AU2014200205B2 - Preparation of (3aS,7aR)-hexahydroisobenzofuran-1(3H)-one by catalyzed biological resolution of dimethyl cyclohexane-1,2-dicarboxylate - Google Patents

Abstract

PREPARATION OF (3AS,7AR)-HEXAHYDROISOBENZOFURAN-1(3H) ONE BY CATALYZED BIOLOGICAL RESOLUTION OF DIMETHYL CYCLOHEXANE-1 ,2-DICARBOXYLATE Processes for the synthesis of (3aS,7aR)-hexahydroisobenzofuran-1-(3H)-one, comprising enzymatic hydrolysis of dimethyl cyclohexane-1,2-dicarboxylate to form (iS, 2R)-2 (methoxycarbonyl)-cyclohexanecarboxylic acid. The enzyme can be from a non-mammalian source.

Description

-1 PREPARATION OF (3aS,7aR)-HEXAHYDROISOBENZOFURAN-1(3H)-ONE BY CATALYZED BIOLOGICAL RESOLUTION OF DIMETHYL CYCLOHEXANE 1,2-DICARBOXYLATE 5 INTRODUCTION The present application relates to processes for preparing (3aS,7aR) hexahydroisobenzofuran-1(3H)-one 1, an intermediate in the synthesis of (2S,3aR,7aS)-benzyloctahydro-1 H-indole-2-carboxylate hydrochloride. (S) 0 0<0 10 1 A prior synthetic process utilizes pig liver esterase. It would be desirable to replace the pig liver esterase in this process with a non-mammalian derived enzyme. Furthermore, the (1 R,2S)-2-(methoxycarbonyl)cyclohexane carboxylic acid 4 obtained from this pig liver esterase biological resolution has only 80% e.e. 15 which means that a salt upgrade is required to produce material of >98% e.e. An alternative enzyme that would deliver a higher e.e. product, thus eliminating the need for a salt upgrade step in the process, would be simpler and lower the production costs. Furthermore, the use of an immobilized enzyme would facilitate the recycling of biocatalyst. O(S ,\COOMe "COOH 20 Various patents and journal articles disclose processes for the preparation of optically enriched 2-(methoxycarbonyl) cyclohexanecarboxylic acid. Pig liver esterase catalyzed biological resolution of dimethyl cyclohexane-1,2-dicarboxylate 2 is described by: U.S. Patent No. 4,879,392; F. Brion et al., "Stereoselective 25 Synthesis of a trans-Octahydroindole Derivative, Precursor of Trandolapril, an Inhibitor of Angiotensin Converting Enzyme," Tetrahedron Letters, Vol. 33, No. 34, pages 4889-4892, 1992; R. M. Borzilleriet al., "Total Synthesis of the Unusual 2 Marine Alkaloid (-)-Papuamine Utilizing a Novel Imino Ene Reaction," Journal of the American Chemical Society, Vol. 117, pages 10905-10913, 1995. SUMMARY An aspect of the present invention provides a process for preparing (3aS,7aR)-hexahydroisobenzofuran-1 (3H)-one, comprising: (a) hydrolyzing dimethyl cyclohexane-1,2-dicarboxylate in the presence of Candida antarctica Lipase B to produce (1 S,2R)-2-(methoxycarbonyl) cyclohexanecarboxylic acid; and (b) carrying out reductive cyclization. An aspect of the present invention provides a process for preparing (1 S,2R)-2 (methoxycarbonyl) cyclohexanecarboxylic acid, comprising hydrolyzing dimethyl cyclohexane-1,2- dicarboxylate in the presence of Candida antarctica Lipase B. An aspect of the present application provides processes for the synthesis of (3aS,7aR)-hexahydroisobenzofuran-1-(3H)-one of 1. In an aspect, the present application provides processes for preparing (1 S,2R)-2-(methoxycarbonyl) cyclohexanecarboxylic acid 3, an intermediate in the preparation of 1. (S) ** /COOMe IR) 3 1 0 BRIEF DESCRIPTION OF THE DRAWING Fig. 1 is a listing of the sequences for three enzymes, identified as Chirotech Esterase K, Chirotech Esterase N, and Candida Antarctica Lipase. DETAILED DESCRIPTION An aspect of the present application provides processes for the synthesis of (1 S,2R)-2-(methoxycarbonyl) cyclohexanecarboxylic acid 3, comprising enzymatic hydrolysis of dimethyl cyclohexane-1,2-dicarboxylate 2. COOMe ,4COOH COOMe COOMe 2 3 (11006620 1):GGG 2a An aspect of the present application provides processes for preparing (3aS,7aR)-hexahydroisobenzofuran-1-(3H)-one 1, comprising reductive cyclization of 3. L((R) 'COOMC 3 1 C An aspect of the present application provides processes wherein an enzymatic hydrolysis uses an immobilized enzyme formulation. (11006620 1):GGG -3 An aspect of the present application provides processes using an immobilized enzyme formulation having a matrix that is cross-linked by, for example, treatment with glutaraldehyde. Aspects of the present application provide processes wherein an enzymatic 5 hydrolysis uses an enzyme such as, but not limited to, any of the lipases Chirotech Esterase K or Chirotech Esterase N (their sequence listings, as well as the listing for a useful native CAL-B enzyme, being shown in Fig. 1), Novozym TM 435, NZL-1 07 LYO, and 42044 from Novozymes A/S, ICR-1 10 CALB from Codexis, CV-CALB and CALB-Y from Chiralvision, and the serine esterase 10 cutinase. Mixtures of enzymes are also useful. The enzymes are useful in any physical forms, such as their solutions and as their dispersions in resins that immobilize the enzymes. Among the useful enzymes are those derived from Candida antarctica, including those described by: J. Uppenberg et al., "The Sequence, Crystal 15 Structure Determination and Refinement of Two Crystal Forms of Lipase B from Candida Antarctica," Structure, Vol. 2(4), pages 293-308, 1994; and J. Uppenberg et al., "Crystallographic and Molecular-Modeling Studies of Lipase B from Candida Antarctica Reveal a Stereospecifity Pocket for Secondary Alcohols," Biochemistry, Vol. 34(51), pages 16838-16851, 1995. 20 Embodiments of the present application provide processes wherein an enzymatic hydrolysis uses Novozym T M 435 enzyme. Embodiments of the present application provide processes wherein a substrate concentration is about 10-200 g/L. Embodiments of the present application provide processes wherein a 25 substrate concentration is at least about 75 g/L. Embodiments of the present application provide processes wherein enzyme loading is about 1 % to about 20%, with respect to the weight of substrate. Embodiments of the present application provide processes wherein enzyme loading is less than about 10%, with respect to the weight of substrate. 30 Embodiments of the present application provide processes wherein enzymatic hydrolysis temperatures are in the range of about 1 0 0 C to about 50 0 C. Embodiments of the present application provide processes wherein enzymatic hydrolysis temperature is about 40 0

C.

-4 Embodiments of the present application provide processes wherein an enzymatic hydrolysis pH is in the range of about 6 to about 9. Embodiments of the present application provide processes wherein an enzymatic hydrolysis pH is in the range of about 7 to about 8. 5 An aspect of the present application provides processes wherein a hydrolysis enzyme is added directly to a reaction vessel, recovered by filtration after the biological resolution is complete, then is washed with fresh buffer and added to a fresh batch of substrate/buffer. In embodiments, a fresh buffer is a phosphate buffer. 10 An aspect of the present application provides processes wherein a hydrolysis enzyme is contained within a column reactor, a biological resolution batch is continuously circulated through the column, after the biological resolution is complete the column is washed with fresh buffer, and the next batch of substrate/buffer can be circulated through the column. 15 In embodiments, a fresh buffer is a phosphate buffer. An aspect of the present application provides processes wherein reductive cyclization of (1S,2R)-2-(methoxycarbonyl) cyclohexanecarboxylic acid (3) utilizes a C1-C6 alkyl chloroformate, followed by reduction with a boron hydride. An aspect of the present application provides processes wherein a C1-C6 20 alkylchloroformate is ethyl chloroformate. An aspect of the present application provides processes wherein a boron hydride is sodium borohydride. The enzyme Novozym T M 435 is used herein to exemplify enzyme hydrolysis processes. This product is an immobilized granulate Candida 25 antarctica lipase B having a macroporous acrylic resin polymeric matrix. Novozym 435 is not mammalian-derived and can yield products with e.e. of 98%, thus eliminating the need for a salt upgrade step in the process. This enzyme source has been recycled at least eight times, in experiments. In embodiments of this application, (3aS,7aR)-hexahydroisobenzofuran-1 30 (3H)-one (1) is prepared by initial treatment of (1S,2R)-2-(methoxycarbonyl) cyclohexanecarboxylic acid (3) with ethyl chloroformate, to yield the intermediate mixed anhydride, and a subsequent reduction with sodium borohydride yields the -5 corresponding hydroxy ester, which cyclizes in situ to produce the desired cis lactone product. Novozym TM 435 catalyzed biological resolution of dimethyl cyclohexane 1,2-dicarboxylate (2) produces (1 S,2R)- rather than (1 R,2S)-2-(methoxycarbonyl) 5 cyclohexanecarboxylic acid. However, reduction of the acid moiety, rather than the ester moiety, in the following synthetic step leads to cis-lactone with the same stereochemistry as that obtained using pig liver esterase. Furthermore, biological resolution yields product of significantly higher e.e. than is known in the art (98% vs. 80%). Novozym T M 435 is an immobilized enzyme preparation, which allows 10 the biocatalyst to be recycled. A non-mammalian enzyme is amenable to recycling and delivers higher e.e. product. This eliminates the requirement for a salt upgrade to improve product e.e. DEFINITIONS 15 The following definitions are used in connection with the compounds of the present application unless the context indicates otherwise. In general, the number of carbon atoms present in a given group is designated "C-Cy", where x and y are the lower and upper limits, respectively. For example, a group designated as "C1 C6" contains from 1 to 6 carbon atoms. The carbon number as used in the 20 definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions and the like. "Alkyl" refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. In the 25 absence of any numerical designation, "alkyl" is a chain, straight or branched, having 1 to 6 (inclusive) carbon atoms in it. Examples of C1-C6 alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl. "C1-C6 alkyl chloroformate" refers to a compound of the formula R-O-C(O) 30 Cl, where R is a C1-C6 alkyl group. A "boron hydride" is a reducing agent, which will reduce an acid in the presence of an ester. Examples of these include but are not limited to sodium borohydride, zinc borohydride, diborane, BH 3 /THF, and 9-BBN.

-6 The term "e.e." means the enantiomeric excess of a substance, which is defined as the absolute difference between the mole fractions of each enantiomer and expressed as a percentage. The material sold as CeliteTM is flux-calcined diatomaceous earth. CeliteTM 5 is a registered trademark of World Minerals Inc. GC is gas chromatography. NMR is nuclear magnetic resonance spectroscopy. MTBE is methyl t-butyl ether or 2 methoxy-2-methylpropane. Novozym T M NZL-107 LYO is a lipase of fungal origin. Novozym TM 435 is an immobilized form of lipase B from Candida antarctica. Novozym TM is a registered trademark of Novozymes A/S, Novo Industri A/S 10 Bagsvaerd DK-2880 Denmark. PLE is pig liver esterase. Chirotech Esterase K 310-903 catalyses the stereoselective hydrolysis of esters, especially carboxylate esters. Chirotech Esterase K 310-903 is a recombinant enzyme originally isolated from the fungus Ophiostoma. Chirotech Esterase N 310-902 catalyses the stereoselective hydrolysis of esters, especially carboxylate esters, and is a 15 recombinant enzyme originally isolated from the fungus Ophiostoma. Certain aspects of the process of the present application will be explained in more detail with reference to the following Examples 1 and 2, which are provided for purposes of illustration only and should not be construed as limiting the scope of the disclosure in any manner. 20 EXAMPLE 1: Preparation of (1 S,2R)-2-(methoxycarbonyl) cyclohexanecarboxylic acid (3). Into a 100 mL jacketed vessel was placed dimethyl cyclohexane-1,2 dicarboxylate (2, 4g, 20mmol) and 39 mL of 0.1 M potassium phosphate buffer, pH 25 8. The mixture was continuously stirred at 400C and Novozym T M 435 (320 mg) was added. Stirring was continued at 400C for 43 hours and pH was maintained at 8 by addition of 2M NaOH solution. A sample from the reaction was analyzed by GC to confirm that less than 5% of the starting material remained. The reaction mixture was filtered to remove the enzyme and the filtrate was extracted 30 with toluene (20 mL) to remove any residual starting material. The pH of the aqueous phase was readjusted to 3.5 with 2M HCI and it was extracted with 2x50 mL of MTBE. The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure to yield 3.2 g (86%) of (1 S,2R)-2- -7 (methoxycarbonyl) cyclohexane carboxylic acid (3) as a colorless oil with e.e.=98%. The isolated enzyme is washed with fresh buffer for reuse with a second batch of substrate/buffer. 'H-NMR (d 6 -DMSO): 12.17 (brs; 1H), 3.57 (s; 3H), 2.82-2.72 (m; 2H), 1.97 5 1.79 (m; 2H), 1.79-1.59 (m; 2H), 1.48-1.26 (m; 4H); 13 C-NMR (d 6 -DMSO): 174.61, 173.62, 51.16, 41.63, 25.96, 25.60, 23.34, 23.17. The GC analytical conditions are: Chirasil Dex-CB 25 mx0.25 mm column; helium carrier gas, 20 psi; oven program is 1400C hold for 30 minutes, then 5 0 C/minute to 2000C and hold for 5 minutes (about 47 minutes run time); detector 10 and injector temperatures 2000C; retention times 36.99 minutes for 2 (methoxycarbonyl) cyclohexanecarboxylic acid (1 S,2R) and 37.28 minutes for 2 (methoxycarbonyl) cyclohexanecarboxylic acid (1 R,2S). COOMe Novozym 435 COOH COOMe Phosphate Buffer ( CO 2 pH 8; 40'C 3 15 EXAMPLE 2: Preparation of (3aS,7aR)-hexahydroisobenzofuran-1 -(3H)-one (1). Into a 25 mL jacketed vessel cooled to below 00C was placed a solution of (1S,2R)-2-(methoxycarbonyl) cyclohexane carboxylic acid (3, 880 mg, 4.72 mmol) and triethylamine 659 pL, 4.72mmol) in THF (6.6 mL). A solution of ethyl chloroformate (512 pL, 4.72mmol) in 1.2 mL of THF was added slowly over a few 20 minutes and the resulting mixture was stirred for 30 minutes. The precipitated triethylamine hydrochloride salt was removed by filtration and the filtrate was added drop-wise to a suspension of sodium borohydride in 4.6 mL of water at 120C. After the addition was complete, the reaction mixture was stirred at 200C for a further 3.5 hours. The reaction mixture was then cooled to below 10 C, 25 acidified to pH 4 with 2M HCI solution, and extracted with 2x15 mL of dichloromethane. The combined organic extracts were dried over magnesium sulfate and solvent was removed under reduced pressure, to yield 450 mg of a colorless oil. The material was purified by short path distillation to yield 170 mg of colorless oil with e.e.=98% and [a]o20=-39.30 (c 1, methanol).

-8 COOH ethyl chloroformate (S) THF O )COOMe NaBH 4 / H 2 0 0R) 3 1 0 COMPARATIVE EXAMPLE: Preparation of (1 R,2S)-2-(methoxycarbonyl) cyclohexane carboxylic acid. 5 Into a 2-L jacketed vessel set at 300C was placed dimethyl cyclohexane 1,2-dicarboxylate (2, 84.6 g, 0.42 mol) and 900 mL of 0.1M potassium phosphate buffer, pH 8. The mixture was continuously stirred at 300C and PLE (600 mg, 10200 units) was added. The mixture was stirred for 91 hours and the pH was maintained at 8 by addition of 5M NaOH solution. An aliquot from the mixture was 10 analyzed by GC to confirm that residual starting material was less than 5%. The reaction mixture was then filtered through a Celite T M bed and the filtrate was extracted with 250 mL MTBE to remove residual starting material. The aqueous phase was then acidified to pH 4 with concentrated HCI and extracted with 3x500 mL MTBE. The combined extracts were dried over magnesium sulfate and 15 solvent was removed under reduced pressure, to yield 69.28g (88% yield) of (1 R,2S)-2-(methoxycarbonyl)cyclohexane carboxylic acid (4) as a colorless oil with e.e.=79%. COOMe PL\()\COOMe a COOMe Phosphate Buffer ''e/COOH 2 pH 8; 30'C 4 20 While particular embodiments of the present application have been illustrated and described, it will be apparent to those skilled in the art that various changes and modifications can be made, without departing from the spirit and scope of the disclosure. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this disclosure. 25

Claims (10)

1. A process for preparing (3aS,7aR)-hexahydroisobenzofuran-1 (3H) one, comprising: (a) hydrolyzing dimethyl cyclohexane-1,2-dicarboxylate in the presence of Candida antarctica Lipase B to produce (1 S,2R)-2 (methoxycarbonyl) cyclohexanecarboxylic acid; and (b) carrying out reductive cyclization.

2. The process of claim 1, wherein an enzyme has a sequence shown in Sequence ID No.3 of Fig. 1, or a fragment or mutation thereof capable of the hydrolyzing.

3. The process of claim 1 or 2 where the enzyme is in immobilized form.

4. The process of any of claims 1 to 3, wherein (3aS,7aR) hexahydroisobenzofuran-1 (3H)-one is prepared with an e.e. at least 95%.

5. The process of any of claims 1 to 4, wherein (3aS,7aR) hexahydroisobenzofuran-1 (3H)-one is prepared with an e.e. at least 98%.

6. A process for preparing (1 S,2R)-2-(methoxycarbonyl) cyclohexanecarboxylic acid, comprising hydrolyzing dimethyl cyclohexane-1,2 dicarboxylate in the presence of Candida antarctica Lipase B.

7. The process of claim 6, wherein an enzyme has a sequence shown in Sequence ID No.3 of Fig. 1, or a fragment or mutation thereof capable of the hydrolyzing.

8. The process of claim 6 or 7 where the enzyme is in immobilized form. (8644230_1):GGG 10

9. The process of any of claims 6 to 8, wherein (1S,2R)-2-(methoxycarbonyl) cyclohexanecarboxylic acid is prepared with an e.e. at least 95%.

10. The process of any of claims 6 to 9, wherein (1S,2R)-2 (methoxycarbonyl) cyclohexanecarboxylic acid is prepared with an e.e. at least 98%. Abbott Products Operations AG Patent Attorneys for the Applicant/Nominated Person SPRUSON & FERGUSON (8644230_1):GGG 2014200205 14 Jan 2014 2014200205 14 Jan 2014 2014200205 14 Jan 2014 2014200205 14 Jan 2014 2014200205 14 Jan 2014 2014200205 14 Jan 2014