JP2001048863A - Production of 3-(3-pyridyl)-1-propanol derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To simply obtain a 3-(3-pyridyl)-1-propanol derivative useful as an intermediate, etc. for a tryptase inhibitor by reacting an excessive amount of a specific metal salt of a methylpyridine with a specific epoxy compound. SOLUTION: A metal salt of 3-methylpyridine of formula I (M is lithium, sodium or the like) which is obtained by making a strong base (preferably lithium diisopropylamide) act on 3-methylpyridine for preferably 0.5-3 h is reacted with an epoxy compound of formula II [R1 is a (substituted) 1-20C alkyl or the like], (e.g. propylene oxide) preferably in the coexistence of an amine (preferably pyridine or triethylamine) at >=-20 deg.C for 0.5-3 h to thereby obtain the objective compound of formula III. The 3-methylpyridine is used in an excessive molar amount, preferably in a molar amount of >=1.5 times based on the strong base. The amine is preferably used in the equivalent amount or more based on the strong base.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a 3- (3-
The present invention relates to a method for producing a pyridyl) -1-propanol derivative.

[0002]

2. Description of the Related Art Conventionally, the following methods have been known as methods for producing 3- (3-pyridyl) -1-propanol derivatives. (1) Using 3- (3-pyridyl) -1-propionaldehyde as a starting material, coupling with trimethylsulfoxonium iodide is performed to synthesize 3- (2-oxiranylethyl) pyridine, which is then phenol derivative or Method for reacting a thiol derivative (WO97 / 2081)
5).

(2) Starting from 3- (3-pyridyl) -1-propionaldehyde as a starting material, it is reacted with aryloxymethyl lithium or arylthiomethyl lithium prepared from aryloxymethane or arylthiomethane and butyllithium, Synthesis method (WO97 / 2)
0815).

(3) Reaction of (3-pyridyl) methyllithium prepared from 3-methylpyridine and a base with epichlorohydrin to synthesize α- (chloromethyl) -3-pyridinepropanol, A phenol derivative or a thiol derivative with an epoxide derivative obtained by the reaction (WO 97/20815).

(4) Starting from 3-pyridylmethyltriphenylphosphonium chloride hydrochloride as a starting material,
Coupling with 3-O-isopropylideneglyceraldehyde gives the resulting 4- (3-pyridyl) -1,2-
A method of synthesizing O-isopropylidenebut-3-ene-1,2-diol through olefin reduction and deacetonide steps (WO98 / 42669).

However, the prior arts (1) and (2)
Is an expensive raw material as a starting material, and the product is in a racemic form, requiring optical resolution. Further, in the prior art (3), the yield of the coupling reaction in the first step is extremely low and is not practical. Conventional technology (4)
These methods are not efficient methods for industrial production because, for example, extremely expensive raw materials are used as starting materials.

[0007]

In view of the above, an object of the present invention is to provide the following general formula (3) useful as a pharmaceutical intermediate:

[0008]

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(Wherein, R ¹ represents an optionally substituted alkyl group having 1 to 20 carbon atoms, an aryl group optionally having 6 to 20 carbon atoms, or an optionally substituted carbon group. Represents 7 to 20 aralkyl groups)
An object of the present invention is to provide a method for easily producing (3-pyridyl) -1-propanol from inexpensive raw materials.

[0010]

Means for Solving the Problems The present inventors have conducted intensive studies in view of the above-mentioned current situation, and as a result, have found that the following general formula (3) can be obtained from inexpensive and easily available raw materials:

[0011]

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(Wherein R ¹ represents an optionally substituted alkyl group having 1 to 20 carbon atoms, an optionally substituted aryl group having 6 to 20 carbon atoms, or an optionally substituted carbon number Represents 7 to 20 aralkyl groups)
A simple method for producing (3-pyridyl) -1-propanol has been developed. That is, the present invention provides the following general formula (1) which is prepared by allowing a strong base to act on 3-methylpyridine:

[0013]

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(Wherein M represents lithium, sodium, potassium or magnesium halide, and halide represents chloride or bromide) and a metal salt of 3-methylpyridine represented by the following general formula (2):

[0015]

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(Wherein, R ¹ represents an optionally substituted alkyl group having 1 to 20 carbon atoms, an aryl group optionally having 6 to 20 carbon atoms, or an optionally substituted carbon group. (Representing an aralkyl group of 7 to 20) represented by the following general formula (3);

[0017]

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(Wherein R ¹ is the same as above)
A method for producing a-(3-pyridyl) -1-propanol derivative, which comprises using an excess molar amount of 3-methylpyridine with respect to a strong base.

Although an example in which a metal salt generated from 3-methylpyridine is reacted with epichlorohydrin (WO97 / 20815) is known, there is a problem in the yield, Although it is described that the metal salt generated from pyridine reacts with the aryloxyglycidol derivative, no specific example is disclosed, and the metal salt generated from 3-methylpyridine and the epoxy derivative are efficiently used. There is no known specific example in which the reaction is carried out at a proper and practical yield.

[0020]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.
In the above general formula (1), M represents lithium, sodium, potassium, or magnesium halide, and halide represents chloride or bromide. Preferably,
Lithium.

In the above general formulas (2) and (3), R
¹ represents an alkyl group having 1 to 20 carbon atoms which may be substituted, an aryl group having 6 to 20 carbon atoms which may be substituted, or an aralkyl group having 7 to 20 carbon atoms which may be substituted. . Specifically, for example, methyl group, ethyl group, n-propyl group, isopropyl group, sec-butyl group, tert-butyl group, phenyl group, benzyl group,
2-phenylethyl group, 2- (2-naphthyl) ethyl group, 2-phenylvinyl group, 2- (2-naphthyl) acetylene group, chloromethyl group, hydroxymethyl group, paratoluenesulfonyloxymethyl group, acetyloxymethyl Group, pivaloyloxymethyl group, benzoyloxymethyl group, phenyloxymethyl group, 4- (phenyl)
Phenyloxymethyl group, 4- [3 ′-(N, N-dimethylphenylacetamido) phenyl] phenyloxymethyl group, 2-naphthyloxymethyl group, 2- (6-bromonaphthyl) oxymethyl group, 2- [6 -(3-
(N, N-dimethyl) propanamide) naphthyl] oxymethyl group, benzyloxymethyl group, tert-butyloxymethyl group, allyloxymethyl group, tert-
Butyldimethylsilyloxymethyl group, 2-tetrahydropyranyloxymethyl group, 1- (phenyloxy) ethyl group, 1- (phenyloxy) -1-methylethyl group, phenylthiomethyl group, 2-naphthylthiomethyl group, N, N-dibenzylamino group or N-phenyl-
Examples include, but are not limited to, an N-ethylaminomethyl group.

In the above general formula (4), R ² and R ³
Independently represents hydrogen, an alkyl group having 1 to 18 carbon atoms, an aryl group having 6 to 18 carbon atoms, or an aralkyl group having 7 to 18 carbon atoms, or together represent 3 to 18 carbon atoms.
Represents a cycloalkyl group. Specifically, for example, methyl group, ethyl group, n-propyl group, isopropyl group, s
An ec-butyl group, a tert-butyl group, a phenyl group, a benzyl group, a cyclopropyl group, a cyclohexyl group, or the like. Of these, R ² and R ³ are preferably hydrogen.

R ⁴ is hydrogen, an alkyl group having 1 to 18 carbon atoms which may be substituted, an aryl group having 6 to 18 carbon atoms which may be substituted, or a carbon atom which may be substituted
Represents an aralkyl group having from 18 to 18 or a silyl group having 3 to 18 carbon atoms which may be substituted. Specifically, for example, methyl group, ethyl group, methoxyethyl group, 2-trimethylsilylethyl group, n-propyl group, isopropyl group, s
ec-butyl, tert-butyl, cyclopropyl, cyclohexyl, allyl, 2-tetrahydropyranyl, phenyl, p-nitrophenyl, o-chlorophenyl, 4- (phenyl) phenyl, 4 −
(3′-N, N-dimethylphenylacetamido) phenyl group, 2-naphthyl group, 2- (6-bromo) naphthyl group, 2- (6- (3-N, N-dimethyl) propanamido) naphthyl group, Benzyl group, p-nitrobenzyl group,
Examples thereof include a p-methoxybenzyl group, a phenethyl group, a trimethylsilyl group, a triethylsilyl group, a tert-butyldimethylsilyl group, and a tert-butyldiphenylsilyl group. Of these, R ⁴ represents a phenyl group, a benzyl group, a tert-butyl group, or a tert-butyl group.
It is preferably a butyldimethylsilyl group. X is an oxygen atom or a sulfur atom, and is preferably an oxygen atom.

Next, a method for producing the 3- (3-pyridyl) -1-propanol derivative in the present invention will be described. That is, the present invention provides 3- (3) by reacting a 3-methylpyridine metal salt prepared by reacting a strong base with 3-methylpyridine with an epoxy compound.
-Pyridyl) -1-propanol derivative, characterized by using an excess molar amount of 3-methylpyridine with respect to a strong base.

Heretofore, this reaction has generally been low in yield and impractical due to many side reactions (for example, WO97 /
20815). The present inventors have found that the use of an excess molar amount of 3-methylpyridine with respect to the strong base significantly improves the target yield, and has completed the present invention.

The epoxy derivative represented by the general formula (2) is not particularly restricted but includes, for example, 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, 1,2-epoxy-4-phenylbutene, 1,2-epoxy-4- (2-naphthyl)
Butyne, epichlorohydrin, glycidol, glycidyl tosylate, O-acetylglycidol, O-pivaloylglycidol, O-benzoylglycidol, phenylglycidyl ether, 4- (phenyl) phenylglycidyl ether, 4- [3 '-( N, N-dimethylphenylacetamido) phenyl] phenylglycidyl ether, 2-naphthylglycidylether, 2- (6-
Bromonaphthyl) glycidyl ether, 2- [6- (3
-(N, N-dimethyl) propanamide) naphthyl] glycidyl ether, benzyl glycidyl ether, te
rt-butyl glycidyl ether, allyl glycidyl ether, tert-butyldimethylsilyl glycidyl ether, 2-tetrahydropyranyl glycidyl ether, 1,2-epoxy-3-phenoxybutane, 1,2
-Epoxy-3-phenoxy-3-methylbutane, phenylglycidylthioether, 2-naphthylglycidylthioether, 2- (dibenzylamino) methyloxirane, 2-([ethyl (phenyl) amino] methyl) oxirane, and the like. . Further, in the present invention, even if an optically active epoxy derivative is used as a starting material, the target compound can be produced without lowering the optical purity. Therefore, more preferably, for example, optically active phenyl glycidyl ether, benzyl glycidyl ether, tert-butyl glycidyl ether, tert-
Butyldimethylsilylglycidyl ether, phenylglycidylthioether and the like.

The strong base is not particularly restricted but includes, for example, alkyllithiums such as methyllithium, n-butyllithium, sec-butyllithium and tert-butyllithium, n-butylmagnesium chloride and n-butylmagnesium bromide. , Grignard reagents such as tert-butylmagnesium chloride and ethylmagnesium iodide, metal amides such as lithium amide, sodium amide and potassium amide, lithium diisopropylamide,
Lithium dialkylamides such as lithium dicyclohexylamide; lithium disilylamides such as lithium hexamethyldisilazide; sodium dialkylamides such as sodium diisopropylamide; potassium dialkylamides such as potassium diisopropylamide; or Grignard reagent and secondary Examples thereof include halomagnesium dialkylamides such as magnesium chloride diisopropylamide, magnesium bromide diisopropylamide, and magnesium chloride dicyclohexylamide prepared from amines. Preferably, for example, lithium dialkylamides such as lithium diisopropylamide and lithium dicyclohexylamide, lithium disilylamides such as lithium hexamethyldisilazide, or magnesium chloride diisopropylamide, magnesium bromide diisopropylamide, magnesium chloride dicyclohexylamide and the like And halomagnesium dialkylamides. More preferred are lithium dialkylamides such as lithium diisopropylamide and lithium dicyclohexylamide, among which lithium diisopropylamide is more preferred. These may be used alone or in combination of two or more. The amount of the strong base to be used is preferably 1 to 5 times, more preferably 1 to 2 times the molar amount of the epoxy derivative.

In the present reaction, the yield of the target compound can be remarkably improved by using an excess molar amount of 3-methylpyridine with respect to the strong base. Specifically, it is effective to use, for example, at least 1.5 times the molar amount of the strong base. The molar amount is preferably 1.5 to 20 times, more preferably 2 to 5 times.

This reaction can improve the yield of the target compound by coexisting amines. The amines are not particularly restricted but include, for example, ammonia or primary amines such as methylamine, cyclohexylamine and aniline, or secondary amines such as dimethylamine, piperidine, morpholine and diisopropylamine, or N-methyl. Morpholine, pyridine, N, N,
N ′, N′-tetramethylethylenediamine, triethylamine, N, N-dimethylaniline, 1,8-diazabicyclo- [5,4,0] -undec-7-ene (DB
U) and tertiary amines such as N, N-dimethylaminopyridine. Among them, particularly, N-methylmorpholine, pyridine, N, N, N ', N'-tetramethylethylenediamine, triethylamine, N, N-dimethylaniline, 1,8-diazabicyclo- [5,4,
Tertiary amines such as [0] -undec-7-ene (DBU) and N, N-dimethylaminopyridine are preferable for improving the yield. More preferably, it is pyridine or triethylamine. These may be used alone or in combination of two or more. The amount of the amine used is preferably at least equivalent to the strong base, preferably 1 to 20 times the molar amount of the strong base, more preferably 1 to 20 times.
About 5 times the molar amount.

The reaction solvent used in this reaction is not particularly restricted but includes, for example, ether solvents such as diethyl ether, 1,2-dimethoxyethane, tert-butyl methyl ether, tetrahydrofuran, 1,4-dioxane, hexane, Aliphatic hydrocarbon solvents such as pentane, aromatic hydrocarbon solvents such as benzene, toluene, and xylene; urea solvents such as N, N-dimethylpropyleneurea and N, N-dimethylethyleneurea; hexamethylphosphoric acid Phosphate amide solvents such as triamide can be exemplified. Preferably, for example, diethyl ether, 1,2
Ether solvents such as -dimethoxyethane, tert-butyl methyl ether, tetrahydrofuran, and 1,4-dioxane, and more preferably tetrahydrofuran. These may be used alone or in combination of two or more. The reaction temperature of this reaction is -20 ° C.
Or more, preferably -20 ° C to 80 ° C.
° C, more preferably -10 ° C to 40 ° C.

The order of addition of the reagents in this reaction is arbitrary. For example, 3-methylpyridine is added to a base solution, and the reaction is carried out for preferably 0.5 to 24 hours, more preferably 0.5 to 3 hours. , An epoxy derivative, preferably 0.5 to 24 hours, more preferably 0.5 to 24 hours.
The reaction can be performed by reacting for 3 hours.

As the post-treatment of this reaction, general post-treatment for obtaining a product from the reaction solution may be performed. For example, the reaction solution after the completion of the reaction is mixed with water, and an extraction operation is performed using a common extraction solvent, for example, ethyl acetate, diethyl ether, methylene chloride, toluene, hexane, tetrahydrofuran and the like. When the reaction solvent and the extraction solvent are distilled off from the obtained extract by an operation such as heating under reduced pressure, the desired product is obtained. The target product thus obtained may be purified by a general technique such as crystallization purification, fractional distillation, or column chromatography to further increase the purity.

[0033]

The present invention will be described in more detail with reference to the following examples.
As will be described, the present invention is limited to only these examples.
is not. Example 11-O-benzyl-4- (3-pyridyl)-
Production of 1,2-butanediol  Under an argon gas atmosphere, n-butyllithium (1.53
M hexane solution, 19.6 mL, 30 mmol)
Of isopropylamine (3.34 g, 33 mmol)
A solution of trihydrofuran (5 mL) was added dropwise at 5 ° C.
Minutes. Here, 3-methylpyridine (2.794)
g, 30 mmol) in tetrahydrofuran (5 mL)
The solution was added dropwise at 5 ° C. and stirred for 30 minutes. Next, benzil
Of ricidyl ether (3.284 g, 20 mmol)
Add a solution of trahydrofuran (5 mL) at 5 ° C for 2 hours
Reacted. 20 mL of water is added to the reaction solution, and the mixture is hydrolyzed.
Ethyl acid (30 mL) was added for extraction. Organic layer 20m water
After washing twice with L and evaporating the solvent under reduced pressure, a dark red
6.248 g of an oil was obtained. Silica gel column chromatography
Matography (Kieselge16 manufactured by Merck)
0, hexane / ethyl acetate = 1/2).
O-benzyl-4- (3-pyridyl) -1,2-butane
1.50 g of diol (yellow oil) (isolation yield 26
%).¹ H-NMR (400 MHz, CDCl
_Three ) Δ: 1.63-1.83 (m, 2H), 2.53-
2.92 (m, 2H), 3.38 (dd, 1H), 3.
49 (dd, 1H), 3.80 (m, 1H), 4.57
(S, 2H), 7.21 (m, 1H), 7.25-7.
40 (m, 5H), 7.53 (d, 1H), 8.43
(M, 1H), 8.47 (s, 1H)

Embodiment 2:1-O-benzyl-4- (3-
Production of (pyridyl) -1,2-butanediol  Under an argon gas atmosphere, n-butyllithium (1.53
M hexane solution, 19.6 mL, 30 mmol)
Of isopropylamine (3.34 g, 33 mmol)
A solution of trihydrofuran (5 mL) was added dropwise at 5 ° C.
Minutes. Here, 3-methylpyridine (4.191)
g, 45 mmol) in tetrahydrofuran (5 mL)
The solution was added dropwise at 5 ° C. and stirred for 30 minutes. Next, benzil
Of ricidyl ether (3.284 g, 20 mmol)
Add a solution of trahydrofuran (5 mL) at 5 ° C for 2 hours
Reacted. 20 mL of water is added to the reaction solution, and the mixture is hydrolyzed.
Ethyl acid (30 mL) was added for extraction. Organic layer 20m water
Washed twice with L and evaporated under reduced pressure to give a yellow oil
7.189 g of a solid were obtained. This oil is converted to a high-speed liquid
Chromatography (column: Cos by Nakarai Tesque)
Mosil 5CN-R (4.6 mm x 250 mm), elution
Liquid: acetonitrile / phosphate buffer (pH = 2.
4) = 1/100, flow rate: 0.5 mL / min. , Inspection
Source: UV 210nm, Column temperature: 40 ° C)
As a result, 1-O-benzyl-4- (3-pyridyl)-
The production yield of 1,2-butanediol was 73%.

Embodiment 31-O-benzyl-4- (3-
Production of (pyridyl) -1,2-butanediol  Under an argon gas atmosphere, n-butyllithium (1.53
M hexane solution, 19.6 mL, 30 mmol)
Of isopropylamine (3.34 g, 33 mmol)
A solution of trihydrofuran (5 mL) was added dropwise at 5 ° C.
Minutes. Here, 3-methylpyridine (5.588)
g, 60 mmol) in tetrahydrofuran (5 mL)
The solution was added dropwise at 5 ° C. and stirred for 30 minutes. Next, benzil
Of ricidyl ether (3.284 g, 20 mmol)
Add a solution of trahydrofuran (5 mL) at 5 ° C for 2 hours
Reacted. 20 mL of water is added to the reaction solution, and the mixture is hydrolyzed.
Ethyl acid (30 mL) was added for extraction. Organic layer 20m water
Washed twice with L and evaporated under reduced pressure to give a yellow oil
8.587 g of a product was obtained. This oil is converted to a high-speed liquid
Chromatography (column: Cos by Nakarai Tesque)
Mosil 5CN-R (4.6 mm x 250 mm), elution
Liquid: acetonitrile / phosphate buffer (pH = 2.
4) = 1/100, flow rate: 0.5 mL / min. , Inspection
Source: UV 210nm, Column temperature: 40 ° C)
As a result, 1-O-benzyl-4- (3-pyridyl)-
The production yield of 1,2-butanediol was 93%.

Embodiment 4:1-O-benzyl-4- (3-
Production of (pyridyl) -1,2-butanediol  Under an argon gas atmosphere, n-butyllithium (1.53
M hexane solution, 19.6 mL, 30 mmol)
Of isopropylamine (3.34 g, 33 mmol)
A solution of trihydrofuran (5 mL) was added dropwise at 5 ° C.
Minutes. Here, 3-methylpyridine (2.794)
g, 30 mmol) in tetrahydrofuran (5 mL)
The solution was added dropwise at 5 ° C. and stirred for 30 minutes. Next, pyridine
(2.370 g, 30 mmol) and further added at 5 ° C.
Stir for 30 minutes. Where benzyl glycidyl ether
(3.284 g, 20 mmol) of tetrahydrofuran
(5 mL) solution was added at 5 ° C. and reacted for 2 hours. reaction
20 mL of water was added to the solution to hydrolyze, and 30 mL of ethyl acetate was added.
And extracted. The organic layer was washed twice with 20 mL of water,
Evaporation of the solvent under reduced pressure gave a yellow oil, 8.100.
g were obtained. This oil is subjected to high performance liquid chromatography.
-(Column: Cosmosil 5CN-R manufactured by Nacalai Tesque, Inc.)
(4.6 mm x 250 mm), Eluent: acetonitrile
/ Phosphate buffer (pH = 2.4) = 1/100, flow
Speed: 0.5 mL / min. , Detection: UV 210 nm, power
Ram temperature: 40 ° C.).
Jil-4- (3-pyridyl) -1,2-butanediol
The production yield for the production of was 59%.

Embodiment 5:1-O-benzyl-4- (3-
Production of (pyridyl) -1,2-butanediol  Under an argon gas atmosphere, n-butyllithium (1.53
M hexane solution, 19.6 mL, 30 mmol)
Of isopropylamine (3.34 g, 33 mmol)
A solution of trihydrofuran (5 mL) was added dropwise at 5 ° C.
Minutes. Here, 3-methylpyridine (2.794)
g, 30 mmol) in tetrahydrofuran (5 mL)
The solution was added dropwise at 5 ° C. and stirred for 30 minutes. Next, N, N,
N, N-tetramethylethylenediamine (2.794)
g, 30 mmol) and further stirred at 5 ° C. for 30 minutes.
Was. Here, benzyl glycidyl ether (3.284)
g, 20 mmol) in tetrahydrofuran (5 mL)
The solution was added at 5 ° C. and reacted for 2 hours. Water 20
Add 30 mL of water and hydrolyze, add 30 mL of ethyl acetate and extract
did. The organic layer is washed twice with 20 mL of water, and the solvent is removed under reduced pressure.
After distillation, 7.512 g of a yellow oily substance was obtained.
This oil was subjected to high performance liquid chromatography (column:
Cosmosil 5CN-R (4.6 mm, manufactured by Nakarai Tesque)
Eluent: acetonitrile / phosphate buffer
Fur (pH = 2.4) = 1/100, flow rate: 0.5 m
L / min. , Detection: UV 210 nm, column temperature: 4
0 ° C.), 1-O-benzyl-4-.
(3-Pyridyl) -1,2-butanediol production yield
42%.

Embodiment 6:1-O-benzyl-4- (3-
Production of (pyridyl) -1,2-butanediol  Under an argon gas atmosphere, n-butyllithium (1.53
M hexane solution, 19.6 mL, 30 mmol)
Of isopropylamine (3.34 g, 33 mmol)
A solution of trihydrofuran (5 mL) was added dropwise at 5 ° C.
Minutes. Here, 3-methylpyridine (2.794)
g, 30 mmol) in tetrahydrofuran (5 mL)
The solution was added dropwise at 5 ° C. and stirred for 30 minutes. Then, triethyl
The amine (3.040 g, 30 mmol) was added and
The mixture was stirred at 5 ° C for 30 minutes. Where benzyl glycidyl
-Tetrahydro (3.284 g, 20 mmol)
A furan (5 mL) solution was added at 5 ° C. and reacted for 2 hours.
Was. The reaction solution was hydrolyzed by adding 20 mL of water, and ethyl acetate was added.
30 mL was added for extraction. The organic layer is washed twice with 20 mL of water
Wash and evaporate the solvent under reduced pressure to yield a yellow oil.
7.266 g were obtained. This oil is converted to high-performance liquid
Tography (column: Cosmosil manufactured by Nakarai Tesque)
5CN-R (4.6 mm x 250 mm), Eluent: Ase
Tonitrile / phosphate buffer (pH = 2.4) = 1 /
100, flow rate: 0.5 mL / min. , Detection: UV21
0 nm, column temperature: 40 ° C.).
—O-benzyl-4- (3-pyridyl) -1,2-buta
The production yield for the production of diol was 55%.

Example 7:1-O-benzyl-4- (3-
Production of (pyridyl) -1,2-butanediol  Under an argon gas atmosphere, n-butyllithium (1.53
M hexane solution, 19.6 mL, 30 mmol)
Of isopropylamine (3.34 g, 33 mmol)
A solution of trihydrofuran (5 mL) was added dropwise at 5 ° C.
Minutes. Here, 3-methylpyridine (2.794)
g, 30 mmol) in tetrahydrofuran (5 mL)
The solution was added dropwise at 5 ° C. and stirred for 30 minutes. Next, 1,8-di
Azabicyclo- [5,4,0] -undec-7-ene
(DBU) (4.56 g, 30 mmol) was added and further
At 5 ° C. for 30 minutes. Where benzyl glycidyl
Tetrahydr of ether (3.284 g, 20 mmol)
A solution of lofuran (5 mL) was added at 5 ° C. and reacted for 2 hours.
Was. The reaction solution was hydrolyzed by adding 20 mL of water, and ethyl acetate was added.
30 mL was added for extraction. The organic layer is washed twice with 20 mL of water
Wash and evaporate the solvent under reduced pressure to yield a yellow oil.
7.266 g were obtained. This oil is converted to high-performance liquid
Tography (column: Cosmosil manufactured by Nakarai Tesque)
5CN-R (4.6 mm x 250 mm), Eluent: Ase
Tonitrile / phosphate buffer (pH = 2.4) = 1 /
100, flow rate: 0.5 mL / min. , Detection: UV21
0 nm, column temperature: 40 ° C.).
—O-benzyl-4- (3-pyridyl) -1,2-buta
The production yield for the production of diol was 52%.

Embodiment 8:1-O-benzyl-4- (3-
Production of (pyridyl) -1,2-butanediol  Under an argon gas atmosphere, n-butyllithium (1.53
M hexane solution, 19.6 mL, 30 mmol)
Of isopropylamine (3.34 g, 33 mmol)
A solution of trihydrofuran (5 mL) was added dropwise at 5 ° C.
Minutes. Here, 3-methylpyridine (2.794)
g, 30 mmol) in tetrahydrofuran (5 mL)
The solution was added dropwise at 5 ° C. and stirred for 30 minutes. Next, N, N-di
Methylaniline (3.64 g, 30 mmol) was added,
The mixture was further stirred at 5 ° C. for 30 minutes. Here, benzylglyci
The tetrazyl ether (3.284 g, 20 mmol)
Add a solution of hydrofuran (5 mL) at 5 ° C and react for 2 hours
I let it. The reaction solution is hydrolyzed by adding 20 mL of water, and
30 mL of chill was added for extraction. Organic layer with 20 mL of water
After washing twice and evaporating the solvent under reduced pressure, a yellow oily substance is obtained.
7.266 g were obtained. This oily product is
Matography (Column: Cosmosi manufactured by Nakarai Tesque)
5CN-R (4.6 mm x 250 mm), eluent:
Setonitrile / phosphate buffer (pH = 2.4) = 1
/ 100, flow rate: 0.5 mL / min. , Detection: UV2
10 nm, column temperature: 40 ° C.)
1-O-benzyl-4- (3-pyridyl) -1,2-bu
The production yield of the production of tandiol was 42%.

Embodiment 9: (2R) -1-O-benzyl-
Production of 4- (3-pyridyl) -1,2-butanediol  Under an argon gas atmosphere, n-butyllithium (1.53
M hexane solution, 147 mL, 225 mmol)
Isopropylamine (25.04 g, 247.5 mmol
l) solution of tetrahydrofuran (30 mL) at 10 ° C
The mixture was added dropwise and stirred for 30 minutes. Where 3-methylpyridine
(41.85 g, 300 mmol) of tetrahydrofura
(30 mL) solution was added dropwise at 5 ° C., and the mixture was stirred for 30 minutes.
Next, (R) -benzyl glycidyl ether (25.1)
1 g, 150 mmol, 98.8% ee) tetrahydride
A solution of lofuran (30 mL) was added dropwise at 10 ° C. for 30 minutes.
The reaction was performed at 5 ° C. for 1.5 hours. 225 mL of water was added to the reaction solution.
And hydrated, and extracted with 225 mL of ethyl acetate.
Was. The organic layer is washed twice with 100 mL of water, and the solvent is removed under reduced pressure.
After distilling off, 74.00 g of a yellow oily substance was obtained.
This oil was purified by silica gel column chromatography (M
Eerck Kieselge160, hexane / acetic acid
(Til = 1/2) and purified by (2R) -1-O-benzyl
4- (3-pyridyl) -1,2-butanediol
35.15 g (purity: 91.1 wt%)
(Isolation yield 83%).

Embodiment 10:4- (3-pyridyl) -1,
Production of 2-butanediol  Under an argon gas atmosphere, n-butyllithium (1.57
M hexane solution, 31.8 mL, 50 mmol)
Isopropylamine (5.57 g, 55 mmol)
A solution of trihydrofuran (5 mL) was added dropwise at 5 ° C.
Minutes. Here, 3-methylpyridine (5.588)
g, 30 mmol) in tetrahydrofuran (5 mL)
The solution was added dropwise at 5 ° C. and stirred for 30 minutes. Next, N, N-di
Methylaniline (3.64 g, 30 mmol) was added,
The mixture was further stirred at 5 ° C. for 30 minutes. Here, glycidol
(1.480 g, 20 mmol) in tetrahydrofuran
(5 mL) solution was added at 5 ° C. and reacted for 2 hours. reaction
30 mL of water is added to the liquid to hydrolyze it, and concentrated under reduced pressure.
Was extracted twice with ethyl acetate (200 mL), and the organic layers were combined.
It was then dried over anhydrous magnesium sulfate. Filtered
After that, the solvent was distilled off under reduced pressure.
Column chromatography (Kiesel manufactured by Merck)
ge160, MeOH / ethyl acetate = 1/9)
And 4- (3-pyridyl) -1,2-butanediol
(Yellow oil) 2.505 g (75% isolation yield) obtained
Was.

¹ H-NMR (400 MHz, CDCl
₃ ) δ: 1.65-1.88 (m, 2H), 2.63-
2.78 (m, 2H), 2.79-2.95 (m, 2
H), 3.50 (dd, 1H), 3.62-3.73
(M, 2H), 7.22 (dd, 1H), 7.54
(D, 1H), 8.38-8.50 (m, 2H)

Embodiment 11:1-O-tert-butyl-
Production of 4- (3-pyridyl) -1,2-butanediol  Under an argon gas atmosphere, n-butyllithium (1.53
M hexane solution, 19.6 mL, 30 mmol)
Of isopropylamine (3.34 g, 33 mmol)
A solution of trihydrofuran (5 mL) was added dropwise at 5 ° C.
Minutes. Here, 3-methylpyridine (5.588)
g, 60 mmol) in tetrahydrofuran (5 mL)
The solution was added dropwise at 5 ° C. and stirred for 30 minutes. Next, tert-
Butyl glycidyl ether (2.60 g, 20 mmo
l) in tetrahydrofuran (5 mL) at 5 ° C.
And reacted for 2 hours. Add 20 mL of water to the reaction solution
The mixture was hydrolyzed and extracted with 30 mL of ethyl acetate. Organic layer
Is washed twice with 20 mL of water, and the solvent is distilled off under reduced pressure
9.375 g of a dark red oil was obtained. Silage
Column chromatography (Kiese manufactured by Merck)
lge160, hexane / ethyl acetate = 1/2)
1-O-tert-butyl-4- (3-pyridi
) -1,2-butanediol (yellow oil) in 3.4
73 g (78% isolated yield) were obtained.

¹ H-NMR (400 MHz, CDCl
₃ ) δ: 1.19 (s, 9H), 1.69-1.81
(M, 2H), 2.58 (bs, 1H), 2.67-
2.75 (m, 1H), 2.81-2.88 (m, 1H)
H), 3.20 (dd, 1H), 3.37 (dd, 1
H), 3.67-3.71 (bs, 1H), 7.20-
7.27 (m, 1H), 7.52-7.55 (m, 1H)
H), 8.43-8.48 (m, 2H)

Embodiment 12:1-O- (tert-butyl
Dimethylsilyl) -4- (3-pyridyl) -1,2-bu
Manufacture of tandiol  Under an argon gas atmosphere, n-butyllithium (1.53
M hexane solution, 14.71 mL, 22.5 mmol)
In addition, diisopropylamine (2.51 g, 24.75 m
mol) in tetrahydrofuran (5 mL) at 5 ° C.
The mixture was added dropwise and stirred for 30 minutes. Where 3-methylpyridine
(4.19 g, 45 mmol) of tetrahydrofuran
(5 mL) The solution was added dropwise at 5 ° C. and stirred for 30 minutes. Next
Tert-butyldimethylsilyl glycidyl ether
(2.82 g, 15 mmol) in tetrahydrofuran
(5 mL) solution was added at 5 ° C. and reacted for 2 hours. reaction
20 mL of water was added to the solution to hydrolyze, and 30 mL of ethyl acetate was added.
And extracted. The organic layer was washed twice with 20 mL of water,
The solvent was distilled off under reduced pressure to give a dark red oil at 6.16.
4 g were obtained. Silica gel column chromatography
(Kieselge160 manufactured by Merck, hexane / vinegar
(Ethyl acetate = 1/2) and purified by 1-O- (tert-
Butyldimethylsilyl) -4- (3-pyridyl) -1,
2.39 g of 2-butanediol (yellow oil) (isolated)
(Yield 66%).

¹ H-NMR (400 MHz, CDCl
₃ ) δ: 0.07 (s, 6H), 0.90 (s, 9)
H), 1.65-1.98 (m, 2H), 2.63-
2.74 (m, 3H), 3.36-3.57 (m, 3
H), 7.19-7.22 (m, 1H), 7.50-
7.55 (m, 1H), 8.43-8.44 (m, 2
H)

Embodiment 13:1-O-phenyl-4- (3
-Pyridyl) -1,2-butanediol  Under an argon gas atmosphere, n-butyllithium (1.53
M hexane solution, 9.8 mL, 15 mmol)
Of isopropylamine (1.67 g, 16.5 mmol)
A tetrahydrofuran (5 mL) solution is added dropwise at 5 ° C.
Stirred for 0 minutes. Here, 3-methylpyridine (2.79
4 g, 30 mmol) of tetrahydrofuran (5 mL)
The solution was added dropwise at 5 ° C. and stirred for 30 minutes. Next, phenyl
Of glycidyl ether (1.50 g, 10 mmol)
Add a solution of trahydrofuran (5 mL) at 5 ° C for 2 hours
Reacted. 20 mL of water is added to the reaction solution, and the mixture is hydrolyzed.
Ethyl acid (30 mL) was added for extraction. Organic layer 20m water
After washing twice with L and evaporating the solvent under reduced pressure, a dark red
An oil was obtained. Silica gel column chromatography
-(Kieselge 160 manufactured by Merck, hexane /
(Ethyl acetate = 1/2) and purified by 1-O-phenyl-
4- (3-pyridyl) -1,2-butanediol (yellow
Oily product) was obtained in 1.911 g (79% isolated yield).

¹ H-NMR (400 MHz, CDCl
₃ ) δ: 1.83-1.96 (m, 2H), 2.74-
2.82 (m, 1H), 2.87-2.95 (m, 1
H) 3.86-3.90 (m, 1H), 3.95-
4.03 (m, 2H), 6.88-6.98 (m, 3
H), 7.21-7.30 (m, 3H), 7.56
(D, 1H), 8.44-8.50 (m, 2H)

Embodiment 14:1- (phenylsulfani
Preparation of 4-)-4-pyridin-3-ylbutan-2-ol
Construction  Under an argon gas atmosphere, n-butyllithium (1.53
M hexane solution, 4.9 mL, 7.5 mmol)
Isopropylamine (0.835 g, 8.25 mmol
l) Tetrahydrofuran (5 mL) solution is added dropwise at 5 ° C
And stirred for 30 minutes. Where 3-methylpyridine
(1.40 g, 15 mmol) of tetrahydrofuran
(5 mL) The solution was added dropwise at 5 ° C. and stirred for 30 minutes. Next
Phenylglycidyl thioether (0.83 g, 5
mmol) in 5 mL of tetrahydrofuran (5 mL).
And reacted for 2 hours. 10 mL of water was added to the reaction solution.
And extracted with 20 mL of ethyl acetate. Yes
The organic layer is washed twice with 10 mL of water, and the solvent is distilled off under reduced pressure.
This gave a dark red oil. Silica gel column
Chromatography (Kieselge16 manufactured by Merck)
0, hexane / ethyl acetate = 1/2).
(Phenylsulfanyl) -4-pyridin-3-ylbu
0.521 g of tan-2-ol (yellow oil) (isolated)
(Yield 41%).

¹ H-NMR (400 MHz, CDCl
₃ ) δ: 1.81-1.86 (m, 2H), 2.65-
2.72 (m, 1H), 2.79-2.93 (m, 3
H), 3.13 (dd, 1H), 3.65-3.71
(M, 1H), 7.18-7.38 (m, 6H), 7.
49 (d, 1H), 8.41-8.43 (m, 2H)

Embodiment 15:1-pyridin-3-yl pen
Production of tan-3-ol  Under an argon gas atmosphere, n-butyllithium (1.57
M hexane solution, 18.2 mL, 30 mmol)
Of isopropylamine (3.34 g, 33 mmol)
A solution of trihydrofuran (5 mL) was added dropwise at 5 ° C.
Minutes. Here, 3-methylpyridine (5.588)
g, 60 mmol) in tetrahydrofuran (5 mL)
The solution was added dropwise at 5 ° C. and stirred for 30 minutes. Next, 1,2-d
Tetra of poxybutane (1.420 g, 20 mmol)
Add a solution of hydrofuran (5 mL) at 5 ° C and react for 2 hours
I let it. 30 mL of water is added to the reaction solution to hydrolyze,
30 mL of chill was added for extraction. Organic layer with 30 mL of water
After washing twice and evaporating the solvent under reduced pressure, a yellow oily substance is obtained.
5.538 g were obtained. Silica gel column chromatography
Raffy (Kieselge160 from Merck, Heki
Purified with 1 / pyridine).
-3-ylpentan-3-ol (a pale yellow oil)
1.840 g (53% isolated yield) were obtained.

¹ H-NMR (400 MHz, CDCl
₃ ) δ: 0.95 (t, 3H), 1.42-1.58
(M, 2H), 1.68-1.86 (m, 2H), 2.
19-2.30 (bs, 1H), 2.62-2.73
(M, 1H), 2.77-2.90 (m, 1H), 3.
52-3.59 (m, 1H), 7.18-7.26
(M, 1H), 7.52 (d, 1H), 8.39-8.
50 (m, 2H)

Embodiment 16:1- [ethyl (phenyl) a
Mino] -4-pyridin-3-ylbutan-2-ol
Manufacture  Under an argon gas atmosphere, n-butyllithium (1.53
M hexane solution, 9.8 mL, 15 mmol)
Of isopropylamine (1.67 g, 16.5 mmol)
A tetrahydrofuran (5 mL) solution is added dropwise at 5 ° C.
Stirred for 0 minutes. Here, 3-methylpyridine (2.79
4 g, 30 mmol) of tetrahydrofuran (5 mL)
The solution was added dropwise at 5 ° C. and stirred for 30 minutes. Next, 2-
([Ethyl (phenyl) amino] methyl) oxirane
(1.77 g, 10 mmol) of tetrahydrofuran
(5 mL) solution was added at 5 ° C. and reacted for 2 hours. reaction
The solution was hydrolyzed by adding 20 mL of water, and 20 mL of ethyl acetate was added.
And extracted. The organic layer was washed twice with 20 mL of water,
Evaporation of the solvent under reduced pressure gave a yellow oil.
Silica gel column chromatography (Merck K
ieselge 160, hexane / ethyl acetate = 1 /
Purified in 1), 1- [ethyl (phenyl) amino]-
4-pyridin-3-ylbutan-2-ol (yellow oil
Was obtained in 2.322 g (86% isolated yield).

¹ H-NMR (400 MHz, CDCl
₃ ) δ: 1.12 (t, 3H), 1.77-1.83
(M, 2H), 2.70-2.77 (m, 1H), 2.
88-2.95 (m, 1H), 3.13-3.19
(M, 1H), 3.29-3.48 (m, 3H), 3.
88-3.93 (m, 1H), 6.73-6.79
(M, 3H), 7.20-7.26 (m, 3H), 7.
54 (d, 1H), 8.43-8.49 (m, 2H)

[0056]

According to the present invention, there is provided the above structure,
A 3- (3-pyridyl) -1-propanol derivative useful as a pharmaceutical intermediate, particularly as a tryptase inhibitor intermediate, can be produced from inexpensive and readily available raw materials.

 ──────────────────────────────────────────────────の Continued on the front page F term (reference) 4C048 AA01 BB09 BC01 CC01 4C055 AA01 BA01 CA02 CA16 CA21 CB01 CB02 CB04 DA01 FA11 FA32 FA37

Claims (15)

[Claims] 1. A compound represented by the following general formula (1) which is prepared by allowing a strong base to act on 3-methylpyridine: (Wherein M represents lithium, sodium, potassium, or magnesium halide, and halide represents chloride or bromide) and a 3-methylpyridine metal salt represented by the following general formula (2): (In the formula, R ¹ has 1 to 20 carbon atoms which may be substituted.
An alkyl group, an optionally substituted aryl group having 6 to 20 carbon atoms, or an optionally substituted 7 to 2 carbon atoms
By reacting an epoxy compound represented by the following general formula (3): (Wherein R ¹ is the same as described above), which is a process for producing a 3- (3-pyridyl) -1-propanol derivative represented by the formula: The manufacturing method characterized by the above-mentioned. 2. The method according to claim 1, wherein the strong base is lithium dialkylamide, lithium disilylamide, or halomagnesium dialkylamide. 3. The method according to claim 1, wherein the strong base is lithium dialkylamide. 4. The method according to claim 1, wherein the strong base is lithium diisopropylamide. 5. A method according to claim 1, wherein 3-methylpyridine is added to a strong base in an amount of 1: 1.
5. The production method according to claim 1, wherein the molar amount is 5 times or more. 6. The reaction according to claim 1, wherein the reaction is carried out in the presence of an amine.
The production method according to 2, 3, 4 or 5. 7. The method according to claim 6, wherein the amine is a tertiary amine. 8. The method according to claim 7, wherein the tertiary amine is pyridine or triethylamine. 9. The process according to claim 6, wherein the amine is used in an equivalent amount or more based on the strong base. 10. The process according to claim 1, wherein the reaction temperature is -20 ° C. or higher. 11. An epoxy derivative represented by the general formula (2), wherein R ¹ is represented by the following general formula (4): (Wherein, R ² and R ³ independently represent hydrogen, C 1-18
Represents an alkyl group having 6 to 18 carbon atoms, an aryl group having 6 to 18 carbon atoms, or an aralkyl group having 7 to 18 carbon atoms, or together represents a cycloalkyl group having 3 to 18 carbon atoms. R ⁴
Is hydrogen, an alkyl group having 1 to 18 carbon atoms which may be substituted, an aryl group having 6 to 18 carbon atoms which may be substituted, an aralkyl group having 7 to 18 carbon atoms which may be substituted, or Represents an optionally substituted silyl group having 3 to 18 carbon atoms. X represents an oxygen atom or a sulfur atom. )
Claims 1, 2, 3, 4, 5, 6, 7, 8, 9 represented by
Or the production method according to 10. 12. The method according to claim 11, wherein in the general formula (4), R ² and R ³ are hydrogen. 13. The method according to claim 11, wherein in the general formula (4), X is an oxygen atom. 14. In the general formula (4), R ⁴ is a phenyl group, a benzyl group, a tert-butyl group, or a tert-butyl group.
11. A butyldimethylsilyl group.
3. The production method according to 3. 15. The epoxy derivative represented by the general formula (2) is optically active.
The production method according to 8, 9, 10, 11, 12, 13 or 14.