DE1518029B1 - Stereospecific process for the production of l (-) - 3,4-Dimethoxyphenyl-acetyl-carbinol - Google Patents

Description

The invention relates to a process for the preparation of l (-) - 3,4-dimethoxyphenyl-acetyl-carbinol. These Connection is new. It serves as a starting product for Preparation of L - «- methyl-3,4-dihydroxyphenylalanine, a known agent for the treatment of high blood pressure.

It is known from US Pat. No. 1 962 476, optically active aryl acetyl carbinols, e.g. B. L- (3-Hydroxy-4-methoxyphenyl) -acetyl-carbinol, from the corresponding aldehydes with the help of a fermentative Method using yeast to produce.

The stereospecific process of the invention for the preparation of l (-) - 3,4-dimethoxyphenyl-acetylcarbinol is characterized in that veratraldehyde with a growing culture of Aerobacter aerogenic A. T. C. C. No. 211 brings into intimate contact with the reaction, the l (-) - 3,4-dimethoxyphenylacetyl-carbinol formed in the process extracted with a water-immiscible solvent and recovered in a known manner.

The known processes for the preparation of L -οι -Methyl -3,4-dihydroxyphenylalanine have the disadvantage that the L-form must be separated from the D-form at some point in the synthesis. In contrast, the process according to the invention only gives the D-form of 3,4-dimethoxyphenylacetyl-carbinol. The reaction of this compound with a water-soluble cyanide salt and ammonium carbonate leads, for example, to 4 - carbamoyl - 4 - methyl - 5 - (3,4 - dimethoxyphenyl) -2-oxazolidinone, in which there is the asymmetric carbon atom which is bonded to the carbinol substituent , is in the desired L-configuration. If the oxazolidinone derivative mentioned is heated under reflux with hydrogen iodide and red phosphorus in aqueous acetic acid, La-methyl-3,4-dihydroxyphenylalanine is obtained.

The process according to the invention is generally carried out ^{at from about 25 to 30 ° C.} The compound produced is then separated from the fermentation broth by extraction and is recovered in a known manner.

The method according to the invention proceeds roughly as follows:

Inoculate a suitable sterile nutrient medium which contains assimilable carbon and nitrogen contains, with Aerobacter aerogenes A. T. C. C. No. 211 and aerated and agitated until substantial growth of the microorganism occurs. In general, a period of 1 to 7 days is required for this. Suitable media for the process according to the invention are given in the tables below. Medium I.

Molasses 6 g

Water sufficient for 100 ml

pH adjusted to 5.5 with phosphoric acid
Medium II

Commercial yeast extract 20 g

Dextrose 20 g

MgSO ₄ -7H ₂ O 0.5 g

KH ₂ PO ₄ 0.2 g

Na ₂ HPO ₄ 0.2 g

Water sufficient for 1.0 liter

pH adjusted to 7

Following the growth period, veratraldehyde is added in a concentration of about 1 to 10 g of the compound per liter of medium and the mixture is allowed to incubate with agitation at about 28 ^° C. for a period of 1 to 10 hours.

Subsequent to the breeding period, the fermented broth, which contains the desired compound, is extracted together with other metabolic products, with a water-immiscible solvent for l (-) - 3,4-dimethoxyphenyl-acetyl-carbinol, e.g. B. with an ester of a lower aliphatic Acid, preferably with ethyl acetate.

The solvent extract contains in addition to the desired l (-) - 3,4-dimethoxyphenyl-acetyl-carbinol unreacted aldehyde as well as the corresponding substituted benzyl alcohol and the substituted Benzoic acid. 1 (-) - 3,4-Dimethoxyphenyl-acetyl-carbinol is separated from the related compounds by methods such as partition chromatography on an inert material, e.g. B. Diatomaceous earth, fractional crystallization or extraction with aqueous sodium bisulfite solution.

example

A fermentation medium having the composition of Medium II is inoculated with a strain of Aerobacter aerogenes ATCC No. 211. The medium is then ventilated and ^{agitated at 28 °} C. for approximately 48 hours in order to achieve optimal growth of the fungus. Aeration and agitation are stopped and veratraldehyde is added to the medium in a concentration of 4 g per liter of medium. Then vented to the addition of the Veratraldehyds and moves to the medium again at 28 ⁰ C for a period of about 7 hours.

After the incubation period, the fermentation liquid is filtered to separate the cell bodies, and extracted with ethyl acetate. The ethyl acetate extract containing the product is extracted one with aqueous bisulfite solution and subjects it to partition chromatography on a column Diatomaceous earth, with a solvent system consisting of petroleum ether, benzene, methyl alcohol, Water used in a ratio of 6: 4: 5: 5. The material obtained is L-3,4-dimethoxyphenylacetyl-carbinol, essentially free from verataldehyde and veratryl alcohol.

The oil shows the following nuclear magnetic spectrum:

TMS
(Acetone-d _e ) Multiplicity Typical for 3.01
4.86
5.23
6.20
7.94 d (/ = 3.6)
d (/ = 3.6)
S.
S. Aryl
> CHOH
> CHOH
-OCH ₃
- CO - CH ₃

Claims (1)

Claim: Stereospecific process for the preparation of l (-) - 3,4-dimethoxyphenyl-acetyl-carbinol, characterized in that veratraldehyde with a growing culture of Aerobacter aerogenes A. T. C. C. No. 211 in more intimate Contact brings about implementation, the l (-) - 3,4-dimethoxyphenyl-acetyl-carbinol formed extracted with a water-immiscible solvent and recovered in a known manner.