JPH07247246A - 1-phenyl-3-butyne derivative and its production - Google Patents

Abstract

PURPOSE:To produce 2-methanesulfonyloxy-1-phenyl-3-butyne useful as an inter mediate for synthesis of an HIV protease inhibitor, a resin inhibitor, etc. CONSTITUTION:Methaneouslfonyl chloride is reacted with 2-hydroxy-1-phenyl-3- butyne in the presence of a base to synthesize 2-methanesulfonyloxy-1-phenyl-3- butyne and an ammonia source (e.g. ammonia water) is then reacted therewith to obtain 2-amino-1-phenyl-3-butyne. Further, racemic 2-amino-1-phenyl-3-butyne is converted to an acid adduct between it and an economic optically active acid to obtain (S)-2-amino-1-phenyl-3-butyne. The obtained compound is hydrogenated in the presence of Lindlar catalyst, thus producing (S)-2-amino-1-phenyl-3- butene useful as an intermediate for synthesis of medicines such as an HIV protease inhibitor.

Description

Detailed Description of the Invention

[0001]

The present invention is useful as a pharmaceutical intermediate for HIV protease inhibitors, renin inhibitors, etc. (S)
(S) -2-Amino-, which can also be used as a precursor of 2-amino-1-phenyl-3-butene and its derivatives
The present invention relates to 1-phenyl-3-butyne and its derivatives, and an industrially advantageous production method thereof.

[0002]

2. Description of the Related Art (S) -2-Amino-1-phenyl-3
-Butene and its derivatives, and examples of use thereof for HIV protease inhibitors are described in, for example, JP-A-4-
257520, JP-A-5-294916,
Examples of the use as a renin inhibitor include, for example, JP-A-61-1
33152, USP 5,114,937 (199
No. 2) is known.

(S) -2-Amino-1-phenyl-3-
The following methods are known as methods for obtaining butene and its derivatives. For example, (S) -tert-
By reacting butoxycarbonylphenylalaninal with methylidenetriphenylphosphorane obtained from a base such as methyltriphenylphosphonium bromide and butyllithium, (S) -2-tert-butoxycarbonylamino-1-phenyl-3 -It is known to obtain butenes (see, for example, JP-A-63-1315).
No. 2, gazette, J. Org. Chem. , 1987, 52,
1487, JP-A-2-191243, etc.
Prior art 1).

Further, it is derived from (S) -tert-butoxycarbonylphenylalaninal (3RS, 2).
S) -2-tert-Butoxycarbonylamino-3-
It is known to obtain (S) -2-amino-1-phenyl-3-butene by reacting hydroxy-1-phenyl-4-trimethylsilylbutane with boron trifluoride etherate (for example, Japanese Patent Laid-Open No. 4-257
520, J. Med. Chem. , 1992, 3
5, 1685, etc., hereinafter referred to as Prior Art 2).

In the presence of tributylphosphine,
Hydrogen peroxide solution was added to (S) -3-tert-butoxycarbonylamino-4-phenylbutyl o-nitrophenyl selenide obtained from (S) -tert-butoxycarbonylphenylalaninol and o-nitrophenyl selenocyanate. By acting, (S)-
It is known to obtain 2-tert-butoxycarbonylamino-1-phenyl-3-butene (Heter
Cycles, 1989, 29, 1835, hereinafter referred to as Prior Art 3).

(S) -2-Amino-1-phenyl-3-
The following methods are known as methods for obtaining butyne and its derivatives. For example, (S) -tert-butoxycarbonylphenylalaninal, dimethyl
By reacting diazophosphonate, (S)-
It is known to obtain 2-tert-butoxycarbonylamino-1-phenyl-3-butyne (Tetra
hedron. Lett. , 1992, 33, 371
5, hereinafter referred to as prior art 4).

Further, (2S) -2-methoxymethyl-N
-(3-Trimethylsilyl-2-propynyl) -1-pyrrolidine Methanimine was used with butyllithium as a base and reacted with benzyl bromide, followed by hydrazine treatment,
Subsequent detrimethylsilylation produces (S) -2
It is known to obtain -amino-1-phenyl-3-butyne (Liebigs Ann. Chem., 19
83, 1668, hereinafter referred to as Prior Art 5).

Racemic 2-amino-1-phenyl-3
The following methods are known as methods for obtaining -butene or racemic 2-amino-1-phenyl-3-butyne and derivatives thereof. 4-phenyl-2
2-Trichloroacetylamino-by heating trichloroacetimidate obtained from -buten-1-ol and trichloroacetonitrile in xylene.
It is known to obtain 1-phenyl-3-butene (Japanese Patent Laid-Open No. 61-22055 and J. Chem. So.
c. Chem. Commun. , 1984, 770, hereinafter referred to as Prior Art 6).

Further, 2-amino-1-phenyl-3-butyne is obtained by reacting 2-p-toluenesulfonyloxy-1-phenyl-3-butyne with sodium (producing sodium amide) in liquid ammonia. (J. Med. Chem., 196).
6, 9, 469, hereinafter referred to as prior art 7).

Further, 2-benzylamino-1-phenyl-3-butyne obtained by reacting 2-p-toluenesulfonyloxy-1-phenyl-3-butyne with benzylamine is hydrogenated in the presence of a Lindlar catalyst. 2-benzylamino-1-phenyl-
It is known to obtain 3-butene (J. Chem.
Soc. Perkin Trans. 1,1983,3
87, hereinafter referred to as prior art 8).

[0011]

In the prior arts 1, 2 and 4, (S) -tert-butoxycarbonylphenylalaninal, which is prone to racemization, is used as a starting material, and a special reactant is allowed to act at a low temperature ( S) -2-Amino-1-phenyl-3-butene, (S) -2-amino-
Since 1-phenyl-3-butyne and derivatives thereof have been obtained, it is difficult to industrially produce these compounds.

Further, the prior art 3 has problems such as a bad odor and toxicity of the reaction agent, a problem of treatment with a hydrocyanic acid adduct of phosphine oxide, selenate acid, and diselenide, which are produced in association with the reaction, and is industrially applicable. There are difficulties in producing these compounds. Further, in the prior art 5, (2S) -2-methoxymethyl-N- (3-trimethylsilyl-2-propynyl) -1-pyrrolidinemethanimine, which requires multiple steps for synthesis, is used as a starting material, and benzyl bromide acts at low temperature. To obtain (S) -2-amino-1-phenyl-3-butyne, and further to obtain (S) -2-amino-1
-Phenyl-3-butyne has low optical purity (15% e
Because of e), it is difficult to industrially produce this compound by this method.

In order to obtain (S) -2-amino-1-phenyl-3-butene, (S) -2-amino-1-phenyl-3-butyne and their derivatives, their (R) -(S) -2-amino-1-phenyl-3-butene from the mixture with the body by some optical resolution operation,
Means for obtaining (S) -2-amino-1-phenyl-3-butyne and their derivatives are conceivable. As one of the optical resolution operations, (S) -2-amino-1-phenyl-
A method using an optically active acid addition salt of 3-butene or (S) -2-amino-1-phenyl-3-butyne can be considered. However, 2-amino-1-phenyl-
Up to now, no method has been known for producing a mixture of 3-butene or 2-amino-1-phenyl-3-butyne (S) -form and (R) -form inexpensively and efficiently in an industrial sense. . Therefore, a method for obtaining a (S) -form from a mixture of these (S) -form and (R) -form by some optical resolution operation is not known.

Further, in the prior art 6, the starting material is 4-phenyl-
It has a drawback that 2-buten-1-ol is difficult to obtain. Furthermore, 2-p-toluenesulfonyloxy-1-phenyl- which is a starting material of the prior arts 7 and 8
Although 3-butyne can be derived from 2-hydroxy-1-phenyl-3-butyne, it has a disadvantage of low yield (19%). In the method of obtaining 2-amino-1-phenyl-3-butyne by reacting sodium (sodium amide is generated) in liquid ammonia in Prior Art 7, in addition to using liquid ammonia,
There are difficulties in the reaction equipment and reaction operation due to the use of sodium, which is water-prohibiting and flammable. 2-Benzylamino-1-phenyl-3-butyne obtained by reacting benzylamine in Prior Art 8 is treated with hydrogen in the presence of a Lindlar catalyst to give 2-benzylamino-1-phenyl-3-butyne. The method for obtaining butene has a drawback that there are few means for debenzylation to obtain a derivative other than a benzylamino derivative,
It is difficult to obtain 2-amino-1-phenyl-3-butyne.

[0015]

Means for Solving the Problems As a result of earnest studies, the present inventors have found that a racemic 2-amino-1-phenyl-3-butyne can be produced inexpensively and efficiently in an industrial sense, a racemic form. The present inventors have found a method for producing (S) -2-amino-1-phenyl-3-butyne by converting 2-amino-1-phenyl-3-butyne of 1. into an inexpensive acid addition salt of an optically active acid. Further, (S) -2-amino-1 obtained by this
-Phenyl-3-butyne and its derivatives are hydrogenated in the presence of a Lindlar catalyst to give (S) -2-amino-1-phenyl-3-butene useful as a pharmaceutical intermediate such as an HIV protease inhibitor and its derivative. Derivatives can be prepared.

That is, the present invention relates to a novel compound, 2-methanesulfonyloxy-1-phenyl-3-butyne. The present invention also relates to 2-methanesulfonyloxy-1-
It relates to a method for producing 2-amino-1-phenyl-3-butyne, which comprises reacting phenyl-3-butyne with an ammonia source. It also relates to a method for producing 2-amino-1-phenyl-3-butyne using aqueous ammonia as the ammonia source. The present invention also relates to 2-amino-
The present invention relates to a purification method using 1-phenyl-3-butyne as an acid addition salt. The present invention also relates to an optically active acid addition salt of (S) -2-amino-1-phenyl-3-butyne. The present invention also includes both optical antipodes.
-Amino-1-phenyl-3-butyne is reacted with an optically active acid to form an addition salt, and the addition salt is crystallized (S) -2-amino-1-phenyl-3-butyne To a method for producing an optically active acid addition salt of. Further, the present invention is characterized in that (S) -2-amino-1-phenyl-3-butyne is hydrolyzed with an optically active acid addition salt of (S) -2-amino-1-phenyl-3-. The present invention relates to a method for producing butyne. The present invention also provides (R) -2-amino-1
-Phenyl-3-butyne with optically active acid addition salts. The present invention also includes 2-containing both antipodes.
(R) -2-Amino-1-phenyl-3-butyne, characterized in that amino-1-phenyl-3-butyne is reacted with an optically active acid to form an addition salt, and the addition salt is crystallized. The present invention relates to a method for producing an optically active acid addition salt. Further, the present invention is a salt obtained by reacting 2-amino-1-phenyl-3-butyne containing both optical antipodes with D-tartaric acid,
It relates to a method for producing (R) -2-amino-1-phenyl-3-butyne.D-tartrate, which is characterized by crystallizing this salt. Further, the present invention is characterized by hydrolyzing an optically active acid addition salt of (R) -2-amino-1-phenyl-3-butyne (R) -2-amino-1-phenyl-3-. The present invention relates to a method for producing butyne. Further, the present invention is
(R) -2-Amino-1-phenyl-3-butyne / D-
Characterized by hydrolyzing a tartrate salt (R) -2-
It relates to a method for producing amino-1-phenyl-3-butyne.

The present invention will be described in detail below in the order of the steps of the following reaction process scheme.

[0018]

[Chemical 1]

(Step 1) 2-hydroxy-1 as a starting material
2-phenyl-3-butyne was quantitatively treated with methanesulfonyl chloride in the presence of a base in a solvent inert to this reaction (or without solvent) to give 2-methanesulfonyloxy-1-phenyl-. 3-butyne can be synthesized. The 2-methanesulfonyloxy-1-phenyl-3-butyne thus obtained is subjected to the reaction shown in Step 2 described below to give a reaction device of Prior Art 7,
The difficulty in the reaction operation can be solved, the reaction can be performed by a simple operation, and 2-amino-1-phenyl-3-butyne can be obtained in a higher yield than that of the conventional technique 7.
As the base, a base used for methanesulfonylation of usual alcohols (for example, triethylamine,
Organic bases such as pyridine) can be used. The amount of base used is 1 to 50 molar equivalents relative to 2-hydroxy-1-phenyl-3-butyne, and the amount of methanesulfonyl chloride used is 2-hydroxy-1-phenyl-3-butyne.
1 to 1.5 molar equivalents relative to butyne are suitable. The reaction is carried out in the temperature range of 0 to 50 ° C, preferably 0 to 20 ° C. As the solvent that can be used, ethers (for example,
Diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, dioxane, dimethoxyethane etc.), nitriles (eg acetonitrile etc.), esters (eg methyl acetate, ethyl acetate etc.), hydrocarbons (eg hexane, heptane, etc.) Benzene, toluene, xylene, etc., halogenated hydrocarbons (eg methylene chloride, chloroform, 1,2-
Dichloroethane, chlorobenzene etc.), ketones (eg acetone, methyl ethyl ketone etc.), nitromethane, pyridine, dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide etc. and can be used alone or as a mixture thereof. .

(Step 2) 2-methanesulfonyloxy-
The conversion of 1-phenyl-3-butyne to 2-amino-1-phenyl-3-butyne can be performed by reacting with an ammonia source (for example, aqueous ammonia, liquid ammonia). When aqueous ammonia is used, aqueous ammonia alone or alcohols (eg, methanol, ethanol, propanol, isopropanol, butanol, tert-butyl alcohol, etc.), ethers (eg, diethyl ether, diisopropyl ether, dibutyl ether, Tetrahydrofuran, dioxane, dimethoxyethane, etc.), nitriles (eg,
Acetonitrile etc.), hydrocarbons (eg hexane, heptane, benzene, toluene, xylene etc.),
It can be used as a mixture with halogenated hydrocarbons (for example, methylene chloride, chloroform, 1,2-dichloroethane, chlorobenzene, etc.), nitromethane, pyridine, dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, etc. However, the cosolvent is preferably an alcohol, and more preferably isopropanol. The concentration of ammonia in the ammonia water may be 25 to 28% which is usually commercially available. The amount of ammonia water used is 1 to 10 relative to 2-methanesulfonyloxy-1-phenyl-3-butyne.
It can be set to 0 molar equivalent. The amount of the cosolvent that can be used is appropriately 0 to 3 times the volume of aqueous ammonia. Reaction is 0
It is carried out in a temperature range of -100 ° C, preferably 20-80 ° C. The produced 2-amino-1-phenyl-3-butyne, when using a cosolvent that dissolves in water in a large amount, removes the cosolvent to such an extent that it does not hinder the extraction operation, and then ethers, esters, hydrocarbons , Can be extracted with halogenated hydrocarbons. When liquid ammonia is used, it can be usually performed without using a solvent.
The amount of liquid ammonia used is 1 to 10,000 with respect to 2-methanesulfonyloxy-1-phenyl-3-butyne.
It can be set to 0 molar equivalent, preferably 1 to 100 molar equivalent. The reaction can be carried out within the range of -75 ° C to the boiling point of the solvent or liquid ammonia under the reaction pressure (about 100 ° C). The produced 2-amino-1-phenyl-3-butyne should be extracted with ethers, esters, hydrocarbons and halogenated hydrocarbons after removing liquid ammonia etc. to the extent that it does not hinder the extraction operation. You can After concentrating the solvent, it is also possible to obtain 2-amino-1-phenyl-3-butyne by a distillation operation, but inorganic acids, carboxylic acids,
Sulfonic acids were added in an amount of 0.5 to 2 mol times the theoretical amount of 2-amino-1-phenyl-3-butyne to give 2-amino-
Purification by obtaining an acid addition salt of 1-phenyl-3-butyne is also possible. That is, 2-hydroxy-1-phenyl-3-butyne produced along with this reaction,
1-phenylbut-1-en-3-yne (PhCH = C
It is possible to remove neutral substances such as HC3CH).

More specifically, the acid addition salts derived from the inorganic acid of 2-amino-1-phenyl-3-butyne include, for example, hydrochloride, hydrobromide, hydroiodide,
Examples thereof include sulfates, hydrogen sulfates, phosphates, monohydrogen phosphates, dihydrogen phosphates, nitrates and thiocyanates. Examples of the acid addition salt derived from carboxylic acid of 2-amino-1-phenyl-3-butyne include, for example, formate salt, acetate salt, propionate salt, butyrate salt, isobutyrate salt,
Cinnamate, benzoate, p-methylbenzoate, p-
Methoxybenzoate, p-nitrobenzoate, phenylacetate, oxalate, malonate, succinate, glutarate, adipate, maleate, fumarate, phthalate, terephthalic acid Examples include salt. further,
Examples of acid addition salts derived from sulfonic acid of 2-amino-1-phenyl-3-butyne include, for example, methanesulfonate, ethanesulfonate, benzenesulfonate,
Examples thereof include p-toluene sulfonate, p-chlorobenzene sulfonate, p-bromobenzene sulfonate, 2-naphthalene sulfonate and the like. Of the above, from the viewpoint of reaction operability and price, hydrochloride, formate, acetate,
Benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate and p-toluenesulfonate are preferable. Of these, hydrochloride is preferable.

The acid addition salt of 2-amino-1-phenyl-3-butyne is an inorganic base usually used (for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, etc.) or the above-mentioned salts. 2-amino-1-phenyl-3-butyne can be restored by treatment with an aqueous solution of an inorganic base or an organic base (eg, triethylamine, diisopropylethylamine), that is, by neutralizing the acid added thereto. it can.

(Step 3) Purified 2-amino-1-phenyl-3-butyne or crude 2-amino-1-phenyl-3-butyne is a mixture containing both optical antipodes, From the mixture and the optically active acid, an acid addition salt of the optically active 2-amino-1-phenyl-3-butyne and the optically active acid can be obtained. The optically active acid used for obtaining the addition salt of the optically active acid is not particularly limited, but an optically active carboxylic acid or an optically active sulfonic acid is used. By obtaining these acid addition salts, 2-hydroxy-1-phenyl-3-butyne, 1-, which is produced in association with the reaction shown in step 2
Phenylbut-1-en-3-yne (PhCH = CHC
The effect of removing neutral substances such as (3CH) is also obtained at the same time.

Specific examples of the optically active carboxylic acid include lactic acid, tartaric acid, malic acid, mandelic acid, amino acids (for example, alanine, valine, aspartic acid, glutamic acid, etc.) and derivatives thereof. Specific examples of the optically active sulfonic acid include camphor sulfonic acid. From the viewpoint of good crystallinity, purification effect and price, (S) -2-amino-1-phenyl-3
-As an optically active acid for obtaining the acid addition salt of butyne,
L-tartaric acid is preferred. Further, mandelic acid is preferable from the viewpoint of the recovery rate of the optically active acid after neutralization of the acid in step 4 described later.

On the other hand, 2-amino-1-phenyl-3-butyne containing both the (S) -form and the (R) -form is treated with the above-mentioned optically active acid such as D-tartaric acid to add an acid. By forming a salt, (R) -2-amino-1-phenyl-
It can be an optically active acid addition salt of 3-butyne.
This product has (R) -2-
It can be converted to amino-1-phenyl-3-butene and its derivatives. The resulting (R) -2-amino-
Among 1-phenyl-3-butene and its derivatives, for example, (R) -2-benzyloxycarbonylamino-1
-Phenyl-3-butene is a useful intermediate of bestatin (trade name) known as an anticancer antibiotic (see, for example, JP-A-60-199884, Tetrah).
edron, Lett. , 1984, 25, 507
9).

The acid is usually 2-amino-1-phenyl-
0.2 to 10 mol times 3-butyne, preferably 0.3
-5 mol times, more preferably 0.4-2 mol times. The solvent used is 2-amino-1-phenyl-3.
-No reaction with butyne, 2-amino-1-phenyl-3-
The optically active acid addition salt of butyne may be a solvent that precipitates from the mixture, and is not particularly limited, and examples thereof include water and
Alcohols (eg, methanol, ethanol, propanol, isopropanol, butanol, tert-
Butyl alcohol), ethers (eg, diethyl ether, diisopropyl ether, dibutyl ether,
Tetrahydrofuran, dioxane, dimethoxyethane etc.), nitriles (eg acetonitrile etc.), esters (eg methyl acetate, ethyl acetate etc.), hydrocarbons (eg hexane, heptane, benzene, toluene, xylene etc.), halogen Hydrocarbons (for example, methylene chloride, chloroform, 1,2-dichloroethane, chlorobenzene, etc.), nitromethane, dimethyl sulfoxide, N, N-dimethylformamide, N, N
-Dimethylacetamide, etc., which can be used alone or as a mixture thereof. Water, alcohols, ethers, nitrites, esters and hydrocarbons and mixtures thereof are preferable from the viewpoint of convenience of post-treatment after the reaction and cost. Among them, water, alcohols and mixtures thereof are more preferable. Alcohol is particularly preferable. The precipitated optically active acid addition salt can be filtered and, if necessary, dried to obtain the desired optically active acid addition salt.

(Step 4) The optically active acid addition salt of (S) -2-amino-1-phenyl-3-butyne obtained in Step 3 is treated with an inorganic base (eg sodium hydroxide, potassium hydroxide). Alternatively, by treating with an organic base (eg, triethylamine, diisopropylethylamine, etc.), that is, by neutralizing the added acid,
(S) -2-Amino-1-phenyl-3-butyne can be obtained.

(Step 5) The (S) -2-amino-1-phenyl-3-butyne obtained in Step 4 is represented by the general formula (1) by the usual chemical reaction procedure (S) -2-amino-. 1-
It can be converted to a phenyl-3-butyne derivative.

[0029]

[Chemical 2]

When R ¹ is a hydrogen atom, preferable R ² is, for example, an acyl group, an alkyloxycarbonyl group, an arylalkyloxycarbonyl group, an alkylsulfonyl group, an arylalkylsulfonyl group or an arylsulfonyl group.

When R ¹ is a hydrogen atom, specific examples of the acyl group of R ² include formyl group, acetyl group, propionyl group, 2-methylpropionyl group, 2,2-dimethylpropionyl group and benzoyl group. , P-methylbenzoyl group, p-methoxybenzoyl group, p-nitrobenzoyl group, phenylacetyl group, 2-pyridylmethoxycarbonylvalyl group, 3-pyridylmethoxycarbonylvalyl group, 4-pyridylmethoxycarbonylvalyl group, 2
-Pyridylmethylaminocarbonylvalyl group, 6-methyl-2-pyridylmethylaminocarbonylvalyl group, 2
-Pyridylmethylaminocarbonyl isoleucyl group and the like.

Of these acyl groups, the formyl group, the post-treatment after the reaction, the convenience of using the (S) -2-amino-1-phenyl-3-butyne derivative and the price of the reagent, Acetyl group, propionyl group, 2-methylpropionyl group, 2,2-dimethylpropionyl group, benzoyl group, p-methylbenzoyl group, p-methoxybenzoyl group, p-nitrobenzoyl group and phenylacetyl group are preferable. Specific compounds in which R ¹ is a hydrogen atom and R ² is an acyl group include (S) -2-formylamino-1-phenyl-3-butyne and (S) -2-acetylamino-1- Phenyl-3-butyne, (S) -2-propionylamino-1-phenyl-3-butyne, (S)
-2- (2'-methylpropionyl) amino-1-phenyl-3-butyne, (S) -2- (2 ', 2'-dimethylpropionyl) amino-1-phenyl-3-butyne,
(S) -2-Benzoylamino-1-phenyl-3-butyne, (S) -2- (p-methylbenzoyl) amino-
1-phenyl-3-butyne, (S) -2- (p-methoxybenzoyl) amino-1-phenyl-3-butyne,
(S) -2- (p-nitrobenzoyl) amino-1-phenyl-3-butyne, (S) -2-phenylacetylamino-1-phenyl-3-butyne and the like can be mentioned.

When R ¹ is a hydrogen atom, specific examples of the alkyloxycarbonyl group of R ² include methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, sec-butoxycarbonyl group, Isobutoxycarbonyl group, tert
-Butoxycarbonyl group and the like. From the viewpoint of the post-treatment after reaction, the convenience of using the (S) -2-amino-1-phenyl-3-butyne derivative and the price of the reagent,
Methoxycarbonyl group, ethoxycarbonyl group, isopropoxycarbonyl group, isobutoxycarbonyl group, t
An ert-butoxycarbonyl group is preferred. Specific compounds in which R ¹ is a hydrogen atom and R ² is an alkyloxycarbonyl group include (S) -2-methoxycarbonylamino-1-phenyl-3-butyne and (S) -2-
Ethoxycarbonylamino-1-phenyl-3-butyne, (S) -2-isopropoxycarbonylamino-1
-Phenyl-3-butyne, (S) -2-isobutoxycarbonylamino-1-phenyl-3-butyne, (S)-
2-tert-butoxycarbonylamino-1-phenyl-3-butyne and the like can be mentioned.

When R ¹ is a hydrogen atom, specific examples of the arylalkyloxycarbonyl group for R ² include benzyloxycarbonyl group, p-methylphenylmethoxycarbonyl group, p-methoxyphenylmethoxycarbonyl group and 2 -Pyridylmethoxycarbonyl group, 3-pyridylmethoxycarbonyl group, 4-pyridylmethoxycarbonyl group, 1- (3'-pyridyl) ethoxycarbonyl group, 2-thiazolylmethoxycarbonyl group, 4-thiazolylmethoxycarbonyl group, Examples thereof include a 5-thiazolylmethoxycarbonyl group, a pyrazinylmethoxycarbonyl group, a 2-furanylmethoxycarbonyl group and a 3-furanylmethoxycarbonyl group. Post-treatment after reaction, (S)
A benzyloxycarbonyl group, a p-methylphenylmethoxycarbonyl group, and a p-methoxyphenylmethoxycarbonyl group are preferable from the viewpoints of convenience in using a 2-amino-1-phenyl-3-butyne derivative and the price of a reagent. . Specific compounds in which R ¹ is a hydrogen atom and R ² is an arylalkyloxycarbonyl group include
(S) -2-benzyloxycarbonylamino-1-phenyl-3-butyne, 2- (S)-(p-methylphenylmethoxycarbonyl) amino-1-phenyl-3-butyne, (S) -2- ( p-methoxyphenylmethoxycarbonyl) amino-1-phenyl-3-butyne and the like.

When R ¹ is a hydrogen atom, specific examples of the alkylsulfonyl group for R ² include a methanesulfonyl group, an ethanesulfonyl group, a propanesulfonyl group and an isopropanesulfonyl group. Specific compounds in which R ¹ is a hydrogen atom and R ² is an alkylsulfonyl group include (S) -2-methanesulfonylamino-1-phenyl-3-butyne and (S) -2-ethanesulfonylamino. -1-Phenyl-3-butyne, (S) -2
-Propanesulfonylamino-1-phenyl-3-butyne, (S) -2-isopropanesulfonylamino-1-
Phenyl-3-butyne and the like can be mentioned.

When R ¹ is a hydrogen atom, specific examples of the arylsulfonyl group for R ² include benzenesulfonyl group, p-toluenesulfonyl group, p-methoxyphenylsulfonyl group, p-nitrophenylsulfonyl group and the like. Is mentioned. Specific compounds in which R ¹ is a hydrogen atom and R ² is an arylsulfonyl group include (S) -2
-Benzenesulfonylamino-1-phenyl-3-butyne, (S) -2- (p-toluenesulfonyl) amino-
1-phenyl-3-butyne, (S) -2- (p-methoxyphenylsulfonyl) amino-1-phenyl-3-butyne, (S) -2- (p-nitrophenylsulfonyl)
Amino-1-phenyl-3-butyne and the like can be mentioned.

Among the above-mentioned cases where R ¹ is a hydrogen atom, after-treatment after the reaction or (S) -2-amino-1-phenyl-3
R ² is preferably an acyl group, an alkyloxycarbonyl group, an arylalkyloxycarbonyl group or an aryloxycarbonyl group for the convenience of using a butyne derivative.

When R ¹ and R ² are combined to form a divalent acyl group, post-treatment after the reaction, (S) -2-amino-1-
From the viewpoints of convenience when using the phenyl-3-butyne derivative and the cost of the reagent, preferred examples include a phthaloyl group, a succinyl group, and a maleinyl group. R
^{When 1} and R ² are bonded to each other to form a divalent acyl group, specific compounds include (S) -2-phthalimido-1-phenyl-3-butyne and (S) -2-succinimido-1-
Phenyl-3-butyne, (S) -2-maleinimide-
1-phenyl-3-butyne and the like can be mentioned.

The compound represented by the above general formula (1) is
(S) -2-Amino-1-phenyl-3-butyne, a commonly used formylating agent (eg, formic acid, ethyl formate, etc.), an acetylating agent (eg, acetic anhydride, acetyl chloride, etc.), Benzoylating agents (for example, benzoyl chloride), phthaloylating agents (for example, N-carboethoxyphthalimide, phthalic anhydride, etc.), methoxycarbonylating agents (for example, methyl chloroformate, dimethyldicarbonate, etc.), tert- Butoxycarbonylating agent (eg, di-tert-butyl dicarbonate), benzyloxycarbonylating agent (eg, benzyl chloroformate), methanesulfonylating agent (eg, methanesulfonyl chloride), p-toluenesulfonyl An agent (p-toluenesulfonyl chloride) or the like is added under ordinary conditions as shown in the examples. By use can be obtained as the corresponding (S) -2- amino-1-phenyl-3-butyne derivatives.

(Step 6) (S) -2-obtained in Step 5
The amino-1-phenyl-3-butyne derivative can be converted to the (S) -2-amino-1-phenyl-3-butene derivative represented by the general formula (2) by hydrogenating in the presence of a metal catalyst. it can.

[0041]

[Chemical 3]

Typical examples of metal catalysts are Lindlar catalysts (Pd-CaCO ₃ -PbO, Pd-CaCO _3-).
Pb, and the like may be employed _{Pd-Al 2 O 3 -Zn)} . This hydrogenation reaction is carried out at a normal pressure in a temperature range of 0 to 100 ° C. under a hydrogen atmosphere by adding 0.00001 to 30% by weight of a metal catalyst to the 2-amino-1-phenyl-3-butyne derivative. be able to. Moreover, you may add quinoline as needed. The amount of quinoline added is 2-amino-1-
It is 0 to 30% by weight based on the phenyl-3-butyne derivative.

The solvent to be used may be a solvent which does not react with the 2-amino-1-phenyl-3-butyne derivative represented by the general formula (1) and can control the hydrogenation selectivity, and is not particularly limited. However, for example, water, alcohols (eg, methanol, ethanol, propanol, isopropanol, butanol, tert-butyl alcohol, etc.), ethers (eg, diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, dioxane, dimethoxyethane, etc.) ), Nitriles (eg acetonitrile), esters (eg methyl acetate, ethyl acetate etc.), hydrocarbons (eg hexane, heptane, benzene, toluene, xylene etc.), halogenated hydrocarbons (eg Methylene chloride, chloroform , 1,2-dichloroethane, chlorobenzene etc.), ketones (eg acetone, methyl ethyl ketone etc.), pyridine, dimethylsulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide etc. used alone or as a mixture thereof. it can. From the viewpoint of convenience of post-treatment after the reaction and cost, esters and hydrocarbons and mixtures thereof are preferable. Of these, toluene, hexane and mixtures thereof are more preferable.

Specific compounds obtained in this step include (S) -2-formylamino-1-phenyl-3.
-Butene, (S) -2-acetylamino-1-phenyl-3-butene, (S) -2-propionylamino-1-
Phenyl-3-butene, (S) -2- (2′-methylpropionyl) amino-1-phenyl-3-butene,
(S) -2- (2 ′, 2′-Dimethylpropionyl) amino-1-phenyl-3-butene, (S) -2-benzoylamino-1-phenyl-3-butene, (S) -2-
(P-Methylbenzoyl) amino-1-phenyl-3-
Butene, (S) -2- (p-methoxybenzoyl) amino-1-phenyl-3-butene, (S) -2- (p-nitrobenzoyl) amino-1-phenyl-3-butene,
(S) -2-Phenylacetylamino-1-phenyl-
3-butene, (S) -2-methoxycarbonylamino-
1-phenyl-3-butene, (S) -2-ethoxycarbonylamino-1-phenyl-3-butene, (S) -2
-Isopropoxycarbonylamino-1-phenyl-3
-Butene, (S) -2-isobutoxycarbonylamino-1-phenyl-3-butene, (S) -2-tert-
Butoxycarbonylamino-1-phenyl-3-butene, (S) -2-methanesulfonylamino-1-phenyl-3-butene, (S) -2-ethanesulfonylamino-1-phenyl-3-butene, (S) ) -2-Propanesulfonylamino-1-phenyl-3-butene, (S)-
2-isopropanesulfonylamino-1-phenyl-3
-Butene, (S) -2-benzenesulfonylamino-1
-Phenyl-3-butene, (S) -2- (p-toluenesulfonyl) amino-1-phenyl-3-butene,
(S) -2- (p-methoxyphenylsulfonyl) amino-1-phenyl-3-butene, (S) -2- (p-nitrophenylsulfonyl) amino-1-phenyl-3-
Butene, (S) -2-phthalimido-1-phenyl-3
-Butene, (S) -2-succinimide-1-phenyl-3-butene, (S) -2-maleinimide-1-phenyl-3-butene and the like.

(Step 7) (S) -2-obtained in Step 4
Amino-1-phenyl-3-butyne was hydrogenated in the presence of a metal catalyst to give (S) -2-amino-1-phenyl-3-
Can be converted to butene. A typical example of the metal catalyst is a Lindlar catalyst (Pd—CaCO ₃ —Pb).
O, Pd-CaCO ₃ -Pb, and the like may be employed _{Pd-Al 2 O 3 -Zn)} . This hydrogenation reaction is a 2-amino-
0.0000 for 1-phenyl-3-butyne derivative
Add 1 to 30% by weight of metal catalyst and add 0-1 under hydrogen atmosphere.
It can be carried out at normal pressure in the temperature range of 00 ° C. Moreover, you may add quinoline as needed. The amount of quinoline added is 0 to 30% by weight with respect to the 2-amino-1-phenyl-3-butyne derivative. The solvent used may be any solvent that does not react with 2-amino-1-phenyl-3-butyne and can control the selectivity of hydrogenation, and is not particularly limited, and examples thereof include water and alcohols (for example, methanol). ,
Ethanol, propanol, isopropanol, butanol, tert-butyl alcohol, etc.), ethers (eg, diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, dioxane, dimethoxyethane, etc.), nitriles (eg, acetonitrile, etc.), esters (eg, For example, methyl acetate, ethyl acetate, etc.), hydrocarbons (eg, hexane, heptane, benzene, toluene, xylene, etc.),
Halogenated hydrocarbons (eg, methylene chloride, chloroform, 1,2-dichloroethane, chlorobenzene, etc.), pyridine, dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, etc., alone or as a mixture thereof. Can be used. From the viewpoint of convenience of post-treatment after the reaction and cost, esters and hydrocarbons and mixtures thereof are preferable. Of these, toluene, hexane and mixtures thereof are more preferable.

(Step 8) The (S) -2-amino-1-phenyl-3-butene obtained in Step 7 is (S) -2-amino represented by the above general formula (2) by a usual chemical reaction procedure. −
It can be converted into a 1-phenyl-3-butene derivative.

[0047]

[Chemical 4]

When R ¹ is a hydrogen atom, preferable R ² includes, for example, an acyl group, an alkyloxycarbonyl group, an arylalkyloxycarbonyl group, an alkylsulfonyl group, an arylalkylsulfonyl group or an arylsulfonyl group.

When R ¹ is a hydrogen atom, specific examples of the acyl group of R ² include formyl group, acetyl group, propionyl group, 2-methylpropionyl group, 2,2-dimethylpropionyl group and benzoyl group. , P-methylbenzoyl group, p-methoxybenzoyl group, p-nitrobenzoyl group, phenylacetyl group, 2-pyridylmethoxycarbonylvalyl group, 3-pyridylmethoxycarbonylvalyl group, 4-pyridylmethoxycarbonylvalyl group, 2
-Pyridylmethylaminocarbonylvalyl group, 6-2-
Examples thereof include a pyridylmethylaminocarbonylvalyl group and a 2-pyridylmethylaminocarbonylisoleucyl group.

Of these acyl groups, the formyl group and the post-treatment after the reaction, the convenience of using the (S) -2-amino-1-phenyl-3-butene derivative and the cost of the reagent, Acetyl group, propionyl group, 2-methylpropionyl group, 2,2-dimethylpropionyl group, benzoyl group, p-methylbenzoyl group, p-methoxybenzoyl group, p-nitrobenzoyl group and phenylacetyl group are preferable. Specific compounds in which R ¹ is a hydrogen atom and R ² is an acyl group include (S) -2-formylamino-1-phenyl-3-butene and (S) -2-acetylamino-1-. Phenyl-3-butene, (S) -2-propionylamino-1-phenyl-3-butene, (S)
-2- (2'-methylpropionyl) amino-1-phenyl-3-butene, (S) -2- (2 ', 2'-dimethylpropionyl) amino-1-phenyl-3-butene,
(S) -2-benzoylamino-1-phenyl-3-butene, (S) -2- (p-methylbenzoyl) amino-
1-phenyl-3-butene, (S) -2- (p-methoxybenzoyl) amino-1-phenyl-3-butene,
(S) -2- (p-nitrobenzoyl) amino-1-phenyl-3-butene, (S) -2-phenylacetylamino-1-phenyl-3-butene and the like can be mentioned.

When R ¹ is a hydrogen atom, specific examples of the alkyloxycarbonyl group of R ² include methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, sec-butoxycarbonyl group, Isobutoxycarbonyl group, tert
-Butoxycarbonyl group and the like. From the viewpoints of post-treatment after the reaction, convenience in using the (S) -2-amino-1-phenyl-3-butene derivative, and the price of the reagent,
Methoxycarbonyl group, ethoxycarbonyl group, isopropoxycarbonyl group, isobutoxycarbonyl group, t
An ert-butoxycarbonyl group is preferred. Specific compounds in which R ¹ is a hydrogen atom and R ² is an alkyloxycarbonyl group include (S) -2-methoxycarbonylamino-1-phenyl-3-butene and (S) -2-
Ethoxycarbonylamino-1-phenyl-3-butene, (S) -2-isopropoxycarbonylamino-1
-Phenyl-3-butene, (S) -2-isobutoxycarbonylamino-1-phenyl-3-butene, (S)-
2-tert-butoxycarbonylamino-1-phenyl-3-butene and the like can be mentioned.

When R ¹ is a hydrogen atom, specific examples of the arylalkyloxycarbonyl group for R ² are benzyloxycarbonyl group, p-methylphenylmethoxycarbonyl group, p-methoxyphenylmethoxycarbonyl group and 2 -Pyridylmethoxycarbonyl group, 3-pyridylmethoxycarbonyl group, 4-pyridylmethoxycarbonyl group, 1- (3'-pyridyl) ethoxycarbonyl group, 2-thiazolylmethoxycarbonyl group, 4-thiazolylmethoxycarbonyl group, Examples thereof include a 5-thiazolylmethoxycarbonyl group, a pyrazinylmethoxycarbonyl group, a 2-furanylmethoxycarbonyl group and a 3-furanylmethoxycarbonyl group. Post-treatment after reaction, (S)
A benzyloxycarbonyl group, a p-methylphenylmethoxycarbonyl group, and a p-methoxyphenylmethoxycarbonyl group are preferable from the viewpoints of convenience when using the 2-amino-1-phenyl-3-butene derivative and the price of the reagent. . Specific compounds in which R ¹ is a hydrogen atom and R ² is an arylalkyloxycarbonyl group include
(S) -2-benzyloxycarbonylamino-1-phenyl-3-butene, 2- (S)-(p-methylphenylmethoxycarbonyl) amino-1-phenyl-3-butene, (S) -2- ( p-methoxyphenylmethoxycarbonyl) amino-1-phenyl-3-butene and the like.

When R ¹ is a hydrogen atom, specific examples of the alkylsulfonyl group for R ² include a methanesulfonyl group, an ethanesulfonyl group, a propanesulfonyl group and an isopropanesulfonyl group. Specific compounds in which R ¹ is a hydrogen atom and R ² is an alkylsulfonyl group include (S) -2-methanesulfonylamino-1-phenyl-3-butene and (S) -2-ethanesulfonylamino. -1-Phenyl-3-butene, (S) -2
-Propanesulfonylamino-1-phenyl-3-butene, (S) -2-isopropanesulfonylamino-1-
Phenyl-3-butene and the like can be mentioned.

When R ¹ is a hydrogen atom, specific examples of the arylsulfonyl group for R ² include benzenesulfonyl group, p-toluenesulfonyl group, p-methoxyphenylsulfonyl group, p-nitrophenylsulfonyl group and the like. Is mentioned. Specific compounds in which R ¹ is a hydrogen atom and R ² is an arylsulfonyl group include (S) -2
-Benzenesulfonylamino-1-phenyl-3-butene, (S) -2- (p-toluenesulfonyl) amino-
1-phenyl-3-butene, (S) -2- (p-methoxyphenylsulfonyl) amino-1-phenyl-3-butene, (S) -2- (p-nitrophenylsulfonyl)
Amino-1-phenyl-3-butene and the like can be mentioned.

Among the above-mentioned cases where R ¹ is a hydrogen atom, after-treatment after the reaction or (S) -2-amino-1-phenyl-3
R ² is preferably an acyl group, an alkyloxycarbonyl group, an arylalkyloxycarbonyl group or an aryloxycarbonyl group for the convenience of using a butene derivative.

When R ¹ and R ² are combined to form a divalent acyl group, post-treatment after the reaction, (S) -2-amino-1-
From the viewpoints of convenience in using the phenyl-3-butene derivative and the price of the reagent, preferable examples include a phthaloyl group, a succinyl group, and a maleinyl group. R
^{When 1} and R ² are combined to form a divalent acyl group, specific compounds include (S) -2-phthalimido-1-phenyl-3-butene and (S) -2-succinimido-1-
Phenyl-3-butene, (S) -2-maleinimide-
1-phenyl-3-butene and the like can be mentioned.

The compound represented by the above general formula (2) is
(S) -2-Amino-1-phenyl-3-butene, usually used formylating agent (eg, formic acid, ethyl formate, etc.), acetylating agent (eg, acetic anhydride, acetyl chloride, etc.), Benzoylating agents (for example, benzoyl chloride), phthaloylating agents (for example, N-carboethoxyphthalimide, phthalic anhydride, etc.), methoxycarbonylating agents (for example, methyl chloroformate, dimethyldicarbonate, etc.), tert- Butoxycarbonylating agent (eg, di-tert-butyl dicarbonate), benzyloxycarbonylating agent (eg, benzyl chloroformate), methanesulfonylating agent (eg, methanesulfonyl chloride), p-toluenesulfonyl An agent (p-toluenesulfonyl chloride) or the like is added under ordinary conditions as shown in the examples. By use can be obtained as the corresponding (S) -2- amino-1-phenyl-3-butene derivative.

[0058]

EXAMPLES The present invention will now be described in more detail with reference to examples, but the present invention is not limited to these examples. The starting material 2-hydroxy-1-phenyl-3-butyne can be prepared by a known method {for example, USP.
3,212,900 (1965), J. Med.
Chem. , 1966, 9, 469, etc.}.

(Example 1) "Production of 2-methanesulfonyloxy-1-phenyl-3-butyne" 2-hydroxy-1-phenyl-3-butyne 296.6 g (2.029 mol), triethylamine 225.8 g ( 2.232 mol) and 1.5 liter of methylene chloride were stirred under cooling with an ice water bath. Methanesulfonyl chloride 244.0 g (2.130 mol) was added dropwise thereto over about 2 hours while maintaining the liquid temperature at 5 to 10 ° C. After stirring for another 30 minutes, 1 liter of water was poured. After separating the methylene chloride layer, the aqueous layer was extracted with 1 liter of methylene chloride. The combined methylene chloride solution was concentrated under reduced pressure to give a crude product of 2-methanesulfonyloxy-1-phenyl-3-butyne 5
00.0 g (theoretical 455.0 g) was obtained as an orange oil. 0.50 g of this crude product was subjected to silica gel column chromatography (developing solvent: chloroform) to measure the physical property value of 2-methanesulfonyloxy-1-phenyl-3-butyne, and 2-methanesulfonyloxy 0.44 g of -1-phenyl-3-butyne was obtained as a pale yellow oil. The remaining crude 2-methanesulfonyloxy-1-phenyl-3-butyne 495.5 g (theoretical value 450.9 g, 2.011 mol) was used in Example 3 without purification.

¹ H NMR (500 MHz, CDCl ₃ -TMS) δ ppm 7.37-7.2
6 (m, 5H), 5.32 (td, J = 6.8and2.3Hz, 1H), 3.24-3.16 (m, 2H),
2.93 (s, 3H), 2.71 (d, J = 2.2Hz, 1H); IR (neat) 3282,3032,2
939,2126,1605,1497,1456,1415,1360,1174,1083,998,97
3,896,866,827,800,750,701,666,552,521,506cm ^-1; mass spectroscopy (FD) m / z224 (M +); Elemental analysis C ₁₁ H ₁₂ O ₃ S Calculated: C, 58.91; H, 5.40 %, measured value: C, 58.70; H, 5.29%.

Example 2 Production of 2-Methanesulfonyloxy-1-phenyl-3-butyne 109.2 g (0.747 mol) of 2-hydroxy-1-phenyl-3-butyne, 83.2 g of triethylamine ( 0.822 mol) and toluene 0.
The solution consisting of 55 liters was stirred under cooling with an ice water bath. While keeping the liquid temperature at 5 to 10 ° C, about 90 g of methanesulfonyl chloride (89.8 g, 0.784 mol) was added.
It was dripped over a period of minutes. After stirring for an additional 1 hour, water was added to 0.
I poured 4 liters. After separating the toluene layer, the aqueous layer was extracted with 0.3 l of toluene. The combined toluene solution was concentrated under reduced pressure to give a crude product of 2-methanesulfonyloxy-1-phenyl-3-butyne 184.5.
g (theoretical 167.5 g) were obtained as an orange oil.

(Example 3) "Production of 2-amino-1-phenyl-3-butyne monohydrochloride" Crude 2-methanesulfonyloxy-obtained in Example 1
1-phenyl-3-butyne 495.5 g (theoretical value 45
0.9 g, 2.011 mol), isopropanol 1.
3 liters and 25% ammonia water 2.8 liters (40.98 mol) were mixed, and the mixture was stirred in a warm bath heated to 65 ° C. for 9 hours. During this period, the liquid temperature was 38 to 59 ° C. After distilling off 1 liter of the solvent, the oily matter was extracted with toluene (2.5 liters in total). While stirring the obtained toluene solution while cooling with an ice water bath, 200 ml of concentrated hydrochloric acid was poured therein. The precipitate was collected by filtration, washed with toluene, and dried to obtain 2-amino-1-phenyl-3-butyne monohydrochloride (277.0 g, 1.52 mol) as a slightly yellow solid. .

Melting point 223 ° C. (decomposition); ¹ H NMR (500 MHz, D ₂
O) δppm 7.43-7.33 (m, 5H), 4.37 (ddd, J = 8.3,6.5and2.3H
z, 1H), 3.20-3.10 (m, 2H), 2.95 (d, J = 2.4Hz, 1H) (However,
The shift value of H ₂ O was 4.75 ppm); IR (KBr) 3280,3102,29
51,2660,2123,1576,1503,1486,1455,1195,1168,745,69
4,652,646,534 cm ^-1 .

(Example 4) "Production of 2-amino-1-phenyl-3-butyne" 2-amino-1-phenyl-3-butyne monohydrochloride obtained in Example 3 (250.0 g, 1. 38 mol) to 6.5% Na
In addition to 1.07 liter of OH aqueous solution, it was extracted twice with 1 liter of toluene. The combined toluene solution was washed with 0.3 liter of saturated saline and then concentrated under reduced pressure.
176.0 g of amino-1-phenyl-3-butyne (1.
212 mol) was obtained as an orange oil.

¹ H NMR (500 MHz, CDCl ₃ -TMS) δ ppm 7.34-7.2
0 (m, 5H), 3.83 (td, J = 6.7and2.2Hz, 1H), 2.96 (dd, J = 13.1an
d6.4Hz, 1H), 2.88 (dd, J = 13.5and6.5Hz, 1H), 2.31 (d, J = 2.5
Hz, 1H), 1.42 (broad s, 2H); IR (neat) 3369,3288,3028,292
3,2106,1602,1495,1454,743,700,648cm ^-1 .

Example 5 "(S) -2-Amino-1-phenyl-3-butyne.L"
-Production of tartaric acid salt "L-tartaric acid 181.9 g (1.21)
2 mol) was dissolved in 1.8 liter of methanol, and a solution consisting of 176.0 g (1.212 mol) of 2-amino-1-phenyl-3-butyne obtained in Example 4 and 0.2 liter of methanol was refluxed. It dripped over about 30 minutes. Then, the mixture was allowed to stand overnight at room temperature to obtain (S) -2-amino-1-phenyl-3-butyne.L-tartrate (10
(6.5 g, 0.361 mol) was obtained as colorless crystals.
The yield based on (S) -2-amino-1-phenyl-3-butyne in the starting material (RS) -2-amino-1-phenyl-3-butyne was 60%. The obtained (S)-
The optical purity of 2-amino-1-phenyl-3-butyne / L-tartrate was 98% or more as determined by HPLC analysis using CHIRALPAK AD (trade name).

Melting point 188 ° C. (decomposition); ¹ H NMR (500 MHz, D ₂ O)
δppm 7.44-7.34 (m, 5H), 4.48 (s, 2H), 4.38 (ddd, J = 8.2,6.
5and2.4Hz, 1H), 3.18 (dd, J = 13.7and6.6Hz, 1H), 3.14 (dd, J
= 13.7and8.2Hz, 1H), 2.96 (d, J = 2.4Hz, 1H) (however, H ₂ O
Shift value of 4.75 ppm); IR (KBr) 3476,3320,3270,
3229,3031,2976,2122,1736,1719,1560,1496,1482,1412,
1305,1264,1215,1135,1077,1068,696,678cm ^-1 ; [α] _D ²⁵ +
21.7 ° (c = 0.95, H ₂ O); mass spectrum (FD) m / z 296 (M ⁺ +1); elemental analysis calculated as C ₁₄ H ₁₇ NO ₆ calculated: C, 56.94; H, 5.80; N, 4.74%,
Measurements: C, 56.67; H, 5.74; N, 4.72%.

Example 6 "(S) -2-Amino-1-phenyl-3-butyne.L"
-Production of tartaric acid salt "L-tartaric acid 15.01 g (0.10
mol) was dissolved in 90 ml of methanol, and 2-amino-1-phenyl-3 obtained in the same manner as in Example 4 under reflux.
-A solution of 14.52 g (0.10 mol) of butyne and 30 ml of methanol was added dropwise over about 30 minutes. Then, the mixture was left at room temperature for 2 hours to obtain (S) -2-amino-
1-phenyl-3-butyne L-tartrate (10.77)
g, 36.5 mmol) was obtained as colorless crystals. The yield based on (S) -2-amino-1-phenyl-3-butyne in the raw material (RS) -2-amino-1-phenyl-3-butyne was 73%. The obtained (S) -2-
The optical purity of amino-1-phenyl-3-butyne.L-tartrate was 94% or more by HPLC analysis using CHIRALPAK AD (trade name).

Example 7 "(S) -2-Amino-1-phenyl-3-butyne.L"
-Production of tartaric acid salt "L-tartaric acid 75.0 g (0.50 m
2-amino-1-phenyl-3 obtained by the same method as in Example 4 under reflux.
-A solution of butyne 72.6 g (0.50 mol) and ethanol 0.5 liter was added dropwise over about 100 minutes. After that, it was left overnight at room temperature to give crude 2-amino-
1-Phenyl-3-butyne.L-tartrate salt was obtained as a colorless solid. This crude solid was recrystallized from a mixed solvent of 4 liters of ethanol and 1 liter of methanol to give (S) -2-amino-1-phenyl-3-butyne / L-tartrate (39.70 g, 134 mmol) as colorless. Obtained as crystals. The yield based on (S) -2-amino-1-phenyl-3-butyne in the starting material (RS) -2-amino-1-phenyl-3-butyne was 54%. The obtained (S) -2-amino-1-phenyl-3-
The optical purity of butyne / L-tartrate is CHIRALPAK
It was 97% or more by HPLC analysis using AD (trade name).

(Example 8) "(S) -2-tert-butoxycarbonylamino-"
Production of 1-phenyl-3-butyne ”(S) -2-amino-1-phenyl-having an optical purity of 98% or more obtained in Example 5.
3-butyne / L-tartrate 103.0 g (0.349 m
ol) was added to 0.53 liter of a 5.6% NaOH aqueous solution, and the mixture was extracted twice with 0.5 liter of toluene. The combined toluene solution was concentrated to a total amount of 192 g. 76.13 g of di-tert-butyl dicarbonate in this concentrated liquid
A solution consisting of (0.349 mol) and 0.15 liter of toluene was added dropwise over 90 minutes. After stirring for a further 10 minutes, concentration under reduced pressure yields (S) -2-tert-
89.0 g of the crude product of butoxycarbonylamino-1-phenyl-3-butyne (theoretical 85.6 g, 0.349).
mol) was obtained as a colorless powder. This crude product was used in Reference Example 1 without purification. In addition, the obtained (S) -2-tert-butoxycarbonylamino-1
-Phenyl-3-butyne has an optical purity of CHIRALPA
It was 98% or more by HPLC analysis using K AS (trade name).

Melting point 64.5-65.0 ° C .; ¹ H NMR (500 MHz, CDCl ₃ -TM
S) δppm 7.34-7.24 (m, 5H), 4.69 (broad s, 1H), 3.03-2.91
(m, 2H), 2.28 (broad s, 1H), 1.43 (s, 9H); IR (KBr) 3366,336
0,3277,2978,2117,1700,1692,1516,1514,1504,1247,117
2,1155,1215,1135,1077,756,662cm ^-1 ; [α] _D ²⁵ -13.1 ° (c
= 0.98, CDCl ₃ ).

(Example 9) "Production of (S) -2-amino-1-phenyl-3-butyne" (S) -2- with an optical purity of 97% or more obtained in Example 7
Amino-1-phenyl-3-butyne / L-tartrate 3
9.45 g (0.134 mol) was added to 0.33 liter of 3.4% NaOH aqueous solution, and extracted with 0.5 liter of toluene. When the toluene solution is concentrated, 19.9 g of a crude product of (S) -2-amino-1-phenyl-3-butyne is obtained.
(Theoretical value 19.4 g) was obtained as a pale yellow oil. This crude product was used in Reference Example 3 without purification. The optical purity of the obtained (S) -2-amino-1-phenyl-3-butyne was CHIRALPAK AD.
It was 97% or more by HPLC analysis using (trade name).

¹ H NMR (500 MHz, CDCl ₃ -TMS) δ ppm 7.34-7.2
0 (m, 5H), 3.83 (td, J = 6.7and2.2Hz, 1H), 2.96 (dd, J = 13.1an
d6.4Hz, 1H), 2.88 (dd, J = 13.5and6.5Hz, 1H), 2.31 (d, J = 2.5
Hz, 1H), 1.42 (broad s, 2H); IR (neat) 3369,3288,3028,292
3,2106,1602,1495,1454,743,700,648cm ^-1 .

Reference Example 1 "(S) -2-tert-butoxycarbonylamino-"
Production of 1-phenyl-3-butene ”88.5 g of (S) -2-tert-butoxycarbonylamino-1-phenyl-3-butyne having an optical purity of 98% or more obtained in Example 8
(Theoretical value 85.1 g, 0.347 mol) was dissolved in 0.6 liter of toluene to give 0.30 g of Lindlar catalyst.
(5% Pd-CaCO ₃ -Pb) and quinoline 0.04 g
Was added and the mixture was stirred under a hydrogen atmosphere. After 9 hours, the reaction mixture was filtered through Celite, and the solvent was evaporated under reduced pressure. (S) -2
85.1 g of the crude product of -tert-butoxycarbonylamino-1-phenyl-3-butene (theoretical 85.8).
g) was obtained as a colorless powder. The crude product contained 1.6% of the raw material (S) -2-tert-butoxycarbonylamino-1-phenyl-3-butyne and (R) -2-
tert-butoxycarbonylamino-1-phenyl-
It contained 2.7% of 3-butane. In addition, the obtained (S) -2-tert-butoxycarbonylamino-1
-Phenyl-3-butene has an optical purity of CHIRALPA
It was 98% or more by HPLC analysis using K AS (trade name).

Melting point 65.0-66.1 ° C .; ¹ H NMR (500 MHz, CDCl ₃ -TM
S) δppm 7.31-7.17 (m, 5H), 5.83-5.76 (m, 1H), 5.14-5.07
(m, 2H), 4.42 (broad s, 1H), 2.84 (broad d, J = 6.2Hz, 2H),
1.41 (s, 9H); IR (KBr) 3370,2980,1688,1682,1524,1522,11
74,914,702cm ^-1 ; [α] _D ²⁵ + 33.61 ° (c = 0.95, CDCl ₃ ).

(Example 10) "Production of (S) -2-formylamino-1-phenyl-3-butyne" (S) -2-amino-1- with an optical purity of 94% or more obtained in Example 6 Phenyl-3-butyne / L-
Tartrate salt 10.33 g (0.035 mol) 6.5%
It was added to 53 ml of an aqueous solution of NaOH and extracted twice with 50 ml of toluene. The combined toluene solution was concentrated to a total amount of 20 g. 7.1 g (0.349 m) of ethyl formate was added to this concentrated liquid.
ol) was added and the mixture was stirred under reflux for 10 hours and then concentrated under reduced pressure to obtain 6.20 g of a crude product of (S) -2-formylamino-1-phenyl-3-butyne (theoretical value: 6.06).
g, 0.035 mol) was obtained as a colorless powder.
The crude product was recrystallized from isopropyl ether to obtain 4.78 g of (S) -2-formylamino-1-phenyl-3-butyne as pale yellow crystals. The obtained (S) -2-formylamino-1-phenyl-3-
The optical purity of butyne is CHIRALCELOJ (trade name)
It was 99% or more by HPLC analysis using.

Melting point 77.2-78.0 ° C .; ¹ H NMR (500 MHz, CDCl ₃ -TM
S) δppm 8.13 (s, 0.8H), 8.00 (d, J = 11.8Hz, 0.2H), 7.36-7.
21 (m, 5H), 5.66and5.60 (2broad s, 1H), 5.15-5.09 (m, 0.8
H), 4.45-4.40 (m, 0.2H), 3.12-2.94 (m, 2H), 2.47 (d, J = 2.4H
z, 0.2H), 2.31 (d, J = 2.4Hz, 0.8H); IR (KBr) 3304,3248,302
6,2121,1650,1640,1522,1383,1221,700,666cm ^-1 ; [α] _D ^2
5 -58.4 ° (c = 1.00, CH ₃ OH); mass spectrum (FD) m / z 173 (M ⁺ ); elemental analysis calculated as C ₁₁ H ₁₁ NO: C, 76.27; H, 6.40; N, 8.09
%, Measured value: C, 76.36; H, 6.56; N, 8.08%.

(Reference Example 2) "Production of (S) -2-formylamino-1-phenyl-3-butene" (S) -2-formylamino-1 having an optical purity of 99% or more obtained in Example 10. -Phenyl-3-butyne (4.50 g, 0.26 mol) was dissolved in 27 ml of toluene, and 0.02 g of Lindlar catalyst (10% Pd-Al) was dissolved.
₂ O ₃ —Zn) was added, and the mixture was stirred under a hydrogen atmosphere. After 5 hours, the reaction mixture was filtered through Celite, and the solvent was evaporated under reduced pressure. (S) -2-formylamino-1-phenyl-3-
4.63 g of crude butene product (theoretical 85.8 g) were obtained as a pale yellow oil. This crude product contains (R)
2-formylamino-1-phenyl-3-butane is 1
The content was 2.7%. 0.20 g of this crude product
Was subjected to silica gel column chromatography (developing solvent: chloroform-methanol) to measure the physical properties of (S) -2-formylamino-1-phenyl-3-butene, and (S) -2-formylamino-1. -Phenyl-3-
0.17 g of butene was obtained as a colorless oil.

¹ H NMR (500 MHz, CDCl ₃ -TMS) δ ppm 8.17 (s,
0.75H), 7.85 (d, J = 11.9Hz, 0.25H), 7.34-7.15 (m, 5H), 5.92
(ddd, J = 17.3,10.4and5.1Hz, 0.25H), 5.84 (ddd, J = 17.3,1
0.4and5.1Hz, 0.75H), 5.46and5.41 (2broad s, 1H), 5.25-
5.12 (m, 2H), 4.89 (quint, J = 6.8Hz, 0.8H), 4.25-4.17 (m, 0.
2H), 2.99-2.75 (m, 2H); IR (neat) 3270,3029,2858,1678,16
74,1666,1660,1533,1497,1384,700cm ^-1 ; mass spectrometry (FD) m /
z175 (M ⁺ ).

Reference Example 3 "Production of (S) -2-amino-1-phenyl-3-butene" (S) -2- having an optical purity of 97% or more obtained in Example 9
Amino-1-phenyl-3-butyne 19.7 g (theoretical value 19.2 g), Lindlar catalyst 0.25 g (5% Pd-
40 ml of toluene and 100 ml of hexane were added to 0.05 g of CaCO ₃ -Pb) and quinoline, and the mixture was stirred under a hydrogen atmosphere. After 11 hours, the reaction mixture was filtered through Celite,
The solvent was distilled off under reduced pressure. 19.1 g of a crude product of (S) -2-amino-1-phenyl-3-butene (theoretical value: 19.
5 g) was obtained as a pale yellow oil. This crude product contained 8.0% of (R) -2-amino-1-phenyl-3-butane. The optical purity of the obtained (S) -2-amino-1-phenyl-3-butene was CHIR.
9 by HPLC analysis using ALPAK AD (trade name)
It was 7% or more.

¹ H NMR (500 MHz, CDCl ₃ -TMS) δ ppm 7.31-7.1
7 (m, 5H), 5.89 (ddd, J = 17.2,10.4and6.1Hz, 1H), 5.14 (dt, J
= 17.3and1.5Hz, 1H), 5.04 (dt, J = 10.4and1.2Hz, 1H), 3.60
(dd, J = 13.6and6.5Hz, 1H), 2.82 (dd, J = 13.4and5.1Hz, 1H),
2.62 (dd, J = 13.4and8.4Hz, 1H); IR (neat) 3365,3292,3083,
3062,3027,2917,2849,1642,1602,1496,1454,994,918,74
6,700 cm ^-1 .

(Example 11) "Production of 2-formylamino-1-phenyl-3-butyne" 2-amino-1-phenyl-3-butyne obtained in the same manner as in Example 4 14.5 g (0 Ethyl formate (50 ml) was added to the mixture (.100 mol) and the mixture was stirred under reflux for 6 hours.
Concentration under reduced pressure gave 17.02 g of the crude product of 2-formylamino-1-phenyl-3-butyne (theory 6.06).
g, 0.035 mol) was obtained as a yellow oil. Of this crude product, 0.20 g was subjected to silica gel column chromatography (developing solvent: chloroform-methanol) to measure the physical properties of 2-formylamino-1-phenyl-3-butene, and 2-formylamino -1
0.19 g of -phenyl-3-butene was obtained as a pale yellow powder.

Melting point 79.5-81.0 ° C .; ¹ H NMR (500 MHz, CDCl ₃ ) δ
ppm 8.13 (s, 0.8H), 8.00 (d, J = 11.8Hz, 0.2H), 7.36-7.21
(m, 5H), 5.66and5.60 (2broad s, 1H), 5.15-5.09 (m, 0.8H),
4.45-4.40 (m, 0.2H), 3.12-2.94 (m, 2H), 2.47 (d, J = 2.4Hz,
0.2H), 2.31 (d, J = 2.4Hz, 0.8H); IR (neat) 3256,3250,3031,
2946,2871,1659,1650,1643,1606,1542,1496,1391,1257,
768,700,548 cm ^-1 .

(Reference Example 4) "Production of 2-formylamino-1-phenyl-3-butene" 8.66 g (0.050 mol) of 2-formylamino-1-phenyl-3-butyne obtained in Example 11 Was dissolved in 50 ml of toluene, and 0.34 g of the Lindlar catalyst (5
% Pd-CaCO ₃ -Pb) and quinoline 0.01 g
Was added and the mixture was stirred under a hydrogen atmosphere. After 82 hours, the reaction mixture was filtered through Celite, and the solvent was evaporated under reduced pressure. Crude product of 2-formylamino-1-phenyl-3-butene 8.
80 g (theory 8.76 g) were obtained as a yellow oil. The crude product contained 0.9% 2-formylamino-1-phenyl-3-butyne and 2-formylamino-1-phenyl-3-butyne.
It contained 0.7% of phenyl-3-butane. Of this crude product, 0.20 g was subjected to silica gel column chromatography (developing solvent: chloroform-methanol) to measure the physical properties of (S) -2-formylamino-1-phenyl-3-butene. 2-formylamino-1
0.19 g of -phenyl-3-butene was obtained as a pale yellow oil.

¹ H NMR (500 MHz, CDCl ₃ -TMS) δ ppm 8.17 (s,
0.75H), 7.85 (d, J = 11.9Hz, 0.25H), 7.34-7.15 (m, 5H), 5.92
(ddd, J = 17.3,10.4and5.1Hz, 0.25H), 5.84 (ddd, J = 17.3,1
0.4and5.1Hz, 0.75H), 5.46and5.41 (2broad s, 1H), 5.25-
5.12 (m, 2H), 4.89 (quint, J = 6.8Hz, 0.8H), 4.25-4.17 (m, 0.
2H), 2.99-2.75 (m, 2H); IR (neat) 3270,3029,2858,1678,16
74,1666,1660,1533,1497,1384,700cm ^-1 .

(Example 12) "Production of 2-tert-butoxycarbonylamino-1-phenyl-3-butyne" 2-amino-1-phenyl-3-butyne obtained in the same manner as in Example 4.11. 42 g
Di-tert-butyl dicarbonate 17.15 was added to a solution of (0.079 mol) in 25 ml of toluene.
What melt | dissolved g (0.079 mol) in 35 ml of toluene was dripped over 30 minutes. After stirring for another 30 minutes, the mixture was concentrated under reduced pressure to give 2-tert-butoxycarbonylamino-1-phenyl-3-butyne crude product 1
9.8 g (theoretical value 19.3 g, 0.79 mol) were obtained as a colorless powder. The crude product was recrystallized from isopropyl alcohol to obtain 18.0 g of 2-tert-butoxycarbonylamino-1-phenyl-3-butyne as colorless crystals.

Melting point 112.5-113.0 ° C .; ¹ H NMR (500 MHz, CDCl _3-
TMS) δppm 7.34-7.24 (m, 5H), 4.69 (broad s, 1H), 3.03-2.
91 (m, 2H), 2.28 (broad s, 1H), 1.43 (s, 9H); IR (KBr) 3330,3
324,3280,2982,2117,1688,1676,1518,1296,1170,674,65
6 cm ^-1 .

Reference Example 5 "Production of 2-tert-butoxycarbonylamino-1-phenyl-3-butene" 2-ter obtained in Example 12
t-Butoxycarbonylamino-1-phenyl-3-butyne 9.00 g (36.7 mmol) was added to toluene 0.1.
Dissolve in 8 liters, 0.05 g of Lindlar catalyst (5%
Pd-CaCO ₃ -Pb) and quinoline 0.01g was added, and stirred under a hydrogen atmosphere. After 6 hours, the reaction mixture was filtered through Celite, and the solvent was evaporated under reduced pressure. 2-tert-
9.17 g (theoretical value 9.07 g) of crude butoxycarbonylamino-1-phenyl-3-butene product were obtained as a colorless powder. The crude product contained 2-tert-butoxycarbonylamino-1-phenyl-3-butane 5.9%.

Melting point 53.0-54.0 ° C .; ¹ H NMR (500 MHz, CDCl ₃ -TM
S) δppm 7.31-7.17 (m, 5H), 5.83-5.76 (m, 1H), 5.14-5.07
(m, 2H), 4.42 (broad s, 1H), 2.84 (broad d, J = 6.2Hz, 2H),
1.41 (s, 9H); IR (KBr) 3370,3342,2979,1696,1692,1688,16
84,1678,1676,1528,1524,1518,1250,1170,700cm ^-1 .

Reference Example 6 "Production of 2-amino-1-phenyl-3-butene" 2-amino-1-phenyl-3 obtained by the same method as in Example 4.
- butyne 0.59 g (4.06 mmol), Lindlar catalyst _{0.01g (5% Pd-CaCO 3} -Pb) and quinoline 0.01g in toluene 2 ml, hexane 10m
1 was added and the mixture was stirred under a hydrogen atmosphere. After 5 hours, the reaction mixture was filtered through Celite, and the solvent was evaporated under reduced pressure. Amino-
0.59 g (theoretical 0.60 g) of crude 1-phenyl-3-butene product was obtained as a yellow oil. The crude product contains 1.5 amino-1-phenyl-3-butyne.
%, And amino-1-phenyl-3-butane 5.0%.

Reference Example 7 "(S) -2-tert-butoxycarbonylamino-"
Production of 1-phenyl-3-butene] (S) -2-amino-1-phenyl-having an optical purity of 97% or more obtained in Reference Example 3.
To a solution composed of 11.42 g (77.6 mmol) of 3-butene and 35 ml of toluene, a solution composed of 16.93 g (77.6 mmol) of di-tert-butyl dicarbonate and 25 ml of toluene was added dropwise over 30 minutes. After stirring for another 30 minutes, it is concentrated under reduced pressure to yield (S) -2.
19.30 g of the crude product of -tert-butoxycarbonylamino-1-phenyl-3-butene (theoretical value 19.2).
g, 77.6 mmol) was obtained as a colorless powder.
The optical purity of the obtained (S) -2-tert-butoxycarbonylamino-1-phenyl-3-butene was C.
It was 97% or more by HPLC analysis using HIRALPAK AS (trade name).

[0092]

INDUSTRIAL APPLICABILITY According to the present invention, it is a precursor of (S) -2-amino-1-phenyl-3-butene and its derivatives, which are useful as pharmaceutical intermediates such as HIV protease inhibitors and renin inhibitors. (S) -2-Amino-1-phenyl-3-butyne and derivatives thereof can be industrially advantageously produced.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical display location C07C 209/84 209/88 309/66 7419-4H // A61K 31/13 AED 9454-4C C07M 7 : 00

Claims (18)

[Claims] 1. 2-Methanesulfonyloxy-1-phenyl-3-butyne. 2. A method for producing 2-amino-1-phenyl-3-butyne, which comprises reacting 2-methanesulfonyloxy-1-phenyl-3-butyne with an ammonia source. 3. The 2-amino-1-phenyl-3 according to claim 2, wherein the ammonia source uses aqueous ammonia.
-Method for producing butyne. 4. A purification method using 2-amino-1-phenyl-3-butyne as an acid addition salt. 5. The 2-amino-acid according to claim 4, wherein the acid is an inorganic acid, a carboxylic acid or a sulfonic acid.
A method for purifying 1-phenyl-3-butyne. 6. The method for purifying 2-amino-1-phenyl-3-butyne according to claim 4, wherein the acid is hydrochloric acid. 7. (S) -2-Amino-1-phenyl-3
An optically active acid addition salt of butyne. 8. (S) -2-Amino-1-phenyl-3
-Butyne L-tartrate. 9. An optically active acid is reacted with 2-amino-1-phenyl-3-butyne containing both optical antipodes to form an addition salt, and the addition salt is crystallized. A method for producing an optically active acid addition salt of (S) -2-amino-1-phenyl-3-butyne. 10. A method of reacting 2-amino-1-phenyl-3-butyne containing both optical antipodes with L-tartaric acid to form a salt, and crystallizing the salt (S). )
A method for producing 2-amino-1-phenyl-3-butyne / L-tartrate. 11. (S) -2-Amino-1-phenyl-
A method for producing (S) -2-amino-1-phenyl-3-butyne, which comprises hydrolyzing an optically active acid addition salt of 3-butyne. 12. (S) -2-Amino-1-phenyl-
A method for producing (S) -2-amino-1-phenyl-3-butyne, which comprises hydrolyzing 3-butyne / L-tartrate. 13. (R) -2-Amino-1-phenyl-
An optically active acid addition salt of 3-butyne. 14. (R) -2-Amino-1-phenyl-
3-butyne D-tartrate. 15. An optically active acid is reacted with 2-amino-1-phenyl-3-butyne containing both optical antipodes to form an addition salt, and the addition salt is crystallized. A method for producing an optically active acid addition salt of (R) -2-amino-1-phenyl-3-butyne. 16. A method of reacting 2-amino-1-phenyl-3-butyne containing both optical antipodes with D-tartaric acid to form a salt, and crystallizing the salt (R )
A method for producing 2-amino-1-phenyl-3-butyne.D-tartrate. 17. (R) -2-Amino-1-phenyl-
A method for producing (R) -2-amino-1-phenyl-3-butyne, which comprises hydrolyzing an optically active acid addition salt of 3-butyne. 18. (R) -2-Amino-1-phenyl-
A method for producing (R) -2-amino-1-phenyl-3-butyne, which comprises hydrolyzing 3-butyne / D-tartrate.