# Patent

## Title
Process for the production of acid chlorides

## Abstract

A process for the preparation of acid halides of formula I




which are useful as intermediates in the preparation of i.a. pharmaceutically active compounds.

## Background
PRIORITY TO RELATED APPLICATIONS
This application claims the benefit of European Application No. 05110177.2, filed Oct. 31, 2005, which is hereby incorporated by reference in its entirety.
The present invention is directed to a process for the preparation of acid halides which are useful as intermediates in the preparation of i.a. pharmaceutically active compounds. In one aspect the present invention provides a process for the preparation of a compound of formula I




wherein

    R1 is hydrogen, C1-C8alkyl or C2-C8alkenyl which are unsubstituted or substituted by one or more substituents selected from C1-C8alkoxy and C3-C8cycloalkyl; and
    R2 and R3 together are C3-alkylenyl or C3-alkenylenyl; comprising reacting a compound of formula II






wherein R1, R2 and R3 have the above meanings;

    with thionylchloride in the presence of a tri-C1-C5alkylamine.
    In another aspect the present invention provides a process for the preparation of a compound of formula I






wherein

    R1 is hydrogen, C1-C8alkyl or C2-C8alkenyl which are unsubstituted or substituted by one or more substituents selected from C1-C8alkoxy and C3-C8cycloalkyl; and
    R2 and R3 are combined with the carbon atom to which they are attached to form C3-C7cycloalkyl or C5-C8cycloalkenyl;
    comprising reacting a compound of formula II






wherein R1, R2 and R3 have the above meanings;

    with thionylchloride in the presence of a tri-C1-C5alkylamine.


The compounds of formula I may be used as intermediates in the synthesis of valuable pharmaceutical compounds, e.g. those as described in e.g. EP 1,020,439.
Accordingly, in another embodiment the present invention provides a process comprising the synthetic steps represented in the following scheme:




wherein R1, R2 and R3 are as defined above and R4 is C1-C8alkyl. In particular, the process comprises reacting a compound of formula I with bis(2-aminophenyl)disulfide to acylate the amino groups of the (2-aminophenyl)disulfide, reducing the amino-acylated disulfide product with a reducing agent such as triphenylphosphine, zinc or sodium borohydride to yield the thiol product, and acylating the thiol group in the thiol product with R4C(O)Cl.

The additional steps may be performed, e.g., according to the procedures described in Shinkai et al., J. Med. Chem. 43:3566-3572 (2000).
Examples for C1-C8alkyl include methyl, ethyl, straight and branched propyl, butyl, pentyl, hexyl, e.g. CH2CH(CH2CH3)2, heptyl and octyl. For R1, C1-C8alkyl is preferably CH2CH(CH2CH3)2. For R4, C1-C8alkyl is preferably isopropyl.
Examples for C2-C8alkenyl include unsaturated carbon chains containing one or more double bonds at any possible position, e.g. vinyl, allyl, butenyl, pentenyl, hexenyl, heptenyl and octenyl.
Examples for C3-C7cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Preferred is e.g. cyclohexyl. Examples for C5-C8cycloalkenyl include cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclopentadienyl, cyclohexadienyl, cycloheptadienyl and cyclooctadienyl. Preferred are cyclopentenyl, cyclohexenyl and cycloheptenyl.
The term “tri-C1-C5alkylamine” denotes a compound of formula R4N(R5)R6 wherein R4, R5 and R6 independently are a C1-C8alkyl, and includes triethylamine, tributylamine, diethyl-methylamine, dimethyl-ethylamine and methylethylbutylamine. The process may take place at a temperature in the range from 20 to 60° C., e.g. in a range from 40 to 55° C.
The process maybe performed without a solvent or in the presence of a solvent, e.g. in the presence of an aromatic or chlorinated solvent, e.g. in the presence of methylene chloride, chloroform, toluene or benzene, e.g. in the presence of toluene.
The acylating steps of the present invention are preferably conducted in the presence of a base. Preferred bases include organic bases with pyridine being a preferred organic base.
The amount of thionylchloride in relation to the compound of formula I in the reaction mixture may be in the range from 1.0 to 2.0 equivalents of thionylchloride, e.g. from 1.0 to 1.2 equivalents, e.g. 1.2 equivalents.
The amount of the tri-C1-C5alkylamine in relation to the amount of the compound of formula I maybe at a ratio of from 5 mol % to 0.1 mol %, e.g. from 0.3 mol % to 0.5 mol %, e.g. 0.3 mol %.
In another aspect the present invention provides a process for the preparation of a compound of formula I as above, comprising reacting a compound of formula II as above in the presence of a tri-C1-C5alkylamine by continuously adding thionylchloride.
The term “continuously adding” denotes the addition of thionylchloride to a solution of compound I and optionally a solvent during a period of time from 10 minutes to 5 hours, depending on the batch size. The solution of compound I and optionally a solvent is heated to the desired temperature prior to the addition of thionylchloride. This method is different from the batch mode where all components are mixed at RT and the mixture is heated to the desired temperature.
In one embodiment the present invention provides a process for the preparation of a compound of formula I wherein R1 is —CH2CH(CH2CH3)2. In another embodiment the present invention provides a process for the preparation of a compound of formula I wherein the tri-C1-C5alkylamine is triethylamine or tributylamine. In still another embodiment the present invention provides a process for the preparation of a compound of formula I wherein the tri-C1-C5alkylamine is tributylamine.
The compounds of formula II are commercially available or can be prepared by procedures known to the skilled person.
In general, the nomenclature used in this Application is based on AUTONOMTMv.4.0, a Beilstein Institute computerized system for the generation of IUPAC systematic nomenclature. Chemical structures shown herein were prepared using ISIS® version 2.2. Any open valency appearing on a carbon, oxygen or nitrogen atom in the structures herein indicates the presence of a hydrogen atom.


EXAMPLE 1
Preparation of 1-(2-Ethyl-butyl)-cyclohexanecarbonyl Chloride in the Absence of a Catalyst
A mixture of 103.0 mmol 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid and 38.9 mmol cyclohexanecarboxylic acid was warmed to 50° C. 12.4 mL (170.3 mmol=1.2 Eq. relative to the sum of both acids) of thionyl chloride was added during 16 minutes at a temperature of 44-50° C. (reaction is endothermic) and the reaction mixture was kept at 52-53° C. After 1 hr the reaction was incomplete (5.2% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid and 13.8% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid anhydride), after 6 hrs still incomplete (1.9% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid and 2.8% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid anhydride). After addition of another 4.0 mL (55 mmol) thionylchloride and 3 hr at 52-53° C. the reaction was almost complete (0.18% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid and 0.47% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid anhydride). After removing volatile components in vacuo (60° C. bath, 3.3-3.7 mbar followed by 120° C. bath, 9.3-9.6 mbar) 20.21 g of residue was obtained (assay 96.6% 1-(2-ethyl-butyl)-cyclohexanecarbonyl chloride, yield 82.1%).
EXAMPLE 2 
Preparation of 1-(2-Ethyl-butyl)-cyclohexanecarbonyl Chloride in the Presence of 0.02 Eq. Triethylamine
A mixture of 103.0 mmol 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid, 38.9 mmol cyclo-hexanecarboxylic acid and 396 μL triethylamine (2.84 mmol=0.02 eq. relative to the sum of both acids) was warmed to 50° C. 12.4 mL (170.3 mmol=1.2 Eq. relative to the sum of both acids) of thionyl chloride was added during 18 minutes at a temperature of 40-54° C. (reaction is endothermic, vigorous gas evolution) and the reaction mixture was kept at 54-55° C. After 1 hr reaction was complete (0.03% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid and no 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid anhydride). After removing volatile components in vacuo (60° C. bath, 3.5-4.3 mbar followed by 120° C. bath, 10-11 mbar) 25.44 g of residue was obtained (assay 92.9% 1-(2-ethyl-butyl)-cyclohexanecarbonyl chloride, yield 99.4%).
EXAMPLE 3 
Preparation of 1-(2-Ethyl-butyl)-cyclohexanecarbonyl Chloride in the Presence of 0.005 Eq. Triethylamine
A mixture of 103.0 mmol 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid, 38.9 mmol cyclo-hexanecarboxylic acid and 100 μL triethylamine (0.72 mmol=0.005 eq. relative to the sum of both acids) was warmed to 50° C. 12.4 mL (170.3 mmol=1.2 Eq. relative to the sum of both acids) of thionyl chloride was added during 22 minutes at a temperature of 41-51° C. (reaction is endothermic, vigorous gas evolution) and the reaction mixture was kept at 54-55° C. After 10 minutes the reaction was almost complete (0.13% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid and 0.13% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid anhydride). After 1.5 hr the reaction was complete (0.04% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid and no 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid anhydride). After removing volatile components in vacuo (60° C. bath, 3.5-4.3 mbar followed by 120° C. bath, 10-11 mbar) 26.19 g of residue was obtained (assay 92.9% 1-(2-ethyl-butyl)-cyclohexanecarbonyl chloride, yield 100%).
EXAMPLE 4 
Preparation of 1-(2-Ethyl-butyl)-cyclohexanecarbonyl Chloride in the Presence of 0.005 Eq. Tributylamine
A mixture of 103.0 mmol 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid, 38.9 mmol cyclo-hexanecarboxylic acid and 173 μL tributylamine (0.71 mmol=0.005 eq. relative to the sum of both acids) was warmed to 50° C. 12.4 mL (170.3 mmol=1.2 Eq. relative to the sum of both acids) of thionyl chloride was added during 16 minutes at a temperature of 44-51° C. (reaction is endothermic, vigorous gas evolution) and the reaction mixture was kept at 53-55° C. After 15 minutes the reaction was complete (0.08% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid and no 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid anhydride). After removing volatile components in vacuo (60° C. bath, 2.7-1.9 mbar followed by 120° C. bath, 8.8-13 mbar) 24.86 g of the residue was obtained (assay 95.8% 1-(2-ethyl-butyl)-cyclohexanecarbonyl chloride, yield 100%).

## Claims

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




wherein
R1 is hydrogen, C1-C8alkyl or C2-C8alkenyl which are unsubstituted or substituted by one or more substituents selected from C1-C8alkoxy and C3-C8cycloalkyl; and
R2 and R3 are combined with the carbon atom to which they are attached to form C3-C7-cycloalkyl or C5-C8cycloalkenyl;
comprising reacting a compound of formula II




wherein R1, R2 and R3 have the above meanings;
with thionyichloride in the presence of tributylamine by continuously adding the thionyl chloride to the reaction mixture.

2. The process according to claim 1 additionally comprising the step of acylating a compound of the formula III




with a compound of formula I to yield a compound of formula IV




wherein R1, R2 and R3 are as defined in claim 1.

3. The process according to claim 2 additionally comprising the step of reducing the compound of formula IV with a reducing agent to yield a compound of formula V




wherein R1, R2 and R3 are as defined in claim 1.

4. The process according to claim 3 additionally comprising the step of acylating the compound of formula V with R4C(O)Cl to yield a compound of formula VI




wherein R1, R2 and R3 are as defined in claim 1 and R4 is C1-C8alkyl.

5. The process according to claim 4 wherein R4 is isopropyl.

6. The process according to claim 1 wherein the amount of the tributylamine in relation to the amount of the compound of formula I is at a ratio of from 5 mol % to 0.1 mol %.

7. The process according to claim 1 wherein in formula I R2 and R3 are combined with the carbon atom to which they are attached to form C3-C7cycloalkyl.

8. The process according to claim 1 wherein in formula I R1 is CH2CH(CH2CH3)2 and R2 and R3 are combined with the carbon atom to which they are attached to form cyclohexyl.

9. The process according to claim 2 wherein the acylating step is performed in the presence of a base.

10. The process according to claim 4 wherein the acylating step is performed in the presence of a base.

11. The process according to claim 9 wherein the base is an organic base.

12. The process according to claim 10 wherein the base is an organic base.