# Patent

## Title
Synthesis of intermediate for treprostinil production

## Abstract

The compound according to Formula I is an intermediate in the synthesis of prostacylin analogs. The present invention provides an efficient method for synthesizing a Formula I compound.

## Background
RELATED APPLICATIONS
The present application is a Continuation of U.S. application Ser. No. 14/002,446, which is the U.S. National Stage of PCT/US2012/027234, filed Mar. 1, 2012, which claims priority to U.S. provisional application No. 61/448,317 filed Mar. 2, 2011, which are incorporated herein by reference in their entirety.


FIELD
The present application relates generally to the field of pharmaceutical production and more specifically to methods of synthesizing an intermediate for producing prostacyclin derivatives, such as Treprostinil.
SUMMARY
One embodiment is a method for synthesizing a compound according to Formula I.




According to the method, the compound of Formula I may be synthesized by hydrolyzing a compound represented by Formula A.




For Formula A compounds, “x” may be an integer between 0 and 4 inclusive. Substituent R may be selected from the group consisting of H, straight or branched (C1-C6)alkyl, (C6-C14)aryl, and (C6-C14)aryl(C1-C6)alkylene-, while substituent groups Ra, Rb and Rc are each independently selected from the group consisting of H, straight or branched (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C14)aryl, (C3-C14)aryl(C1-C6)alkylene- and (C3-C6)cycloalkyl(C1-C6)alkylene-.
In some embodiments, the hydrolysis of a Formula A compound may be accomplished by contact with water, aqueous mineral acid, or an aqueous solution of sodium sulfite.
Another embodiment may be a method for synthesizing a Formula A compound. Such synthesis may be accomplished by contacting a Formula B compound with an organolithium reagent, such as phenyllithium or butyllithium to form an otho-lithiated intermediate which may be converted to a cuprate using copper cyanide.




The obtained cuprate may be then contacted with an allyl halide, for example, with an allyl chloride, an allyl bromide, or an allyl iodide synthesize a compound according to Formula A.
In some embodiments, Ra, Rb and Rc may be each independently (C1-C6)alkyl and “x” is 2. In one embodiment, Ra, Rb and Re are each methyl and “x” is 2.
R may be an alcohol protecting group, straight or branched (C1-C6)alkyl; (C6-C14)aryl and (C6-C14)aryl(C1-C6)alkylene-. For example, R may be selected from methyl, ethyl, propoyl, isopropyl, butyl, iso-butyl, tert-butyl, pentyl, neo-pentyl, hexyl and branched hexyl. For example, in one embodiment substituent R may be methyl. Alternatively, R may be a (C6-C14)aryl(C1-C6)alkylene-, for example a benzyl group.
The allylating agent may be, for example, an allyl halide, such as an allyl bromide or an allyl iodide, although other allylating reagents may also be used.
Yet another embodiment may be a method for synthesizing a Formula I compounds, which may include the following:

    (a) contacting an aldehyde represented by Formula C with a compound selected from the group consisting of Ra—NH2, RaRbN—(CHR′)x—NHRa and R′—OH in the presence of an organolitium;






    (b) contacting the product from step (a) with an organolithium to form an ortho-lithiated product which is contacted with copper cyanide to form a cuprate;
    (c) contacting the cuprate from step (b) with an allyl halide selected from the group consisting of allyl chloride, allyl bromide and allyl iodide to form a Formula A compound which is hydrolyzed to give a Formula I compound.




DETAILED DESCRIPTION
Unless otherwise specified, “a” or “an” means one or more.
(+)-Treprostinil (also known as UT-15) is the active ingredient in Remodulin®, a commercial drug approved by FDA for the treatment of pulmonary arterial hypertension (PAH). It was first described in U.S. Pat. No. 4,306,075. Treprostinil is a stable analog of prostacyclin (PGI2) belonging to a class of compounds known as benzindene prostacyclins, which are useful pharmaceutical compounds possessing activities such as platelet aggregation inhibition, gastric secretion reduction, lesion inhibition, and bronchodilation.




U.S. Pat. Nos. 5,153,222, 6,054,486; 6,521,212; 6,756,033; 6,803,386; 7,199,157; 7,879,909 and 7,999,007 as well as U.S. patent application publications Nos. 2005/0165111; 2008/0200449; 2008/0280986; 2009/0124697; 2009/0281189; 2009/0036465; 2010/0076083; 2010/0282622; 2011/0092599; 2011/0144204; 2011/0224236; 2012/0004307 and 2012/0010159 disclose various applications of treprostinil. U.S. Pat. Nos. 7,417,070, 7,384,978 and 7,544,713 as well as U.S. publications Nos. 2005/0282901; 2007/0078095; 2008/0249167 and 2011/0118213 describe oral formulations of treprostinil and other prostacyclin analogs as well as their use for treatment of a variety of conditions.
The following documents provide information, which may be useful for preparing treprostinil and/or other prostacyclin derivatives: Moriarty, et al in J. Org. Chem. 2004, 69, 1890-1902, Drug of the Future, 2001, 26(4), 364-374, Aristoff et al. JACS 107(26), 1985, 7967-74; Aristoff et al. Advances in Prostaglandin, Thromboxane and Leukotriene Research, vol. 11, 267, 1983; U.S. Pat. Nos. 4,306,075, 4,668,814; 4,683,330; 6,441,245, 6,528,688, 6,700,025, 6,765,117, 6,809,223; US Publications Nos. 2009/0163738 and 2011/0319641 as well as PCT publication WO2012009816.
A compound of Formula I may be a key intermediate in the syntheses of (+) Treprostinil and other prostacyclin derivatives, such as the ones disclosed in U.S. Pat. Nos. 6,441,245, 6,528,688, 6,700,025, 6,765,117, 6,809,223 and US Publications Nos. 2009/0163738 and 2011/0319641 as well as PCT publication WO2012009816:




The present inventor developed a novel method for synthesizing a Formula I compound. Specifically, the inventor provide a synthesis for Formula I compounds, which may be performed efficiently in one pot using commercially available starting materials.
Definitions
In the context of the present invention, “alkyl” refers to straight, branched chain, or cyclic hydrocarbyl groups including from 1 to about 20 carbon atoms. For instance, an alkyl can have from 1 to 10 carbon atoms or 1 to 5 carbon atoms. Exemplary alkyl includes straight chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, and the like, and also includes branched chain isomers of straight chain alkyl groups, for example without limitation, —CH(CH3)2, —CH(CH3)(CH2CH3), —CH(CH2CH3)2, —C(CH3)3, —C(CH2CH3)3, —CH2CH(CH3)2, —CH2CH(CH3)(CH2CH3), —CH2CH(CH2CH3)2, —CH2C(CH3)3, —CH2C(CH2CH3)3, —CH(CH3)CH(CH3)(CH2CH3), —CH2CH2CH(CH3)2, —CH2CH2CH(CH3)(CH2CH3), —CH2CH2CH(CH2CH3)2, —CH2CH2C(CH3)3, —CH2CH2C(CH2CH3)3, —CH(CH3)CH2CH(CH3)2, —CH(CH3)CH(CH3)CH(CH3)2, and the like. Thus, alkyl groups include primary alkyl groups, secondary alkyl groups, and tertiary alkyl groups.
The phrase “substituted alkyl” refers to alkyl substituted at one or more positions, for example, 1, 2, 3, 4, 5, or even 6 positions, which substituents are attached at any available atom to produce a stable compound, with substitution as described herein. “Optionally substituted alkyl” refers to alkyl or substituted alkyl.
“Alkene” refers to straight, branched chain, or cyclic hydrocarbyl groups including from 2 to about 20 carbon atoms having 1-3, 1-2, or at least one carbon to carbon double bond. “Substituted alkene” refers to alkene substituted at 1 or more, e.g., 1, 2, 3, 4, 5, or even 6 positions, which substituents are attached at any available atom to produce a stable compound, with substitution as described herein. “Optionally substituted alkene” refers to alkene or substituted alkene. The terms “allyl” or “allylene” belongs to the genus “alkene” and refers to a compound having the following generic structure CH2═CH—CH2—. Suitable allylating reagents include without limitation allyl chloride, allyl bromide, allyl iodide, allyl carbonate, allyl alcohol and allyl diphenylphosphine oxide.
The term “alkenylene” refers to divalent alkene. Examples of alkenylene include without limitation, ethenylene (—CH═CH—) and all stereoisomeric and conformational isomeric forms thereof “Substituted alkenylene” refers to divalent substituted alkene. “Optionally substituted alkenylene” refers to alkenylene or substituted alkenylene.
Each of the terms “halogen,” “halide,” and “halo” refers to —F, —Cl, —Br, or —I.
The term “aryl,” alone or in combination refers to an aromatic monocyclic or bicyclic ring system such as phenyl or naphthyl. “Aryl” also includes aromatic ring systems that are optionally fused with a cycloalkyl ring, as herein defined.
A “substituted aryl” is an aryl that is independently substituted with one or more substituents attached at any available atom to produce a stable compound, wherein the substituents are as described herein. “Optionally substituted aryl” refers to aryl or substituted aryl.
“Arylene” denotes divalent aryl, and “substituted arylene” refers to divalent substituted aryl. “Optionally substituted arylene” refers to arylene or substituted arylene.
A “hydroxyl” or “hydroxy” refers to an —OH group.
The term “alkoxy” refers to an —O-alkyl group having the indicated number of carbon atoms. For example, a (C1-C6)alkoxy group includes —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-sec-butyl, —O-tert-butyl, —O-pentyl, —O-isopentyl, —O-neopentyl, —O-hexyl, —O— isohexyl, and —O-neohexyl.
The term “(C3-C14)aryl-(C1-C6)allylene” refers to a divalent alkylene wherein one or more hydrogen atoms in the C1-C6 alkylene group is replaced by a (C3-C14)aryl group. Examples of (C3-C14)aryl-(C1-C6)alkylene groups include without limitation 1-phenylbutylene, phenyl-2-butylene, 1-phenyl-2-methylpropylene, phenylmethylene, phenylpropylene, and naphthylethylene.
The phrase “protecting group” as used herein means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively. The field of protecting group chemistry has been reviewed (Greene, T. W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 3rd ed.; Wiley: New York, 1999). Suitable alcohol protecting groups are well know in the chemical art, and include without limitation actetyl, benzoyl, benzyl, p-methoxyethoxymethyl ether, methoxymethyl ether, dimethoxytrityl, p-methoxybenzyl ether, trityl, silyl ether (e.g., trimethylsilyl (TMS), tert-butyldimethylsilyl (TBMDS), tert-butyldimethylsilyloxymethyl (TOM) or triisopropylsilyl (TIPS) ether), tetrahydropyranyl (THP), methyl ether and ethoxyethyl ether.
The term “cycloalkyl” refer to monocyclic, bicyclic, tricyclic, or polycyclic, 3- to 14-membered ring systems, which are either saturated, unsaturated or aromatic. The heterocycle may be attached via any atom. Cycloalkyl also contemplates fused rings wherein the cycloalkyl is fused to an aryl or hetroaryl ring as defined above. Representative examples of cycloalkyl include, but are not limited to cyclopropyl, cycloisopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropene, cyclobutene, cyclopentene, cyclohexene, phenyl, naphthyl, anthracyl, benzofuranyl, and benzothiophenyl. A cycloalkyl group can be unsubstituted or optionally substituted with one or more substituents as described herein below.
The term “cycloalkylene” refers to divalent cycloalkylene. The term “optionally substituted cycloalkylene” refers to cycloalkylene that is substituted with 1 to 3 substituents, e.g., 1, 2 or 3 substituents, attached at any available atom to produce a stable compound, wherein the substituents are as described herein.
The present compounds may exist in various isomeric forms, including configurational, geometric, and conformational isomers, including, for example, cis- or trans-conformations. The present compounds may also exist in one or more tautomeric forms, including both single tautomers and mixtures of tautomers. The term “isomer” is intended to encompass all isomeric forms of a compound of this invention, including tautomeric forms of the compound. All forms are included in the invention.
Some compounds described here may have asymmetric centers and therefore exist in different enantiomeric and diastereomeric forms. A compound of the invention may be in the form of an optical isomer or a diastereomer. Accordingly, the invention encompasses compounds of the invention and their uses as described herein in the form of their optical isomers, diastereoisomers and mixtures thereof, including a racemic mixture. Optical isomers of the compounds of the invention may be obtained by known techniques such as asymmetric synthesis, chiral chromatography, simulated moving bed technology or via chemical separation of stereoisomers through the employment of optically active resolving agents.
Unless otherwise indicated, “stereoisomer” means one stereoisomer of a compound that is substantially free of other stereoisomers of that compound. Thus, a stereomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, for example greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, or greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound.
If there is a discrepancy between a depicted structure and a name given to that structure, then the depicted structure controls. Additionally, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it. In some cases, however, where more than one chiral center exists, the structures and names may be represented as single enantiomers to help describe the relative stereochemistry. Those skilled in the art of organic synthesis will know if the compounds are prepared as single enantiomers from the methods used to prepare them.
Methods for Synthesizing Formula I Compounds
The present application relates to a compound according to Formula I and to methods for making Formula I compounds.




For Formula I compounds R may be an alcohol protecting group or R may be selected from the group consisting of H, straight or branched (C1-C6)alkyl, (C6-C14)aryl and (C6-C14)aryl(C1-C6)alkylene-. For example, R may be one of the alcohol protecting groups disclosed above. In some embodiments, R may be selected from the group consisting of actetyl, benzoyl, benzyl, p-methoxyethoxymethyl ether, methoxymethyl ether, dimethoxytrityl, p-methoxybenzyl ether, trityl, say′ ether (e.g., trimethylsilyl (TMS), tert-butyldimethylsilyl (TBMDS), tert-butyldimethylsilyloxymethyl (TOM) or triisopropylsilyl (TIPS) ether), tetrahydropyranyl (THP), methyl ether and ethoxyethyl ether. In some embodiments, R may be methyl, p-methoxybenzyl or benzyl.
Also contemplated is a facile and efficient synthesis for Formula I compounds. Although, synthesis of a Formula I compound by direct allylation of a meta-substituted arylaldehyde which was protected as an imine has been carried out, gas chromatography analysis showed the obtained product to be a mixture of three components, namely, a Formula I compound and a mixture of its positional regioisomers depicted below as compounds (A) and (B).




While the above process simplified synthesis of a Formula I, the obtained product contained the desired Formula I compound as well as undesired regioisomers. In an attempt to improve yields and eliminate undesired side products, the present inventor undertook a study to develop an alternate methodology for synthesizing a Formula I compound. In one embodiment, therefore, is provided a one pot synthesis for a Formula I compound.
The overall protocol is illustrated in Scheme 1. Synthesis of the target compound according to the inventive process may begin with the in-situ protection of aldehyde (6) using, for example, N,N,N-trimethylethylene diamine in the presence of phenyllithium or butyllithium to give (6a). Ortho-lithiation of the protected aldehyde (6a) may follow conversion of the ortho-lithiated intermediate to the corresponding cuprate (6c), and allylation may give intermediate (6d) which may be hydrolyzed in-situ to afford the target compound (7). As illustrated below, the conversion of lithiated intermediate (6b) to the corresponding cuprate (6c) helps to improve yield by stabilizing the ortho-anion and promoting allylation.




There are several advantages of the present method over previous synthetic processes for making a Formula I compound. For example, the target compound may be synthesized by the direct allylation of an appropriately substituted commercially available aldehyde. Because synthesis is achieved in “one-pot,” there is no need to isolate and purify intermediates. Accordingly, the present method may reduce the overall number of synthetic steps, save time and avoid the use of extra chemicals, manpower, and large volume of solvents. Another advantage of the present method may be that it may permit the synthesis to be carried out at ambient temperature (no need for cryogenic equipment), and eliminates tedious column chromatographic purifications. Moreover, the yield and chemical purity of the desired product is greatly improved.
Other differences between the inventive process for ortho-lithiation of aromatic aldehydes and processes disclosed in the prior art (e.g., Comins et al., J. Org. Chem., 1984, 49, 1078 and J. Org. Chem., 1989, 54, 3730), are the stabilization of ortho-lithiated anion intermediate by copper cyanide (3c, scheme 2), and the use of solvent MTBE in place of THF as the solvent. The present inventor also found allyl iodide to be a better allylating reagent than allyl bromide used in many prior art processes. Based on these initial observations, a study was undertaken in which the following parameters listed in Table 1 were altered for improving the synthesis of a Formula I compound.







TABLE 1







Tabular summary of variable parameters











S. No.
Parameters
Option 1
Option 2
Option 3





1
Solvent
Toluene
THF
MTBE


2
Lithium
n-Butyl
Phenyl
Combination



Reagent
lithium
lithium
of option




(2.5M in
(1.8M in
1 & 2




hexanes
dibutyl ether)



3
Temperature
≦0° C.
Ambient
Ambient to



and Time of
to Ambient
(≧16 hours)
35 ± 2° C.



the reaction
(≧16 hours)

(≦10 hours)


4
Allylating
Allyl bromide
Allyl iodide
NA



reagent





5
Copper
Presence of
Absence of
NA



Cyanide
CuCN
CuCN



6
Purification
NaHSO3
Distillation
Column



procedure
method
method
chroma-






tography









A total of fourteen experiments were carried out to identify experimental parameters that provided the target compound in high yield and purity. The experimental details are set forth in Table 2a-2c below.







TABLE 2a







Details of experiments












Experimental 







Parameters
Experiment 1
Experiment 2
Experiment 3
Experiment 4
Experiment 5





Lot number
R-UT-1041-197
R-UT-1041-198A
R-UT-1041-198B
R-UT-1059-001
R-UT-1059-004


Scale
100 mg
100 mg
100 mg
100 mg
100 mg


Allylating agent
Allyl bromide
Allyl bromide
Allyl bromide
Allyl bromide
Allyl bromide


Reaction Temp
≦O° C.
≦O° C.
≦O° C.
≦O° C.
≦O° C.


Copper Cyanide
Yes
Yes
Yes
Yes
Yes


Reagent for protection
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi


of TMDA







Reagent for ortho
n-BuLi
n-PhLi
n-PhLi
n-PhLi
n-PhLi


lithiation of 3







Reaction solvent
Toluene
THF
MTBE
MTBE
MTBE


Reaction Time
Overnight
Overnight
Overnight
Overnight
Overnight


Comments
Small amount
Small amount
Major product and
Major product and
Major product and



of product (TLC)
of product (TLC)
minor starting
minor starting
minor starting





material (TCL)
material (TCL)
material (TCL)
















TABLE 2b







Details of experiments












Experimental







Parameters
Experiment 6
Experiment 7
Experiment 8
Experiment 9
Experiment 10





Lot number
R-UT-1059-005
R-UT-1059-010
R-UT-1059-015
R-UT-1059-021
R-UT-1059-022


Scale
100 mg
1.0 g
100 mg
500 mg
500 mg


Allylating agent
Allyl iodide
Allyl iodide
Allyl iodide
Allyl iodide
Allyl iodide


Reaction Temp
≦O° C.
≦O° C.
≦O° C.
≦O° C.
RT


Copper Cyanide
Yes
Yes
Yes
Yes
Yes


Reagent for
n-BuLi
n-BuLi
n-BuLi
n-PhLi
n-BuLi


protection of







TMDA







Reagent for
n-PhLi
n-PhLi
n-PhLi
n-PhLi
n-PhLi


ortho lithiation







of 3







Reaction solvent
MTBE
MTBE
MTBE
MTBE
MTBE


Reaction time
Overnight
Overnight
Overnight
Overnight
6-8 hours


Comments
Major product
Yield was 50%
Yield ~75%
Yield ~75%
Yield ~83%



and no starting
Purification by
Purification by
Purification by
Purification by



material (TLC)
column
column
column
column
















TABLE 2c







Details of experiments











Experi-






mental
Experi-
Experi-
Experi-
Experi-


Parameters
ment 11
ment 12
ment 13
ment 14





Lot 
R-UT-
R-UT-
R-UT-
R-UT-


number
1059-030
1059-031
1059-039
1059-042


Scale
100 mg
100 mg
6.0 g
3.0 g


Allylating 
Allyl 
Allyl 
Allyl 
Allyl 


agent
iodide
iodide
iodide
iodide


Reaction 
RT
RT
RT
RT


Temp






Copper 
Yes
NO
Yes
Yes


Cyanide






Reagent for
n-PhLi
n-PhLi
n-BuLi (2.5M)
n-PhLi


protection 






of TMDA






Reagent for
n-PhLi
n-PhLi
n-PhLi 
n-PhLi 


ortho 
(Heated to
(Heated to
(Heated to
(Heated to


lithiation 
30-35° C.)
30-35° C)
35 ± 2° C.)
35 ± 2° C.)


of 3






Reaction 
MTBE
MTBE
MTBE
MTBE


solvent






Reaction 
6-8 hours
6-8 hours
6-8 hours
6-8 hours


time






Comments
Better 
Trace 
Product purified by
Yield ~73%



result
amount of
distillation (7.3 g)
Purification 



after 
product
contaminated with
by NaHSO3 



heating

small amount of
method





allylbenzene









As illustrated from this study, synthesis of a Formula I compound was improved when ortho-lithiation is carried out at a temperature between 30° C. and 35° C. using phenyllithium or butyllithium. Furthermore, the target compound (7) was obtained in good yield and high purity when allylation is carried out at ambient temperatures, for example at room temperature.
The invention is further illustrated by, though in no way limited to, the following examples.
EXAMPLES
1. In situ Protection of Aldehyde as Lithium ((2-(dimethylamino) ethyl(methyl)amino)(3-methoxyphenyl)methanolate (6a)
A 500-mL, three-necked, round-bottom flask equipped with a mechanical stirrer and an adapter for bubbling argon was charged with N,N,N-trimethyl ethylenediamine (2.926 g) and MTBE (20 mL) under an inert atmosphere at room temperature. To this solution was added phenyl lithium or n-butyllithium (16 mL or 11.5 mL, respectively), and the reaction mixture was stirred at for 15-30 minutes at ambient temperature. A solution of 3-methoxybenzaldehyde (3, 3.0 g) in MTBE (5 mL) was then added to the flask over a period of 10-15 minutes and the reaction mixture was allowed to stir for another 20-30 minutes to generate the titled compound lithium ((2-(dimethylamino)ethyl)(methyl)amino)(3-methoxyphenyl)methanolate (6a), in situ.
2. Allylation Reaction
To the solution of the protected aldehyde was added phenyl lithium (49 mL, 1.8 M in butyl ether) drop wise over a period of 15-30 minutes. The reaction mixture was heated at 35±2° C. for 3-4 hours and then allowed to cool to room temperature. Copper cyanide (8.5 g) was then Added and the reaction mixture was stirred for 30-60 minutes at the room temperature. To the resulting suspension was added allyl iodide (9.1 mL) added drop wise over a 20-30 minute interval of time. Following the addition of allyl iodide, the reaction mixture was stirred for an additional 30-60 minutes and the progress of the allylation reaction was monitored by TLC using a mixture of dichloromethane:ethylacetate:hexane (15:85:15) as the eluting solvent. If needed, TLC plates were eluted more than once to improve resolution.
Following completion, the reaction mixture was quenched with sodium sulfite (12 g dissolved in water (30 mL)), followed by the addition of Celite (10-12 g). After stirring the reaction mixture vigorously, it was filtered through a pad of Celite, followed by a wash step using ethyl acetate. The organic layer containing the crude was washed with saturated NaHS03 (2×50 mL) solution and concentrated in vacuo.
The obtained crude product was dissolved in ethanol (50 mL). Sodium bisulfate (3.6 g) was added to the ethanolic solution and the mixture was heated at a temperature between 40-60° C. Water (25 mL) and ethyl acetate (25 mL) were added to during heating to prevent precipitation and keep the reaction mixture clear.
Following heating, the solution is cooled and the solvent removed under reduced pressure to obtain solid material. Tituration of the solid material with hexanes/MTBE (2:1 solution) removed impurities as judged by TLC. The solid material which is the sodium bisulfate adduct of the target compound (7) was isolated by filtration, dissolved in saturated sodium bicarbonate (50 mL) and extracted with ethyl aceate or MTBE (3×50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield compound 7 (2.82 g, 73%).
A similar synthetic strategy (see Scheme 2), was employed to allylate 3-(benzyloxy) benzaldehyde (8). Briefly, protection of the aldehyde using N,N,N-trimethyl ethylenediamine followed by ortho-lithiation and treatment with copper cyanide generates the corresponding cuperate in situ. Allylation of the cooperate using allyl iodide followed by hydrolysis gave the target compound (9) in 70% yield.




Inventive compounds (7) or (9) have been used to synthesize the prostacyclin analog (+)-Treprostinil.
All references and publications cited in the specification are incorporated by reference herein to the same extent as if individually incorporated by reference.
Although the foregoing refers to particular preferred embodiments, it will be understood that the present invention is not so limited. It will occur to those of ordinary skill in the art that various modifications may be made to the disclosed embodiments and that such modifications are intended to be within the scope of the present invention.

## Claims

1. A method for synthesizing a compound of Formula I, comprising:



hydrolyzing a compound of Formula A




the method further comprising synthesizing the compound of Formula A by:
(i) contacting a compound of Formula B




with an organolithium;
(ii) contacting the lithiated product from step (i) with copper cyanide to form a cuprate; and
(iii) contacting the cuprate from step (ii) with an allyl halide selected from the group consisting of allyl chloride, allyl bromide and allyl iodide;
wherein,
x is an integer between 2 and 4 inclusive;
R is selected from the group consisting of straight or branched (C1-C6)alkyl, (C6-C14)aryl, and (C6-C14 aryl(C1-C6)alkylene-; and
Ra, Rb and Rc are each independently selected from the group consisting of straight or branched (C1-C6)alkyl, (C3-C6)cycloalkyl, (C6-C14) aryl, (C6-C14)aryl(C1-C6)alkylene, and (C3-C6)cycloalkyl(C1-C6)alkylene-.

2. The method of claim 1, wherein Ra, Rb and Rc are each independently (C1-C6)alkyl.

3. The method of claim 2, wherein Ra, Rb and Rc are each methyl.

4. The method of claim 1, wherein Ra is (C1-C6)alkyl and Rb and Rc are each independently (C3-C6)cycloalkyl.

5. The method of claim 1, wherein integer x is 2.

6. The method of claim 1, wherein R is straight or branched (C1-C6)alkyl.

7. The method of claim 1, wherein R is methyl.

8. The method of claim 1, wherein R is (C6-C14)aryl(C1-C6)alkylene-.

9. The method of claim 1, wherein R is benzyl.

10. The method of claim 1, wherein the organolithium is phenyllithium, or butyllithium.

11. The method of claim 1, wherein said hydrolyzing comprises contacting the compound of Formula A with an agent selected from the group consisting of water, aqueous mineral acid, and an aqueous solution of sodium sulfite.

12. The method of claim 1, wherein said hydrolyzing comprises contacting the compound of Formula A with an aqueous solution of sodium sulfite.

13. A method for synthesizing a compound of Formula I, comprising:



(a) contacting an aldehyde of Formula C





with a compound of formula RcRbN—(CHR′)x —NHRa in the presence of an organolithium;
wherein
x is an integer between 0 and 4 inclusive;
R′ is H,
R is an alcohol protecting group or is selected from the group consisting of straight or branched (C1-C6)alkyl, (C6-C14)aryl, and (C6-C14)aryl(C1-C6)alkylene-; and
Ra, Rb and Rcare each independently selected from the group consisting of straight or branched (C1-C6)alkyl, (C3-C6)cycloalkyl, (C6-C14) aryl, (C6-C14)aryl(C1-C6)alkylene, and (C3-C6)cycloalkyl(C1-C6)alkylene-;

(b) contacting the product from step (a) with an organolithium to form an ortho-lithiated product, and then contacting the ortho-lithiated product with copper cyanide to form a cuprate;
(c) contacting the cuprate from step (b) with an allyl halide selected from the group consisting of allyl chloride, allyl bromide and allyl iodide; and
(d) hydrolyzing the product of step (c) to give the Formula I compound.

14. The method of claim 13, wherein said organolithium is phenyllithium.

15. The method of claim 13, wherein integer x is 1 and Ra, Rb and Rc are methyl and wherein the allyl halide is allyl iodide.