Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-08-02
2002-05-14
Morris, Patricia L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06388086
ABSTRACT:
TECHNICAL FIELD
The present invention is related to production of a pharmaceutical intermediate, particularly a 3-(3-pyridyl)-1-propanol derivative which is of value as an intermediate of tryptase inhibitors, especially a 4-(3-pyridyl)-1,2-butanediol.
PRIOR ART
Up to the present, the following processes are known for the production of 3-(3-pyridyl)-1-propanol derivatives.
(1) A process starting with 3-(3-pyridyl)-1-propionaldehyde
which comprises subjecting the starting compound and trimethylsulfoxonium iodide to coupling reaction to synthesize 3-(2-oxiranylethyl)pyridine and reacting it with a phenol derivative or a thiol derivative (WO97/20815).
(2) A synthetic process starting with 3-(3-pyridyl)-1-propionaldehyde
which comprises reacting this starting compound with an aryloxymethyllithium or arylthiomethyllithium prepared from an aryloxymethane or arylthiomethane and butyllithium (WO97/20815).
(3) A process
which comprises reacting 3-(pyridyl)methyllithium prepared from 3-methylpyridine and the lithium base with epichlorohydrin to synthesize &agr;-(chloromethyl)-3-pyridinepropanol, cyclizing it with a base to give an epoxide derivative and reacting this derivative with a phenol derivative or a thiol derivative (WO97/20815).
(4) A synthetic process starting with 3-pyridylmethyltriphenylphosphonium chloride hydrochloride
which comprises subjecting this starting compound and 2,3-O-isopropylideneglyceraldehyde to coupling reaction and further subjecting the resulting 4-(3-pyridyl)-1,2-O-isoproylidenebut-3-ene-1,2-diol to olefin reduction and deacetonylation (WO98/42669).
However, the prior art processes (1) and (2) require expensive starting materials and, in addition, the product is invariably a racemic mixture which requires optical resolution. The prior art process (3) is not practically useful because the yield of the coupling reaction in the first step is low. The prior art process (4) uses very expensive starting materials. For these and other reasons, none of the prior art processes are efficient enough for commercial production.
SUMMARY OF THE INVENTION
In view of the above state of the art, the present invention has for its object to provide a process for producing a 3-(3-pyridyl)-1-propanol derivative of use as a pharmaceutical intermediate, particularly an 4-(3-pyridyl)-1,2-butanediol expediently with an inexpensive material.
The present invention, therefore, is directed to a process for producing a 3-(3-pyridyl)-1-propanol derivative (3):
in the formula, R
1
represents an alkyl group of 1 to 20 carbon atoms, aryl group of 6 to 20 carbon atoms or aralkyl group of 7 to 20 carbon atoms, which may be substituted,
which comprises reacting a 3-methylpyriding with a strong base to prepare a 3-methylpyridine metal (1):
in the formula, M represents lithium, sodium, potassium or a magnesium halide, where the halide is chloride or bromide,
and then reacting said metal salt with an epoxy compound (2):
in the formula, R
1
is as defined above,
to give a 3-(3-pyridyl)-1-propanol derivative,
wherein the 3-methylpyridine is used in molar in excess of said strong base,
and/or the reaction between said metal salt and said epoxy compound is conducted in the presence of an amine.
The present invention is further directed to a process for producing a 4-(3-pyridyl)-1,2-butanediol (7):
which comprises reacting a 3-methylpyridine with a strong base to prepare a 3-methylpyridine metal salt (1),
then reacting said metal salt with an O-protected glycidol (5):
in the formula, R
5
represents a hydroxy-protecting group,
to give a 1-O-protected-4-(3-pyridyl)-1,2-butanediol (6):
and deprotecting the same.
In addition, the present invention is directed to a process for producing an 1-O-protected-4-(3-pyridyl)-1,2-butanediol (6)
which comprises reacting 3-methylpyridine with a strong base to prepare a 3-methylpyridine metal salt (1)
and reacting said metal salt with an O-protected glycidol (5).
The present invention is now described in detail.
DETAILED DESCRIPTION OF THE INVENTION
Referring to the above general formula (1), M represents lithium, sodium, potassium or a magnesium halide, where the halide means chloride or bromide. Preferred is lithium.
Referring to the above general formulas (2) and (3), R
1
represents an alkyl group of 1 to 20 carbon atoms, aryl group of 6 to 20 carbon atoms or aralkyl group of 7 to 20 carbon atoms, which may be substituted. More particularly, R
1
includes but is not limited to methyl, ethyl, n-propyl, isopropyl, sec-butyl, tert-butyl, phenyl, benzyl, 2-phenylethyl, 2-(2-naphthyl)ethyl, 2-phenylvinyl, 2-(2-naphthyl)acetylene, chloromethyl, hydroxymethyl, p-toluenesulfonyloxymethyl, acetyloxymethyl, pivaloyloxymethyl, benzoyloxymethyl, phenyloxymethyl, 4-(phenyl)phenyloxymethyl, 4-[3′-(N,N-dimethylphenylacetamido)phenyl]phenyloxymethyl, 2-naphthyloxymethyl, 2-(6-bromonaphthyl)oxymethyl, 2-[6-(3-(N,N-dimethyl)propanamide)naphthyl]oxymethyl, benzyloxymethyl, tert-butyloxymethyl, aryloxymethyl, tert-butyldimethylsilyloxymethyl, 2-tetrahydropyranyloxymethyl, 1-(phenyloxy)ethyl, 1-(phenyloxy)-1-methylethyl, phenylthiomethyl, 2-naphthylthiomethyl, N,N-dibenzylamino, and N-phenyl-N-ethylaminomethyl.
In the epoxy compound represented by general formula (2), R
1
is preferably a group of the following general formula (4):
In the above general formula (4), R
2
and R
3
each independently represents hydrogen, an alkyl group of 1 to 18 carbon atoms, an aryl group of 6 to 18 carbon atoms or an aralkyl group of 7 to 18 carbon atoms, or R
2
and R
3
, taken together, represent a cycloalkyl group of 3 to 18 carbon atoms. As specific groups, these include methyl, ethyl, n-propyl, isopropyl, sec-butyl, tert-butyl, phenyl, benzyl, cyclopropyl and cyclohexyl, among others. Particularly preferred is the case in which both R
2
and R
3
represent hydrogen.
R
4
represents hydrogen, an alkyl group of 1 to 18 carbon atoms, aryl group of 6 to 18 carbon atoms, aralkyl group of 7 to 18 carbon atoms or silyl group of 3 to 18 carbon atoms, which may be substituted. More particularly, R
4
includes methyl, ethyl, methoxyethyl, 2-trimethylsilylethyl, n-propyl, isopropyl, sec-butyl, tert-butyl, cyclopropyl, cyclohexyl, allyl, 2-tetrahydropyranyl, phenyl, p-nitrophenyl, o-chlorophenyl, 4-(phenyl)phenyl, 4-(3′-N,N-dimethylphenylacetamido)phenyl, 2-naphthyl, 2-(6-bromo)naphthyl, 2-(6-(3-N,N-dimethyl)propanamido)naphthyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, phenethyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl and tert-butyldiphenylsilyl. Among these, R
4
is preferably phenyl, benzyl, tert-butyl or tert-butyldimethylsilyl.
X represents an oxygen atom or a sulfur atom. Preferred is an oxygen atom.
The process for producing a 3-(3-pyridyl)-1-propanol derivative in accordance with the present invention is now described.
Thus, the present invention is directed to a process for producing a 3-(3-pyridyl)-1-propanol derivative comprising permitting a strong base to act upon 3-methylpyridine to prepare a 3-methylpyridine metal salt and reacting said metal salt with an epoxy compound, wherein 3-methylpyridine is used in molar in excess of said strong base and/or the reaction between said metal salt and said epoxy compound is conducted in the presence of an amine.
Heretofore, this reaction involves many side reactions so that the yield is generally too low for commercial exploitation (e.g. WO97/20815). The present inventors discovered that the yield of the objective compound can be improved dramatically by reacting a molar excess of 3-methylpyridine with the strong base and/or conducting the reaction between said metal salt and epoxy compound in the presence of an amine. The present invention has been developed on the basis of the above finding.
The epoxy compound of the general formula (2) is not particularly restricted but includes, among others, propylene oxide, 1,2-epoxybutane, 1,2-epoxypentane, 1,2-epoxy-3-methylbutane, 1,2-epoxy-4-methylpentane, 1,2-epoxy-3,3-dimethylbutane, styrene oxide, 1,2-epoxy-4-phenylbutane, 1,2-epoxy-4-(2-naphthyl)butane,
Inoue Kenji
Nishiyama Akira
Okuro Kazumi
Kaneka Corporation
Morris Patricia L.
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