189
H
Cl
CF3
Br
CH2CF3
585
H
Cl
CF3
Br
CH2CH3


190
Br
Cl
CF3
Br
CH2CF3
586
Br
Cl
CF3
Br
CH2CH3


191
Cl
Cl
CF3
Br
CH2CF3
587
Cl
Cl
CF3
Br
CH2CH3


192
F
Cl
CF3
Br
CH2CF3
588
F
Cl
CF3
Br
CH2CH3


193
CF3
Cl
CF3
Br
CH2CF3
589
CF3
Cl
CF3
Br
CH2CH3


194
H
F
CF3
Br
CH2CF3
590
H
F
CF3
Br
CH2CH3


195
Br
F
CF3
Br
CH2CF3
591
Br
F
CF3
Br
CH2CH3


196
Cl
F
CF3
Br
CH2CF3
592
Cl
F
CF3
Br
CH2CH3


197
F
F
CF3
Br
CH2CF3
593
F
F
CF3
Br
CH2CH3


198
CF3
F
CF3
Br
CH2CF3
594
CF3
F
CF3
Br
CH2CH3


199
Br
H
H
Cl
CH2CF3
595
Br
H
H
Cl
CH2CH3


200
Cl
H
H
Cl
CH2CF3
596
Cl
H
H
Cl
CH2CH3


201
F
H
H
Cl
CH2CF3
597
F
H
H
Cl
CH2CH3


202
CF3
H
H
Cl
CH2CF3
598
CF3
H
H
Cl
CH2CH3


203
H
Br
H
Cl
CH2CF3
599
H
Br
H
Cl
CH2CH3


204
Br
Br
H
Cl
CH2CF3
600
Br
Br
H
Cl
CH2CH3


205
Cl
Br
H
Cl
CH2CF3
601
Cl
Br
H
Cl
CH2CH3


206
F
Br
H
Cl
CH2CF3
602
F
Br
H
Cl
CH2CH3


207
CF3
Br
H
Cl
CH2CF3
603
CF3
Br
H
Cl
CH2CH3


208
H
Cl
H
Cl
CH2CF3
604
H
Cl
H
Cl
CH2CH3


209
Br
Cl
H
Cl
CH2CF3
605
Br
Cl
H
Cl
CH2CH3


210
Cl
Cl
H
Cl
CH2CF3
606
Cl
Cl
H
Cl
CH2CH3


211
F
Cl
H
Cl
CH2CF3
607
F
Cl
H
Cl
CH2CH3


212
CF3
Cl
H
Cl
CH2CF3
608
CF3
Cl
H
Cl
CH2CH3


213
H
F
H
Cl
CH2CF3
609
H
F
H
Cl
CH2CH3


214
Br
F
H
Cl
CH2CF3
610
Br
F
H
Cl
CH2CH3


215
Cl
F
H
Cl
CH2CF3
611
Cl
F
H
Cl
CH2CH3


216
F
F
H
Cl
CH2CF3
612
F
F
H
Cl
CH2CH3


217
CF3
F
H
Cl
CH2CF3
613
CF3
F
H
Cl
CH2CH3


218
H
H
Br
Cl
CH2CF3
614
H
H
Br
Cl
CH2CH3


219
Br
H
Br
Cl
CH2CF3
615
Br
H
Br
Cl
CH2CH3


220
Cl
H
Br
Cl
CH2CF3
616
Cl
H
Br
Cl
CH2CH3


221
F
H
Br
Cl
CH2CF3
617
F
H
Br
Cl
CH2CH3


222
CF3
H
Br
Cl
CH2CF3
618
CF3
H
Br
Cl
CH2CH3


223
H
Br
Br
Cl
CH2CF3
619
H
Br
Br
Cl
CH2CH3


224
Br
Br
Br
Cl
CH2CF3
620
Br
Br
Br
Cl
CH2CH3


225
Cl
Br
Br
Cl
CH2CF3
621
Cl
Br
Br
Cl
CH2CH3


226
F
Br
Br
Cl
CH2CF3
622
F
Br
Br
Cl
CH2CH3


227
CF3
Br
Br
Cl
CH2CF3
623
CF3
Br
Br
Cl
CH2CH3


228
H
Cl
Br
Cl
CH2CF3
624
H
Cl
Br
Cl
CH2CH3


229
Br
Cl
Br
Cl
CH2CF3
625
Br
Cl
Br
Cl
CH2CH3


230
Cl
Cl
Br
Cl
CH2CF3
626
Cl
Cl
Br
Cl
CH2CH3


231
F
Cl
Br
Cl
CH2CF3
627
F
Cl
Br
Cl
CH2CH3


232
CF3
Cl
Br
Cl
CH2CF3
628
CF3
Cl
Br
Cl
CH2CH3


233
H
F
Br
Cl
CH2CF3
629
H
F
Br
Cl
CH2CH3


234
Br
F
Br
Cl
CH2CF3
630
Br
F
Br
Cl
CH2CH3


235
Cl
F
Br
Cl
CH2CF3
631
Cl
F
Br
Cl
CH2CH3


236
F
F
Br
Cl
CH2CF3
632
F
F
Br
Cl
CH2CH3


237
CF3
F
Br
Cl
CH2CF3
633
CF3
F
Br
Cl
CH2CH3


238
H
H
Cl
Cl
CH2CF3
634
H
H
Cl
Cl
CH2CH3


239
Br
H
Cl
Cl
CH2CF3
635
Br
H
Cl
Cl
CH2CH3


240
Cl
H
Cl
Cl
CH2CF3
636
Cl
H
Cl
Cl
CH2CH3


241
F
H
Cl
Cl
CH2CF3
637
F
H
Cl
Cl
CH2CH3


242
CF3
H
Cl
Cl
CH2CF3
638
CF3
H
Cl
Cl
CH2CH3


243
H
Br
Cl
Cl
CH2CF3
639
H
Br
Cl
Cl
CH2CH3


244
Br
Br
Cl
Cl
CH2CF3
640
Br
Br
Cl
Cl
CH2CH3


245
Cl
Br
Cl
Cl
CH2CF3
641
Cl
Br
Cl
Cl
CH2CH3


246
F
Br
Cl
Cl
CH2CF3
642
F
Br
Cl
Cl
CH2CH3


247
CF3
Br
Cl
Cl
CH2CF3
643
CF3
Br
Cl
Cl
CH2CH3


248
H
Cl
Cl
Cl
CH2CF3
644
H
Cl
Cl
Cl
CH2CH3


249
Br
Cl
Cl
Cl
CH2CF3
645
Br
Cl
Cl
Cl
CH2CH3


250
Cl
Cl
Cl
Cl
CH2CF3
646
Cl
Cl
Cl
Cl
CH2CH3


251
F
Cl
Cl
Cl
CH2CF3
647
F
Cl
Cl
Cl
CH2CH3


252
CF3
Cl
Cl
Cl
CH2CF3
648
CF3
Cl
Cl
Cl
CH2CH3


253
H
F
Cl
Cl
CH2CF3
649
H
F
Cl
Cl
CH2CH3


254
Br
F
Cl
Cl
CH2CF3
650
Br
F
Cl
Cl
CH2CH3


255
Cl
F
Cl
Cl
CH2CF3
651
Cl
F
Cl
Cl
CH2CH3


256
F
F
Cl
Cl
CH2CF3
652
F
F
Cl
Cl
CH2CH3


257
CF3
F
Cl
Cl
CH2CF3
653
CF3
F
Cl
Cl
CH2CH3


258
H
H
F
Cl
CH2CF3
654
H
H
F
Cl
CH2CH3


259
Br
H
F
Cl
CH2CF3
655
Br
H
F
Cl
CH2CH3


260
Cl
H
F
Cl
CH2CF3
656
Cl
H
F
Cl
CH2CH3


261
F
H
F
Cl
CH2CF3
657
F
H
F
Cl
CH2CH3


262
CF3
H
F
Cl
CH2CF3
658
CF3
H
F
Cl
CH2CH3


263
H
Br
F
Cl
CH2CF3
659
H
Br
F
Cl
CH2CH3


264
Br
Br
F
Cl
CH2CF3
660
Br
Br
F
Cl
CH2CH3


265
Cl
Br
F
Cl
CH2CF3
661
Cl
Br
F
Cl
CH2CH3


266
F
Br
F
Cl
CH2CF3
662
F
Br
F
Cl
CH2CH3


267
CF3
Br
F
Cl
CH2CF3
663
CF3
Br
F
Cl
CH2CH3


268
H
Cl
F
Cl
CH2CF3
664
H
Cl
F
Cl
CH2CH3


269
Br
Cl
F
Cl
CH2CF3
665
Br
Cl
F
Cl
CH2CH3


270
Cl
Cl
F
Cl
CH2CF3
666
Cl
Cl
F
Cl
CH2CH3


271
F
Cl
F
Cl
CH2CF3
667
F
Cl
F
Cl
CH2CH3


272
CF3
Cl
F
Cl
CH2CF3
668
CF3
Cl
F
Cl
CH2CH3


273
H
F
F
Cl
CH2CF3
669
H
F
F
Cl
CH2CH3


274
Br
F
F
Cl
CH2CF3
670
Br
F
F
Cl
CH2CH3


275
Cl
F
F
Cl
CH2CF3
671
Cl
F
F
Cl
CH2CH3


276
F
F
F
Cl
CH2CF3
672
F
F
F
Cl
CH2CH3


277
CF3
F
F
Cl
CH2CF3
673
CF3
F
F
Cl
CH2CH3


278
H
H
CF3
Cl
CH2CF3
674
H
H
CF3
Cl
CH2CH3


279
Br
H
CF3
Cl
CH2CF3
675
Br
H
CF3
Cl
CH2CH3


280
Cl
H
CF3
Cl
CH2CF3
676
Cl
H
CF3
Cl
CH2CH3


281
F
H
CF3
Cl
CH2CF3
677
F
H
CF3
Cl
CH2CH3


282
CF3
H
CF3
Cl
CH2CF3
678
CF3
H
CF3
Cl
CH2CH3


283
H
Br
CF3
Cl
CH2CF3
679
H
Br
CF3
Cl
CH2CH3


284
Br
Br
CF3
Cl
CH2CF3
680
Br
Br
CF3
Cl
CH2CH3


285
Cl
Br
CF3
Cl
CH2CF3
681
Cl
Br
CF3
Cl
CH2CH3


286
F
Br
CF3
Cl
CH2CF3
682
F
Br
CF3
Cl
CH2CH3


287
CF3
Br
CF3
Cl
CH2CF3
683
CF3
Br
CF3
Cl
CH2CH3


288
H
Cl
CF3
Cl
CH2CF3
684
H
Cl
CF3
Cl
CH2CH3


289
Br
Cl
CF3
Cl
CH2CF3
685
Br
Cl
CF3
Cl
CH2CH3


290
Cl
Cl
CF3
Cl
CH2CF3
686
Cl
Cl
CF3
Cl
CH2CH3


291
F
Cl
CF3
Cl
CH2CF3
687
F
Cl
CF3
Cl
CH2CH3


292
CF3
Cl
CF3
Cl
CH2CF3
688
CF3
Cl
CF3
Cl
CH2CH3


293
H
F
CF3
Cl
CH2CF3
689
H
F
CF3
Cl
CH2CH3


294
Br
F
CF3
Cl
CH2CF3
690
Br
F
CF3
Cl
CH2CH3


295
Cl
F
CF3
Cl
CH2CF3
691
Cl
F
CF3
Cl
CH2CH3


296
F
F
CF3
Cl
CH2CF3
692
F
F
CF3
Cl
CH2CH3


297
CF3
F
CF3
Cl
CH2CF3
693
CF3
F
CF3
Cl
CH2CH3


298
Br
H
H
CF3
CH2CF3
694
Br
H
H
CF3
CH2CH3


299
Cl
H
H
CF3
CH2CF3
695
Cl
H
H
CF3
CH2CH3


300
F
H
H
CF3
CH2CF3
696
F
H
H
CF3
CH2CH3


301
CF3
H
H
CF3
CH2CF3
697
CF3
H
H
CF3
CH2CH3


302
H
Br
H
CF3
CH2CF3
698
H
Br
H
CF3
CH2CH3


303
Br
Br
H
CF3
CH2CF3
699
Br
Br
H
CF3
CH2CH3


304
Cl
Br
H
CF3
CH2CF3
700
Cl
Br
H
CF3
CH2CH3


305
F
Br
H
CF3
CH2CF3
701
F
Br
H
CF3
CH2CH3


306
CF3
Br
H
CF3
CH2CF3
702
CF3
Br
H
CF3
CH2CH3


307
H
Cl
H
CF3
CH2CF3
703
H
Cl
H
CF3
CH2CH3


308
Br
Cl
H
CF3
CH2CF3
704
Br
Cl
H
CF3
CH2CH3


309
Cl
Cl
H
CF3
CH2CF3
705
Cl
Cl
H
CF3
CH2CH3


310
F
Cl
H
CF3
CH2CF3
706
F
Cl
H
CF3
CH2CH3


311
CF3
Cl
H
CF3
CH2CF3
707
CF3
Cl
H
CF3
CH2CH3


312
H
F
H
CF3
CH2CF3
708
H
F
H
CF3
CH2CH3


313
Br
F
H
CF3
CH2CF3
709
Br
F
H
CF3
CH2CH3


314
Cl
F
H
CF3
CH2CF3
710
Cl
F
H
CF3
CH2CH3


315
F
F
H
CF3
CH2CF3
711
F
F
H
CF3
CH2CH3


316
CF3
F
H
CF3
CH2CF3
712
CF3
F
H
CF3
CH2CH3


317
H
H
Br
CF3
CH2CF3
713
H
H
Br
CF3
CH2CH3


318
Br
H
Br
CF3
CH2CF3
714
Br
H
Br
CF3
CH2CH3


319
Cl
H
Br
CF3
CH2CF3
715
Cl
H
Br
CF3
CH2CH3


320
F
H
Br
CF3
CH2CF3
716
F
H
Br
CF3
CH2CH3


321
CF3
H
Br
CF3
CH2CF3
717
CF3
H
Br
CF3
CH2CH3


322
H
Br
Br
CF3
CH2CF3
718
H
Br
Br
CF3
CH2CH3


323
Br
Br
Br
CF3
CH2CF3
719
Br
Br
Br
CF3
CH2CH3


324
Cl
Br
Br
CF3
CH2CF3
720
Cl
Br
Br
CF3
CH2CH3


325
F
Br
Br
CF3
CH2CF3
721
F
Br
Br
CF3
CH2CH3


326
CF3
Br
Br
CF3
CH2CF3
722
CF3
Br
Br
CF3
CH2CH3


327
H
Cl
Br
CF3
CH2CF3
723
H
Cl
Br
CF3
CH2CH3


328
Br
Cl
Br
CF3
CH2CF3
724
Br
Cl
Br
CF3
CH2CH3


329
Cl
Cl
Br
CF3
CH2CF3
725
Cl
Cl
Br
CF3
CH2CH3


330
F
Cl
Br
CF3
CH2CF3
726
F
Cl
Br
CF3
CH2CH3


331
CF3
Cl
Br
CF3
CH2CF3
727
CF3
Cl
Br
CF3
CH2CH3


332
H
F
Br
CF3
CH2CF3
728
H
F
Br
CF3
CH2CH3


333
Br
F
Br
CF3
CH2CF3
729
Br
F
Br
CF3
CH2CH3


334
Cl
F
Br
CF3
CH2CF3
730
Cl
F
Br
CF3
CH2CH3


335
F
F
Br
CF3
CH2CF3
731
F
F
Br
CF3
CH2CH3


336
CF3
F
Br
CF3
CH2CF3
732
CF3
F
Br
CF3
CH2CH3


337
H
H
Cl
CF3
CH2CF3
733
H
H
Cl
CF3
CH2CH3


338
Br
H
Cl
CF3
CH2CF3
734
Br
H
Cl
CF3
CH2CH3


339
Cl
H
Cl
CF3
CH2CF3
735
Cl
H
Cl
CF3
CH2CH3


340
F
H
Cl
CF3
CH2CF3
736
F
H
Cl
CF3
CH2CH3


341
CF3
H
Cl
CF3
CH2CF3
737
CF3
H
Cl
CF3
CH2CH3


342
H
Br
Cl
CF3
CH2CF3
738
H
Br
Cl
CF3
CH2CH3


343
Br
Br
Cl
CF3
CH2CF3
739
Br
Br
Cl
CF3
CH2CH3


344
Cl
Br
Cl
CF3
CH2CF3
740
Cl
Br
Cl
CF3
CH2CH3


345
F
Br
Cl
CF3
CH2CF3
741
F
Br
Cl
CF3
CH2CH3


346
CF3
Br
Cl
CF3
CH2CF3
742
CF3
Br
Cl
CF3
CH2CH3


347
H
Cl
Cl
CF3
CH2CF3
743
H
Cl
Cl
CF3
CH2CH3


348
Br
Cl
Cl
CF3
CH2CF3
744
Br
Cl
Cl
CF3
CH2CH3


349
Cl
Cl
Cl
CF3
CH2CF3
745
Cl
Cl
Cl
CF3
CH2CH3


350
F
Cl
Cl
CF3
CH2CF3
746
F
Cl
Cl
CF3
CH2CH3


351
CF3
Cl
Cl
CF3
CH2CF3
747
CF3
Cl
Cl
CF3
CH2CH3


352
H
F
Cl
CF3
CH2CF3
748
H
F
Cl
CF3
CH2CH3


353
Br
F
Cl
CF3
CH2CF3
749
Br
F
Cl
CF3
CH2CH3


354
Cl
F
Cl
CF3
CH2CF3
750
Cl
F
Cl
CF3
CH2CH3


355
F
F
Cl
CF3
CH2CF3
751
F
F
Cl
CF3
CH2CH3


356
CF3
F
Cl
CF3
CH2CF3
752
CF3
F
Cl
CF3
CH2CH3


357
H
H
F
CF3
CH2CF3
753
H
H
F
CF3
CH2CH3


358
Br
H
F
CF3
CH2CF3
754
Br
H
F
CF3
CH2CH3


359
Cl
H
F
CF3
CH2CF3
755
Cl
H
F
CF3
CH2CH3


360
F
H
F
CF3
CH2CF3
756
F
H
F
CF3
CH2CH3


361
CF3
H
F
CF3
CH2CF3
757
CF3
H
F
CF3
CH2CH3


362
H
Br
F
CF3
CH2CF3
758
H
Br
F
CF3
CH2CH3


363
Br
Br
F
CF3
CH2CF3
759
Br
Br
F
CF3
CH2CH3


364
Cl
Br
F
CF3
CH2CF3
760
Cl
Br
F
CF3
CH2CH3


365
F
Br
F
CF3
CH2CF3
761
F
Br
F
CF3
CH2CH3


366
CF3
Br
F
CF3
CH2CF3
762
CF3
Br
F
CF3
CH2CH3


367
H
Cl
F
CF3
CH2CF3
763
H
Cl
F
CF3
CH2CH3


368
Br
Cl
F
CF3
CH2CF3
764
Br
Cl
F
CF3
CH2CH3


369
Cl
Cl
F
CF3
CH2CF3
765
Cl
Cl
F
CF3
CH2CH3


370
F
Cl
F
CF3
CH2CF3
766
F
Cl
F
CF3
CH2CH3


371
CF3
Cl
F
CF3
CH2CF3
767
CF3
Cl
F
CF3
CH2CH3


372
H
F
F
CF3
CH2CF3
768
H
F
F
CF3
CH2CH3


373
Br
F
F
CF3
CH2CF3
769
Br
F
F
CF3
CH2CH3


374
Cl
F
F
CF3
CH2CF3
770
Cl
F
F
CF3
CH2CH3


375
F
F
F
CF3
CH2CF3
771
F
F
F
CF3
CH2CH3


376
CF3
F
F
CF3
CH2CF3
772
CF3
F
F
CF3
CH2CH3


377
H
H
CF3
CF3
CH2CF3
773
H
H
CF3
CF3
CH2CH3


378
Br
H
CF3
CF3
CH2CF3
774
Br
H
CF3
CF3
CH2CH3


379
Cl
H
CF3
CF3
CH2CF3
775
Cl
H
CF3
CF3
CH2CH3


380
F
H
CF3
CF3
CH2CF3
776
F
H
CF3
CF3
CH2CH3


381
CF3
H
CF3
CF3
CH2CF3
777
CF3
H
CF3
CF3
CH2CH3


382
H
Br
CF3
CF3
CH2CF3
778
H
Br
CF3
CF3
CH2CH3


383
Br
Br
CF3
CF3
CH2CF3
779
Br
Br
CF3
CF3
CH2CH3


384
Cl
Br
CF3
CF3
CH2CF3
780
Cl
Br
CF3
CF3
CH2CH3


385
F
Br
CF3
CF3
CH2CF3
781
F
Br
CF3
CF3
CH2CH3


386
CF3
Br
CF3
CF3
CH2CF3
782
CF3
Br
CF3
CF3
CH2CH3


387
H
Cl
CF3
CF3
CH2CF3
783
H
Cl
CF3
CF3
CH2CH3


388
Br
Cl
CF3
CF3
CH2CF3
784
Br
Cl
CF3
CF3
CH2CH3


389
Cl
Cl
CF3
CF3
CH2CF3
785
Cl
Cl
CF3
CF3
CH2CH3


390
F
Cl
CF3
CF3
CH2CF3
786
F
Cl
CF3
CF3
CH2CH3


391
CF3
Cl
CF3
CF3
CH2CF3
787
CF3
Cl
CF3
CF3
CH2CH3


392
H
F
CF3
CF3
CH2CF3
788
H
F
CF3
CF3
CH2CH3


393
Br
F
CF3
CF3
CH2CF3
789
Br
F
CF3
CF3
CH2CH3


394
Cl
F
CF3
CF3
CH2CF3
790
Cl
F
CF3
CF3
CH2CH3


395
F
F
CF3
CF3
CH2CF3
791
F
F
CF3
CF3
CH2CH3


396
CF3
F
CF3
CF3
CH2CF3
792
CF3
F
CF3
CF3
CH2CH3









In an all reactions the pressure is preferably atmospheric pressure unless stated otherwise.
Where a temperature is stated as from X to Y, X and Y are included in the temperature range.
The reactions conditions described above are also applicable when the compounds of formula (I), (III), (IV), (V) and (VI) are compounds of formula (I*), (III*), (IV*), (V*) and (VI*).
The invention will now be described by way of non-limiting Examples.


EXAMPLES
Example 1
Preparation of (R)-4-amino-2-ethylisoxazolidin-3-one




To a solution of N-ethyl(hydroxy)ammonium oxalate (5.5 g, 25.7 mmol) in a mixture of ethanol (70 ml) and water (14 ml), was added dropwise triethylamine (9.8 ml, 70.2 mmol) at ambient temperature and the solution was stirred for 15 min. To this solution (S)-4-(chloromethyl)oxazolidine-2,5-dione (7.0 g, 46.8 mmol) was added in several portions. The resulting reaction mixture was stirred at room temperature for 12 h. The reaction mixture was evaporated under reduced pressure to afford a residue which was purified by trituration with DCM (300 ml) to afford (R)-4-amino-2-ethylisoxazolidin-3-one (3.6 g) as a white solid. 1H NMR (400 MHz, CD3OD) δ 4.6 (t, 1H), 4.2-3.9 (m, 2H), 3.7-3.5 (m, 2H), 1.2 (t, 3H).
Example 2
preparation of (R)-4-amino-2-ethylisoxazolidin-3-one




To a solution of N-ethyl(hydroxy)ammonium oxalate (0.42 g, 1.8 mmol) and triethylamine (0.7 ml, 5.0 mmol) in chloroform (3 ml) was added (S)-4-(chloromethyl)oxazolidine-2,5-dione (0.50 g, 3.34 mmol) slowly (in several portions) at room temperature. The resulting reaction mixture was stirred at room temperature for 1 h and then at 50° C. for 1.5 h. The reaction mixture was evaporated under reduced pressure and the desired product was isolated by trituration with DCM to afford (R)-4-amino-2-ethylisoxazolidin-3-one (196 mg) as a white solid. 1H NMR (400 MHz, CD3OD) δ 4.6 (t, 1H), 4.2-3.9 (m, 2H), 3.7-3.5 (m, 2H), 1.2 (t, 3H).
Example 3
4-acetyl-N-[(4R)-2-ethyl-3-oxo-isoxazolidin-4-yl)]-2-methyl-benzamide




To a suspension of 4-acetyl-2-methyl-benzoic acid (5.0 g, 28 mmol) in dichloromethane (20 ml) was added dimethylformamide (0.2 ml) followed by a dropwise addition of oxalyl chloride (4.6 g, 36.48 mmol). The reaction mixture was stirred at ambient temperature until the end of gas evolution (ca. 4 h). The solvent was evaporated under reduced pressure to afford crude 4-acetyl-2-methyl-benzoyl chloride and it was diluted with acetonitrile (20 ml). The above prepared solution was added dropwise to a solution of (R)-4-amino-2-ethylisoxazolidin-3-one (4.6 g, 36 mmol) and potassium carbonate (15.0 g, 110 mmol) in acetonitrile (80 ml) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for further 2 h before being evaporated under reduced pressure. Additional water was added and the aqueous phase was extracted with DCM (3×50 ml). The organic phase was evaporated under reduced pressure. The crude product was purified by silica gel chromatography (0-40% ethyl acetate in hexane) to afford 4-acetyl-N-[(4R)-2-ethyl-3-oxo-isoxazolidin-4-yl)]-2-methyl-benzamide (4.3 g) as a pale yellow solid. Chiral HPLC analysis (Chiralpack IA, acetonitrile:THF:water=58:2:40, 0.81 ml/min, retention time 5.29 minutes (major enantiomer 98.3%) and 4.67 minutes (minor enantiomer 1.7%) 1H NMR (400 MHz, CDCl3) δ 7.8 (s, 1H), 7.76 (d, 1H), 7.54 (d, 1H), 6.54 (brs, 1H), 4.97 (t, 1H), 4.90-4.80 (m, 1H), 4.10-4.00 (m, 1H), 3.80-3.60 (m, 2H), 2.60 (s, 3H), 2.5 (s, 3H), 1.25 (t, 3H). LC-MS (methanol, ESI): m/z=291 (M+H, RT=1.33).
Example 4
preparation of tert-butyl N-[(4R)-2-ethyl-3-oxo-isoxazolidin-4-yl]carbamate (one pot, step a and 1-3)




A solution of N-ethyl(hydroxy)ammonium oxalate (0.16 g, 0.74 mmol) in the mixture of ethanol (2 ml) and water (0.5 ml) was treated with N,N-diisopropylethylamine (0.26 g, 2 mmol) at room temperature for 10 min. (S)-4-(chloromethyl)oxazolidine-2,5-dione (0.2 g, 1.34 mmol) in ethanol (3 ml) was added at 0° C. in one portion. The resulting reaction mixture was stirred at room temperature for 12 h. The reaction mixture was evaporated under reduced pressure to afford crude 4-amino-2-ethylisoxazolidin-3-one as pale yellow gummy mass, diluted with water (5 ml) and THF (10 ml). Triethylamine (0.18 ml, 1.34 mmol) and di-tert-butyl dicarbonate (0.3 g, 1.34 mmol) were added at 0° C. sequentially. The reaction mixture was allowed to warm to room temperature and stirred for further 5 h before being evaporated under reduced pressure. Water (10 ml) was added and the aqueous phase was extracted with DCM (2×25 ml). The combined organic phases were dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by silica gel chromatography (0-10% EtOAc in cyclohexane) to afforded tert-butyl N-[(4R)-2-ethyl-3-oxo-isoxazolidin-4-yl]carbamate (0.16 g) as a colorless liquid. Chiral HPLC analysis (Chiralpack IA, acetonitrile:THF:water=58:2:40, 0.81 ml/min, retention time 5.43 minutes (major 96.6%) and 4.89 minutes (minor 2.8%).
1H NMR (400 MHz, CDCl3) δ 5.11 (brs, 1H), 4.78-4-67 (m, 1H), 4.59-4.47 (m, 1H), 3.95 (dd, 1H), 3.72-3.54 (m, 2H), 1.45 (s, 9H), 1.23 (t, 3H)
Example 5
preparation of (2S)-2-amino-3-chloro-N-hydroxy-N-(2,2,2-trifluoroethyl)propanamide hydrochloride




Acetic acid (2 ml) was added to a mixture of (S)-4-(chloromethyl)oxazolidine-2,5-dione (0.50 g, 3.34 mmol) and N-(2,2,2-trifluoroethyl)hydroxylamine hydrochloride (0.56 g, 3.68 mmol). The reaction mixture was stirred at room temperature for 12 h and evaporated under reduced pressure to afford 985 mg of the title compound (75% Quantitative NMR mass purity) as white solid.
1H NMR (400 MHz, CD3OD) δ=4.88-4.85 (m, 1H), 4.51-4.48 (m, 2H), 4.21-4.09 (m, 2H) ppm.
19F NMR (400 MHz, DMSO) δ=−71.5 ppm.
Example 6
preparation of (4R)-4-amino-2-(2,2,2-trifluoroethyl)isoxazolidin-3-one




(2S)-2-amino-3-chloro-N-hydroxy-N-(2,2,2-trifluoroethyl)propanamide hydrochloride (0.10 g, 0.27 mmol, 75 mass % purity), potassium carbonate (0.11 g, 0.80 mmol) and acetonitrile (1 ml) was stirred at 0° C. for 1 h and at room temperature for 12 h. The reaction mixture was filtered and evaporated evaporated under reduced pressure giving 25 mg of the title compound (60% Quantitative NMR mass purity) as a white solid.
1H NMR (400 MHz, CD3CN) δ 4.48 (t, 1H), 4.23-4.05 (m, 2H), 3.92-3.81 (m, 2H).
19F NMR (400 MHz, DMSO) δ=−69.2 ppm.
Example 7
4-acetyl-2-methyl-N-[(4R)-3-oxo-2-(2,2,2-trifluoroethyl)isoxazolidin-4-yl]benzamide




(2S)-2-amino-3-chloro-N-hydroxy-N-(2,2,2-trifluoroethyl)propanamide hydrochloride (150 mg, 0.43 mmol, 75 mass % purity), potassium carbonate (0.28 g, 2.0 mmol) and acetonitrile (2 ml) was stirred at 0° C. for 1 h. A solution of 4-acetyl-2-methyl-benzoyl chloride (138 mg, 0.70 mmol) in acetonitrile (2 ml) was added dropwise at 0° C., and then the reaction mixture was allowed to warm up to room temperature and stirred at this temperature for 1 h. The reaction mixture was filtered and evaporated under reduced pressure. The crude product was purified by silica gel chromatography (0-100% ethyl acetate in hexane) to afford 4-acetyl-2-methyl-N-[(4R)-3-oxo-2-(2,2,2-trifluoroethyl)isoxazolidin-4-yl]benzamide (107 mg) as a white solid. Chiral HPLC analysis (Chiralpack IA, hexane:2-propanol=90:10, 1 ml/min, retention time 13.2 minutes (major 98%) and 15.1 minutes (minor 2%).
1HNMR (CDCl3): δ 7.82 (s, 1H), 7.79 (d, 1H, 8 Hz), 7.52 (d, 1H, 8 Hz), 6.46 (bs, 1H), 5.06-4.93 (m, 1H), 4.31-4.06 (m, 2H), 2.52 (s, 3H) ppm.
19F NMR (CDCl3): δ −70.28 ppm
Example 8
preparation of (4R)—N-ethyl-N-hydroxy-2-oxo-oxazolidine-4-carboxamide




To a suspension of (4R)-2-oxooxazolidine-4-carboxylic acid (0.500 g, 3.81 mmol) in 1,2-dichloroethane (5 ml) was added 3 drops dimethylformamide followed by a dropwise addition of oxalyl chloride (0.543 g, 4.20 mmol). The reaction mixture was stirred at ambient temperature until the end of gas evolution (ca. 1 h). The above prepared solution was added dropwise to a solution of N-ethyl(hydroxy)ammonium oxalate (0.874 g, 4.12 mmol) and triethylamine (1.38 g, 13.5 mmol) in 1,2-dichloroethane (5 ml) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for further 2 h before being evaporated under reduced pressure. Tetrahydrofuran (20 ml) was added to the residue and the mixture was heated to 40 C for 15 min. The precipitate was filtered off and the filtrate was evaporated under reduced pressure. The crude product was purified by silica gel chromatography (0-5% MeOH in DCM) to afford (4R)—N-ethyl-N-hydroxy-2-oxo-oxazolidine-4-carboxamide (0.409 g) as a light yellow solid. Chiral HPLC analysis (Chiralpack IC, Ethanol:2-propanol=05:95, 1 ml/min, retention time 4.54 minutes (only enantiomer)).
1H NMR (400 MHz, CD3OD) δ 4.84 (m, 1H), 4.67 (t, 1H), 4.33 (dd, 1H), 3.64 (dq, 2H), 1.19 (t, 3H)
Example 9
preparation of (4R)-4-amino-2-ethyl-isoxazolidin-3-one




To a solution of (4R)—N-ethyl-N-hydroxy-2-oxo-oxazolidine-4-carboxamide (0.030 g, 0.172 mmol) in THF (0.4 ml) and water (0.13 ml) was added triethylamine (0.035 g, 0.34 mmol) and the resulting reaction mixture was stirred at room temperature for 16 h. Additional water was added and the aqueous phase was extracted with DCM (3×). The aqueous phase was evaporated under reduced pressure to afford (4R)-4-amino-2-ethyl-isoxazolidin-3-one (0.0175 g) as a white solid.
1H NMR (400 MHz, CD3OD) δ 4.6 (t, 1H), 4.2-3.9 (m, 2H), 3.7-3.5 (m, 2H), 1.2 (t, 3H).
Example 10
preparation of tert-butyl N-[(4R)-2-ethyl-3-oxo-isoxazolidin-4-yl]carbamate




To a solution of (4R)—N-ethyl-N-hydroxy-2-oxo-oxazolidine-4-carboxamide (0.100 g, 0.574 mmol) in THF (1.2 ml) and water (0.4 ml) was added triethylamine (0.117 g, 1.15 mmol) and the resulting reaction mixture was stirred at room temperature for 16 h. Di-tert-butyl dicarbonate (0.136 g, 0.603 mmol) was added and the reaction mixture was stirred for a further 1 h. Additional water was added and the aqueous phase was extracted with ethyl acetate (3×). The combined organic phases were dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by silica gel chromatography (0-70% EtOAc in cyclohexane) to afford tert-butyl N-[(4R)-2-ethyl-3-oxo-isoxazolidin-4-yl]carbamate (0.0850 g) as a white crystalline solid. Chiral HPLC analysis (Chiralpack IC, heptane:ethanol=80:20, 1 ml/min, retention time 2.85 minutes (minor enantiomer 0.4%) and 4.73 minutes (major enantiomer 99.6%)). 1H NMR (400 MHz, CDCl3) δ 5.11 (brs, 1H), 4.78-4-67 (m, 1H), 4.59-4.47 (m, 1H), 3.95 (dd, 1H), 3.72-3.54 (m, 2H), 1.45 (s, 9H), 1.23 (t, 3H)
Alternatively, the Title Compound can be Obtained by Carrying Out the Following Procedure:
To a solution of (4R)—N-ethyl-N-hydroxy-2-oxo-oxazolidine-4-carboxamide (0.100 g, 0.574 mmol) in THF (1.2 ml) and water (0.4 ml) was added K2CO3 (0.0794 g, 0.574 mmol) and the resulting reaction mixture was stirred at room temperature for 16 h. Di-tert-butyl dicarbonate (0.136 g, 0.603 mmol) was added and the reaction mixture was stirred for a further 1 h. Additional water was added and the aqueous phase was extracted with ethyl acetate (3×). The combined organic phases were dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by silica gel chromatography (0-70% EtOAc in cyclohexane) to afford tert-butyl N-[(4R)-2-ethyl-3-oxo-isoxazolidin-4-yl]carbamate (0.070 g) as a white crystalline solid. Chiral HPLC analysis (Chiralpack IC, heptane:ethanol=80:20, 1 ml/min, retention time 2.85 minutes (minor enantiomer 0.4%) and 4.73 minutes (major enantiomer 99.6%)).
Example 11
preparation of (4R)—N-hydroxy-2-oxo-N-phenyl-oxazolidine-4-carboxamide




To a suspension of (4R)-2-oxooxazolidine-4-carboxylic acid (0.150 g, 1.14 mmol) in dry THF (1.5 ml) was added a drop of dimethylformamide followed by a dropwise addition of oxalyl chloride (0.11 ml, 1.25 mmol). The reaction mixture was stirred at ambient temperature for 20 minutes. The above prepared solution was added dropwise to a suspension of N-phenylhydroxylamine (0.158 g, 1.37 mmol) and Na2CO3 (0.182 g, 1.72 mmol) in THF (1.5 ml) at 0° C. The resulting reaction mixture was stirred at ambient temperature for 1.5 h. The precipitate was filtered off and to the filtrate was added aqueous saturated NaHCO3 and ethyl acetate. The phases were separated and the aqueous phase was extracted with EtOAc (3×). The combined organic phases were dried over anhydrous MgSO4 and evaporated under reduced pressure. The crude product was purified by silica gel chromatography (0-5% MeOH in DCM) to afford (4R)—N-hydroxy-2-oxo-N-phenyl-oxazolidine-4-carboxamide (0.1802 g) as a beige solid.
1H NMR (400 MHz, CD3OD) δ 7.71-7.61 (m, 2H), 7.45-7.34 (m, 2H), 7.26-7.18 (m, 1H), 5.04 (dd, J=9.2, 5.0 Hz, 1H), 4.78 (t, J=9.2 Hz), 4.50 (dd, J=8.8, 5.0 Hz, 1H).
Example 12
preparation of tert-butyl N-[(4R)-3-oxo-2-phenyl-isoxazolidin-4-yl]carbamate




To a solution of (4R)—N-hydroxy-2-oxo-N-phenyl-oxazolidine-4-carboxamide (0.100 g, 0.450 mmol) in THF (1.0 ml) and water (0.3 ml) was added triethylamine (0.127 ml, 0.900 mmol). The resulting solution was stirred in a closed vial at 70° C. for 2.5 h. The reaction mixture was cooled to ambient temperature and di-tertbutyldicarbonate (0.111 g, 0.495 mmol) was added. The reaction mixture was stirred for another 1.5 h, diluted with water and extracted with EtOAc (3×). The combined organic phases were dried over anhydrous MgSO4 and evaporated under reduced pressure. The crude product was purified by silica gel chromatography (0-23% EtOAc in cyclohexane) to afford tert-butyl N-[(4R)-3-oxo-2-phenyl-isoxazolidin-4-yl]carbamate (0.0902 g) as a beige solid.
1H NMR (400 MHz, CDCl3) δ 7.73-7.67 (m, 2H), 7.43-7.36 (m, 2H), 7.22-7.16 (m, 1H), 5.23 (br, 1H), 5.00-4.89 (m, 1H), 4.85-4.74 (m, 1H), 4.19 (dd, J=8.5, 11.0 Hz, 1H), 1.48 (s, 9H).
Example 13
preparation of N-hydroxy-N-methyl-2-oxo-oxazolidine-4-carboxamide




To a suspension of 2-oxooxazolidine-4-carboxylic acid (0.200 g, 1.53 mmol) in dry 1,2-dichloroethane (2.0 ml) was added a drop of dimethylformamide followed by a dropwise addition of oxalyl chloride (0.144 ml, 1.68 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes. The above prepared solution was added dropwise to a suspension prepared by mixing triethylamine (0.52 ml, 3.66 mmol) and N-methylhydroxylamine hydrochloride (0.143 g, 1.68 mmol) in 1,2-dichloroethane (2.0 ml). The resulting brownish reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was evaporated under reduced pressure and the residue was suspended in THF (8.0 ml). This suspension was heated at 50° C. for 10 min and the remaining brown precipitate was filtered off. The filtrate was evaporated under reduced pressure to provide the crude product as a sticky yellow oil. Purification by silica gel chromatography (0-10% MeOH in DCM) afforded N-hydroxy-N-methyl-2-oxo-oxazolidine-4-carboxamide (0.120 g) as a colorless oil which solidified upon standing.
1H NMR (400 MHz, CD3OD) δ 4.87 (dd, J=9.5, 5.1 Hz, 1H), 4.67 (t, J=9.4 Hz, 1H), 4.36 (dd, J=9.0, 5.3 Hz, 1H), 3.23 (s, 3H).
Example 14
preparation of tert-butyl N-(2-methyl-3-oxo-isoxazolidin-4-yl)carbamate




To a solution of N-hydroxy-N-methyl-2-oxo-oxazolidine-4-carboxamide (0.120 g, 0.749 mmol) in a mixture of THF (1.5 ml) and water (0.50 ml) was added triethylamine (0.21 ml, 1.50 mmol) and the resulting solution was stirred at ambient temperature for 18 h. Di-tertbutyldicarbonate (0.173 g, 0.787 mmol) was added and the reaction mixture was stirred for another 2 h. The reaction mixture was diluted with DCM and water, aqueous phase was extracted with DCM (3×) and the combined organic layers were dried over anhydrous MgSO4 and evaporated under reduced pressure. The crude product was purified by silica gel chromatography (0-50% EtOAc in cyclohexane) to afford tert-butyl N-(2-methyl-3-oxo-isoxazolidin-4-yl)carbamate (0.0546 g) as a white powder.
1H NMR (400 MHz, CDCl3) δ 5.32 (br, 1H), 4.71-4.60 (m, 1H), 4.58-4.44 (m, 1H), 3.96 (dd, J=10.3, 8.4 Hz, 1H), 3.17 (s, 3H), 1.41 (s, 9H).
Example 15
preparation of (4R)—N-ethyl-N-hydroxy-2-oxo-oxazolidine-4-carboxamide




To a suspension of (4R)-2-oxooxazolidine-4-carboxylic acid (10.0 g, 75.9 mmol) in dry THF (50 ml) was added three drops of DMF followed by a dropwise addition of oxalyl chloride (7.31 ml, 83.5 mmol) at 0° C. After the addition the reaction mixture was stirred for another 30 min at ambient temperature. In a separate flask triethylamine (37.2 ml, 266 mmol) was slowly added to a solution of N-ethylhydroxylamine hydrochloride in THF (100 ml). To this formed thick white suspension was added a solution of acid chloride prepared above over 45 min at 0 C. After finishing of addition the reaction mixture was warmed up to ambient temperature, additional THF (50 ml) was added and the reaction mixture was brought to reflux. The remaining precipitate (triethylamine hydrochloride) was filtered off and the filtrate was concentrated under reduced pressure to afford crude product (15.9 g). Quantitative NMR analysis using trimethoxy benzene as an internal standard indicated that the mixture contains (4R)—N-ethyl-N-hydroxy-2-oxo-oxazolidine-4-carboxamide (11.39 g) as the major component. Crystallization of the crude product from methanol afforded (4R)—N-ethyl-N-hydroxy-2-oxo-oxazolidine-4-carboxamide (8.86 g) as a white powder.
1H NMR (400 MHz, D2O) δ 5.01 (dd, J=9.9, 5.9 Hz), 4.77 (t, J=9.2 Hz, 1H), 4.39 (dd, J=9.0, 5.7 Hz, 1H), 3.65 (q, J=7.1 Hz, 2H), 1.16 (t, J=7.1 Hz, 3H).
Example 16
preparation of (4R)-4-amino-2-ethyl-isoxazolidin-3-one hydrochloride




To a suspension of (4R)—N-ethyl-N-hydroxy-2-oxo-oxazolidine-4-carboxamide (13.09 g, 74.8 mmol) in water (35 ml) was added triethylamine (1.05 ml, 7.48 mmol) and the resulting mixture was heated at 70° C. for 2 h (clear solution at this temperature). The reaction mixture was cooled to ambient temperature and 37% aq HCl (7.5 ml, 89.7 mmol) was slowly added. The resulting mixture was evaporated under reduced pressure and the residue dried under vacuum to afford (4R)-4-amino-2-ethyl-isoxazolidin-3-one hydrochloride (13.6 g) as a white powder mixed with 10% of triethylamine hydrochloride. Stereochemical integrity was checked by converting a small portion of the product to tert-butyl N-[(4R)-2-ethyl-3-oxo-isoxazolidin-4-yl]carbamate (see example 10) by treating hydrochloride salt with triethylamine (1.1 eq) and di-tertbutyldicarbonate (1.2 eq) in THF. Chiral HPLC analysis (Chiralpack IA, heptane:ethanol=80:20, 1 ml/min, retention time 2.82 minutes (minor enantiomer 0%) and 4.10 minutes (major enantiomer 100%)) 1H NMR (400 MHz, D2O) δ 4.58 (t, J=8.1 Hz, 1H), 4.10-4.04 (m, 1H), 4.02-3.96 (m, 1H), 3.68-3.51 (m, 2H), 1.18 (t, J=7.0 Hz, 3H).
Alternatively, the Title Compound can be Obtained by Carrying Out the Following Procedure:
At 0-5° C., a suspension of sodium (4R)-2-oxooxazolidine-4-carboxylate (10.06 g, 85.1% purity, 55.9 mmol) and Aliquat® 336 (0.56 g, 1.39 mmol) in 2-methyl-tetrahydrofurane (70 ml) was successively treated with N,N-dimethylformamide (0.21 g, 2.87 mmol) and oxalyl chloride (8.58 g, 67.6 mmol). The reaction mixture was stirred for 90 min at ambient temperature and added dropwise to a suspension of triethylamine (13.1 g, 0.129 mol) and N-ethylhydroxylamine hydrochloride (4.99 g, 89.9% purity, 0.046 mol) in 2-methyl-tetrahydrofurane (40 ml) at −5° C. The resulting brownish mixture was stirred for 30 min at ambient temperature and washed with water (2×75 ml). The combined aqueous layers containing the intermediate (4R)—N-ethyl-N-hydroxy-2-oxo-oxazolidine-4-carboxamide were heated to 45° C., treated with aq. NaOH (30% (w/w) soln., 2.95 g, 22.1 mmol), and stirred for additional 60 min. A part of water (35 g) was removed by distillation and the mixture was treated with aq. HCl (32% (w/w), 9.3 g, 81.6 mmol) to reach pH 1. The distillation was continued to finally obtain crude (4R)-4-amino-2-ethyl-isoxazolidin-3-one hydrochloride (56 g, ca. 9% solution in water as analyzed by quantitative 1H-NMR analysis).
Alternatively, the Title Compound can be Obtained by Carrying Out the Following Procedure:
A suspension of sodium (4R)-2-oxooxazolidine-4-carboxylate (10.0 g, 95.0% purity, 62.1 mmol) and Aliquat® 336 (0.66 g, 1.63 mmol) in ethyl acetate (80 ml) was successively treated with HCl in dioxane (4 M soln., 3.1 ml, 12.4 mmol) and N,N-dimethylformamide (0.23 g, 3.15 mmol). The resulting mixture was treated with a solution of thionyl chloride (9.0 g, 75.6 mmol) in ethyl acetate (10 ml) at 10-15° C. within 70 min, stirred at ambient temperature for additional 2 h and added dropwise to a suspension of triethylamine (15.4 g, 0.152 mol) and N-ethylhydroxylamine hydrochloride (6.4 g, 77.0% purity, 50.5 mol) in ethyl acetate (65 ml) at 0-5° C. The resulting brownish mixture was stirred at ambient temperature for 60 min and washed with water (2×50 ml). The combined aqueous layers containing the intermediate (4R)—N-ethyl-N-hydroxy-2-oxo-oxazolidine-4-carboxamide were heated to 40° C., treated with aq. NaOH (30% (w/w) soln., 13.6 g, 0.102 mol), and stirred for additional 60 min. A part of water (25 g) was removed by distillation and the mixture was treated with aq. HCl (32% (w/w) soln., 12.2 g, 0.107 mol) to reach pH 1. The mixture was completely evaporated to obtain crude (4R)-4-amino-2-ethyl-isoxazolidin-3-one hydrochloride (27.1 g, ca. 11.8% purity as determined by quantitative 1H NMR analysis) as orange solid.
Example 17
preparation of (4R)—N-benzyl-N-hydroxy-2-oxo-oxazolidine-4-carboxamide




To a solution of (4R)-2-oxooxazolidine-4-carboxylic acid (0.300 g, 2.29 mmol) in dry tetrahydrofuran (3.0 ml) was added 2 drops of DMF followed by oxalyl chloride (0.22 ml, 2.52 mmol) at 0° C. After stirring at rt for 20 min the resulting solution was slowly added at 0° C. to a suspension of sodium carbonate (0.603 g, 7.1 mmol) and N-benzylhydroxylamine hydrochloride (0.438 g, 2.75 mmol) in tetrahydrofuran (6.0 ml). The reaction mixture was stirred at rt for 2 h. The remaining precipitate was filtered off and aq sat. NaHCO3 was added to the filtrate. The aqueous phase was extracted with EtOAc (3×) and combined organic layers were dried over MgSO4 and evaporated under reduced pressure. The crude product was purified by silica gel chromatography (0-5% MeOH in dichloromethane) to afford (4R)—N-benzyl-N-hydroxy-2-oxo-oxazolidine-4-carboxamide (0.393 g) as a white powder.
1H NMR (400 MHz, CD3OD) δ 7.38-7.27 (m, 5H), 4.88 (dd, J=9.7, 5.3 Hz, 1H), 4.77 (s, 2H), 4.65 (t, J=9.4 Hz, 1H), 4.32 (dd, J=9.0, 5.3 Hz, 1H), 3.35 (s, 1H).
Example 18
preparation of tert-butyl N-[(4R)-2-benzyl-3-oxo-isoxazolidin-4-yl]carbamate




To a solution of (4R)—N-benzyl-N-hydroxy-2-oxo-oxazolidine-4-carboxamide (0.200 g, 0.847 mmol) in a mixture of THF (1.0 ml) and water (2.0 ml) was added triethylamine (0.24 ml, 1.69 mmol). The resulting reaction mixture was heated in a sealed vial at 70° C. for 3 h. The reaction mixture was diluted with water and extracted with dichloromethane (3×). The combined organic layers were dried over MgSO4 and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (0-40% EtOAc in CyH) to afford tert-butyl N-[(4R)-2-benzyl-3-oxo-isoxazolidin-4-yl]carbamate (0.136 g) as a colorless oil which solidified upon standing.
1H NMR (400 MHz, CD3OD) δ 7.39-7.29 (m, 5H), 5.16 (br, 1H), 4.78 (d, J=15.4 Hz, 1H), 4.75-4.68 (m, 1H), 4.68 (d, J=15.8 Hz, 1H), 4.64-4.55 (m, 1H), 3.94 (dd, J=10.6, 8.4 Hz, 1H), 1.46 (s, 9H).
Example 19
preparation of sodium (4R)-2-oxooxazolidine-4-carboxylate




(2R)-2-(Ethoxycarbonylamino)-3-hydroxy-propanoic acid (80 g, 0.452 mol) was dissolved in ethanol (800 ml) at 35° C. and treated in several portions with sodium hydroxide (24.0 g, 0.600 mol, microprills) at 25° C. After complete addition, the reaction mixture was warmed to 40° C. and stirred overnight. The precipitated solid was filtered off, washed with ethanol, and dried under reduced pressure to give sodium (4R)-2-oxooxazolidine-4-carboxylate (50.7 g) as a white powder containing ca. 20% of the residual solvent.
1H NMR (400 MHz, D2O) δ 4.57-4.63 (m, 1H), 4.25-4.31 (m, 2H).
1H NMR (400 MHz, D2O/DMSO-d6 4:1) δ 4.63 (dd, J=9.6, 8.5 Hz, 1H), 4.33 (dd, J=8.5, 5.8 Hz, 1H), 4.27 (dd, J=9.6, 5.7 Hz, 1H).
Alternatively, the Title Compound can be Obtained by Carrying Out the Following Procedure:
At 21° C., a solution of methyl (4R)-2-oxooxazolidine-4-carboxylate (20.0 g, 91.0% purity, 0.125 mol) in acetonitrile (100 g) was treated with sodium hydroxide (microprills) in methanol (16.2% (w/w) soln., 37.0 g, 0.150 mol) within 60 min and stirred at the ambient temperature for additional 30 min. The resulting precipitate was filtered off, washed with acetonitrile (3×25 g) and dried at 100° C. under vacuum to give sodium (4R)-2-oxooxazolidine-4-carboxylate (20 g, 83.2% purity as determined by quantitative 1H NMR analysis) as slightly yellow solid.
Example 20
preparation of lithium 2-oxooxazolidine-4-carboxylate




At 0-5° C., a solution of methyl 2-oxooxazolidine-4-carboxylate (1.0 g, 6.89 mmol) in 2-methyl-tetrahydrofurane (5 g) was treated with a solution of lithium hydroxide (0.167 g, 6.97 mmol) in methanol (2 ml) within 15 min. After complete addition, more methanol (1 ml) was added and the reaction mixture was stirred at 0-5° C. for additional 60 min. The resulting precipitate was filtered off and dried under vacuum to give lithium 2-oxooxazolidine-4-carboxylate (610 mg) as a white solid containing ca. 3% of the residual solvent.
1H NMR (400 MHz, D2O) δ 4.57-4.63 (m, 1H), 4.25-4.31 (m, 2H).

## Claims

1. A process for the preparation of a compound of formula (I)



comprising
i. reacting a compound of formula (II) or a salt thereof




with a compound of formula (V)




in the presence of a suitable base to produce a compound of formula (VI)




and
ii. converting the compound of formula (VI) to a compound of formula (I) by treatment of the compound of formula (VI) with an aqueous base
wherein
R1 is C1-C8alkyl, C1-C8haloalkyl, C3-C6 cycloalkyl, aryl or aryl substituted by one to five R11, or aryl-C1-C4alkylene or aryl-C1-C4alkylene substituted by one to five R11; and
each R11 is independently C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, cyano or halogen;
R7 is hydroxy or halogen or OM where M is Na, K, Li.

2. A compound of formula (V)



wherein R7 is is OM where M is Na, K, Li.

3. A compound of formula (VI)



wherein
R1 is C1-C8alkyl, C1-C8haloalkyl, C3-C6 cycloalkyl, aryl or aryl substituted by one to five R11, or aryl-C1-C4alkylene or aryl-C1-C4alkylene substituted by one to five R11;
each R11 is independently C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, cyano or halogen;
or a salt or N-oxide thereof.

4. The process according to claim 1, wherein the process further comprises reacting the compound of formula (I) with a second compound, wherein the second compound comprises a carboxylic acid, acid halide, ester or thioester functional group, and the reaction comprises reacting the amine functional group of the compound of formula (I) with the carboxylic acid, acid halide, ester or thioester functional group of the second compound such that the compound of formula (I) is coupled to the second compound via an amide functional group, or wherein the second compound comprises a dicarbonate group, and the reaction comprises reacting the amine functional group of the compound of formula (I) with the dicarbonate group of the second compound, such that the compound of formula (I) is coupled to the second compound via a carbamate functional group.

5. The process according to claim 4, wherein the second compound is a compound of formula (XII)



and the process results in a compound of formula (VIII)




wherein
X is a leaving group selected from halogen, C1-C8alkylsulfonyloxy, C1-C8haloalkylsulfonyloxy, C1-C8arylsulfonyloxy or C1-C8arylsulfonyloxy substituted by one to five R11, or a phosphonate ester, cyano, formyl, acetyl, C(O)CH═C(R3)R4, C(O)CH2C(OH)(R3)R4 or group A




—B1—B2—B3— is —C═N—O—, —C═N—CH2—, —C═CH2—O— or —N—CH2—CH2—;
A1, A2, A3 and A4 are independently of one another C—H, C—R5, or nitrogen;
R3 is C1-C8haloalkyl;
R4 is aryl or aryl substituted by one to three R6, or R4 is heterocyclyl or heterocyclyl substituted by one to three R6;
each R5 is independently halogen, cyano, nitro, C1-C8alkyl, C3-C8cycloalkyl, C1-C8haloalkyl, C2-C8alkenyl, C2-C8haloalkenyl, C2-C8alkynyl, C2-C8haloalkynyl, C1-C8alkoxy, C1-C8haloalkoxy, C1-C8alkoxycarbonyl-, or two R5 on adjacent carbon atoms together form a —CH═CH—CH═CH— bridge or a —N═CH—CH═CH— bridge;
each R6 is independently halogen, cyano, nitro, C1-C8alkyl, C1-C8haloalkyl, C1-C8alkoxy, or C1-C8haloalkoxy;
R8 is hydroxy, C1-C6alkoxy, fluoro, chloro, bromo, or SRx wherein Rx is H, C1-C6alkyl, imidazole or pyrrole; and
each R11 is independently C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, cyano or halogen;
R1 is C1-C8alkyl, C1-C8haloalkyl, aryl or aryl substituted by one to five R11, or aryl-C1-C4alkylene or aryl-C1-C4alkylene substituted by one to five R11; and
each R11 is independently C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, cyano or halogen;
or
the second compound is a compound of formula (XIII)




wherein and the process results in a compound of formula (IX)




wherein
R1 is C1-C8alkyl, C1-C8haloalkyl, aryl or aryl substituted by one to five R11, or aryl-C1-C4alkylene or aryl-C1-C4alkylene substituted by one to five R11; and
R9 is hydrogen, C1-C8alkyl or C1-C8haloalkyl and R8 is as defined for compound of formula (XII);
each R11 is independently C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, cyano or halogen;
or
the second compound is a compound of formula (XIVa) or (XIVb)




and the process results in a compound of formula X




wherein
R1 is C1-C8alkyl, C1-C8haloalkyl, aryl or aryl substituted by one to five R11, or aryl-C1-C4alkylene or aryl-C1-C4alkylene substituted by one to five R11;
each R10 is independently C1-C8alkyl, C1-C8haloalkyl, aryl-C1-C4alkylene- or aryl-C1-C4alkylene-substituted by one to five R11;
each R11 is independently C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, cyano or halogen.