WO1997044318B1

WO1997044318B1 - PREPARATION OF LACTAMS FROM ALIPHATIC α,φ-DINITRILES

Info

Publication number: WO1997044318B1
Application number: PCT/US1997/007796
Authority: WO
Filing date: 1997-05-07
Publication date: 1998-01-15

Abstract

A process for the preparation of five-membered or six-membered ring lactams from aliphatic α,φ-dinitriles has been developed. In the process an aliphatic α,φ-dinitrile is first converted to an ammonium salt of an φ-nitrilecarboxylic acid in aqueous solution using a catalyst having an aliphatic nitrilase (EC 3.5.5.7) activity, or a combination of nitrile hydratase (EC 4.2.1.84) and amidase (EC 3.5.1.4) activities. The ammonium salt of the φ-nitrilecarboxylic acid is then converted directly to the corresponding lactam by hydrogenation in aqueous solution, without isolation of the intermediate φ-nitrilecarboxylic acid or φ-aminocarboxylic acid. When the aliphatic α,φ-dinitrile is also unsymmetrically substituted at the α-carbon atom, the nitrilase produces the φ-nitrilecarboxylic acid ammonium salt resulting from hydrolysis of the φ-nitrile group with greater than 98 % regioselectivity, thereby producing only one of the two possible lactam products during the subsequent hydrogenation. A heat-treatment process to select for desirable regioselective nitrilase or nitrile hydratase activities while destroying undesirable activities is also provided.

Claims

AMENDED CLAIMS

[received by the International Bureau on 4 December 1997 (04.12.97); original claims 2, 13 and 14 amended; remaining claims unchanged (3 pages)]

1 A process for the preparation of five-membered ring lactams or six- membered ring lactams from aliphatic a.w-dinitriles, comprising:

(a) contacting an aliphatic α,ω-dinitrile in an aqueous reaction mixture with an enzyme catalyst characterized by cither

1) an aliphatic nitrilase activity, or

2) a combination of nitrile hydratase and amidase activities, whereby the aliphatic α,ω-dinitrile is converted to an ω-nitrilecarboxylic acid ammonium salt; (b) contacting the aqueous product mixture resulting from step (a) with hydrogen and a hydrogenation catalyst, whereby the ω-nitrilecarboxylic acid ammonium salt is converted directly to the corresponding lactam without isolation of the intermediate ω-nitrilecarboxylic acid, ω-nitrilecarboxylic acid ammonium salt, ω-aminocarboxylic acid or ω-aminocarboxylic acid ammonium salt; and (c) recovering the lactam from the aqueous product mixture resulting from step (b).

2. The process of Claim 1 wherein the aliphatic α.ω-dinitrile has the formula

NCCX_a(R)(CH₂)_nCN,

where a = 0 or 1 , where X = hydrogen when a = 1 , and R = H, alkyl or substituted alkyl, or alkcnyl or substituted alkenyl, or alkylidene or substituted alkylidene, and where n = 1 or 2.

3. The process of Claim 1 wherein the enzyme catalyst is in the form of whole microbial cells, permeabilized microbial cells, one or more cell components of a microbial cell extract, partially purified enzyme(s), or purified enzyme(s).

4. The process of Claim 3 wherein the enzyme catalyst is characterized by an aliphatic nitrilase activity and is in the form of whole microbial cells of Acidovoraxfacilis 72-PF-15 (ATCC 557 7), Acidovoraxfacilis 72-PF-17 (ATCC 55745), or Aciάovorax facilis 72W (ATCC 55746).

5. The process of Claim 3 wherein the enzyme catalyst is characterized by a combination of nitrile hydratase and amidase activities and is in the form of whole microbial cells of Comamonas testosteroni 5-MGAM-4D (ATCC 55744).

6. The process of Claim 3 wherein the enzyme catalyst is in the form of whole microbial cells immobilized in or on an insoluble support.

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7. The process of Claim 3 wherein the enzyme catalyst is partially- purified or purified enzyme(s) immobilized on a soluble or insoluble support.

8. The process of Claim 1 wherein the aliphatic α,ω-dinitrile is unsymmetrically substituted at the α-caxbon atom, and the enzyme catalyst is characterized by aliphatic nitrilase activity that produces the ω-nitrilecarboxylic acid ammonium salt resulting from regioselective hydrolysis of the ω-nitrile group, thereby producing only one of the two possible lactam products during the subsequent hydrogenation reaction.

9. The process of Claim I further comprising adding ammonium hydroxide, ammonia gas or methylamine to the aqueous product mixture containing the ω-nitrilecarboxylic acid ammonium salt prior to the hydrogenation reaction of step (b),

10. The process of Claim 9 wherein the amount of ammonium hydroxide, ammonia gas or methylamine added to the aqueous product mixture is from 0 to 4 molar equivalents relative to the amount of ω-nitrilecarboxylic acid ammonium salt present.

11. The process of Claim 9 wherein methylamine is added to the aqueous product mixture containing the ω-nitrilecarboxylic acid ammonium salt prior to the hydrogenation reaction of step (b) and the product of the hydrogenation reaction is an N-methyllactam.

12 The process of Claim 1 wherein the temperature of the hydrogenation reaction is from 45 °C to 200 "C.

13. A process for the preparation of five-membered πng lactams or six- membered ring lactams from aliphatic α,ω-dinitriles, comprising: (a) contacting an aliphatic α,α>-d_nitrile of either the formula:

I π

where Ri and R_j are both H, and,

R₃, R₄, _ζ and R^ are each independently selected from the group consisting of H. alkyl or substituted alkyl. or alkcnyl or substituted alkenyl, or R₃ and R₄ taken together are alkylidene or substituted alkylidene, or independently R₅ and R_$ taken together are alkylidene or substituted alkylidene,

60 in an aqueous reaction mixture with an enzyme catalyst selected from the group consisting of:

Acidovoraxfacilis 72 (ATCC 55746), Acidovoraxfacilis 72-PF-15 (ATCC 55747), Acidovoraxfacilis 72-PF-l 7 (ATCC 55745), and

Comamonas testosteroni 5-MGAM-4D (ATCC 55744), whereby the aliphatic α,ω-dinitrile is converted to an ω-nitπlecaxboxylic acid ammonium salt; b) contacting the aqueous product mixture resulting from step (a) with hydrogen and a hydrogenation catalyst, whereby the ω-nitrilecarboxylic acid ammonium salt is converted directly to the corresponding lactam without isolation of the intermediate ω-mtrilecarboxyhc acid, ω-mtrilecarboxyhc acid ammonium salt, ω-aminocarboxylic acid or ω-aminocarboxylic acid ammonium salt; and c) recovering the lactam from the aqueous product mixture resulting from step (b).

14 A process for the preparation of five-mcmbercd rmg lactams or six- membered ring lactams from aliphatic α,ω-dinitrϋes, comprising: (a) contacting an aliphatic α,ω-dinitrile of either formula

where R , Rg, R₉, R₁₀, π and R_J2 are each independently selected from the group consisting of H, alkyl or substituted alkyl, or alkenyl or substituted alkenyl, or R₃ and R₄ taken together are alkylidene or substituted alkylidene, oτ independently R₅ and Rg taken together are alkylidene or substituted alkylidene. and where either or both R₇ or R₈ is not H; in an aqueous reaction mixture with Comamonas testosteroni 5-MGAM-4D (ATCC 55744). whereby the aliphatic α,ω-dinitrile is converted to an ω-nitrilecarboxyhc acid ammonium salt;

61 STATEMENT UNDER ARTICLE 19

Applicants have amended Claims 2, 13 and 14 to properly describe the scope of the formula for the aliphatic α,ω-dinitrile as including alkylidenes and substituted alkylidenes. Support for this amendment is found in Example 18 where 2-methyleneglutaronitrile

CH₂

I NC-C-CH₂-CH₂-CN

containing the CH₂ branch (an alkylidene group, as defined in Claim 2) is taken to 4-cyano-4-pentenoic acid. The same reaction is described at page 9 of the specification and listed as part of Table 1. In the interest of full disclosure, attention is drawn to the fact that no working example of a substituted alkylidene iε found in the case. However, the original scope included substituted groups and substituted alkylidenes are reasonably part of the subject matter of the invention.

Additionally, Claims 2, 13 and 14 have been amended to use the commonly accepted nonenclature "alkyl or substituted alkyl" to replace the original phrase "unsubstituted or substituted alkyl". This format is also applied to the alkenyl and alkylidene groups .

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