Title of Invention

NOVEL PROCESS FOR THE PREPARATION 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.
Full Text 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 1

wherein
R' is hydrogen, C1-C8alkyl or C1-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 R , R and R 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 R , R and R are as defined above. In particular, the process comprises reacting a compound of formula 1 with bis(2-aminophenyl)disulfide to acylate the amino groups of the (2-aminophenyl)disulfide, reacting the amino-acylated disulfide product with triphenylphosphine to yield the thiol product, and acylating the thiol group in the thiol product with an acyl chloride. A preferred solvent for the acylation reactions is pyridine.
The additional steps may be performed, e.g., according to the procedures described in Shinkai et ah, 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.
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.
The term „tri-C1-C5aIkylamine" denotes a compound of formula R4N(R5)R6 wherein R4, R5 and R6 independently are a C1-C8alkyl, and includes triethylamine, tributylamine, di-ethyl-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 may be 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 amout of thionylchloride in relation to the compound of formula 1 in the reaction mixture may be in the range from 1.0 to 2.0 equivalents of thionylchloride, e.g. from 1.0 to L2 equivalents, e.g. 1.2 equivalents.
The amount of the tri-Ci-Csalkylamine in relation to the amount of the compound of formula I may be 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 com¬pound 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 mixtuse is heated to the desired temperature.
In one embodiment the present invention provides a process for the preparation of a com¬pound of formula I wherein R' 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 pre¬sent invention provides a process for the preparation of a compound of formula 1 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 AUTONOM v.4.0, a Beilstein Institute computerized system for the generation of lUPAC systematic nomen¬clature. 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 l-(2-Ethyl-butyI)-cyclohexanecarbonyl chloride in the absence of a catalyst
A mixture of 103.0 mmol l-(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% l-(2-ethyl-butyl)-cycIohexanecarboxylic acid and

13.8% l-(2-ethyl-butyl)-cyclohexanecarboxylic acid anhydride), after 6 hrs still incomplete (1,9% l-(2-ethyl-butyl)-cyclohexanecarboxylic acid and 2.8% l-(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% l-(2-ethyl-butyl)-cyclohexanecarboxyIic acid and 0.47% l-(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% l-(2-ethyl-butyl)-cyclohexanecarbonyl chloride, yield 82,1%).
Example 2: Preparation of l-(2-Ethyl-butyl)-cyclohexanecarbonyI chloride in the presence of 0.02 Eq, triethylamine
A mixture of 103.0 mmol l-(2-ethyl-butyl)-cyclohexanecarboxylic acid, 38,9 mmol cyclo-hexanecarboxylic acid and 396µL triethylamine (2.84 mmol=0.02 eq. relative to the sum of both acids) was warmed to SOX. 12.4 mL (170.3 mmol µL2 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% l-(2-ethyl-butyI)-cyclohexanecarboxylic acid and no l-(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% l-(2-ethyl-butyl)-cyclohexane-carbonyl chloride, yield 99.4%)
Example 3: Preparation of l-(2-Ethyl-butyl)-cyclohexanecarbonyl chloride in the presence of 0.005 Eq. triethylamine
A mixture of 103.0 mmol l-(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% l-(2"ethyl-butyl)-cyclo-hexanecarboxylic acid and 0.13% l-(2-ethyl-butyl)-cyclohexanecarboxylic acid anhydride). After 1.5 hr the reaction was complete (0.04% I-(2-ethyl-butyl)-

cyclohexanecarboxylic acid and no l-(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% l-(2-ethyl-butyl)-cyclohexanecarbonyl chloride, yield 100%).
Example 4: Preparation of l-(2-Ethyl-butyl)-cyclohexanecarbonyi chloride in the presence of 0,005 Eq. tributylamine
A mixture of 103.0 mmol l-(2-ethyl-butyl)-cyclohexanecarboxylic acid, 38.9 mmol cyclo¬hexanecarboxylic acid and 173 nL 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)-cyclohexane-carboxylic acid and no l"(2-ethyl-butyl)-cyclohexanecarboxylic acid anhydride). After re¬moving 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% l-(2-ethyI-butyI)-cycIo-hexanecarbonyl chloride, yield 100%).












Claims
1. A process for the preparation of a compound of formula 1
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-C8alkylamine.
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 reacting the
compound of formula IV with triphenylphosphine 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 (H3C)2CHC(O)C1 to yield a compound of formula VI

wherein R1 , R2 and R3 are as defined in claim 1.
5. The process according to claim 1 wherein the thionyl chloride is present in the range from 1.0 to 2.0 equivalents of thionylchloride in relation to the compound of formula I.
6. The process according to claim 1 wherein the amount of the tri-C1-C8alkylamine in relation to the amount of the compound of formula 1 is at a ratio of from 5 mol% to 0.1 mol%.
7. The process according to claim 1 wherein thionylchloride is continuously added.
8. The process according to claim 1 wherein in formula I R1 is CH2CH(CH2CH3)2.
9. The process according to claim 1 wherein the tri-C1-C8alkylamine is triethylamine or tributylamine.

10. The process according to claim 1 wherein the tri-C1- C5alkylamine is tributylamine.
11. The process according to claims 2 and 4 wherein the acylating steps are performed using pyridine as a solvent.
12. A compound of formula VI according to claim 4 when prepared according to claim 4.

13. The invention as hereinbefore described. Dated this 30 day of April 2008

Documents:

2155-CHENP-2008 AMENDED PAGES OF SPECIFICATION 16-01-2013.pdf

2155-CHENP-2008 AMENDED CLAIMS 16-01-2013.pdf

2155-CHENP-2008 CORRESPONDENCE OTHERS 04-02-2013.pdf

2155-CHENP-2008 FORM-13 16-01-2013.pdf

2155-CHENP-2008 PRIORITY DOCUMENT 16-01-2013.pdf

2155-CHENP-2008 CORRESPONDENCE OTHERS 15-03-2012.pdf

2155-CHENP-2008 EXAMINATION REPORT REPLY RECEIVED 16-01-2013.pdf

2155-CHENP-2008 FORM-3 16-01-2013.pdf

2155-CHENP-2008 OTHER PATENT DOCUMENT 16-01-2013.pdf

2155-chenp-2008-abstract.pdf

2155-chenp-2008-claims.pdf

2155-chenp-2008-correspondnece-others.pdf

2155-chenp-2008-description(complete).pdf

2155-chenp-2008-form 1.pdf

2155-chenp-2008-form 18.pdf

2155-chenp-2008-form 26.pdf

2155-chenp-2008-form 3.pdf

2155-chenp-2008-form 5.pdf


Patent Number 255418
Indian Patent Application Number 2155/CHENP/2008
PG Journal Number 08/2013
Publication Date 22-Feb-2013
Grant Date 20-Feb-2013
Date of Filing 30-Apr-2008
Name of Patentee F. HOFFMANN-LA ROCHE AG
Applicant Address 124 GRENZACHERSTRASSE CH-4070 BASEL
Inventors:
# Inventor's Name Inventor's Address
1 HOFFMANN, URSULA BASELSTRASSE 40L CH-4132 MUTTENZ
2 RIMMLER, GOESTA, ST TRUDPERTSTRASSE 33 D-79189 BAD KROZINGEN
PCT International Classification Number C07C51/60
PCT International Application Number PCT/EP06/67570
PCT International Filing date 2006-10-19
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 05110177.2 2005-10-31 EUROPEAN UNION