JPH03218376A - 3-aminoquinuclidine compound and production of optically active 3-aminoquinuclidine using the same - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (Am is residue of N-protected amino acid) and its optically active isomer. EXAMPLE:(S)-N-[(S)-3-quinuclidinyl]-alpha-tosylphenylalanylamide. USE:A synthetic intermediate for pharmaceuticals. Useful for the synthetics of optically active 3-aminoquinuclidine which is an intermediate for antiemetic. PREPARATION:The compound of formula I can be produced by reacting an optically active N-protected amino acid of formula II with racemic 3- aminoquinuclidine. The compound of formula I can be converted to an optically active 3-aminoquinuclidine by hydrolysis after separating a diastereomer.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention provides a novel 3-aminoquinuclidine compound and an optically active 3-aminoquinuclidine that is useful as a synthetic intermediate for pharmaceuticals using the same. Concerning the manufacturing method.

[Conventional technology]

JP-A-63-196583 discloses a method for dividing N-(3-aminoquinuclidinyl)-3-chloropenzamide and then hydrolyzing it to obtain S-(-)-3-aminoquinuclidine; After reacting 3-aminoquinuclidinone with (R)-α-methylbenzylamine, it is reduced with sodium borohydride to yield N-((R)-α-methylbenzyl]-3-aminoquinuclidine. , the diastereomers are separated by recrystallization and then hydrogenolyzed in acid medium to give S-
A method for obtaining (-)-3-aminoquinuclidine is described.

Further, JP-A-1-199969 describes a method for synthesizing R-(+)-3-aminoquinuclidine using a similar method. In addition, a method of introducing from S-(-)3-quinuclidinol is also described.

[Problem to be solved by the invention]

The division method disclosed in JP-A-63-196583 is as follows:
Since the resolving agent D monotartaric acid is non-natural and very expensive, it is not suitable for production on an industrial scale. In addition, in the production method using (R)-α-methylbenzylamine, the reagent itself is expensive, and expensive reductions such as sodium borohydride, palladium, platinum oxide, etc. during hydrogenolysis are required. agents and catalysts must be used;
This cannot be said to be a manufacturing method that can supply S-C-)-3-aminoquinuclidine in large quantities at low cost. Also, JP-A-1-19
In the method of Publication No. 9969, 3-quinuclidinol must be produced using the S monoisomer synthesized by resolution.
It's not an advantageous method.

[Means to solve the problem]

As a result of a series of studies by the present inventors, we have synthesized a novel 3-aminoquinuclidine compound represented by the general formula (■) below, and by using this, optically active 3-aminoquinuclidine can be produced. They found that it can be easily manufactured and completed the present invention.

The present invention provides optically active N-protected amino acids and racemic-3-
After separating the diastereomer of the compound represented by the general formula (wherein Am represents an N-monoprotected amino acid residue) and the compound of general formula (I) obtained by reacting with aminoquinuclidine, , relates to a method for producing optically active 3-aminoquinuclidine, which is characterized by subjecting it to a hydrolysis reaction.

In this specification, the amino acid in the N-protected amino acid refers to optically active natural and unnatural amino acids, and the N-protecting group in the N-protected amino acid refers to acyl, alkylsulfonyl, arylsulfonyl, carbonate residues, Carbamoyl, substitution power refers to rubamoyl.

Suitable examples of natural and non-natural amino acids include alanine, parine, leucine, isoleucine, methionine, phenylglycine, phenylalanine, tributophane, histidine, O-methyltyrosine, O-pendyltyrosine, proline, etc. . Acyl in the N-protecting group is aliphatic and aromatic acyl, such as formyl, acetyl, propionyl, butyryl, pivaloyl, valeryl, benzoyl, substituted benzoyl, naphthoyl, substituted naphthoyl, phthaloyl, succinyl, trifluoroacetyl, ζ Nnamoil is mentioned. Alkylsulfonyl is a straight or branched alkyl having 1 to 4 carbon atoms, and includes, for example, methanesulfonyl, ethanesulfonyl, propanesulfonyl, and butanesulfonyl. Suitable examples of arylsulfonyl include pencenesulfonyl, substituted pencenesulfonyl, naphthylsulfonyl, and substituted naphthylsulfonyl. Suitable examples of carbonate residues include methoxycarbonyl, ethoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl, penzyloxycarbonyl, and substituted penzyloxycarbonyl. Suitable examples of substituted carbamoyl include methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, phenylcarbamoyl, substituted phenylcarbamoyl, penzylcarbamoyl, substituted penzylcarbamoyl, naphthylcarbamoyl, and substituted naphthylcarbamoyl.

Substituted benzoyl, substituted naphthoyl, substituted benzene 6 Sulfonyl, substituted naphthylsulfonyl, substituted penzylcarbamoyl, substituted phenylcarbamoyl, substituted penzylcarbamoyl, substituted naphthylcarbamoyl are halogens such as chlorine, bromine, and fluorine, alkoxy such as methoxy, ethoxy, and bropoxy. , methyl, ethyl, probyl, isobrobyl, lower alkyl such as butyl, and an N-protecting group having 1 to 2 nitro atoms on the aromatic ring.

Examples of optically active 3-aminoquinuclidine salts for the purpose of the present invention include inorganic acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid, or fumaric acid, maleic acid, mandelic acid, citric acid, tartaric acid, and salicylic acid. Examples include acid addition salts of organic acids and the like.

The compound of general formula (I) is obtained by reacting a compound represented by the general formula Am-OH (II) (wherein Am has the same meaning as above) or a reactive derivative thereof with racemic-3-aminoquinuclidine. Manufactured by

(1) When the compound of general formula (n) is a free carboxylic acid, the reaction is performed with dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminoprobyl)carbodiimide, 1-cyclohexyl-3( in an inert solvent in the presence of a condensing agent such as 2-morpholinoethyl)carbodiimide,
It is carried out under cooling, at room temperature, or under heating. Note that Compound (I[) can be reacted with phosphorus halide in an inert solvent in advance, and then condensed with racemic-3-aminoquinuclidine. For example, when the phosphorus halide is phosphorus trichloride, about 0.5 mol of phosphorus trichloride is added to the compound (IF) in advance in an inert solvent, and triethylamine, pyridine, N.I. After reacting in the presence of a tertiary base such as N-dimethylaniline or N-methylmorpholine under cooling or at room temperature, it reacts with racemic-3-aminoquinuclidine in an inert solvent at room temperature or under heating. let

(2) When using an acid halide such as acid chloride or acid bromide as the reactive derivative of the carboxylic acid of general formula (II), the reaction is carried out in an inert solvent using triethylamine, pyridine, N, N-dimethylaniline, N-methyl It is carried out under cooling or at room temperature in the presence of a tertiary base such as morpholine.

(3) A mixture of symmetric acid anhydrides or alkyl carbonic acid mixed acid anhydrides, alkyl phosphoric acid mixed acid anhydrides, alkyl phosphorous acid mixed acid anhydrides, sulfuric acid mixed acid anhydrides, etc. as reactive derivatives of compound (It) When using an acid anhydride, the reaction is carried out in an inert solvent in the presence of a tertiary base such as triethylamine, pyridine, N,N-dimethylaminopyridine, N-methylmorpholine, etc., under cooling, at room temperature, or under heating. .

(4) As reactive derivatives of compound (II), p-nitrophenyl ester, p-chlorophenyl ester, p-
It can also be reacted with esters such as nitrothiophenyl ester and N-hydroxysuccinimide ester,
The reaction is carried out in an inert solvent at room temperature or with heating.

Inert solvents used in each of the above condensation reactions include benzene, toluene, xylene, methanol, ethanol, isobrobyl alcohol, ethyl ether, dioxane, tetrahydrofuran, chloroform, dichloromethane, dichloroethane, hexamethylphosphoric triamide. , diethylene glycol, dimethylformamide,
N-methylmorpholine or the like or a mixed solvent thereof, and when compound (II) is a reactive solvent, it can be appropriately selected depending on the type thereof.

The diastereomeric compound of general formula (1) can be separated and purified by conventional methods such as chromatography and recrystallization.

Separation and purification by the recrystallization method is carried out by recrystallizing the compound itself or a salt formed by an acid.

As the acid forming the salt, an inorganic acid or an organic acid is used.

Preferred examples of inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; preferred examples of organic acids include fumaric acid, maleic acid, lactic acid, citric acid, and tartaric acid in addition to the N-monoprotected amino acids mentioned above. , dibenzoyltartaric acid, mandelic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid,
10 Examples include camphorsulfonic acid and malic acid.

Of these, it goes without saying that optically active forms of acids having asymmetric carbon atoms are used.

The diastereomer-separated compound of formula (I) is treated with hydrochloric acid,
An optically active form of 3-aminoquinuclidine can be obtained by hydrolysis in the presence of an acid such as sulfuric acid or an alkali such as sodium hydroxide or potassium hydroxide.

Margin 1 below [Operations and Effects of the Invention] The present invention provides a novel 3-aminoquinuclidine compound and a method for easily producing optically active 3-aminoquinuclidine on an industrial scale using the same. .

Optically active 3-aminoquinuclidine is 5-HT3, which has pharmacological effects such as suppressing emesis induced by administration of anticancer drugs such as cisplatin, as disclosed in JP-A-2-28182. It is useful as an intermediate for antagonistic penzoxazine derivatives.

In the present invention, natural optically active amino acids can be obtained in large quantities at low cost, and by selecting N-protecting group amino acids, it is possible to easily produce the S-form or R-form of 3-aminoquinuclidine, respectively. can.

〔Example〕

EXAMPLES Hereinafter, the present invention will be specifically explained with reference to Examples, but the present invention is not limited thereto.

Example 1 2.0 g of (S)-α-tosylphenylalanine was dissolved in 50 ml of chloroform, and 1.0 g of thionyl chloride was dissolved. Add 2 ml and heat to reflux for 45 minutes. Concentrate the reaction solution under reduced pressure,
(S)-α-tosyl phenylalanyl chloride was obtained.

Racemic-3-aminoquinuclidine 1. 74 g was dissolved in 40 ml of chloroform, a chloroform solution of (S)-α-tosylphenylalanyl chloride was added under water cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, made alkaline with an aqueous potassium carbonate solution, added with ethyl acetate to separate the organic layer, and dried over magnesium sulfate. The solvent is distilled off, the residue is dissolved in ethanol and ethanolic hydrochloric acid is added. The precipitated crystals were collected by filtration and recrystallized from methanol to give a melting point of 282°C (decomposed) and an optical rotation of -1.
(S)-N-((
S)-3-quinuclidinyl]-α-tosylphenylalanylamide was obtained.

Example 2 The crystals obtained in Example 1 were diluted with 30% sulfuric acid to give 4
Heat under reflux for an hour. After cooling, the reaction solution is made alkaline with aqueous sodium hydroxide, the water is dried under reduced pressure, and the residue is extracted with benzene. When the solvent is distilled off, the optical rotation is -63
．． S-(-)-3-aminoquinuclidine with 5° (C=1, water) was obtained. The corresponding hydrochloride has an optical rotation of −2
4.0° (c=1, water).

Example 3 (S)-1-cinnamoylproline 1 2. 5 g triethylamine 13.4 ml and ethyl acetate 100
ml solution was cooled to 0°C and diluted with pivaloyl chloride7.
Add a solution of 0 g in 50 ml of ethyl acetate and stir for 30 minutes. Add racemic-3-aminoquinuclidine 7 to this reaction solution.
．． Add a solution of 0 g in 30 ml of ethyl acetate and stir for 1 hour. After this, add dilute hydrochloric acid, separate the aqueous layer, make alkaline with aqueous sodium hydroxide, then add ethyl acetate,
Separate the organic layer and dry over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was recrystallized twice from ethyl acetate to give (S)-1-cinnamoyl N having a melting point of 202-203°C and an optical rotation of -2.3° (c=1, ethanol). −〔
(R)-3-quinuclidinyl]prolylamide was obtained.

Example 4 The crystals obtained in Example 3 were treated with 30% dilute sulfuric acid,
Heat under reflux for 4 hours. After cooling, the reaction solution is made alkali with aqueous sodium hydroxide, the water is dried under reduced pressure, and the residue is extracted with benzene.

After distilling off the solvent, R-(10)-3-aminoquinuclidine with an optical rotation of +63.2° (c=1, water) was obtained.

Example 5 A solution of 2.4 g of (R)-α-tosylphenylglycine in 1.1 ml of triethylamine and 20 ml of ethyl acetate was cooled to 0°C, a solution of 1.1 g of pivaloyl chloride in 10 ml of ethyl acetate was added, and the mixture was heated for 30 minutes. Stir. A solution of 1.1 g of racemic-3-aminoquinuclidine in 10 ml of ethyl acetate is added to this reaction solution and stirred for 1 hour. Thereafter, dilute hydrochloric acid is added, the aqueous layer is separated and made alkaline with aqueous sodium hydroxide, then ethyl acetate is added, the organic layer is separated and dried over magnesium sulfate. Remove the solvent under reduced pressure,
Dissolve the residue in ethanol and add ethanolic hydrochloric acid.

The precipitated crystals were collected by filtration and recrystallized twice from ethanol to give a melting point of 282°C (decomposed) and an optical rotation of -26.2° (c=
(S)-N-(quinuclidinyl)-(R)-α-tosylphenylglycylamide having (1, methanol)

Example 6 The crystals obtained in Example 5 were treated with 30% dilute sulfuric acid,
Heat under reflux for 4 hours. After cooling, the reaction solution is made alkaline with aqueous sodium hydroxide, the water is dried under reduced pressure, and the residue is extracted with benzene.

When the solvent was distilled off, S-(-)-3-aminoquinuglydine having an optical rotation of -62.9° (c=1, water) was obtained.

Example 7 A solution of 2.3 g of (S)-α-phthalylphenylalanine in 1.1 ml of triethylamine and 20 ml of ethyl acetate was cooled to 0°C, and pivaloyl chloride 1. 1 g
Add 10 ml of ethyl acetate solution and stir for 30 minutes.

Add 1.0% of racemic-3-aminoquinuclidine to this reaction solution.
Add a solution of 1 g in 10 ml of ethyl acetate and stir for 1 hour. After this, add dilute hydrochloric acid, separate the aqueous layer, make alkaline with aqueous sodium hydroxide, then add ethyl acetate,
Separate the organic layer and dry with magnesium sulfate. The solvent is removed under reduced pressure, the residue is dissolved in ethanol, and ethanolic hydrochloric acid is added. The precipitated crystals were collected by filtration and diluted with ethanol.
After recrystallization, melting point: 294°C (decomposed), optical rotation: 105
．． (S)-N- with 5° (c=L methanol)
Quinuclidinyl)-(S)-α-phthalocylphenylalanylamide was obtained.

Example 8 17 The crystals obtained in Example 7 were treated with O using 30% dilute sulfuric acid.
Heat under stirring for 4 hours. After cooling, the reaction solution was made alkaline with sodium hydroxide water, and the water was dried under reduced pressure.
Extract the residue with benzene.

When the solvent was distilled off, S-(=)-3-aminoquinuclidine having an optical rotation of -63.3° (c=1, water) was obtained.

Example 9 2.5 g of racemic-3-aminoquinuclidine was dissolved in 50 ml of acetonitrile, and 6.4 g of (S)-1 metabenzenesulfonyl chloride was added under water cooling, followed by stirring at room temperature for 30 minutes. do.

After concentrating the reaction solution under reduced pressure, a potassium carbonate aqueous solution was added to make it alkaline, and ethyl acetate was added for extraction. After drying over magnesium sulfate, the mixture was filtered.

The filtrate is distilled off under reduced pressure, leaving an oily substance. Ethyl acetate in an amount about 3 times the oil content was added and left to stand overnight to obtain yellow crystals. When these crystals were recrystallized from ethyl acetate, they had a melting point of 202-204°C and an optical rotation of 18:-100.2 ( c=1, chloroform) (S
)-1-methanitobenzenesulfonyl-N-((R)
3.1 g of crystals of -3-quinuclidinyl)prolylamide were obtained.

Example 10 The crystals obtained in Example 9 were refluxed with 15% hydrochloric acid for 20 hours, and the reaction solution was extracted with chloroform, resulting in (S)-
1-methane 1-lobenzenesulfonyl purine is recovered. The aqueous layer was concentrated under reduced pressure, methanol was added to the residue, and when left to stand, R- (+) = 3-aminoquinuclidine 2
The hydrochloride was obtained. Optical rotation: +24.0 (c=1, water)
.

Claims (2)

[Claims] (1) Compounds represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, Am represents an N-protected amino acid residue.) and its optically active form. (2) An optically active N-protected amino acid is reacted with racemic-3-aminoquinuclidine to produce the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) (In the formula, Am is the residue of the N-protected amino acid. An optically active 3 compound, which is characterized by producing a compound represented by
- A method for producing aminoquinuclidine.