Salt forms of 6-n-butylamino-6-deoxy-&agr;-L-sorbofuranose

Details Salt forms of 6-n-butylamino-6-deoxy-&agr;-L-sorbofuranose Salt forms of 6-n-butylamino-6-deoxy-&agr;-L-sorbofuranose

1999-04-14

2003-04-22

Marx, Irene (Department: 1651)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C435S125000, C435S126000, C435S084000, C536S022100

Reexamination Certificate

active

06552176

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a process for production of N-substituted-1-deoxynojirimycin and intermediates for its production.
BACKGROUND OF THE INVENTION
A process for the preparation of 1-deoxynojirimycin in which 1-aminosorbitol is oxidized microbiologically to give 6-aminosorbose, which is then hydrogenated with a catalyst to give 1-deoxynojirimycin is disclosed in U.S. Pat. No. 4,246,345. However, the yields of this process, in particular the low volume yields in the microbiological reaction are related to degradation problems and short reaction times, in addition no process for production of N-substituted derivatives of 1-deoxynojirimycin is disclosed.
It is known that N-substituted derivatives of 1-deoxynojirimycin can be made by protecting aminosorbitols with protecting groups which are stable in subsequent microbial oxidations. The protecting groups can subsequently be removed by catalytic hydrogenation. Such a process is disclosed in U.S. Pat. No. 4,266,025. In the '025 patent, protected amino sugars are oxidized microbiologically to give protected 6-aminosorboses, which are then isolated. The protective group is then removed by catalytic hydrogenation and the ring is reclosed to form the N-substituted derivatives of 1-deoxynojirimycin. However, the '025 process requires a large amount of catalyst in the hydrogenation step. In addition, the unprotected 6-aminosorboses cannot be isolated as such.
U.S. Pat. No. 4,405,714 discloses a process for producing N-substituted derivatives of 1-deoxynojirimycin in which glucose is converted into a 1-aminosorbitol, the 1-aminosorbitol is then protected by a protecting group which is stable in the subsequent microbiological oxidation process. The protecting group can then be removed under acid conditions. The compounds are oxidized microbially to give a protected 6-aminosorbose. The protective group on the 6-aminosorbose is then removed under acid conditions. The 6-aminosorbose salt thus obtained is hydrogenated with a catalyst to give the N-substituted derivative of 1-deoxynojirimycin. The '714 process, like the '025 process, requires the use of protective groups to obtain N-substituted derivatives of 1-deoxynojirimycin.
It has been discovered that N-substituted derivatives of 1-deoxynojirimycin can be made by a process which does not require the use of protecting groups.
SUMMARY OF THE INVENTION
This invention is a process which comprises oxidizing a glucamine of the formula:
or salts thereof, with an oxidizing microbe or extract thereof, and producing compounds of the formula:
or salts thereof, in which R, in each instance, is phenyl, C
1
-C
10
alkyl, C
1
-C
10
alkyl substituted with phenyl or carboxy, or C
2
-C
10
alkyl substituted with hydroxy.
In one embodiment of the invention, a 6-(substituted amino)-6-deoxy-&agr;-L-sorbofuranose produced by the above described reaction is reduced (with or without isolation of the intermediate sorbose) to N-substituted-1-deoxynojirimycin, or salts thereof, of formula III (shown below).
wherein R is the same as described above.
In another embodiment of the invention,
D
-glucose is converted to N-substituted-1-deoxynojirimycin in a one pot process:
Another embodiment of the invention is a process for producing N-substituted glucamines and salts thereof.
In another embodiment, the compound 6-butylamino-6-deoxy-&agr;-L-sorbofuranose and salts thereof are disclosed.
The exact form of the structure of formula II is dictated by the environment in which the sorbose is present (See H. Paulsen et al.,
Chem. Ber.
100:802 (1967)). The use of the sorbofuranose or the sorbose nomenclature is not meant to imply that the compound cannot or does not exist in another of its equivalent forms.
The 6-(substituted amino)-6-deoxy-&agr;-L-sorbofuranose produced by the microbial oxidation of N-substituted glucamines are useful as intermediates for producing N-substituted-1-deoxynojirimycin compounds (which are antiviral agents, antidiuretics, antidiabetics, animal feed additives and antihyperglycemics).
As used herein, the glucamines of the above formula I are referred to as “N-substituted glucamines” (also known as 1-(substituted amino)-1-deoxy-
D
-glucitol). The compounds of the above formula II are hereinafter referred to as “6-substituted amino-6-deoxy-&agr;-L-sorbofuranoses”. The compounds of the above formula III are referred to as “N-substituted-1-deoxynojirimycins” (also known as 1,5-(substituted imino)-1,5-dideoxy-
D
-glucitol and 1-substituted-3,4,5-trihydroxy-2-piperidinylmethanol.)
Straight chain or branched chain alkyls are suitable to practice the process of the invention, with C
1
-C
5
alkyl groups preferred. Examples of suitable alkyl radicals are methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 1,1-dimethylethyl, n-pentyl, 3-methylbutyl, 1-methylbutyl, 2-methylbutyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl. Suitable hydroxy substituted alkyl radicals are 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl, 6-hydroxyhexyl, 7-hydroxyheptyl, 8-hydroxyoctyl, 9-hydroxynonyl, and 10-hydroxydecyl. Suitable carboxy substituted alkyl radicals are carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl, 5-carboxypentyl, 6-carboxyhexyl, 7-carboxyheptyl, 8-carboxyoctyl, 9-carboxynonyl and 10-carboxydecyl. Suitable phenyl substituted alkyl radicals are phenylmethyl (benzyl), 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, 7-phenylheptyl, 8-phenyloctyl, 9-phenylnonyl and 10-phenyldecyl. Phenyl alone is also an acceptable radical.
Examples of 6-substituted amino-6-deoxy-&agr;-L-sorbo-furanoses which are produced by the process of the invention are:
6-methylamino-6-deoxy-&agr;-L-sorbofuranose,
6-ethylamino-6-deoxy-&agr;-L-sorbofuranose,
6-n-propylamino-6-deoxy-&agr;-L-sorbofuranose,
6-(1-methylethyl)amino-6-deoxy-&agr;-L-sorbofuranose,
6-n-butylamino-6-deoxy-&agr;-L-sorbofuranose,
6-(1-methylpropyl)amino-6-deoxy-&agr;-L-sorbofuranose,
6-(1,1-dimethylethyl)amino-6-deoxy-&agr;-L-sorbofuranose,
6-n-pentylamino-6-deoxy-&agr;-L-sorbofuranose,
6-(3-methylbutyl)amino-6-deoxy-&agr;-L-sorbofuranose,
6-(1-methylbutyl)amino-6-deoxy-&agr;-L-sorbofuranose,
6-(2-methylbutyl)amino-6-deoxy-&agr;-L-sorbofuranose,
6-n-hexylamino-6-deoxy-&agr;-L-sorbofuranose,
6-n-heptylamino-6-deoxy-&agr;-L-sorbofuranose,
6-n-octylamino-6-deoxy-&agr;-L-sorbofuranose,
6-n-nonylamino-6-deoxy-&agr;-L-sorbofuranose,
6-n-decylamino-6-deoxy-&agr;-L-sorbofuranose,
6-(2-hydroxyethyl)amino-6-deoxy-&agr;-L-sorbofuranose,
6-(3-hydroxypropyl)amino-6-deoxy-&agr;-L-sorbofuranose,
6-(4-hydroxybutyl)amino-6-deoxy-&agr;-L-sorbofuranose,
6-(5-hydroxypentyl)amino-6-deoxy-&agr;-L-sorbofuranose,
6-(6-hydroxyhexyl)amino-6-deoxy-&agr;-L-sorbofuranose,
6-(7-hydroxyheptyl)amino-6-deoxy-&agr;-L-sorbofuranose,
6-(8-hydroxyoctyl)amino-6-deoxy-&agr;-L-sorbofuranose,
6-(9-hydroxynonyl)amino-6-deoxy-&agr;-L-sorbofuranose,
6-(10-hydroxydecyl)amino-6-deoxy-&agr;-L-sorbofuranose,
6-(carboxymethyl)amino-6-deoxy-&agr;-L-sorbofuranose,
6-(2-carboxyethyl)amino-6-deoxy-&agr;-L-sorbofuranose,
6-(3-carboxypropyl)amino-6-deoxy-&agr;-L-sorbofuranose,.
6-(4-carboxybutyl)amino-6-deoxy-&agr;-L-sorbofuranose,
6-(5-carboxypentyl)amino-6-deoxy-&agr;-L-sorbofuranose,
6-(6-carboxyhexyl)amino-6-deoxy-&agr;-L-sorbofuranose,
6-(7-carboxyheptyl)amino-6-deoxy-&agr;-L-sorbofuranose,
6-(8-carboxyoctyl)amino-6-deoxy-&agr;-L-sorbofuranose,
6-(9-carboxynonyl)amino-6-deoxy-&agr;-L-sorbofuranose,
6-(10-carboxydecyl)amino-6-deoxy-&agr;-L-sorbofuranose,
6-phenylamino-6-deoxy-&agr;-L-sorbofuranose,
6-(phenylmethyl)amino-6-deoxy-&agr;-L-sorbofuranose,
6-(2-phenylethyl)amino-6-deoxy-&agr;-L-sorbofuranose,
6-(3-phenylpropyl)amino-6-deoxy-&agr;-L-sorbofuranose,
6-(4-phenylbutyl)amino-6-deoxy-&agr;-L-sorbofuranose,
6-(5-phenylpentyl)amino-6-deoxy-&agr;-L-sorbofuranose,
6-(6-phenylhexyl)amino-6-deoxy-&agr;-L-sorbofuranose,
6-(7-phenylheptyl)amino-6-deoxy-&agr;-L-sorbofuranose,
6-(8-phenyloctyl)amino-6-deoxy-&agr;-L-sorbofuranose,
6-(9-phenylnonyl)amino-6-deoxy-&agr;-L-sorbofuranose, and
6-(10-p

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