KR100463878B1 - The method of making optically active N-methyl-3-hydroxy-3-phenylpropanamide and their esters by enzymatic method - Google Patents

Abstract

The present invention is an optically active N represented by the following [scheme 1] by an enzymatic method - Preparation of methyl 3-hydroxy-3-phenyl-propanamide (N -methyl-3-hydroxy- 3-phenylpropanamide) and its ester derivatives The method relates more specifically to the racemic N -methyl-3-hydroxy-3-phenylpropanamide in the organic phase or in the presence of only an acyl donor without the organic solvent. The present invention relates to a method for preparing optically active N -methyl-3-hydroxy-3-phenylpropanamide and esters thereof by esterification with a lipase enzyme.

The method of the present invention can produce optically active N -methyl-3-hydroxy-3-phenylpropanamide and esters thereof at low cost and high optical purity using lipases in a manufacturing method not previously reported. .

Description

The method of making optically active N-methyl-3-hydroxy-3-phenylpropanamide and their esters by enzymatic method }

The present invention relates to an optically active N -methyl-3-hydroxy-3-phenyl propanamide and an ester method thereof by an enzyme. More specifically, (S) -N -methyl-3-hydroxy-3-phenylpropanamide and (R)-using lipase enzymes in racemic N -methyl-3-hydroxy-3-phenylpropanamide. It relates to a process for preparing ester derivatives of N -methyl-3-hydroxy-3-phenylpropanamide.

Racemic N -methyl-3-hydroxy-3-phenylpropanamide is composed of (R) -N -methyl-3-hydroxy-3-phenylpropanamide and (S) -N -methyl-3-hydroxy-3 (R)-and (S) -N -methyl-3-hydroxy-3-phenylpropanamide, which are present in half and half as -phenylpropanamide, are used as antidepressants and headache medicines. ) -Fluoxetine, fluoxetine, tomoxetine, nisoxetine, and other intermediates are widely used. (S) -N -methyl-3-hydroxy-3-phenylpropanamide prepared by the present method is used as a conventional chiral intermediate (S) -ethyl 3-hydroxy-3-phenyl propionate (ethyl3). -hydroxy-3-phenyl propionate) is considered to be a much more useful intermediate. The reported production method of (S) -N -methyl-3-hydroxy-3-phenylpropanamide is as follows.

Quiros like (Tetrahedron: Asymmetry, 1997, 8 : 3035-3038) , after 48 hours of reaction in the strain Mortierella isabellina N - methyl-3-oxo-3-phenyl-propanamide (N -methyl-3-oxo- 3-phenylpropanamide) in 43% ee (S) - were prepared N - - methyl-3-hydroxy-3-phenyl-propanamide (N -methyl-3-hydroxy- 3-phenylpropanamide (S)).

Huang et al. (Tetrahedron: Asymmetry, 1998, 9 : 1637-1640) is a BINAP-ruthenium (Ⅱ) with a catalyst 3-oxo-3-phenyl propanoyl acid N - methylamide (3-oxo-3-phenylpropanoic acid N -methyl amide) from (S) - (-) - 3- hydroxy-3-phenyl propanoyl acid N - methyl amide ((S) - (-) - 3-hydroxy-3-phenylpropanoic acid N -methyl amide) Was synthesized, the yield through the recrystallization process was 50%, the optical purity was 99.9% ee or more.

As described above, a compound used as an intermediate, such as 3-chloro-1-phenyl-1-propanol or 3-hydroxy-3-phenyl propanenitrile, has been developed or is in the process of being prepared through ester reaction with lipase. In the case of ethyl 3-hydroxy-3-phenyl propionate, it is obtained by reduction reaction from ethyl benzoyl acetate using Baker yeast. In the case of N -methyl-3-hydroxy-3-phenyl propanamide, a liperoester reaction was carried out to give (S) -N -methyl-3-hydroxy-3-phenylpropanamide and (R) -N -methyl- Considering the fact that no ester derivative of 3-hydroxy-3-phenylpropanamide was prepared and that the compound can be synthesized by various routes from the above-mentioned intermediates, the lipase enzyme was used to synthesize optically active intermediates. . Add acyl donor to racemic N -methyl-3-hydroxy-3-phenylpropanamide and esterify with lipase to give (S) -N -methyl-3-hydroxy-3-phenylpropanamide and (R A process for preparing esters of N -methyl-3-hydroxy-3-phenylpropanamide was developed and the present invention was completed based on this.

Accordingly, an object of the present invention is to provide optically active (S) -N -methyl-3-hydroxy-3-phenylpropanamide from racemic N -methyl-3-hydroxy-3-phenylpropanamide using a lipase enzyme. And (R) -N -methyl-3-hydroxy-3-phenylpropanamide.

The production method for achieving the above object is a racemic N -methyl-3-hydroxy-3-phenylpropanamide in the presence of an acyl donor in an organic solvent, or in the presence of only an acyl donor without a separate organic solvent as a lipase enzyme It is made by esterification.

Looking at the present invention in more detail as follows. As described above, excess amounts of (S) -N -methyl-3-hydroxy-3-phenylpropanamide are present from the racemic N -methyl-3-hydroxy-3-phenylpropanamide using a lipase enzyme. The present invention relates to a process for synthesizing an ester in which an excess of N -methyl-3-hydroxy-3-phenylpropanamide and an ester derivative of (R) -N -methyl-3-hydroxy-3-phenylpropanamide is present. .

Lipases used in the present invention include enzymes or immobilized lipases provided in the form of a powder. In particular, the lipase may be commercially available or may be prepared and used as necessary. Commercially available lipases include but are not limited to Novozyme 435 (CAL) from Novo, Lipase PS-C from Amano, Candida rugosa lipase (CRL) from Sigma, etc. It doesn't happen.

Organic solvents usable in the present invention include isopropyl ether, t-butylmethylether, tetrahydrofuran and the like, and as acyl donor, vinyl acetate used as a solvent. (vinyl acetate), vinyl propionate (vinyl propionate), acetic anhydride (acetic anhydride), hexanoic anhydride (isopropenyl acetate) and the like.

On the other hand, racemic N -methyl-3-hydroxy-3-phenylpropanamide was analyzed by collecting the reactants after the reaction, and the gas chromatography (SGE, 30m x 0.53mm) equipped with a non-polar column ( Quantitation was carried out using Donam Instruments, Model DS6200). At this time, the analysis conditions were heated up to 10 ℃ per minute to 220 ℃ after heating for 5 minutes at 70 ℃, and maintained for 15 minutes at 220 ℃. As a carrier gas, helium gas was flowed at a rate of 2 ml / min and detected using a flame ionization detector (FID) at 230 ° C. At this time racemic N -methyl-3-hydroxy-3-phenylpropanamide was detected at 22.24 min, and N -methyl-3- O -acetyl-3-phenylpropanamide ( N -methyl-3- O- acetyl- 3-phenylpropanamide) is 23.66 minutes, N - methyl-3-O - propionyl-3-phenyl-propanamide (N -methyl-3- O -propionyl- 3-phenylpropanamide) is 25.32 minutes, N - methyl-3-O N -methyl-3- O- hexanoyl-3-phenylpropanamide was detected at 35.50 minutes respectively.

Optically active (R)-and (S) -N -methyl-3-hydroxy-3-phenylpropanamide was prepared by HPLC (Lab Alliance, model) equipped with chiral column OD-H (Daicel, 0.46 cm × 25 cm). 201) was analyzed, and the analysis conditions were hexane and isopropanol were mixed at a ratio of 95: 5 and flowed at 0.7 ml / min, and the UV absorbance of HPLC was analyzed at 220 nm. At this time, (R) -N -methyl-3-hydroxy-3-phenylpropanamide was detected in 32.53 minutes and (S) -N -methyl-3-hydroxy-3-phenylpropanamide in 30.44 minutes, respectively. In addition, (R) -N -methyl-3- O -acetyl-3-phenylpropanamide was detected at 66.82 minutes and (S) -N -methyl-3- O -acetyl-3-phenylpropanamide was detected at 61.68 minutes, respectively. , (R) -N -methyl-3- O -propionyl-3-phenylpropanamide was 55.63 minutes, and (S) -N -methyl-3- O -propionyl-3-phenylpropanamide was 61.85 minutes respectively. Detected.

Hereinafter, the present invention will be described in more detail with reference to the following Examples, but the scope of the present invention is not limited to the following Examples.

Example 1

1% of liquid racemic N -methyl-3-hydroxy-3-phenylpropanamide in a vial containing 5 ml of t-butylmethylether containing 4% of vinyl acetate (v / v) v), and then 4% (w / v) of lipase PS-C (Amanosa) was added, and the reaction was performed at 45 ° C. After about 16 hours, the supernatant was collected and analyzed according to the above analysis method. In this case, the conversion of N -methyl-3-hydroxy-3-phenylpropanamide was 61.9%, and the optical purity of (S) -N -methyl-3-hydroxy-3-phenylpropanamide was 99.5% ee, and (R The optical purity of) -N -methyl-3- O -acetyl-3-phenylpropanamide was 93.8% ee.

Example 2-5

The reaction was carried out using the acyl donors specified in Table 1 below instead of the vinyl acetate used in Example 1. Wherein reaction conversion of N -methyl-3-hydroxy-3-phenylpropanamide and (S) -N -methyl-3-hydroxy-3-phenylpropanamide and (R) -N -methyl-3-hydroxy The optical purity of the ester derivative of -3-phenylpropanamide is as follows.

Table 1

Example Lipase Type Acyl donor Response time (hours) % Conversion Alcohol optical purity (% ee) Ester Optical Purity (% ee) 2 PS-C Vinyl propionate 22 61.5 99.5 94.2 3 PS-C Acetic anhydride 22 58.6 81.8 88.4 4 PS-C Hexonic anhydride 23 58.9 99.3 - 5 PS-C Isopropenyl acetate 23 62.3 99.5 90.8

Example 6-8

In Example 1, the reaction was performed using the lipases shown in Table 2 below instead of the lipase PS-C. Reaction conversion of N -methyl-3-hydroxy-3-phenylpropanamide and (S) -N -methyl-3-hydroxy-3-phenylpropanamide and (R) -N -methyl-3- O -acetyl The optical purity of -3-phenylpropanamide is as follows.

Table 2

Example Lipase Type Response time (hours) % Conversion Alcohol Optical Purity (% EE) Ester optical purity (% ee) 6 AK 70 51.1 99.5 99.3 7 CAL 70 58.9 99.6 86.5 8 CRL 84 17.7 17.5 99.2

Example 9-10

The reaction was performed using tetrahydrofuran (THF) or isopropyl ether (IPE) instead of t-butylmethylether used as the organic solvent in Example 1. Wherein the reaction conversion rate of N -methyl-3-hydroxy-3-phenylpropanamide and (S) -N -methyl-3-hydroxy-3-phenylpropanamide and (R) -N -methyl-3- O- The optical purity of acetyl-3-phenylpropanamide is as follows.

Table 3

Example Organic solvent Response time (hours) % Conversion Alcohol Optical Purity (% EE) Ester optical purity (% ee) 9 THF 84 52.6 99.5 99.3 10 IPE 22 53.4 99.4 99.1

Example 11

Instead of t-butylmethylether used as the organic solvent in Example 1, only acyl donor vinyl acetate was added to the reaction. After 24 hours, the conversion of N -methyl-3-hydroxy-3-phenylpropanamide was 47.7%, and the optical purity of (S) -N -methyl-3-hydroxy-3-phenylpropanamide was 99.0% ee. , (R) -N -methyl-3- O -acetyl-3-phenylpropanamide was 99.5% ee in optical purity.

As can be seen in Examples 1-11, (S) -N -methyl-3-hydroxy-3-phenylpropanamide or (R) -N -methyl-3- O -acyl-3-phenylpropanamide In synthesizing, selecting a suitable lipase enzyme and acyl donor can easily prepare a compound having high optical purity. The method of the present invention has the advantage of being environmentally friendly in that it uses enzymes, and can be used repeatedly, thereby reducing costs in the manufacturing process.

Claims (4)

Optically active N -methyl-3-hydroxy-3-phenylpropanamide characterized by esterifying racemic N -methyl-3-hydroxy-3-phenylpropanamide with a lipase enzyme in the presence of an acyl donor in an organic solvent. And esters thereof Optically active N -methyl-3-hydroxy-3-phenylpropane characterized by esterifying racemic N -methyl-3-hydroxy-3-phenylpropanamide with a lipase enzyme in the presence of an acyl donor in the nonsolvent. Method for preparing amide and its ester The method according to claim 1 or 2, wherein the acyl donor is a vinyl ester compound, isopropenyl acetate, or an organic anhydride. The method of claim 1, wherein the organic solvent is isopropyl ether, t-butyl methyl ether, tetrahydrofuran