JPH09216888A - Production of optically active 3-aminoquinuclidine and thieno(3.2-b)pyridine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject compound useful as a synthetic intermediate for medicines in high yield and purity by reducing (S) or (R)-N-(α- methylbenzyl)-3-quinuclidinimine by a specific method. SOLUTION: (S)- or (R)-N-(α-Methylbenzyl)-3-quinuclidinimine represented by formula I or II is subjected to catalytic hydrogenation in the presence of platinum-based catalyst (preferably Pt/C obtained by supporting platinum or active carbon) to provide the objective (R)-N-[(S)-α-methylbenzyl]-3- aminoquinuclidine or (S)-N-[(R)-α-methylbenzyl]-3-aminoquinuclidine. The reaction is preferably carried out under 1-5kg/cm<2> hydrogen gas partial pressure at 10-30 deg.C. The reaction time is normally 1-20hr. The compound is subjected to hydrogenolysis in an acidic medium and then, reacted with a compound of formula III (R<1> is H, a 1-6C alkyl, etc.; R<2> is H, a halogen, etc.) to provide the objective thieno[3,2-b]pyrimidine derivative.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing optically active 3-aminoquinuclidine, which is useful as a synthetic intermediate for pharmaceuticals, and an optically active thieno [3,3] using the same.
2-b] relates to a method for producing a pyridine derivative. The optically active thieno [3,2-b] pyridine derivative obtained by the method of the present invention is useful as a drug.

[0002]

2. Description of the Related Art A method for synthesizing a racemic form of 3-aminoquinuclidine has long been known (LH Sternb).
ach, S.S. Kaiser, J .; Am. Chem. So
c. 74, p2215-, (1952), (European Patent Publication No. 99,789), but the method for synthesizing the optically active substance has been only partially reported (Michel L.
anglois, Jean Louis Soulie
ret. al. , Synth. Commun. , 22
(13), p1895-, (1992), JP-A-63-
196583, JP-A-1-199969). Japanese Patent Laid-Open No. 63-196583 discloses N- (3
-Aminoquinuclidinyl) -3-chlorobenzamide is optically resolved and then hydrolyzed to obtain S-(-)-3-aminoquinuclidine, and 3-quinuclidinone is converted to (R)
React with -α-methylbenzylamine, reduce the product with sodium borohydride and (S) -N-[(R)-
Method for leading to α-methylbenzyl] -3-aminoquinuclidine, separating diastereomers by recrystallization, and then hydrogenolysis in acid medium to obtain S-(−)-3-aminoquinuclidine Is listed. In addition, JP-A 1-199
969 describes a method for synthesizing R-(+)-3-aminoquinuclidine by the same method, and also describes a method for deriving from R-(-)-3-quinuclidinol. ing. Synth. Commun. ,
22 (13), p1895-, (1992) describes a method for producing an optically active 3-aminoquinuclidine.
Obtained by reacting 3-quinuclidinone (I) with (S) -α-methylbenzylamine (II) in the presence of p-toluenesulfonic acid under a toluene azeotropic condition according to the following reaction formula (1). (R) -N- by reducing (S) -N- (α-methylbenzyl) -3-quinuclidinimine (III) with sodium borohydride.
[(S) -α-methylbenzyl] -3-aminoquinuclidine (IV) was obtained, diastereomers were separated by recrystallization,
A method for hydrogenolysis in an acid medium to obtain R-3-aminoquinuclidine (V) is then described. It also describes a method of obtaining the enantiomer S-3-aminoquinuclidine (IX) by performing the same reaction using (R) -α-methylbenzylamine (VI) as the amine. . Further, in this document, the results of various studies on reducing agents for (S) -N- (α-methylbenzyl] -3-quinuclidinimine (III) are reported, but borohydrides are reported to give good results. Sodium, borane, and sodium cyanoborohydride are listed, and K-Selectride and L-Select are known as those that do not progress the reaction or significantly impair the optical purity even if the reaction proceeds.
Reaction using Ride as reducing agent, Pearlma
A catalytic hydrogenation method using an n catalyst (palladium hydroxide catalyst) is mentioned. In particular, in the catalytic hydrogenation method using a Pearlman catalyst (ethanol solvent, reaction temperature of 60 ° C., long-term (8 days)),% ee (enantiomeric excess) of 3-aminoquinuclidine, which is the final target product Is 20% ee, which is not a satisfactory result.

[0003]

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[0004]

[Chemical 6]

[0005]

The reduction method using an alkali metal borohydride, typified by sodium borohydride, is an exothermic reaction and requires cooling of the reaction system.
Since dangerous hydrogen gas is generated during the reaction, care must be taken to remove it, and purification means such as recrystallization of the product and inorganic salts of alkali metal or boron and diastereomer should be used in the post-treatment after the reaction. There are many problems, such as the fact that they must be separated by using them, and there are great restrictions on their industrial implementation. Although the reduction method by catalytic hydrogenation using a catalyst is widely used industrially, reduction of (S) or (R) -N- (α-methylbenzyl) -3-quinuclidinimine is achieved. In the above, no reduction conditions that satisfy the yield and optical purity have been reported so far. Therefore, the present invention provides (S) by the catalytic hydrogenation method.
Alternatively, a method of reducing (R) -N- (α-methylbenzyl) -3-quinuclidinimine to a corresponding amine with a satisfactory yield and optical purity, and using this amine, the following reaction formula (3) or It is intended to provide a method for producing an optically active thieno [3,2-b] pyridine derivative synthesized according to (4). Formula (3): Production of thieno [3,2-b] pyridine derivative

[0006]

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(In the above formula, R¹Is a hydrogen atom, C₁~ C₆
Alkyl group of C_Two~ C₆An alkenyl group of C_Two~ C₆
An alkynyl group of C_Three~ C₈A cycloalkyl group, C₆
~ C₁₂Aryl group or C₇~ C₁₈The aralkyl group of
Represents, R^TwoIs a hydrogen atom, C₁~ C₆Alkyl group, halo
Gen atom, hydroxyl group, C₁~ C₆The alkoxy of
Group, amino group, C₁~ C₆Alkylamino group of nitro
Group, mercapto group or C ₁~ C₆The alkylthio group of
Represent. ) Formula (4); Production of thieno [3,2-b] pyridine derivative

[0008]

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(In the above formula, R ¹ and R ² are the same as defined above.) The usefulness of the thieno [3,2-b] pyridine derivative obtained in the present invention as a drug is described in Japanese Patent Laid-Open No.
It is specified in Japanese Patent No. 310747.

[0010]

According to the present invention, (S)
Alternatively, (R) -N- (α-methylbenzyl) -3-quinuclidinimine is catalytically hydrogenated in the presence of a platinum-based catalyst to give a corresponding amine in high yield and high optical purity, that is, (R)- N-[(S) -α-methylbenzyl] -3-aminoquinuclidine or (S) -N-
[(R) -α-methylbenzyl] -3-aminoquinuclidine can be produced. When this amine is hydrolyzed by an ordinary method in an acidic medium, the corresponding optically active 3-aminoquinuclidine, that is, dextrorotatory 3-aminoquinuclidine having the absolute configuration R or left-handed rotation having the absolute configuration S is obtained. A sexy 3-aminoquinuclidine is obtained. Furthermore, this optically active 3-aminoquinuclidine and thieno [3,2
An optically active thieno [3,2-b] pyridine derivative can be obtained by reacting a -b] pyridinecarboxylic acid derivative.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention is described in detail below in the case of producing a dextrorotatory 3-aminoquinuclidine having an absolute configuration R (a levorotatory 3-aminoquinuline having an absolute configuration S. In the case of producing clidin, (S) -α-methylbenzylamine may be used instead of (R) -α-methylbenzylamine). The reaction proceeds according to the above formula (1). First, by a conventional method, 3-quinuclidinone (I) is reacted with (R) -α-methylbenzylamine (II), and (S) -N- (α-methylbenzyl) -3-
Produces quinuclidinimine (III). Then, this imine is catalytically hydrogenated in the presence of a platinum-based catalyst to give (R)
Convert to -N-[(S) -α-methylbenzyl] -3-aminoquinuclidine (IV). Platinum or platinum oxide (PtO ₂ ) is used as the platinum-based catalyst, and these may be supported on a carrier. For example, Pt / C in which platinum is supported on activated carbon is one suitable catalyst. In the reaction, imine may be dissolved in a suitable solvent, for example, a lower alcohol such as methanol or ethanol, the platinum catalyst may be suspended therein, and hydrogen gas may be introduced. The amount of the catalyst used varies depending on the kind, but is usually 1 to 100% by weight with respect to the imine. In the case of Pt / C, 5 to 20% by weight based on imine
It is preferable to use Hydrogen gas partial pressure is usually 1 to 50k
g / cm ² . If the hydrogen gas partial pressure is high, side reactions may occur, and it is not advantageous in terms of equipment.
1.0 to 10 kg / cm ² , especially 1.0 to 5.0 kg /
It is preferable to carry out the reaction under a relatively low hydrogen gas partial pressure of cm ² . The reaction temperature is arbitrary, but normally, an appropriate temperature may be selected from 0 ° C. to the boiling point of the solvent. It is advantageous to carry out the reaction at room temperature, that is, at 10 to 30 ° C. The reaction time is usually about 1 to 20 hours.
After completion of the reaction, the catalyst is removed by filtration by a conventional method, and then hydrochloric acid gas is blown into the system to convert the produced amine into an amine / hydrochloride, and then the solvent is distilled off. Alternatively, a hydrochloric acid solution is added to convert the produced amine into an amine / hydrochloride, and then the solvent is distilled off. The hydrochloric acid solution is preferably diluted with a reaction solvent and used at a concentration of about 1N-HCl. The residue was heated and dissolved in a methanol / ethanol 1/1 solution, cooled, and the precipitated crystals were collected by filtration,
The dihydrochloride salt of (R) -N-[(S) -α-methylbenzyl] -3-aminoquinuclidine (IV) can be obtained with high enantio and diastereoselectivity. In this catalytic hydrogenation step, if desired, step analysis can be carried out using a usual analytical means such as thin layer chromatography (TLC) or high performance liquid chromatography (HPLC). In addition, the amine dihydrochloride obtained as described above can be isolated by a known purification means, if desired,
For example, it can be further purified by extraction, chromatography, recrystallization and the like.

(R) -N-obtained by catalytic hydrogenation
[(S) -α-methylbenzyl] -3-aminoquinuclidine (IV) is hydrolyzed in an acidic medium by a conventional method to give a dextrorotatory 3-aminoquinuine having a corresponding absolute configuration R. Convert to clidin (V). In the hydrogenolysis reaction, the amine dihydrochloride obtained above is dissolved in an ethanol / water mixed solvent, Pd / C is added as a catalyst, and hydrogen gas is introduced at 40 to 60 ° C. Hydrogen gas partial pressure is 1 kg / c
About m ² is sufficient. The time required for the reaction is about 2 to 10 hours. After completion of the reaction, the catalyst is removed by filtration, and then the solvent is removed by concentration under reduced pressure. When the residue is repeatedly dissolved in ethanol and concentrated under reduced pressure, water is distilled out to precipitate crystals. The crystals were added to a mixed solution of methanol / ethanol, and dissolved by heating if necessary at room temperature.
That is, when it is aged at about 10 to 30 ° C, the dihydrochloride of (R) -3-aminoquinuclidine (V), which is the target substance, is precipitated, and this is collected by filtration. To convert (R) -3-aminoquinuclidine (V) dihydrochloride into free (R) -3-aminoquinuclidine, the dihydrochloride is suspended in a suitable solvent such as methanol. Then, an equivalent amount of base such as sodium methoxide is added and the mixture is heated to reflux. After concentration and precipitation of the salt, in this case sodium chloride, are removed by filtration, toluene is added thereto. Then, the remaining salt, in this case sodium chloride, precipitates, and this is filtered off, and toluene is distilled off to obtain (R) -3-aminoquinuclidine.

(R) -3-Aminoquinuclidine (V) obtained by hydrogenolysis is thieno [3,2] by a conventional method.
It can be converted to a levorotatory thieno [3,2-b] pyridine derivative (XI) having the corresponding absolute configuration R and its monohydrochloride by condensation with -b] pyridinecarboxylic acid derivative (X). . In this condensation reaction, the thieno [3,2-b] pyridinecarboxylic acid derivative (X) is first dissolved in a suitable solvent, preferably N, N'-dimethylformamide or DMI, and a suitable condensing agent, preferably N. ，
N'-carbonyldiimidazole or dicyclohexylcarbodiimide or the like is added and reacted. The amount of the condensing agent used varies depending on the type, but is usually 1.0 to 3.0 equivalents to the carboxylic acid. In the case of N, N'-carbonyldiimidazole, it is preferable to use 1.0 to 1.5 equivalents, more preferably 1.2 equivalents. The reaction temperature is preferably 40 to 80 ° C. The reaction time is usually about 1 to 3 hours.

The (R) -3-aminoquinuclidine obtained above is added to the carboxylic acid derivative activated by the condensing agent, and the mixture is reacted at the same reaction temperature as above for usually 1 to 3 hours. After completion of the reaction, water is added and the mixture is heated at about 60 ° C. for about 1 hour and then cooled and aged. The precipitated crystals can be collected by filtration to obtain a levorotatory thieno [3,2-b] pyridine derivative (XI) monohydrochloride having an absolute configuration R. In this condensation reaction step, thin layer chromatography (T
In-process analysis can be carried out using ordinary analytical means such as LC) or high performance liquid chromatography (HPLC). If desired, the monohydrochloride of the levorotatory thieno [3,2-b] pyridine derivative (XI) having the absolute configuration R obtained as described above can be purified by a known purification method, such as extraction, chromatography, recrystallization, etc., if desired. Thus, a higher purity can be obtained. Preferably, the monohydrochloride of the levorotatory thieno [3,2-b] pyridine derivative (XI) having the absolute configuration R thus obtained is dissolved in an appropriate amount of water, and activated carbon is added to the mixture.
Stir for hours. After the activated carbon is filtered off, ethanol is added to the aqueous solution to precipitate crystals. When the precipitated crystals are collected by filtration,
Left-handed thieno [3,2-] with high-purity absolute configuration R
b] The monohydrochloride of the pyridine derivative (XI) can be obtained.

The optically active thieno [3, obtained by the present invention,
Among the 2-b] pyridine derivatives, a particularly preferred compound is R-(−)-N- (1-azabicyclo [2.2.2] oct-3-yl) -7-hydroxythieno [3,2-
b] pyridine-6-carboxamide. In this step, the monohydrochloride of the dextrorotatory thieno [3,2-b] pyridine derivative (XII) having the absolute configuration S is used by using (S) -3-aminoquinuclidine as the amine to be used. Obtainable. Further, the optically active 3 produced by the present invention
-Aminoquinuclidine or optically active thieno [3,2-
The b] pyridine derivative can be converted into a physiologically acceptable salt, N-oxide derivative, hydrate, solvate or the like according to a conventional method.

[0016]

The present invention will be described more specifically with reference to the following examples. In addition, in the following examples, (R) -3-aminoquinuclidine is produced using (S) -α-methylbenzylamine, but (R) -α-methylbenzylamine is used. By operating in exactly the same manner, (S) -3-aminoquinuclidine can be produced. (S) -N- (α-methylbenzyl] -3-quinuclide
Synthesis of Nimine (III) 1.24 kg (9.91 mol) of 3-quinuclidinone was dissolved in 10.8 liter of toluene, and 1.21 kg (9.99 mol) of (S) -α-methylbenzylamine was added. The mixture was heated under reflux for 8 hours while distilling off the produced water. After completion of the reaction, the solvent was distilled off under reduced pressure to quantitatively obtain the desired product (S) -N- (α-methylbenzyl) -3-quinuclidinimine (III). I. R. (CHCl ₃ ): 1645 cm ⁻¹ NMR (CDCl ₃ ) δ: 1.3 (d, J = 7.0H
z, 3H); 1.6 (m, 4H); 2.3 (m, 1)
H); 2.7 (m, 4H); 3.3 (m, 2H);
3 (q, J = 7.0 Hz, 1H); 7.0 (m, 5H)

(R) -N-[(S) -α-methylbenzyl
]]-3-Aminoquinuclidine (IV) Synthesis (1) Slightly Impure (S) -N- (α-Methylbenzyl] -3-
5.00 g (20.73 mmol) of quinuclidinimine (III) was dissolved in 50 ml of ethanol, and 58.4 mg of platinum oxide catalyst (PtO ₂ ) was added thereto. Inject hydrogen gas to 4.3 kg / cm ² (hydrogen gas partial pressure),
The reaction was carried out at a reaction temperature of 15 ° C. for 15 hours. During this period, the supplement of hydrogen gas was not performed. After completion of the reaction, the catalyst was filtered off,
66 ml of 1N-HCl / ethanol was added, and the solvent was distilled off under reduced pressure. Methanol / ethanol = 1 / in the residue
61 ml of 1 solution was added and dissolved by heating. Crystals were precipitated when the solution was cooled, and the crystals were collected by filtration to obtain the desired product (R) -N-[(S) -α-methylbenzyl] -3-aminoquinuclidine (IV) dihydrochloride 3 .95 g (yield:
62.8%) was obtained. m. p. :> 260 ° C NMR (D ₂ O) δ: 1.55 (d, J = 6.8 Hz,
3H); 1.68 (m, 1H); 1.88 (m, 3)
H); 2.43 (m, 1H); 2.67 (m, 1H);
2.91 (m, 2H); 3.12 (m, 3H); 3.5
6 (m, 1H); 4.39 (m, 1H); 7.34
(S, 5H)

(R) -N-[(S) -α-methylbenzyl
]] Synthesis of dihydrochloride of 3-aminoquinuclidine (IV)
(Part 2) slightly impure (S) -N- (α-methylbenzyl) -3-
Dissolve 5.00 g (20.73 mmol) of quinuclidinimine (III) in 50 ml of ethanol and add to it.
2.20 g of% Pt / C catalyst (50% wet product) was added. Hydrogen gas was injected under pressure up to 4.3 kg / cm ² (hydrogen gas partial pressure), and the reaction was carried out at a reaction temperature of 20 ° C. for 3.5 hours. During this period, the supplement of hydrogen gas was not performed. After the reaction was completed, the catalyst was filtered off, 1N-HCl / ethanol (66 ml) was added, and the solvent was distilled off under reduced pressure. 61 ml of a methanol / ethanol = 1/1 solution was added to the residue and dissolved by heating. Crystals were precipitated when the solution was cooled, and the crystals were collected by filtration to obtain the desired product (R) -N-[(S) -α-methylbenzyl] -3-aminoquinuclidine (IV) dihydrochloride 3 .93 g (yield: 62.5%) was obtained.

(R) -N-[(S) -α-methylbenzyl
]] Synthesis of dihydrochloride of 3-aminoquinuclidine (IV)
(Part 3) slightly impure (S) -N- (α-methylbenzyl) -3-
5.02 g (20.73 mmol) of quinuclidinimine (III) was dissolved in 8.0 ml of toluene, and 50 ml of ethanol was added thereto. Add 5% P to this solution
0.55 g of d / C catalyst (50% wet product) was added, and hydrogen pressure gas was injected up to 4.3 kg / cm ² (hydrogen gas partial pressure), and the reaction was carried out at a reaction temperature of 23 ° C. for 2.5 hours. During this time,
Hydrogen gas was not replenished. After the reaction was completed, the catalyst was filtered off, 1N-HCl / ethanol (66 ml) was added, and the solvent was distilled off under reduced pressure. 61 ml of a methanol / ethanol = 1/1 solution was added to the residue and dissolved by heating. Crystals were precipitated when the solution was cooled, and the crystals were collected by filtration to obtain the desired product (R) -N-[(S) -α-methylbenzyl] -3.
-4.31 g (yield: 68.5%) of dihydrochloride of aminoquinuclidine (IV) was obtained.

Of (R) -3-aminoquinuclidine (V)
Synthesis of dihydrochloride (R) -N-[(S) -α-methylbenzyl] -3-aminoquinuclidine (IV) dihydrochloride 1.88 kg (6.
20 mol) was dissolved in 6.21 l of 2N-HCl, and 235 g of 10% Pd / C catalyst was added. To this, 10.7 liters of ethanol was further added, the inside of the reaction system was sufficiently replaced with hydrogen gas, and the mixture was reacted at 50 ° C. for 10 hours while stirring. After the reaction was completed, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure at an external temperature of 40 ° C. Next, 13.0 liters of ethanol was added to the residual liquid, and the mixture was again concentrated under reduced pressure at an external temperature of 40 ° C. When this operation was repeated once more, crystals began to precipitate. To this, 13.0 liters of a methanol / ethanol = 1/2 solution was added, and the mixture was heated under reflux for 10 minutes. Crystals began to precipitate when cooled with stirring, so crystals were collected by filtration and the target compound (R) -3-aminoquinuclidine (V) dihydrochloride 1.
00 kg (yield 81.0%) was obtained. [Α] ²⁰ _D = + 24.63 ° (c = 1.007, H ₂
O) m. p. :> 260 ° C. I. R. : 1607, 1521 cm ^-1 NMR (D ₂ O) δ: 1.97 (m, 4H); 2.34
(M, 1H); 3.24 (m, 5H); 3.70 (m,
2H)

(R)-(−)-N- (1-azabicyclo
[2.2.2] Oct-3-yl) -7-hydroxythio
Eno [3,2-b] pyridine-6-carboxamide (one
(Wherein R ¹ and R ² are hydrogen atoms in general formula (X1)) and
Synthesis of monohydrochloride 15 g of 7-hydroxythieno [3,2-b] pyridine-6-carboxylic acid (in the general formula (X), R ¹ and R ² are hydrogen atoms) and N, N′-carbonyldi Imidazole 15
g was dissolved in 213 ml of N, N′-dimethylformamide, and the mixture was stirred at 58 ° C. for 1 hour. (R) -3-
Aminoquinuclidine (V) dihydrochloride was added, and an additional 5
The mixture was stirred at 5-59 ° C for 1 hour. After the reaction, water 42.6
ml was added and the mixture was stirred at 60 ° C. for 1 hour. This solution at 15 ℃
After cooling to room temperature, the precipitated crystals were collected by filtration to obtain 21.98 g of the desired compound (yield: 85%). Further, 10 g of this compound was dissolved in 17 ml of water, 0.5 g of activated carbon was added, and the mixture was stirred for 2 hours. Activated carbon was collected by filtration, and 170 ml of ethanol was added to the filtrate with stirring to precipitate crystals. The precipitated crystals are collected by filtration to give 8.55 g of the highly pure target compound.
(Yield: 85.5%) was obtained. [Α] ²⁰ _D = -17.7 ° (c = 1.000, H
₂ O) m. p. :> 300 ° C. I. R. (KBr lock): 1658, 1610, 773c
m ^-1 NMR (DMSO) δ: 1.75-2.10 (m, 4
H); 2.10-2.25 (m, 1H); 2.95-
3.10 (m, 1H); 3.10-3.60 (m, 4
H); 3.60-3.75 (m, 1H); 4.25-
4.40 (m, 1H); 7.41 (d, 1H); 8.1
6 (d, 1H); 8.66 (s, 1H); 10.66
(D, 1H)

[0022]

INDUSTRIAL APPLICABILITY According to the present invention, 3-quinuclidinone is used as an optically active 3-amino compound useful as a synthetic intermediate for pharmaceuticals.
Aminoquinuclidine can be efficiently synthesized, and furthermore, an optically active thieno [3,2-
b] A pyridine derivative can be synthesized.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Tomei Oguri 14 Sunayama, Hasaki-cho, Kashima-gun, Ibaraki Prefecture Mitsubishi Chemical Co., Ltd. Kashima Plant Pharmaceutical Development Laboratory

Claims (7)

[Claims] 1. (S) -N- (α-methylbenzyl)-
(R) -N-, characterized in that 3-quinuclidinimine or (R) -N- (α-methylbenzyl) -3-quinuclidinimine is catalytically hydrogenated in the presence of a platinum-based catalyst.
[(S) -α-methylbenzyl] -3-aminoquinuclidine or (S) -N-[(R) -α-methylbenzyl)
-3-Aminoquinuclidine production method. 2. A quinuclidinone is reacted with (S) -α-methylbenzylamine to give (S) -N- (α-methylbenzyl) -3-quinuclidinimine, which is catalytically hydrogenated in the presence of a platinum-based catalyst. Then (R) -N-[(S)-
A method for producing dextrorotatory 3-aminoquinuclidine having an absolute configuration R, which comprises converting to [alpha] -methylbenzyl] -3-aminoquinuclidine and then hydrolyzing it in an acidic medium. 3. A quinuclidinone is reacted with (R) -α-methylbenzylamine to give (R) -N- (α-methylbenzyl) -3-quinuclidinimine, which is catalytically hydrogenated in the presence of a platinum-based catalyst. Then (S) -N-[(R)-
A process for producing levorotatory 3-aminoquinuclidine having an absolute configuration S, which comprises converting to [alpha] -methylbenzyl] -3-aminoquinuclidine and then hydrolyzing it in an acidic medium. 4. The method according to claim ² , wherein the catalytic hydrogenation in the presence of a platinum-based catalyst is carried out under a hydrogen gas partial pressure of 1.0 kg / cm ^{2 to} 5.0 kg / cm ² . Process for producing optically active 3-aminoquinuclidine. 5. A quinuclidinone containing (S) -α-methyl ester
(S) -N- (α-methylbenzene)
) And quinuclidinimine as a platinum-based catalyst.
By catalytic hydrogenation in the presence of a medium (R) -N-[(S)-
Converted to α-methylbenzyl] -3-aminoquinuclidine
After that, it undergoes hydrogenolysis in an acidic medium and has an absolute configuration R.
A dextrorotatory 3-aminoquinuclidine was obtained and
Thieno [3,2-b] pyridinecarl represented by formula (X)
Boronic acid derivative:(In the above formula, R¹Is a hydrogen atom, C₁~ C₆The alkyl of
Group, C_Two~ C₆An alkenyl group of C_Two~ C₆The alkini
Group, C_Three~ C₈A cycloalkyl group, C₆~ C₁₂No
Reel base or C₇~ C₁₈Represents an aralkyl group of R^Two
Is a hydrogen atom, C₁~ C₆Alkyl group, halogen atom,
Hydroxyl group, C₁~ C₆The alkoxy group, amino
Group, C₁~ C₆Alkylamino group, nitro group, merca
Put group or C ₁~ C₆Represents an alkylthio group. )When
Characterized by reacting, represented by the following general formula (XI)
Left-handed thieno [3,2-b] pi with absolute configuration R
Method for producing lysine derivative. Embedded image(In the above formula, R¹And R^TwoIs the same as the above definition) 6. A levorotatory chieno [3 having an absolute configuration R [3.
The 2-b] pyridine derivative is R-(−)-N- (1-azabicyclo [2.2.2] oct-3-yl) -7-hydroxythieno [3,2-b] pyridine-6-carboxamide. The manufacturing method according to claim 5, wherein 7. (R) -α-methyl ester containing quinuclidinone
(R) -N- (α-methylbenzene)
) And quinuclidinimine as a platinum-based catalyst.
Catalytic hydrogenation in the presence of a medium (S) -N-[(R)-
Converted to α-methylbenzyl] -3-aminoquinuclidine
After that, it undergoes hydrogenolysis in an acidic medium and has an absolute configuration S.
A dextrorotatory 3-aminoquinuclidine was obtained and
Thieno [3,2-b] pyridinecarl represented by formula (X)
Boronic acid derivative:(In the above formula, R¹Is a hydrogen atom, C₁~ C₆The alkyl of
Group, C_Two~ C₆An alkenyl group of C_Two~ C₆The alkini
Group, C_Three~ C₈A cycloalkyl group, C₆~ C₁₂No
Reel base or C₇~ C₁₈Represents an aralkyl group of R^Two
Is a hydrogen atom, C₁~ C₆Alkyl group, halogen atom,
Hydroxyl group, C₁~ C₆The alkoxy group, amino
Group, C₁~ C₆Alkylamino group, nitro group, merca
Put group or C ₁~ C₆Represents an alkylthio group. )When
Characterized by reacting, represented by the following general formula (XII)
Right-handed thieno [3,2-b] pi with absolute configuration S
Method for producing lysine derivative. Embedded image(In the above formula, R¹And R^TwoIs the same as the above definition)