NOVEL PROCESS FOR THE PREPARATION OF ACID CHLORIDES

The present invention is directed to a process for the preparation of acid halides which are useful as intermediates in the preparation of pharmaceutically active compounds.

In one aspect the present invention provides a process for the preparation of a compound of formula I

wherein

R ¹ is hydrogen, Q-Cealkyl or C ₂ -C ₈ alkenyl which are unsubstituted or substituted by one or more substituents selected from Q-Cβalkoxy and Cs-Cβcycloalkyl; and R ² and R ³ are combined with the carbon atom to which they are attached to form C3-C7- cycloalkyl or Cs-Cβcycloalkenyl; comprising reacting a compound of formula II

wherein R , R and R have the above meanings; with thionylchloride in the presence of a tri-Ci-C ₅ alkylamine and an aliphatic hydrocarbon solvent.

The compounds of formula I maybe 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 ¹ , R ² and R ³ are as defined above and R ⁴ is Ci-C ₈ alkyl. 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 R ⁴ C(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 Ci-C ₈ alkyl include methyl, ethyl, straight and branched propyl, butyl, pentyl, hexyl, e.g. CH ₂ CH(CH ₂ CHs) ₂ , heptyl and octyl. For R ¹ , Ci-Cβalkyl is preferably CH ₂ CH(CH ₂ CH ₃ ) ₂ . For R ⁴ , Ci-Cβalkyl is preferably isopropyl.

Examples for C ₂ -C ₈ alkenyl 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 C ₃ -C ₇ cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Preferred is e.g. cyclohexyl. Examples for C ₅ -C ₈ cycloalkenyl include cyclo- pentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclopentadienyl, cyclohexadienyl, cycloheptadienyl and cyclooctadienyl. Preferred are cyclopentenyl, cyclohexenyl and cycloheptenyl.

The term "tri-Ci-Csalkylamine" denotes a compound of formula R ⁴ N(R ⁵ )R ⁶ wherein R ⁴ , R ⁵ and R ⁶ independently are a Ci-C ₈ alkyl, and includes triethylamine, tributylamine, di- ethyl-methylamine, dimethyl-ethylamine and methylethylbutylamine.

The term "aliphatic hydrocarbon" refers to a branched, straight or cyclic hydrocarbon chain, such as pentane, hexane, heptane, octane, cyclopentane, cyclohexane, or mixtures thereof. The most preferred aliphatic hydrocarbon is heptane.

The process may take place at a temperature in the range from 20 to 60 ⁰ C, e.g. in a range from 40 to 55°C.

The acylating steps of the present invention are preferably conducted in the presence of a base. Preferred bases include organic bases with N-Methylmorpholine being a preferred organic base.

The amount of thionylchloride in relation to the compound of formula II, 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-Ci-Csalkylamine in relation to the amount of the compound of formula II 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 compound of formula I as above, comprising reacting a compound of formula II as above in the presence of a tri-Ci-Csalkylamine and an aliphatic hydrocarbon solvent by continuously adding thionylchloride.

The term "continuously adding" denotes the addition of thionylchloride to a solution of compound II in an aliphatic hydrocarbon solvent, during a period of time from 10 minutes to 5 hours, depending on the batch size. The solution of compound II 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 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-Ci-Csalkylamine is triethylamine or tributylamine. In a preferred embodiment the present invention provides a process for the preparation of a compound of formula I wherein the tri-Ci-Csalkylamine is tributylamine. When using tributylamine no precipitation of the hydrochloride salt of the tertiary amine occurs.

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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 IUPAC 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: Preparation of l-(2-Ethyl-butyl)-cyclohexanecarbonyl chloride in the presence of 0.003 Eq. tributylamine and heptane as the solvent.

A mixture of 6.0 kg (28.3 mol) l-(2-ethyl-butyl)-cyclohexanecarboxylic acid and 20.6 mL tributylamine (0.085 mmol) in 10 L heptane was warmed to 50 ⁰ C. 2.5 L (34.5 mol) of thionyl chloride was added during 40 minutes at a temperature of 40-50 ⁰ C (reaction is endothermic, vigorous gas evolution) and the reaction mixture was kept at 53-55°C. An IPC-control after 60 minutes indicated complete conversion (0.04% l-(2-ethyl-butyl)- cyclohexanecarboxylic acid and no l-(2-ethyl-butyl)-cyclohexanecarboxylic acid anhydride). After removing volatile components under reduced pressure (70 ⁰ C bath, 13-8 mbar) 6.86 kg of the residue was obtained (assay 92.5% l-(2-ethyl-butyl)-cyclo- hexanecarbonyl chloride, yield 97.2%)