Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-11-30
2002-09-17
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06452026
ABSTRACT:
TECHNICAL FIELD
The optically active threo-3-amino-1,2-epoxy compounds in the present invention are used as a synthetic material for intermediates of drugs. For example, they are used for the intermediates of HIV protease inhibitor (JP Laid-Open No.257554/1992) or an enzyme inhibitor. The present invention is expected to be an industrial process for producing the optically active threo-3-amino-1,2-epoxy compounds.
BACKGROUND ART
The known processes for producing the optically active threo-3-amino-1,2-epoxy compounds represented by the formula (3) are as follows:
{circle around (1)} the process, wherein a 3-substituted-3-amino-2-oxo-1-halogenopropane is subject to the reduction at the 2-ketone site to derive the halohydrine compound, and then the halohydrine compound is subject to the dehydrohalogenation with a base to obtain the epoxy compound (U.S. Pat. No. 5,559,256, EP-580402, J. Med. Chem., 37, 1785(1994));
{circle around (2)} the process, wherein a 3-substituted-3-aminoaldedyde derivative is reacted with a diholomethane or a disulfonium ylide to obtain the epoxy compound(WO93/23388, J. Med. Chem., 35, 2525(1992), Tetrahedron Lett., 30,5425(1989), J. Org. Chem., 50,4615(1985));
{circle around (3)} the process, wherein a 3-substituted-3-amino-1-propene derivative is reacted with a peroxy acid to obtain the epoxy compound(WO96/04277, EP-532466, CA-2075666, JP Laid-Open No.257520/1992, J. Org. Chem., 52,1487(1987));
{circle around (4)} the process, wherein a 3-amino-1,2-diol derivative is reacted with p-toluene sulfonyl chloride to give a 3-amino-2-hydroxytoluene sulfonate derivative in pyridine, and then the sulfonate derivative is reacted with potassium carbonate or sodium hydride to obtain the epoxy compound(WO97/42180, U.S. Pat. No. 5,516,784).
However, these processes have their respective drawbacks in the industrial manufacturing, as described below.
In the process {circle around (1)}, since the erythro configuration of a halohydrine derivative is produced preferentially because of reductive selectivity when the 2-ketone group of the 3-substituted-3-amino-2-oxo-1-halogenopropane is reduced to an alcohol group, the threo configuration of the halohydrine derivative, which is unpreferentially produced by the reductive reaction, must be used in order to obtain the optically active threo-3-amino-1,2-epoxy compound.
In the process {circle around (2)}, a ratio of threo- and erythro-epoxy compounds varies depending on the reaction condition or the sort of a 3-substituted group in the reaction in which the 3-substituted-3-aminoaldedyde derivative is reacted with a diholomethane or a disulfonium ylide. Furthermore, 3-substituted-3-aminoaldedyde derivative is defectively liable to a racemization because it is put into a strongly basic reaction system.
For the process {circle around (3)}, which utilizes the 3-substituted-3-amino-1-propene derivative as the reaction material, it is decisively important how the amino derivative or its equivalent can be produced in an industrially reasonable cost. It can be produced from the aminoaldehyde compound through the Wittig Reaction or the Peterson Reaction, but the Wittig Reaction brings troublesomely about racemization and the Peterson Reaction requires a reaction temperature of −65° C. or lower in order to produce the key intermediate, 2-hydroxy-1-trialkylsilyl compound. Furthermore, the epoxydation reaction requires a strict caution in the industrial practice due to peroxy acid used.
With respect to the process {circle around (4)}, it is inconvenient in time and operation for the mass production because a p-toluene sulfonylation is carried out at a relatively low temperature for a long time and, after completion of the reaction, it requires many repetitions of extracting and washing to remove pyridine used for the solvent besides the base and the concentration steps.
Any of {circle around (1)}-{circle around (
4
)} has never isolated highly pure optically active threo-3-amino-1,2-epoxy compound.
It is desired to improve the processe of producing the threo configuration of an optically active 3-amino-1,2-epoxy compound in order to obtain the threo compound having a purity enough to use for a drug material in an industrial scale because the known processes are not satisfied necessarely.
DISCLOSURE OF THE INVENTION
The present inventors made a diligent study to solve the above problem and, as a result, have found that a highly pure optically active threo-3-amino-1,2-epoxy compound can be industrially produced, either by epoxydating a sulfonylated product obtained by sulfonylation, without isolating it from the organic phase, under the presence of a base, or by depositing selectively the sulfonylated product from the sulfonylation reaction solution and then epoxydating, and thereafter purifying with aliphatic hydrocarbon solvents or/and water.
Namely, the present invention relates to the following term 1 to 34:
1. A process for producing an optically active threo-3-amino-1,2-epoxy compound represented by the formula(3),
(where R
1
is a C3-C12 hydrocarbon residual group; R
2
is an amino group or a protected amino group; *2 is, if *3 is S in configuration, R in configuration and, if *3 is R in configuration, S in configuration),
which comprises reacting an optically active threo-3-amino-1,2-diol derivative represented by the formula(1)
(where R
1
, R
2
, *2 and *3 show the same meanings as described above)
with an alkylsulfonyl halogenide or an arylsulfonyl halogenide for sulfonylating under the presence of a base in an organic solvent to obtain site-specifically the optically active threo-3-amino-2-hydroxysulfonate derivative represented by the formula(2)
(where R
1
, R
2
, *2 and *3 show the same meaning as described above, and R
3
is a C1-C12 hydrocarbon residual group)
and then epoxydating, without isolating from the organic phase, under the presence of a base.
2. A process according to term 1, wherein R
1
is a C3-C8 hydrocarbon residual group.
3. A process according to term 1, wherein R
1
is a cyclohexyl group or a phenyl group.
4. A process according to any of term 1-3, wherein R
2
is an amino group or an amino group protected with an urethane-forming protective group.
5. A process according to term 4, wherein R
2
is an amino group protected with an optionally substituted lower alkanoyl group or a lower alkoxycarbonyl group.
6. A process according to term 1, wherein R
1
is a cyclohexyl group or a phenyl group, and R
2
is a tert-butoxycarbonyl amino group, a benzyloxycarbonyl amino group, or a phthalimino group.
7. A process according to any of term 1-6, wherein R
3
is a lower alkyl group or a substituted phenyl group.
8. A process according to any of term 1-7, wherein said organic solvent is an ether type of solvent, an ester type of solvent, an aromatic hydrocarbon type of solvent or a halogenide type of solvent.
9. A process according to term 8, wherein said ether type of solvent is tetrahydrofurane, said ester type of solvent is ethyl acetate, said aromatic hydrocarbon type of solvent is toluene and said halogenide type of solvent is methylene chloride.
10. A process according to term 8, wherein said organic solvent is tetrahydrofurane.
11. A process according to any of term 1-10, wherein said base used for sulfonylating the compound of the formula (1) is a tertiary amine.
12. A process according to term 11, wherein said base is triethylamine.
13. A process according to any of term 1-12, wherein said base used for epoxydating the compound of the formula (2) is an alkali metal alcoholate.
14. A process according to term 13, wherein said base is sodium methylate.
15. A process for producing an optically active threo-3-amino-2-hydroxysulfonate derivative represented by the formula(2)
(where R
1
, R
2
, R
3
, *2 and *3 show the same meanings as described above),
which comprises reacting the optically active threo-3-amino-1,2-diol derivative represented by the formula(1)
(where R
1
, R
2
, *2 and *3 show the same meanings as described above)
with an alkylsulfonyl halogenide or an arylsulfonyl halogenide under the prese
Sagawa Yukihiro
Sato Hisao
Sekine Jouji
McKane Joseph K.
Murray Joseph
Nields & Lemack
Nippon Kayaku Kabushiki Kaisha
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