JP2012153624A - Iminophosphorane compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a 3-amino quinuclidine compound which is useful as a synthetic intermediate of a pharmaceutical or the like, and to provide an iminophosphorane compound which is used for the method for producing the 3-amino quinuclidine compound.SOLUTION: The iminophosphorane compound is represented by a formula (1). The method for producing the 3-amino quinuclidine compound represented by a formula (4) includes the hydrolysis of the iminophosphorane compound (in the formula (1) or (4), Rrepresents a 1-6C alkyl group, an aryl group, a heterocycle group or the like, n represents the number of Rand is either of integers of 0-12, and Rrepresents a 1-6C alkyl group, an aryl group, a 1-6C alkoxy group, an aryloxy group or the like).

Description

  The present invention relates to iminophosphorane compounds. More specifically, the present invention relates to a method for producing a 3-aminoquinuclidine compound that is useful as a synthetic intermediate for pharmaceutical products, and an iminophosphorane compound used in the production method.

3-Aminoquinuclidine compounds are useful as synthetic intermediates for pharmaceuticals such as immune disorders, gastrointestinal disorders, respiratory disorders, cardiovascular disorders, central nervous system disorders, inflammatory diseases, asthma, pain and migraine. A compound.
As a method for producing a 3-aminoquinuclidine compound, for example, in Patent Document 1, N- (3-aminoquinuclidinyl) -3-chlorobenzamide is optically resolved and then hydrolyzed to obtain S-(-)- A method for obtaining 3-aminoquinuclidine and reacting 3-quinuclidinone with (R) -α-methylbenzylamine and reducing the product with sodium borohydride to give (S) -N-[(R)- [alpha] -methylbenzyl] -3-aminoquinuclidine, diastereomers are separated by recrystallization, and then hydrogenolyzed in an acid medium to obtain S-(-)-3-aminoquinuclidine Is described.
Patent Document 2 describes a method for synthesizing R-(+)-3-aminoquinuclidine by a similar method, and also describes a method for deriving from S-(-)-3-quinuclidinol. Has been.

  In Patent Document 3, (S) -α-methylbenzylamine is reacted with quinuclidinone to give (S) -N- (α-methylbenzyl) -3-quinuclidinimine, which is contacted with hydrogen in the presence of a platinum-based catalyst. A right-handed rotation having an absolute configuration R, which is converted to (R) -N-[(S) -α-methylbenzyl] -3-aminoquinuclidine and then hydrocracked in an acidic medium Of 3-aminoquinuclidine, and (R) -N- (α-methylbenzyl) -3-quinuclidinimine by reacting quinuclidinone with (R) -α-methylbenzylamine. Catalytic hydrogenation in the presence of a catalyst to convert to (S) -N-[(R) -α-methylbenzyl] -3-aminoquinuclidine, followed by hydrogenolysis in an acidic medium Levorotatory with absolute configuration S Aminoquinuclidine method for producing 3-is described.

JP-A 63-196583 JP-A-1-199969 JP-A-9-216888

  An object of the present invention is to provide a method for industrially advantageously producing a 3-aminoquinuclidine compound that is useful as a synthetic intermediate for pharmaceuticals and the like, and an iminophosphorane compound used in the production method. .

  The present inventors diligently studied to solve the above problems. As a result, a 3-haloquinuclidine compound or the like is azidated in a polar solvent to obtain a 3-azidoquinuclidine compound, which is reacted with a phosphine compound, and then the polar solvent is removed to obtain an iminophosphorane compound. It has been found that a 3-aminoquinuclidine compound can be advantageously synthesized industrially by hydrolyzing the compound. The present invention has been completed based on these findings.

That is, the present invention includes the following.
[1] An iminophosphorane compound represented by formula (1).

（式（１）中、Ｒ¹は無置換の若しくは置換基を有するＣ１〜６アルキル基、無置換の若しくは置換基を有するアリール基または無置換の若しくは置換基を有するヘテロ環基を示す。ｎはＲ¹の数を示し且つ０〜１２のいずれかの整数である。Ｒ²は無置換の若しくは置換基を有するＣ１〜６アルキル基、無置換の若しくは置換基を有するアリール基、無置換の若しくは置換基を有するＣ１〜６アルコキシ基または無置換の若しくは置換基を有するアリールオキシ基を示す。）

(In formula (1), R ¹ represents an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted aryl group, or an unsubstituted or substituted heterocyclic group. N Represents the number of R ¹ and is an integer of 0 to 12. R ² is an unsubstituted or substituted C 1-6 alkyl group, an unsubstituted or substituted aryl group, an unsubstituted Or a substituted C1-6 alkoxy group or an unsubstituted or substituted aryloxy group.)

[2] A compound represented by the formula (2) is azidated in a polar solvent to obtain a compound represented by the formula (3), and a phosphine compound: PR ² ₃ (where R ² is unsubstituted or substituted) A C1-6 alkyl group having a group, an unsubstituted or substituted aryl group, an unsubstituted or substituted C1-6 alkoxy group or an unsubstituted or substituted aryloxy group. The manufacturing method of the iminophosphorane compound represented by Formula (1) including making it react and then removing a polar solvent.

（式（２)中、Ｒ³はハロゲン原子またはスルホン酸エステル基を示し、Ｒ¹およびｎは式（１)中のそれらと同じ意味を示す。）

(In formula (2), R ³ represents a halogen atom or a sulfonate group, and R ¹ and n have the same meaning as those in formula (1).)

（式（３)中、Ｒ¹およびｎは式（１)中のそれらと同じ意味を示す。）

(In formula (3), R ¹ and n have the same meaning as in formula (1).)

[3] A method for producing a 3-aminoquinuclidine compound represented by formula (4), comprising hydrolyzing an iminophosphorane compound represented by formula (1).

（式（４）中、Ｒ¹およびｎは式（１)中のそれらと同じ意味を示す。）

(In formula (4), R ¹ and n have the same meaning as in formula (1).)

  ADVANTAGE OF THE INVENTION According to this invention, the 3-amino quinuclidine compound useful as a synthetic intermediate of a pharmaceutical etc. can be manufactured industrially advantageously.

[Iminophosphorane compound]
The iminophosphorane compound of the present invention is a compound represented by the formula (1).
The meanings of symbols, terms and the like used in the present specification are as follows.
First, the term “unsubstituted” means that the group is only a parent nucleus. When there is no description of “having a substituent” and only the name of the group serving as a mother nucleus is used, it means “unsubstituted” unless otherwise specified.
On the other hand, the term “having a substituent” means that any hydrogen atom of a group serving as a mother nucleus is substituted with a group having the same or different structure from the mother nucleus. Accordingly, the “substituent” is another group bonded to a group serving as a mother nucleus. The number of substituents may be one, or two or more. Two or more substituents may be the same or different.
Terms such as “C1-6” indicate that the number of carbon atoms of the group serving as the mother nucleus is 1-6. This number of carbon atoms does not include the number of carbon atoms present in the substituent. For example, a butyl group having an ethoxy group as a substituent is classified as a C2 alkoxy C4 alkyl group.

The “substituent” is not particularly limited as long as it is chemically acceptable and has the effects of the present invention.
Examples of groups that can be “substituents” include halogen atoms such as fluorine atom, chlorine atom, bromine atom, iodine atom; methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, s-butyl C1-6 alkyl group such as a group, i-butyl group, t-butyl group, n-pentyl group, n-hexyl group; C3-8 such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group A cycloalkyl group; a vinyl group, a 1-propenyl group, a 2-propenyl group, a 1-butenyl group, a 2-butenyl group, a 3-butenyl group, a 1-methyl-2-propenyl group, a 2-methyl-2-propenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1-methyl-2-butenyl group, 2-methyl-2-butenyl group, 1-hetenyl group C2-6 alkenyl groups such as xenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, 5-hexenyl group; 2-cyclopropenyl group, 2-cyclopentenyl group, 3-cyclohexenyl group, 4- C3-8 cycloalkenyl groups such as cyclooctenyl group; ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-methyl-2-propynyl group, 2- Methyl-3-butynyl group, 1-pentynyl group, 2-pentynyl group, 3-pentynyl group, 4-pentynyl group, 1-methyl-2-butynyl group, 2-methyl-3-pentynyl group, 1-hexynyl group, A C2-6 alkynyl group such as a 1,1-dimethyl-2-butynyl group;

  C1-6 alkoxy groups such as methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, s-butoxy group, i-butoxy group, t-butoxy group; vinyloxy group, allyloxy group, propenyl C2-6 alkenyloxy groups such as oxy group and butenyloxy group; C2-6 alkynyloxy groups such as ethynyloxy group and propargyloxy group; C6-10 aryl groups such as phenyl group and naphthyl group; phenoxy group and 1-naphthoxy group A C7-10 aralkyl group such as a benzyl group or a phenethyl group; a C7-11 aralkyloxy group such as a benzyloxy group or a phenethyloxy group; a formyl group, an acetyl group, a propionyl group, a benzoyl group, C1- such as a cyclohexylcarbonyl group Acyl group; C1-7 acyloxy group such as formyloxy group, acetyloxy group, propionyloxy group, benzoyloxy group, cyclohexylcarbonyloxy group; methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, i-propoxycarbonyl group A C1-6 alkoxycarbonyl group such as n-butoxycarbonyl group and t-butoxycarbonyl group; carboxyl group;

  Hydroxyl group; oxo group; C1-6 haloalkyl such as chloromethyl group, chloroethyl group, trifluoromethyl group, 1,2-dichloro-n-propyl group, 1-fluoro-n-butyl group, perfluoro-n-pentyl group Group; C2-6 haloalkenyl group such as 2-chloro-1-propenyl group and 2-fluoro-1-butenyl group; 4,4-dichloro-1-butynyl group, 4-fluoro-1-pentynyl group, 5- C2-6 haloalkynyl group such as bromo-2-pentynyl group; C1-6 haloalkoxy group such as 2-chloro-n-propoxy group and 2,3-dichlorobutoxy group; 2-chloropropenyloxy group, 3-bromo C2-6 haloalkenyloxy groups such as butenyloxy group; 4-chlorophenyl group, 4-fluorophenyl group, 2,4-dichlorophen C6-10 haloaryl group such as 4-fluorophenyloxy group, C6-10 haloaryloxy group such as 4-fluorophenyloxy group, 4-chloro-1-naphthoxy group; chloroacetyl group, trifluoroacetyl group, trichloroacetyl group, 4- Halogen-substituted C1-7 acyl groups such as chlorobenzoyl groups;

  Cyano group; isocyano group; nitro group; isocyanato group; cyanato group; amino group; C1-6 alkylamino group such as methylamino group, dimethylamino group and diethylamino group; C6-10 arylamino group such as anilino group and naphthylamino group Group: C7-11 aralkylamino group such as benzylamino group, phenylethylamino group; C1-7 such as formylamino group, acetylamino group, propanoylamino group, butyrylamino group, i-propylcarbonylamino group, benzoylamino group Acylamino group; C1-6 alkoxycarbonylamino group such as methoxycarbonylamino group, ethoxycarbonylamino group, n-propoxycarbonylamino group, i-propoxycarbonylamino group; aminocarbonyl group, dimethylaminocarbonyl An unsubstituted or substituted aminocarbonyl group such as phenylaminocarbonyl group, N-phenyl-N-methylaminocarbonyl group; iminomethyl group, (1-imino) ethyl group, (1-imino) -n-propyl A C1-6 alkyl group substituted with an imino group such as a group; hydroxyiminomethyl group, (1-hydroxyimino) ethyl group, (1-hydroxyimino) propyl group, methoxyiminomethyl group, (1-methoxyimino) ethyl A C1-6 alkyl group substituted with a hydroxyimino group such as a group;

  Mercapto group; isothiocyanato group; thiocyanato group; C1-6 alkylthio such as methylthio group, ethylthio group, n-propylthio group, i-propylthio group, n-butylthio group, i-butylthio group, s-butylthio group, t-butylthio group C2-6 alkenylthio groups such as vinylthio groups and allylthio groups; C2-6 alkynylthio groups such as ethynylthio groups and propargylthio groups; C6-10 arylthio groups such as phenylthio groups and naphthylthio groups; thiazolylthio groups and pyridylthio groups A heteroarylthio group of C7-11 aralkylthio group such as benzylthio group and phenethylthio group; (methylthio) carbonyl group, (ethylthio) carbonyl group, (n-propylthio) carbonyl group, (i-propylthio) carbonyl group, ( - butylthio) carbonyl group, (i-butylthio) carbonyl group, (s-butylthio) carbonyl group, (t-butylthio) (Cl to 6 alkylthio, such as carbonyl groups) carbonyl group;

  C1-6 alkylsulfinyl groups such as methylsulfinyl group, ethylsulfinyl group, t-butylsulfinyl group; C2-6 alkenylsulfinyl groups such as allylsulfinyl group; C2-6 alkynylsulfinyl groups such as propargylsulfinyl group; phenylsulfinyl group and the like A heteroarylsulfinyl group such as thiazolylsulfinyl group and pyridylsulfinyl group; a C7-11 aralkylsulfinyl group such as benzylsulfinyl group and phenethylsulfinyl group; a methylsulfonyl group, an ethylsulfonyl group, t- C1-6 alkylsulfonyl group such as butylsulfonyl group; C2-6 alkenylsulfonyl group such as allylsulfonyl group; C2 such as propargylsulfonyl group A C6-10 arylsulfonyl group such as a phenylsulfonyl group; a heteroarylsulfonyl group such as a thiazolylsulfonyl group or a pyridylsulfonyl group; a C7-11 aralkylsulfonyl group such as a benzylsulfonyl group or a phenethylsulfonyl group;

  5-membered heteroaryl groups such as pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl; pyridyl, pyrazinyl Groups, 6-membered heteroaryl groups such as pyrimidinyl groups, pyridinidyl groups, triazinyl groups; saturated heterocyclyl groups such as aziridinyl groups, epoxy groups, pyrrolidinyl groups, tetrahydrofuranyl groups, piperidyl groups, piperazinyl groups, morpholinyl groups; trimethylsilyl groups, triethylsilyl groups A tri-C1-6 alkyl-substituted silyl group such as a t-butyldimethylsilyl group; a triphenylsilyl group;

  These “substituents” may be those in which any hydrogen atom in the group is further substituted with another “substituent”.

(R ¹ )
R ¹ represents an unsubstituted or substituted C 1-6 alkyl group, an unsubstituted or substituted aryl group, or an unsubstituted or substituted heterocyclic group. n shows the number of R < ¹ > and is an integer in any one of 0-12.

The “C1-6 alkyl group” for R ¹ may be linear or branched. As the alkyl group, methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, i-propyl group, i-butyl group, s-butyl group, t-butyl group I-pentyl group, neopentyl group, 2-methylbutyl group, 2,2-dimethylpropyl group, i-hexyl group and the like.

Examples of the “substituted C1-6 alkyl group” in R ¹ include C3-8 such as cyclopropylmethyl group, 2-cyclopropylethyl group, cyclopentylmethyl group, 2-cyclohexylethyl group, 2-cyclooctylethyl group, and the like. Cycloalkyl C1-6 alkyl group; fluoromethyl group, chloromethyl group, bromomethyl group, difluoromethyl group, dichloromethyl group, dibromomethyl group, trifluoromethyl group, trichloromethyl group, tribromomethyl group, 2,2,2 -Trifluoroethyl group, 2,2,2-trichloroethyl group, pentafluoroethyl group, 4-fluorobutyl group, 4-chlorobutyl group, 3,3,3-trifluoropropyl group, 2,2,2-tri Fluoro-1-trifluoromethylethyl group, perfluorohexyl group, perchlorohe C1-6 haloalkyl group such as syl group, 2,4,6-trichlorohexyl group; hydroxy C1-6 alkyl group such as hydroxymethyl group, 2-hydroxyethyl group; methoxymethyl group, dimethoxymethyl group, ethoxymethyl group, A C1-6 alkoxy C1-6 alkyl group such as a methoxyethyl group, ethoxyethyl group, methoxy-n-propyl group, n-propoxymethyl group, i-propoxyethyl group, s-butoxymethyl group, t-butoxyethyl group; C1-7 acyloxy C1-6 alkyl groups such as formyloxymethyl group, acetoxymethyl group, 2-acetoxyethyl group, propionyloxymethyl group, propionyloxyethyl group; iminomethyl group, (1-imino) ethyl group, (1- C1 substituted with an imino group such as an imino) propyl group 6 alkyl groups; substituted with hydroxyimino groups such as hydroxyiminomethyl group, (1-hydroxyimino) ethyl group, (1-hydroxyimino) -n-propyl group, methoxyiminomethyl group, (1-methoxyimino) ethyl group C1-6 alkyl group; C7-11 aralkyl group such as benzyl group, 4-fluorophenethyl group, diphenylmethyl group; (3-pyridyl) methyl group, (2-pyrazinyl) ethyl group, (2-pyrimidinyl) ) C4-11 heteroaralkyl group such as methyl group.

The “aryl group” in R ¹ may be monocyclic or polycyclic. In the polycyclic aryl group, if at least one ring is an aromatic ring, the remaining ring may be a saturated alicyclic ring, an unsaturated alicyclic ring, or an aromatic ring. Examples of the aryl group include a phenyl group, a naphthyl group, an azulenyl group, an indenyl group, an indanyl group, and a tetralinyl group.

The “heterocyclic group” in R ¹ includes 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as atoms constituting the ring. The heterocyclic group may be monocyclic or polycyclic.
Examples of the heterocyclic group include a 5-membered heteroaryl group, a 6-membered heteroaryl group, a condensed heteroaryl group, a saturated heterocyclic group, and a partially unsaturated heterocyclic group.

  Examples of the 5-membered heteroaryl group include pyrrolyl groups such as pyrrol-1-yl group, pyrrol-2-yl group and pyrrol-3-yl group; furyl groups such as furan-2-yl group and furan-3-yl group. A thienyl group such as a thiophen-2-yl group and a thiophen-3-yl group; an imidazolyl group such as an imidazol-1-yl group, an imidazol-2-yl group, an imidazol-4-yl group, and an imidazol-5-yl group; A pyrazolyl group such as a pyrazol-1-yl group, a pyrazol-3-yl group, a pyrazol-4-yl group, and a pyrazol-5-yl group; an oxazol-2-yl group, an oxazol-4-yl group, and an oxazole-5 -Oxazolyl groups such as yl groups; isoxazol-3-yl groups, isoxazol-4-yl groups, isoxazol-5-yl groups and the like Isoxazolyl group; thiazolyl group such as thiazol-2-yl group, thiazol-4-yl group, thiazol-5-yl group; isothiazol-3-yl group, isothiazol-4-yl group, isothiazol-5-yl 1,2,3-triazol-1-yl group, 1,2,3-triazol-4-yl group, 1,2,3-triazol-5-yl group, 1,2,4 -Triazolyl groups such as triazol-1-yl group, 1,2,4-triazol-3-yl group, 1,2,4-triazol-5-yl group; 1,2,4-oxadiazole-3- Oxadiazolyl group such as yl group, 1,2,4-oxadiazol-5-yl group, 1,3,4-oxadiazol-2-yl group; 1,2,4-thiadiazol-3-yl group, 1, , 4-thiadiazol-5-yl group, 1,3,4-thiadiazol-2-yl group and the like thiadiazolyl group; tetrazol-1-yl group, tetrazol-2-yl group and the like; it can.

  Examples of the 6-membered heteroaryl group include pyridyl groups such as pyridin-2-yl group, pyridin-3-yl group and pyridin-4-yl group; pyrazinyl groups such as pyrazin-2-yl group and pyrazin-3-yl group A pyrimidinyl group such as a pyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrimidin-5-yl group; a pyridazinyl group such as a pyridazin-3-yl group and a pyridazin-4-yl group; a triazinyl group; be able to.

  Other heterocyclic groups include: aziridin-1-yl group, aziridin-2-yl group, epoxy group; pyrrolidin-1-yl group, pyrrolidin-2-yl group, pyrrolidin-3-yl group, tetrahydrofuran-2- Yl group, tetrahydrofuran-3-yl group; piperidin-1-yl group, piperidin-2-yl group, piperidin-3-yl group, piperidin-4-yl group, piperazin-1-yl group, piperazin-2-yl Group, morpholin-2-yl group, morpholin-3-yl group, morpholin-4-yl group; 1,3-benzodioxol-4-yl group, 1,3-benzodioxol-5-yl group 1,4-benzodioxan-5-yl group, 1,4-benzodioxan-6-yl group, 3,4-dihydro-2H-1,5-benzodioxepin-6-yl group, , 4-Dihydro-2H-1,5-benzodioxepin-7-yl group, 2,3-dihydrobenzofuran-4-yl group, 2,3-dihydrobenzofuran-5-yl group, 2,3-dihydro A benzofuran-6-yl group, a 2,3-dihydrobenzofuran-7-yl group;

(R ² )
R ² has an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted aryl group, an unsubstituted or substituted C1-6 alkoxy group, or an unsubstituted or substituted group. An aryloxy group is shown.

"C1~6 alkyl group having unsubstituted or substituted" in R ^2, and "aryl group having unsubstituted or substituted group" may include the same as those in R ^1.

As the “C1-6 alkoxy group” in R ² , a methoxy group, an ethoxy group, an i-propoxy group, an n-butoxy group, an i-butoxy group, an s-butoxy group, a t-butoxy group, an n-pentyloxy group, An i-pentyloxy group, n-hexyloxy group, etc. can be mentioned.
Examples of the “substituted C1-6 alkoxy group” in R ² include a fluoromethoxy group, a chloromethoxy group, a bromomethoxy group, a difluoromethoxy group, a dichloromethoxy group, a dibromomethoxy group, a trifluoromethoxy group, a trichloromethoxy group, Tribromomethoxy group, 2,2,2-trifluoroethoxy group, 2,2,2-trichloroethoxy group, pentafluoroethoxy group, 4-fluorobutoxy group, 3,3,3-trifluoropropoxy group, 2, C1-6 haloalkoxy groups such as 2,2-trifluoro-1-trifluoromethylethoxy group and perfluorohexyloxy group; methoxymethoxy group, 1-methoxyethoxy group, 2-methoxyethoxy group, ethoxymethoxy group, 1 -Ethoxyethoxy group, 2-ethoxyethoxy group, 1-methyl A C1-6 alkoxy C1-6 alkoxy group such as a toxi-n-propoxy group, 2-methoxy-n-propoxy group, 3-methoxy-n-propoxy group; cyclopropylmethoxy group, cyclobutylmethoxy group, cyclopentylmethoxy group, C3-8 cycloalkyl C1-6 alkoxy groups such as cyclohexylmethoxy group, 2-methylcyclopropylmethoxy group, 2,3-dimethylcyclopropylmethoxy group, 2-cyclopropylethoxy group; benzyloxy group, phenethyloxy group, etc. C7-11 aralkyloxy group; and the like.

Examples of the “aryloxy group” for R ² include a phenoxy group and a 1-naphthoxy group.
Examples of the “aryloxy group having a substituent” for R ² include a haloaryloxy group such as a 4-fluorophenyloxy group and a 4-chloro-1-naphthoxy group; a 4-methylphenoxy group, a 2-isopropylphenoxy group, 3 An aryloxy group substituted with a C1-6 alkyl group such as a 1,5-dimethylphenoxy group.

[Method for producing iminophosphorane compound and 3-aminoquinuclidine compound]
In the method for producing an iminophosphorane compound of the present invention, a compound represented by the formula (2) is azidated in a polar solvent to obtain a compound represented by the formula (3), and a phosphine compound: PR ² ₃ (provided that R ² represents an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted aryl group, an unsubstituted or substituted C1-6 alkoxy group, or an unsubstituted or substituted group. An aryloxy group having a reaction) and then removing the polar solvent. By this production method, the iminophosphorane compound represented by the formula (1) can be advantageously obtained industrially.
And the manufacturing method of the 3-amino quinuclidine compound of this invention includes hydrolyzing the iminophosphorane compound represented by Formula (1). By this production method, the 3-aminoquinuclidine compound represented by the formula (4) can be advantageously obtained industrially.

(Compound represented by formula (2))
R ¹ and n in the formula (2) have the same meaning as those in the formula (1).
In formula (2), R ³ represents a halogen atom or a sulfonate group.
Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
Sulfonic acid ester group, a group commonly represented by -SO ₃ R ^4. R ⁴ is not particularly limited as long as it does not inhibit the azidation reaction. Examples thereof include an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted aryl group, an unsubstituted or substituted heterocyclic group, and the like.

  The compound represented by the formula (2) can be produced by a known method. For example, 3-quinuclidinol can be obtained by hydrogenating 3-quinuclidinone in the presence of a rhodium, iridium or ruthenium complex having a chiral diphosphine to obtain 3-quinuclidinol by halogenation or sulfonate esterification. it can.

The azidation of the compound represented by the formula (2) can be performed, for example, by reacting the compound represented by the formula (2) with an azide ion S _N 2. By this azidation, an azide compound represented by the formula (3) can be synthesized.
In the formula (3), R ¹ and n have the same meaning as those in the formula (2).
As a source of azide ions, sodium azide, hydrazoic acid, or the like can be used.

  Examples of the polar solvent used in the azidation reaction include polar aprotic solvents such as tetrahydrofuran, acetone, acetonitrile, N, N-dimethylformamide, and dimethyl sulfoxide. Of these, N, N-dimethylformamide is preferred.

  In general, an amine compound can be obtained by allowing a reducing agent such as lithium aluminum hydride to act on the azide compound. However, it is very difficult to separate and remove the polar solvent used in the azidation reaction in the present invention from the azide compound represented by the formula (3). Since the polar solvent inhibits the above reduction reaction, it is industrially difficult to reduce the azide compound represented by the formula (3) to obtain the amine compound represented by the formula (4). . Further, lithium aluminum hydride must be handled under water-free conditions, and the operation is complicated. Further, in the hydrogenolysis of the obtained azide compound, a catalyst containing an expensive metal such as palladium or platinum is often used.

Therefore, in the present invention, the phosphine compound: PR ² ₃ is reacted with the azide compound represented by the formula (3) to synthesize the iminophosphorane compound represented by the formula (1). Separation of the obtained compound represented by formula (1) from the polar solvent can be easily performed by using a known extraction method or the like.

Phosphine compound: R ^{2 in} PR ² ₃ is an unsubstituted or substituted C 1-6 alkyl group, an unsubstituted or substituted aryl group, an unsubstituted or substituted C 1-6 alkoxy group, or An unsubstituted or substituted aryloxy group is shown.

  Next, in the present invention, the iminophosphorane compound represented by the formula (1) is hydrolyzed to obtain a 3-aminoquinuclidine compound represented by the formula (4). The hydrolysis can be performed in the presence of a base such as sodium hydroxide or potassium hydroxide.

After completion of the reaction, the desired product can be isolated by carrying out ordinary purification operations. Examples of purification means include distillation, recrystallization, and column chromatography. The structure of the target product can be identified and confirmed by measuring ¹ H-NMR spectrum, IR spectrum, mass spectrum, elemental analysis, or the like.

  Next, an Example is shown and this invention is demonstrated in detail. However, the present invention is not limited to these examples.

[Example 1] Synthesis of (3-quinuclidylimino) triphenylphosphorane << Synthesis of quinuclidine-3-azide >>
16.07 g (0.126 mol) of 3-quinuclidinol was dissolved in 80 ml of chloroform, and 2 ml of triethylamine was added thereto. After cooling to 0 ° C., 15.15 g (0.132 mol) of methanesulfonyl chloride was added dropwise and stirred at the same temperature for 1 hour. To this, 45 ml of 3N aqueous sodium hydroxide solution was added and stirred. Thereafter, the organic layer was extracted. The obtained organic layer was dried over magnesium sulfate, and the solvent was removed by concentration under reduced pressure to obtain a mesylate form.

  60 ml of dimethylformamide (DMF) was added to the obtained mesylate body and dissolved. To this, 12.3 g (0.189 mol) of sodium azide was added and stirred at 90 ° C. for 18 hours. Insoluble matter was filtered. Thereafter, the solvent was distilled off by concentration under reduced pressure. Liquid separation operation was performed with 60 ml of water and ethyl acetate, and the obtained organic layer was washed with saturated brine. Subsequently, it was dried with magnesium sulfate, and the solvent was distilled off by concentration under reduced pressure to obtain an azide. Further, 7.24 g (yield 38%) of quinuclidine-3-azide was obtained by distillation under reduced pressure (58 ° C./0.15 mmHg).

<< Synthesis of (3-quinuclidylimino) triphenylphosphorane >>
The obtained quinuclidine-3-azide 0.76 g (5 mmol) was dissolved in 2 ml of DMF. 1.31 g (5 mmol) of triphenylphosphine was added and stirred at 60 ° C. for 30 minutes. The reaction solution was added to water and subjected to separation / extraction with toluene, and the obtained organic layer was washed with water. Subsequently, it was dried over magnesium sulfate, and the solvent was distilled off by concentration under reduced pressure to obtain 1.91 g (99% yield) of (3-quinuclidylimino) triphenylphosphorane.

The results of NMR analysis of (3-quinuclidylimino) triphenylphosphorane were as follows.
¹ H-NMR (300 MHz, CDCl ₃ ): δ (ppm) 7.62-7.69 (6H, m), 7.38-7.52 (9H, m), 3.24 (1H, m), 2.94-3.10 (2H, m), 2.50 -2.76 (4H, m), 2.39 (1H, m), 1.54 (1H, m), 1.42 (1H, m), 1.22-1.37 (2H, m).

[Example 2] Synthesis of (3-quinuclidylimino) tributoxyphospholane 0.30 g (2 mmol) of quinuclidine-3-azide was dissolved in 2 ml of toluene. This was heated to 80 ° C., and 0.50 g (2 mmol) of tri-n-butyl phosphite was added dropwise. Then, it stirred for 30 minutes. The solvent was removed by concentration under reduced pressure to obtain 0.72 g (yield 96%) of (3-quinuclidylimino) tributoxyphosphorane.

The results of NMR analysis of (3-quinuclidylimino) tributoxyphosphorane were as follows.
¹ H-NMR (400MHz, CDCl ₃ ): δ (ppm) 3.93 (6H, q, J = 6.7 Hz), 3.37 (1H, m), 3.15 (1H, m), 2.95 (1H, m), 2.62- 2.84 (3H, m), 2.55 (1H, ddd, J = 2.3, 5.0, 13.3 Hz), 2.11 (1H, m), 1.56-1.70 (8H, m), 1.50 (1H, m), 1.40 (6H, m), 1.26 (1H, m), 0.93 (9H, t, J = 7.4 Hz).

[Example 3] Synthesis of 3-aminoquinuclidine dihydrochloride 2.18 g (5.64 mmol) of (3-quinuclidylimino) triphenylphosphorane was dispersed in 4 ml of toluene. 4 ml of 3N aqueous sodium hydroxide solution was added thereto, and the mixture was stirred at 80 ° C. for 1 hour. After cooling to room temperature, 3N hydrochloric acid was added to bring the pH of the reaction solution to 1 or less, liquid separation was performed, and the aqueous layer was extracted with toluene. The resulting aqueous layer was adjusted to pH 12 by adding 50% aqueous sodium hydroxide solution. Then, it extracted with chloroform. 10 ml of 10% hydrochloric acid-methanol solution was added and concentrated to obtain 1.03 g (yield 92%) of 3-aminoquinuclidine dihydrochloride.

[Example 4] Synthesis of (S) -3-aminoquinuclidine dihydrochloride 2.83 g (13.7 mmol) of methanesulfonic acid (R) -3-quinuclidyl ester was dissolved in 9 ml of DMF. To this, 1.78 g (27.4 mmol) of sodium azide was added and stirred at 90 ° C. for 40 hours. The reaction solution was diluted by adding 9 ml of toluene. Thereafter, insoluble matters were removed by filtration. The obtained mother liquor was heated to 50 ° C., and 3.59 g (13.7 mmol) of triphenylphosphine was slowly added thereto. Furthermore, it stirred at 50 degreeC for 1 hour. After cooling to room temperature, the reaction solution was added to water, and 3N aqueous sodium hydroxide solution was added to adjust the pH to 11 or more. Then, it extracted with toluene. The solvent was distilled off from the extract by concentrating under reduced pressure. To this was added 9 ml of 3N aqueous sodium hydroxide solution, and the mixture was stirred at 80 ° C. for 1 hour. After cooling to room temperature, concentrated hydrochloric acid was added to bring the pH to 1 or less. Then, toluene was added and extracted. The aqueous layer was adjusted to pH 12 or higher by adding 50% aqueous sodium hydroxide solution. Then, it extracted with chloroform and the obtained organic layer was dried with sodium sulfate. An excess amount of 10% hydrochloric acid-methanol solution was added and concentrated. The obtained crystals were dispersed in toluene and filtered. Then, it was washed with isopropanol to obtain 1.26 g (yield 46%) of (S) -3-aminoquinuclidine dihydrochloride.

  The obtained (S) -3-aminoquinuclidine dihydrochloride was derived into benzoylamide, and the optical purity was determined by high performance liquid chromatography (mobile phase: hexane / ethanol = 90/10 with 0.2% diethylamine added. , Column: Chiralcel OD-H, manufactured by Daicel Chemical Industries, Ltd.), the optical purity was 98.6% ee.

[Example 5] Synthesis of 3-aminoquinuclidine 3.82 g (30 mmol) of (R) -3-quinuclidinol (> 99% ee) and 0.50 g of triethylamine were dissolved in 20 ml of chloroform. After cooling to 10 ° C., 3.90 g (113 mol%) of methanesulfonyl chloride was slowly added dropwise. Then, it stirred for 30 minutes. The reaction solution was neutralized with 3N aqueous sodium hydroxide solution, and then extracted with chloroform. It was washed with water and dried over magnesium sulfate. The reaction solution was concentrated under reduced pressure until the volume was reduced to about half. To this was added 20 ml of toluene. Subsequently, the solvent was distilled off by concentration under reduced pressure to obtain 5.55 g of a mesylate form.
The obtained mesylate body was dissolved in 13 ml of DMF, 2.11 g (32.4 mmol) of sodium azide was added, and the mixture was stirred at 90 ° C. for 22 hours. After cooling to room temperature, 20 ml of toluene was added, and insoluble matters were filtered.
The mother liquor was heated to 50 ° C. and 7.45 g (28.4 mmol) of triphenylphosphine was added in small portions. Stir at 50 ° C. for 30 minutes. After cooling to room temperature, the reaction solution was added to water and adjusted to pH 11 with 3N aqueous sodium hydroxide solution. Subsequently, extraction with toluene, washing with water, drying with magnesium sulfate, and concentration under reduced pressure were performed to obtain 10.0 g of an iminophosphorane.
The obtained iminophosphorane was dissolved in 5 ml of toluene, 5 ml of 3N aqueous sodium hydroxide solution was added, and the mixture was stirred at 80 ° C. for 1 hour. After cooling to room temperature, 3 ml of concentrated hydrochloric acid was added for liquid separation, followed by washing with toluene. A 50% aqueous sodium hydroxide solution was added to the obtained aqueous layer until the pH reached 12 or more, and then extraction was repeated 5 times with 10 ml of chloroform.

To the obtained chloroform solution were added 6.11 g (27 mmol) of benzoic anhydride and a catalytic amount of triethylamine, and the mixture was stirred at room temperature for 30 minutes. Extraction was performed with 10 ml of 3N hydrochloric acid, and then twice with 5 ml of 3N hydrochloric acid. Thereafter, 50% sodium hydroxide was added until the pH reached 12 or more, and extracted with chloroform. The obtained organic layer was dried over magnesium sulfate and then concentrated under reduced pressure to obtain 2.46 g (yield 36%) of (S) -N- (3-quinuclidyl) benzamide.
The optical purity of the obtained (S) -N- (3-quinuclidyl) benzamide was analyzed by high performance liquid chromatography (mobile phase: hexane / ethanol = 90/10, 0.2% diethylamine was added, column: Chiralcel OD-H Measured by Daicel Chemical Industries, Ltd.), the optical purity was 97.5% ee.

  The iminophosphorane compound of the present invention is useful as an intermediate for the production of 3-aminoquinuclidine compounds that are useful as synthetic intermediates for pharmaceuticals. Since the production method of the present invention via the iminophosphorane compound of the present invention can be easily isolated from the target solvent, a 3-aminoquinuclidine compound can be advantageously obtained industrially.

Claims (3)

An iminophosphorane compound represented by formula (1).

(In formula (1), R ¹ represents an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted aryl group, or an unsubstituted or substituted heterocyclic group. N Represents the number of R ¹ and is an integer of 0 to 12. R ² is an unsubstituted or substituted C 1-6 alkyl group, an unsubstituted or substituted aryl group, an unsubstituted Or a substituted C1-6 alkoxy group or an unsubstituted or substituted aryloxy group.) A compound represented by the formula (2) is azidated in a polar solvent to obtain a compound represented by the formula (3), and a phosphine compound: PR ² ₃ (where R ² is unsubstituted or has a substituent) A C1-6 alkyl group, an unsubstituted or substituted aryl group, an unsubstituted or substituted C1-6 alkoxy group or an unsubstituted or substituted aryloxy group). Then, the manufacturing method of the iminophosphorane compound represented by Formula (1) including removing a polar solvent.

(In formula (1), R ¹ represents an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted aryl group, or an unsubstituted or substituted heterocyclic group. N Represents the number of R ¹ and is an integer of 0 to 12. R ² is an unsubstituted or substituted C 1-6 alkyl group, an unsubstituted or substituted aryl group, an unsubstituted Or a substituted C1-6 alkoxy group or an unsubstituted or substituted aryloxy group.)

(In formula (2), R ³ represents a halogen atom or a sulfonate group, and R ¹ and n have the same meaning as those in formula (1).)

(In formula (3), R ¹ and n have the same meaning as in formula (1).) A method for producing a 3-aminoquinuclidine compound represented by formula (4), comprising hydrolyzing an iminophosphorane compound represented by formula (1).

(In formula (1), R ¹ represents an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted aryl group, or an unsubstituted or substituted heterocyclic group. N Represents the number of R ¹ and is an integer of 0 to 12. R ² is an unsubstituted or substituted C 1-6 alkyl group, an unsubstituted or substituted aryl group, an unsubstituted Or a substituted C1-6 alkoxy group or an unsubstituted or substituted aryloxy group.)

(In formula (4), R ¹ and n have the same meaning as in formula (1).)