Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing nitrogen-containing organic compound
Reexamination Certificate
1999-07-12
2001-01-16
Lilling, Herbert J. (Department: 1651)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing nitrogen-containing organic compound
C435S106000, C435S129000
Reexamination Certificate
active
06174711
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a method for producing L-allysine acetal. More particularly, the present invention relates to a method of biochemical asymmetric hydrolysis of D,L-allysinamide acetal to produce corresponding L-allysine acetal. L-Allysine acetal is an important substance as an intermediate for producing medicines.
2. Description of the Related Art
Hitherto known methods for the production of L-allysine acetal include, for example, the method described in Japanese Patent Application Laid-open No. Hei 7-48259. This method comprises the steps of stereoselectively hydrolyzing N-acetyl-D,L-hydroxynorleucine, which has been derived by a two-step reaction from diethyl acetamidomalonate, with a swine liver acylase to obtain L-hydroxynorleucine, converting an amino group of the L-hydroxynorleucine to phthalimide, and a carboxyl group of the L-hydroxynorleucine to its methyl ester for protection, converting a hydroxyl group thereof to aldehyde by Swern oxidation, and further converting aldehyde thereof to dimethyl acetal, followed by deprotecting the phthalimide to obtain L-allysine dimethyl acetal as methyl ester. The method involves many steps, gives low yield, and requires expensive reagents, so that it cannot be said to be industrially advantageous.
Besides this, Bioorganic & Medicinal Chemistry, Vol.3, 1237-1240 (1995) describes a method for producing D,L-allysine ethylene acetal from 3,4-dihydro-2H-pyrane by 8-step reaction. This method also involves many steps, gives low yield, and requires further expensive reagents, so that it cannot be said to be industrially advantageous. The literature describes only the method for producing racemic modification but fails to describe optically active substance of L-allysine acetal.
SUMMARY OF THE INVENTION
An object of the present invention is to solve the above-mentioned problems encountered by the prior art and provide a method for producing L-allysine acetal by less number of steps at low cost.
The present inventors have made intensive research for a method for producing L-allysine acetal in a small number of steps inexpensively and as a result they have been successful in the synthesis of D,L-allysinamide acetal, a novel compound, and have found that the D,L-allysinamide acetal is biochemically hydrolyzed by the enzymatic action of a microorganism to give L-allysine acetal, thus reaching the present invention.
(1) That is, the present invention relates to a method for producing L-allysine acetal represented by general formula (II), comprising reacting D,L-allysinamide acetal represented by general formula (I) with cells of microorganism or treated cell product having an activity of stereoselectively hydrolyzing L-allysinamide acetal,
wherein R
1
and R
2
, which may be the same or different, each independently represent a lower alkyl group, or R
1
and R
2
are combined to form an alkylene group represented by [CH
2
]
n
, and n is 2 to 3.
(2) Further, the present invention relates to a method for producing L-allysine acetal as described in (1) above, wherein after the cells of microorganism or treated cell product is reacted on D,L-allysinamide acetal, unreacted D-allysinamide acetal is heated in the presence of a strongly basic substance to racemize it to obtain D,L-allysinamide acetal, which is used again as a raw material.
(3) Further, the present invention relates to a compound, D,L-allysinamide acetal, which is used as a raw material for the reaction described in (I) and to a method for producing it.
According to the present invention, L-allysine acetal useful as a raw material for producing medicine can be produced in a smaller number of steps at low cost.
DETAILED DESCRIPTION OF THE INVENTION
Hereafter, the present invention will be described in detail.
A reaction scheme of the present invention is shown below, which illustrates that a novel compound D,L-allysinamide acetal (general formula (I)) is synthesized from a known product of glutaraldehyde monoacetal (general formula (III)) as a starting material and D,L-allysinamide acetal is then stereoselectively hydrolyzed using cells of microorganism to produce L-allysine acetal (general formula (II)), wherein D-allysinamide acetal which remains without undergoing stereoselective hydrolysis is racemized to return to D,L-allysinamide acetal as a raw material.
Hereafter, the present invention will be described in accordance with the reaction scheme.
Glutaraldehyde monoacetal represented by general formula (III) is synthesized by known methods, for example, by monoacetalization of glutaraldehyde (Japanese Patent Application Laid-open No. Sho 48-39416) as well as by oxidation of 5,5-dimethoxy-1-pentanol (J. Am. Chem. Soc., Vol. 104, 1033-1041, (1982)) and hydroformylation of 4,4-diethoxy-1-butene (J. Am. Chem. Soc., Vol. 115, 2066-2068, (1993)) and the like.
D,L-&agr;-aminonitrile (indicated as aminonitrile in the above-mentioned reaction scheme) is synthesized by Strecker reaction, in which glutaraldehyde monoacetal is reacted with hydrocyanic acid and ammonia, or with cyanide and ammonium salt. The method of Strecker reaction includes a 2-step method in which first glutaraldehyde monoacetal is reacted with hydrocyanic acid to produce cyanohydrin and then the cyanohydrin is reacted with ammonia to produce aminonitrile, and a 1-step method in which glutaraldehyde monoacetal is reacted with cyanide and ammonium salt to produce aminonitrile.
The reaction conditions for the step of reacting glutaraldehyde monoacetal with hydrocyanic acid to produce cyanohydrin are not limited particularly but usually the reaction is carried out in the presence of a basic catalyst at reaction temperature of 0 to 20° C. The reaction conditions for the step of reacting cyanohydrin with ammonia to produce D,L-&agr;-aminonitrile are not limited particularly but usually the reaction is carried out using 5- to 10-fold molar amount of ammonia based on cyanohydrin and usually at temperature of 20 to 80° C. because reaction at too low temperature may result in slow reaction rate and too high temperature may result in the decomposition product.
The reaction conditions for the step of reacting glutaraldehyde with cyanide and ammonium salt to produce aminonitrile in one step are not limited particularly but the reaction is carried out at reaction temperature of 0 to 50° C. The cyanide is preferably alkali cyanide, of which potassium cyanide and sodium cyanide are particularly preferred. The ammonium salt is preferably ammonium chloride.
There are two methods for producing D,L-allysinamide acetal represented by general formula (I) from D,L-&agr;-aminonitrile. One is a method in which D,L-&agr;-aminonitrile is partially hydrolyzed and the other is a method in which D,L-&agr;-aminonitrile is reacted with a ketone represented by R
3
COR
4
(wherein R
3
and R
4
are independently a lower alkyl group) to produce oxazolidine and then the oxazolidine is hydrolyzed.
The reaction conditions when D,L-&agr;-aminonitrile is partially hydrolyzed are not limited particularly but usually the partial hydrolysis is carried out in the presence of a basic catalyst and ketone in aqueous solution at reaction temperature of 0 to 30° C.
The reaction conditions when D,L-allysinamide acetal is produced via oxazolidine are not limited particularly but usually the oxazolidine synthesis is carried out in the presence of a basic catalyst and using about 1- to 5-fold molar amount of ketone based on aminonitrile and at reaction temperature of about −10 to 50° C., preferably 0 to 30° C. and then the obtained oxazolidine is hydrolyzed in aqueous solution at reaction temperature of about 0 to 50° C.
The method for producing D,L-allysinamide acetal in this manner is advantageous in point that it can be easily produced from aldehydes, hydrocyanic acid and ammonia which are widely used as industrial raw materials.
In the present invention, typical examples of D,L-allysinamide acetal represented by general formula (I) include D,L-allysinamide dimethyl acetal (D,L-2-amin
Doya Masaharu
Tahara Torakazu
Tanaka Akinori
Uchiyama Takako
Lilling Herbert J.
Mitsubishi Gas Chemical Company
Stockton LLP Kilpatrick
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