WO2012165023A1 - 光学活性α-置換プロリン類の製造方法 - Google Patents
光学活性α-置換プロリン類の製造方法 Download PDFInfo
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- WO2012165023A1 WO2012165023A1 PCT/JP2012/058452 JP2012058452W WO2012165023A1 WO 2012165023 A1 WO2012165023 A1 WO 2012165023A1 JP 2012058452 W JP2012058452 W JP 2012058452W WO 2012165023 A1 WO2012165023 A1 WO 2012165023A1
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- 0 C[C@@]1(*)*CCC1 Chemical compound C[C@@]1(*)*CCC1 0.000 description 4
- PQZAWZGYOZRUFT-UHFFFAOYSA-N C(C1)CN=C1c1ccccc1 Chemical compound C(C1)CN=C1c1ccccc1 PQZAWZGYOZRUFT-UHFFFAOYSA-N 0.000 description 1
- DVHZDPNOAOREHX-UHFFFAOYSA-N CC1(C#N)NCCC1 Chemical compound CC1(C#N)NCCC1 DVHZDPNOAOREHX-UHFFFAOYSA-N 0.000 description 1
- KYJNYMVMZKFIKI-UHFFFAOYSA-N CC1(C(N)=O)NCCC1 Chemical compound CC1(C(N)=O)NCCC1 KYJNYMVMZKFIKI-UHFFFAOYSA-N 0.000 description 1
- ZLQMXRYTSLOUKM-UHFFFAOYSA-N N#CC1(c2ccccc2)N(Cc2ccccc2)CCC1 Chemical compound N#CC1(c2ccccc2)N(Cc2ccccc2)CCC1 ZLQMXRYTSLOUKM-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/20—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P13/00—Preparation of nitrogen-containing organic compounds
- C12P13/04—Alpha- or beta- amino acids
- C12P13/24—Proline; Hydroxyproline; Histidine
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
- C12P41/006—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by reactions involving C-N bonds, e.g. nitriles, amides, hydantoins, carbamates, lactames, transamination reactions, or keto group formation from racemic mixtures
- C12P41/007—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by reactions involving C-N bonds, e.g. nitriles, amides, hydantoins, carbamates, lactames, transamination reactions, or keto group formation from racemic mixtures by reactions involving acyl derivatives of racemic amines
Definitions
- the present invention relates to an industrial method for producing optically active ⁇ -substituted prolines from a chain ketone compound.
- the optically active ⁇ -substituted prolines produced by the present invention are useful compounds in the structural chemistry of peptides and as pharmaceutical intermediates.
- optically active ⁇ -substituted prolines allow only a very limited twist angle in peptides containing the optically active ⁇ -substituted prolines, it is considered that only a peptide having a limited three-dimensional structure is generated with a low degree of rotational freedom.
- it is considered to be useful as a highly selective pharmaceutical partial structure because of its less fluctuation structure, and it is actively used in drug discovery research.
- a method for synthesizing optically active ⁇ -substituted prolines by intramolecular cyclization using an amino acid such as L-alanine as a raw material is also known (see, for example, Non-Patent Document 4 and Patent Document 1).
- an expensive strong base such as potassium hexamethyldisilazide or lithium hexamethyldisilazide is required in the intramolecular cyclization reaction step.
- a method for carrying out a similar reaction using inexpensive potassium hydroxide (see Non-Patent Document 5) has also been reported, but an industrially difficult operation of grinding potassium hydroxide into powder is necessary.
- a catalytic asymmetric synthesis method using an optically active quaternary ammonium salt is also known (for example, see Non-Patent Document 6). Although the stereoselectivity and yield of this method are very high, it is necessary to use tertiary butyl ester as a substrate, iodide as an alkylating agent, and cesium hydroxide as a base. All of these materials are industrially expensive, and this method is not suitable for intermediates for medical and agricultural chemicals that require inexpensive production.
- the E value is an index calculated by the following equation from the conversion rate (c) of the reaction and the optical purity (eeS) of the remaining substrate.
- Pyrrolines especially 2-methylpyrroline
- 2-methylpyrroline are highly useful compounds that are also sold as reagents, but they are expensive and no inexpensive industrial production method has been reported so far.
- a method for producing 2-methylpyrroline using 5-chloro-2-pentanone as a raw material is known (see, for example, Non-Patent Document 10). After replacing a chlorine atom with an azide or the like, triphenylphosphine is used. This is not an industrially preferable method because it requires a two-step reaction, such as cyclization while reducing, and generates a large amount of waste.
- a process for producing 2-methylthiazolines using chloroacetone as a raw material is known (see, for example, Patent Document 3).
- An object of the present invention is to provide a practically suitable industrial method for producing optically active ⁇ -substituted prolines from a linear ketone compound under a short process and mild conditions.
- the chain ketone compound is reacted with at least one selected from ammonia, ammonium salts, primary amines and primary amine salts, and a cyanating agent.
- R 1 represents an optionally substituted alkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group
- R 2 represents a hydrogen atom or optionally substituted.
- the optically active ⁇ -substituted proline or its salt represented by formula (5)
- R 1 and R 3 have the same meanings as described above, and X represents a halogen atom or a sulfonyloxy group
- a chain ketone compound represented by ammonia, ammonium salt, primary amine and primary amine By reacting with at least one selected from the salts of, and a cyanating agent, and optionally protecting the nitrogen atom on the pyrrolidine ring,
- R 1 and R 3 are as defined above, Y is a nitrogen atom or a nitrogen atom substituted with R 2 , Z is a carbon atom or a carbon atom substituted with a cyano group.
- Y is a nitrogen atom
- Z represents a carbon atom
- Z represents a carbon atom substituted with R 2
- Z represents a carbon atom substituted with a cyano group
- the bond between Z is a single bond
- R 2 is as defined above.
- the chain ketone compound represented by [1] is at least one selected from ammonia, ammonium salts, primary amines and primary amine salts, and cyanation. Reaction with an agent and, if necessary, protecting the nitrogen atom on the pyrrolidine ring, the compound represented by the general formula (2)
- the chain ketone compound represented by [1] is at least one selected from ammonia, ammonium salts, primary amines and primary amine salts, and cyanation.
- the cyclic nitrogen-containing compound or its salt represented by General formula (2) is obtained by making it react with an agent and protecting the nitrogen atom on a pyrrolidine ring if necessary.
- General formula (4) including the following step (c)
- the optically active ⁇ -substitution represented by the general formula (4) is obtained by dividing the ⁇ -substitution prolineamide represented by the formula or a salt thereof.
- Proline or a salt thereof, and / or optically active ⁇ -substituted proline amide or a salt thereof represented by the general formula (5) is obtained; The division is any of the following steps (d) to (f).
- E Resolution by diastereomeric salt formation.
- F Separation by column chromatography.
- R 2 represents 1-phenylethyl group, 1- (1-naphthyl) ethyl group, 1- (2-naphthyl) ethyl group, or carbamoylphenylmethyl group. Amides or salts thereof.
- optically active ⁇ -substituted prolines and / or optically active ⁇ -substituted proline amides that are useful in the structural chemistry of peptides and as key synthetic intermediates for pharmaceuticals are obtained from inexpensive and readily available known compounds. Can be manufactured efficiently.
- R 1 represents an optionally substituted alkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group.
- alkyl group of the “optionally substituted alkyl group”, a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms such as a methyl group, an ethyl group, an n-propyl group, an n A linear alkyl group having 1 to 10 carbon atoms such as -butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group, n-nonyl group, n-decyl group; isopropyl group, Examples thereof include branched alkyl groups having 3 to 10 carbon atoms such as 1-methylpropyl group and t-butyl group; cyclic alkyl groups having 3 to 10 carbon atoms such as cyclopropyl group, cyclopentyl group and cyclohexyl group.
- alkyl group may have examples include a fluorine atom; an alkenyl group having 2 to 6 carbon atoms (eg, vinyl group); an alkoxy group having 1 to 6 carbon atoms (eg, methoxy group, ethoxy group).
- Etc . alkyl group having 1 to 6 carbon atoms (eg, methyl group, ethyl group, isopropyl group, etc.), halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), alkenyl having 2 to 6 carbon atoms 6 to 10 carbon atoms which may have 1 to 3 substituents selected from a group (eg, vinyl group), an alkoxy group having 1 to 6 carbon atoms (eg, methoxy group, ethoxy group, etc.), etc.
- Aryl groups eg, phenyl group, naphthyl group, etc. and the like.
- the number of the substituents is not particularly limited, but 1 to 3 is preferable. When there are two or more substituents, the types of substituents may be the same or different. Specific examples of the substituted alkyl group include a benzyl group, a 4-methoxybenzyl group, an allyl group, and a 2-fluoroethyl group.
- aryl group in the “optionally substituted aryl group” include aromatic hydrocarbon groups having 6 to 10 carbon atoms, such as a phenyl group, a 1-naphthyl group, and a 2-naphthyl group.
- the substituent that the aryl group may have include a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom); an alkyl group having 1 to 6 carbon atoms (eg, methyl group, ethyl group, Isopropyl group, etc.); C 2-6 alkenyl group (eg, vinyl group); C 1-6 alkoxy group (eg, methoxy group, ethoxy group, etc.); halogen atom (eg, fluorine atom, chlorine atom) Bromine atom, iodine atom), alkyl group having 1 to 6 carbon atoms (eg, methyl group, ethyl group, isopropyl group, etc.), alkenyl group having 2 to 6 carbon atoms (eg, vinyl group, etc.), 1 to carbon atoms
- An aryl group having 6 to 10 carbon atoms eg, phenyl group, naphthyl group
- heteroaryl group of the “optionally substituted heteroaryl group” includes 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom as a ring-constituting atom.
- 5- or 6-membered aromatic heterocyclic groups such as pyrrolyl (eg 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), furyl (eg 2-furyl, 3-furyl), thienyl (eg 2-phenyl) Thienyl, 3-thienyl), pyrazolyl (eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), imidazolyl (eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), isoxazolyl (eg, 3-isoxazolyl, 4 -Isoxazolyl, 5-isoxazolyl), oxazolyl (eg 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isothiazo (Eg, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), thiazolyl (eg, 2-thiazolyl, 4-thiazolyl
- heteroaryl group may have examples of the substituent that the heteroaryl group may have include a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom); an alkyl group having 1 to 6 carbon atoms (eg, methyl group, ethyl group) An alkenyl group having 2 to 6 carbon atoms (eg, vinyl group); an alkoxy group having 1 to 6 carbon atoms (eg, methoxy group, ethoxy group, etc.); a halogen atom (eg, fluorine atom, chlorine) Atom, bromine atom, iodine atom), alkyl group having 1 to 6 carbon atoms (eg, methyl group, ethyl group, isopropyl group), alkenyl group having 2 to 6 carbon atoms (eg, vinyl group), carbon number 1 An aryl group having 6 to 10 carbon atoms (eg, phenyl group, naphthyl group
- R 1 is preferably an optionally substituted alkyl group, more preferably a methyl group, an ethyl group, an n-propyl group, an n-butyl group, a benzyl group, or an allyl group, and particularly preferably.
- R 2 represents a hydrogen atom, an optionally substituted alkyl group, or an amino group-protecting group.
- alkyl group of the “optionally substituted alkyl group”, a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms such as a methyl group, an ethyl group, an n-propyl group, an n A linear alkyl group having 1 to 10 carbon atoms such as -butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group, n-nonyl group, n-decyl group; isopropyl group, Examples thereof include branched alkyl groups having 3 to 10 carbon atoms such as 1-methylpropyl group and t-butyl group; cyclic alkyl groups having 3 to 10 carbon atoms such as cyclopropyl group, cyclopentyl group and cyclohexyl group.
- alkyl group may have examples of the substituent that the alkyl group may have include a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom); an alkenyl group having 2 to 6 carbon atoms (eg, vinyl group); carbon An alkoxy group having 1 to 6 carbon atoms (eg, methoxy group, ethoxy group, etc.); an alkoxycarbonyl group having 2 to 6 carbon atoms (eg, methoxycarbonyl group, ethoxycarbonyl group, etc.); a carbamoyl group; a carboxyl group; 6 alkyl groups (eg, methyl group, ethyl group, isopropyl group, etc.), halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), alkenyl groups having 2 to 6 carbon atoms (eg, vinyl group, etc.) ), An ary
- the number of the substituents is not particularly limited, but 1 to 3 is preferable.
- the types of substituents may be the same or different.
- the alkyl group which may be substituted has an asymmetric point, it may be R-form, S-form, or a racemate.
- protecting group for amino group examples include, but are not limited to, formyl group, acetyl group, chloroacetyl group, dichloroacetyl group, trichloroacetyl group, trifluoroacetyl group, propionyl group, Acyl groups such as benzoyl group and 4-chlorobenzoyl group; alkoxycarbonyl groups which may be substituted such as methoxycarbonyl group, ethoxycarbonyl group, t-butoxycarbonyl group, benzyloxycarbonyl group and allyloxycarbonyl group; benzyl group 4-methoxybenzyl group, 4-bromobenzyl group, 1-phenylethyl group, 1- (1-naphthyl) ethyl group, 1- (2-naphthyl) ethyl group, carboxyphenylmethyl group, carbamoylphenylmethyl group, 2 -Hydroxy-1-phenyle
- R 2 is preferably a hydrogen atom, an acyl group, an optionally substituted alkoxycarbonyl group, or an optionally substituted arylalkyl group, more preferably a hydrogen atom or an easily removable acetyl.
- each R 3 is independently a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, or optionally substituted.
- a hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, or a halogen atom is shown. If possible, two or more R 3 s may form one or more ring structures.
- alkyl group of the “optionally substituted alkyl group”, a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms such as a methyl group, an ethyl group, an n-propyl group, an n A linear alkyl group having 1 to 10 carbon atoms such as -butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group, n-nonyl group, n-decyl group; isopropyl group, Examples thereof include branched alkyl groups having 3 to 10 carbon atoms such as 1-methylpropyl group and t-butyl group; cyclic alkyl groups having 3 to 10 carbon atoms such as cyclopropyl group, cyclopentyl group and cyclohexyl group.
- Examples of the substituent that the alkyl group may have include a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom); an alkenyl group having 2 to 6 carbon atoms (eg, vinyl group); carbon An alkoxy group having 1 to 6 carbon atoms (eg, methoxy group, ethoxy group); an alkyl group having 1 to 6 carbon atoms (eg, methyl group, ethyl group, isopropyl group), halogen atom (eg, fluorine atom, chlorine atom) , Bromine atom, iodine atom), alkenyl group having 2 to 6 carbon atoms (eg, vinyl group, etc.), alkoxy group having 1 to 6 carbon atoms (eg, methoxy group, ethoxy group, etc.), etc.
- a halogen atom eg, fluorine atom, chlorine atom, bromine atom, iod
- an aryl group having 6 to 10 carbon atoms eg, a phenyl group, a naphthyl group, etc.
- the number of the substituents is not particularly limited, but 1 to 3 is preferable.
- the types of substituents may be the same or different.
- Specific examples of the substituted alkyl group include a benzyl group, a 4-methoxybenzyl group, an allyl group, and a 2-chloroethyl group.
- aryl group in the “optionally substituted aryl group” include aromatic hydrocarbon groups having 6 to 10 carbon atoms, such as a phenyl group, a 1-naphthyl group, and a 2-naphthyl group.
- the substituent that the aryl group may have include a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom); an alkyl group having 1 to 6 carbon atoms (eg, methyl group, ethyl group, Isopropyl group, etc.); C 2-6 alkenyl group (eg, vinyl group); C 1-6 alkoxy group (eg, methoxy group, ethoxy group, etc.); halogen atom (eg, fluorine atom, chlorine atom) Bromine atom, iodine atom), alkyl group having 1 to 6 carbon atoms (eg, methyl group, ethyl group, isopropyl group, etc.), alkenyl group having 2 to 6 carbon atoms (eg, vinyl group, etc.), 1 to carbon atoms
- An aryl group having 6 to 10 carbon atoms eg, phenyl group, naphthyl group
- heteroaryl group of the “optionally substituted heteroaryl group” includes 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom as a ring-constituting atom.
- 5- or 6-membered aromatic heterocyclic groups such as pyrrolyl (eg 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), furyl (eg 2-furyl, 3-furyl), thienyl (eg 2-phenyl) Thienyl, 3-thienyl), pyrazolyl (eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), imidazolyl (eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), isoxazolyl (eg, 3-isoxazolyl, 4 -Isoxazolyl, 5-isoxazolyl), oxazolyl (eg 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isothiazo (Eg, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), thiazolyl (eg, 2-thiazolyl, 4-thiazolyl
- heteroaryl group may have examples of the substituent that the heteroaryl group may have include a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom); an alkyl group having 1 to 6 carbon atoms (eg, methyl group, ethyl group) An alkenyl group having 2 to 6 carbon atoms (eg, vinyl group); an alkoxy group having 1 to 6 carbon atoms (eg, methoxy group, ethoxy group, etc.); a halogen atom (eg, fluorine atom, chlorine) Atom, bromine atom, iodine atom), alkyl group having 1 to 6 carbon atoms (eg, methyl group, ethyl group, isopropyl group), alkenyl group having 2 to 6 carbon atoms (eg, vinyl group), carbon number 1 An aryl group having 6 to 10 carbon atoms (eg, phenyl group, naphthyl group
- Examples of the optionally substituted hydroxyl group include a hydroxyl group and a protected form thereof; methoxy group, ethoxy group, n-propoxy group, n-butoxy group, n-decyloxy group, 1-methylethoxy group, 1,1-dimethylethoxy group Alkoxy groups having 1 to 10 carbon atoms such as cyclopropyloxy group and cyclohexyloxy group; aryloxy groups having 6 to 10 carbon atoms such as phenyloxy group and 2-naphthyloxy group; 2-thienyloxy group and 3-pyridyl group A heteroaryloxy group such as an oxy group, and the alkoxy group, aryloxy group and heteroaryloxy group are each a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom); Alkyl group (eg, methyl group, ethyl group, isopropyl group, etc.);
- the protective group used as a hydroxyl group protector is not particularly limited as long as it can be removed under normal conditions, but specific examples thereof include formyl group, acetyl group, chloroacetyl group, propionyl group, benzoyl group and the like.
- Acyl group arylalkyl group which may be substituted such as benzyl group, 4-methoxybenzyl group, 4-bromobenzyl group and 1-phenylethyl group; acetal such as methoxymethyl group, ethoxyethyl group and benzyloxymethyl group Type protecting groups; silyl groups such as trimethylsilyl and t-butyldimethylsilyl groups.
- the optionally substituted amino group may have one or two arbitrary substituents and / or protecting groups.
- substituents include, but are not limited to, alkyl groups having 1 to 6 carbon atoms (eg, methyl group, ethyl group, isopropyl group, etc.); alkenyl having 2 to 6 carbon atoms Groups (eg, vinyl groups, allyl groups, etc.); hydroxyl groups; C 1-6 alkoxy groups (eg, methoxy groups, ethoxy groups, etc.); arylalkyl groups (eg, benzyl groups, etc.).
- the protecting group include, but are not limited to, formyl group, acetyl group, chloroacetyl group, dichloroacetyl group, trichloroacetyl group, trifluoroacetyl group, propionyl group, benzoyl group, Acyl groups such as 4-chlorobenzoyl group; alkoxycarbonyl groups which may be substituted such as methoxycarbonyl group, ethoxycarbonyl group, t-butoxycarbonyl group, benzyloxycarbonyl group, allyloxycarbonyl group; benzyl group, 4- An arylalkyl group which may be substituted such as methoxybenzyl group, 4-bromobenzyl group and 1-phenylethyl group; and sulfonyl groups such as methanesulfonyl group, p-toluenesulfonyl group and 2-nitrobenzenesulfonyl group.
- Examples of the optionally substituted thiol group include a thiol group and a protected form thereof; methylthio group, ethylthio group, n-propylthio group, n-butylthio group, n-decylthio group, 1-methylethylthio group, 1,1- C 1-10 alkylthio groups such as dimethylethylthio group, cyclopropylthio group, cyclohexylthio group; arylthio groups having 6-10 carbon atoms such as phenylthio group, 2-naphthylthio group; 2-thienylthio group, 3-pyridylthio A heteroarylthio group such as a group, wherein the alkylthio group, arylthio group and heteroarylthio group are halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom); alkyl group
- the protective group used as a thiol group protector is not particularly limited as long as it can be removed under normal conditions, but specific examples thereof include formyl group, acetyl group, chloroacetyl group, propionyl group, benzoyl group, etc.
- acyl group which may be substituted such as benzyl group, 4-methoxybenzyl group, 4-bromobenzyl group, 1-phenylethyl group; methoxymethyl group, ethoxyethyl group, benzyloxymethyl group, etc.
- acetal type protecting groups include acetal type protecting groups; silyl groups such as trimethylsilyl group and t-butyldimethylsilyl group.
- halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
- R 3 is preferably a hydrogen atom.
- X represents a halogen atom or a sulfonyloxy group.
- halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
- the sulfonyloxy group include, but are not limited to, an alkylsulfonyloxy group which may be substituted such as a methanesulfonyloxy group, a chloromethanesulfonyloxy group, and a trifluoromethanesulfonyloxy group.
- An optionally substituted arylsulfonyloxy group such as p-toluenesulfonyloxy group, p-chlorobenzenesulfonyloxy group, 2-nitrobenzenesulfonyloxy group and the like;
- X is preferably a halogen atom, more preferably a corresponding chain ketone compound is an industrially inexpensive chlorine atom.
- Y represents a nitrogen atom substituted by a nitrogen atom or R 2.
- Z represents a carbon atom or a carbon atom substituted with a cyano group.
- the chain ketone compound represented by the general formula (1) is a compound having a leaving group such as a halogen atom at the 4-position of 1-substituted-1-butanone.
- chain ketone compound represented by the general formula (1) examples include 5-fluoro-2-pentanone, 5-chloro-2-pentanone, 5-bromo-2-pentanone, 5-iodo-2- Pentanone, 5- (methanesulfonyloxy) -2-pentanone, 5- (chloromethanesulfonyloxy) -2-pentanone, 5- (toluenesulfonyloxy) -2-pentanone, 6-chloro-3-hexanone, 6-bromo -3-hexanone, 1-chloro-4-octanone, 6-chloro-2-methyl-3-hexanone, 4-chloro-1-cyclopropyl-1-butanone, 4-chloro-1-cyclohexyl-1-butanone, 4-bromo-1-cyclohexyl-1-butanone, 7-chloro-1-hepten-4-one, 4-chloro-1-phenyl-1-
- the cyclic nitrogen-containing compound represented by the general formula (2) is a pyrrolidine which is a saturated 5-membered ring amine or a pyrroline which is an unsaturated 5-membered ring imine having a carbon-nitrogen double bond, Have a substituent.
- the cyclic nitrogen-containing compound represented by the general formula (2) is a pyrrolidine
- the compound is particularly substituted at the 2-position of 2-cyanopyrrolidine represented by the following general formula (7), that is, pyrrolidine.
- the 2-cyanopyrrolidines represented by the following general formula (7) have an asymmetric point at the carbon atom to which the cyano group is bonded. When there is no other asymmetric point in the molecule, it is usually a racemate. When it has a plurality of asymmetric points in the molecule, it is usually a diastereomeric mixture.
- 2-cyanopyrrolidines represented by the general formula (7) include 2-cyano-2-methylpyrrolidine, 1-acetyl-2-cyano-2-methylpyrrolidine, 1- (t-butoxycarbonyl ) -2-Cyano-2-methylpyrrolidine, 1- (chloroacetyl) -2-cyano-2-methylpyrrolidine, 2-cyano-2-methyl-1- (trifluoroacetyl) pyrrolidine, 1-benzoyl-2- Cyano-2-methylpyrrolidine, 1- (benzyloxycarbonyl) -2-cyano-2-methylpyrrolidine, 1-benzyl-2-cyano-2-methylpyrrolidine, 1- (1-phenylethyl) -2-cyano- 2-methylpyrrolidine, 1- (1- (1-naphthyl) ethyl) -2-cyano-2-methylpyrrolidine, 1- (1- (2-naphthyl) ethyl ) -2-cyano-2-methylpyrrolidine, 1-
- the compound represented by the general formula (2) is a pyrroline
- the compound is particularly a pyrroline represented by the following general formula (6), that is, a substituent at the 2-position of 1-pyrroline.
- pyrrolines represented by the general formula (6) include 2-methyl-1-pyrroline, 2-ethyl-1-pyrroline, 2-butyl-1-pyrroline, 2- (1-methylethyl) -1-pyrroline, 2-cyclopropyl-1-pyrroline, 2-cyclohexyl-1-pyrroline, 2-allyl-1-pyrroline, 2-phenyl-1-pyrroline, 2- (4-methoxyphenyl) -1 -Pyrroline, 2- (4-chlorophenyl) -1-pyrroline, 2- (2-thienyl) -1-pyrroline, 2- (3-pyridyl) -1-pyrroline.
- the ⁇ -substituted proline amides represented by the general formula (3) have a substituent and a carbamoyl group at the 2-position of pyrrolidine, a hydrogen atom on the nitrogen atom of pyrrolidine, an optionally substituted alkyl group, Or it is a compound which has a protecting group of an amino group.
- the ⁇ -substituted proline amides represented by the general formula (3) have an asymmetric point at the carbon atom to which the carbamoyl group is bonded.
- optical purity in this case is preferably 80% ee or less, more preferably 60% ee or less, and particularly preferably 50% ee or less.
- the molecule when it has a plurality of asymmetry points, it may be a diastereomer or a diastereomer mixture having any stereochemistry.
- ⁇ -substituted proline amides represented by the general formula (3) include ⁇ -methyl proline amide, N-acetyl- ⁇ -methyl proline amide, N- (t-butoxycarbonyl) - ⁇ -methyl.
- Prolineamide N- (chloroacetyl) - ⁇ -methylprolineamide, N- (trifluoroacetyl) - ⁇ -methylprolineamide, N-benzoyl- ⁇ -methylprolineamide, N- (benzyloxycarbonyl) - ⁇ - Methylproline amide, N-benzyl- ⁇ -methylprolinamide, N- (1-phenylethyl) - ⁇ -methylprolineamide, N- (1- (1-naphthyl) ethyl) - ⁇ -methylprolinamide, N- (1- (2-naphthyl) ethyl) - ⁇ -methylprolinamide, N- (carbamoylphenylmethyl) - ⁇ -methylproline Amide, ⁇ -ethylprolinamide, ⁇ -butylprolinamide, N- (t-butoxycarbonyl) - ⁇ -butylprolineamide, ⁇ - (1-methylethy
- the optically active ⁇ -substituted prolines represented by the general formula (4) have a substituent and a carboxyl group at the 2-position of pyrrolidine, a hydrogen atom on the nitrogen atom of pyrrolidine, and an optionally substituted alkyl group Or a compound having an amino-protecting group.
- the optically active ⁇ -substituted prolines represented by the general formula (4) are optically active substances having an asymmetric point at the carbon atom to which the carboxyl group is bonded, and other asymmetric points are present in the molecule. When it does not have, either S body and R body may be sufficient.
- the optical purity may be any value, but is preferably 80% ee or more, more preferably 90% ee or more, further preferably 95% ee or more. In the case of pharmaceuticals and intermediates thereof, high optical purity is required, Preferably it is 99% ee or more.
- a molecule may be a diastereomer or diastereomer mixture having any stereochemistry.
- optically active ⁇ -substituted prolines represented by the general formula (4) include (R) - ⁇ -methylproline, (R) -N-acetyl- ⁇ -methylproline, (R) -N -(T-butoxycarbonyl) - ⁇ -methylproline, (R) -N- (chloroacetyl) - ⁇ -methylproline, (R) -N- (trifluoroacetyl) - ⁇ -methylproline, (R)- N-benzoyl- ⁇ -methylproline, (R) -N- (benzyloxycarbonyl) - ⁇ -methylproline, (R) -N-benzyl- ⁇ -methylproline, (R) - ⁇ -ethylproline, (R ) - ⁇ -butylproline, (R) -N- (t-butoxycarbonyl) - ⁇ -butylproline, (R) - ⁇ - (1-methylethyl)
- the optically active ⁇ -substituted proline amides represented by the general formula (5) have a substituent and a carbamoyl group at the 2-position of pyrrolidine, a hydrogen atom on the nitrogen atom of pyrrolidine, and an optionally substituted alkyl. Group or a compound having an amino-protecting group.
- the optically active ⁇ -substituted proline amides represented by the general formula (5) are optically active substances having an asymmetric point at the carbon atom to which the carbamoyl group is bonded, and other asymmetric points in the molecule. When it does not have, either S body and R body may be sufficient.
- the optical purity may be any value, but is higher than that of the ⁇ -substituted proline amides represented by the general formula (3), preferably 80% ee or more, more preferably 90% ee or more, and still more preferably Is 95% ee or more. In the case of pharmaceuticals and intermediates thereof, high optical purity is required, so 99% ee is particularly preferable.
- a molecule may be a diastereomer or diastereomer mixture having any stereochemistry.
- optically active ⁇ -substituted proline amides represented by the general formula (5) include (R) - ⁇ -methyl proline amide, (R) -N-acetyl- ⁇ -methyl proline amide, (R ) -N- (t-butoxycarbonyl) - ⁇ -methylproline amide, (R) -N- (chloroacetyl) - ⁇ -methylproline amide, (R) -N- (trifluoroacetyl) - ⁇ -methylproline Amide, (R) -N-benzoyl- ⁇ -methylprolinamide, (R) -N- (benzyloxycarbonyl) - ⁇ -methylprolinamide, (R) -N-benzyl- ⁇ -methylprolinamide, (R ) - ⁇ -ethylprolinamide, (R) - ⁇ -butylprolinamide, (R) -N- (t-butoxycarbonyl)
- the above compound may have a basic or acidic functional group and may form a salt.
- salts include inorganic acid salts (eg, hydrochloride, sulfate, nitrate, phosphate, etc.); organic acid salts (eg, acetate, propionate, methanesulfonate, 4-toluenesulfonate) , Oxalate, maleate, etc.); tartaric acids (L-tartaric acid, D-tartaric acid, (2S, 3S) -dibenzoyltartaric acid, (2R, 3R) -dibenzoyltartaric acid, (2S, 3S) -di (p- Toluoyl) tartaric acid, (2R, 3R) -di (p-toluoyl) tartaric acid, etc.); mandelic acids ((S) -mandelic acid, (R) -mandelic acid etc.); amino acid derivatives (N-acety
- the ⁇ -methylproline amides represented by the general formula (8) have a methyl group and a carbamoyl group at the 2-position of pyrrolidine, and a 1-phenylethyl group, 1- (1-naphthyl) on the nitrogen atom of pyrrolidine.
- the substituent on the nitrogen atom of pyrrolidine is preferably a 1-phenylethyl group or a carbamoylphenylmethyl group, and more preferably a 1-phenylethyl group.
- the ⁇ -methylprolinamides have two asymmetric points, the 2-position of pyrrolidine and the substituent (1′-position) on the pyrrolidine nitrogen atom, and any diastereomer or diastereomer having any stereochemistry It may be a mixture. Since the asymmetric carbon of the substituent on the pyrrolidine nitrogen atom (position 1 ') is derived from the primary amine or salt thereof used in step (a), the primary used when there is no epimerization during the reaction. The optical purity of the amine is an asymmetric purity at the 1 ′ position.
- the ⁇ -methylproline amides represented by the general formula (8) may form a salt with an optically active acid and / or an achiral acid. Because it is useful. Specific examples of such salts include, for example, inorganic acid salts (eg, hydrochloride, sulfate, nitrate, phosphate, etc.); organic acid salts (eg, acetate, propionate, methanesulfonate, 4-toluene) Sulfonates, oxalates, maleates, etc.); tartaric acids (L-tartaric acid, D-tartaric acid, (2S, 3S) -dibenzoyltartaric acid, (2R, 3R) -dibenzoyltartaric acid, (2S, 3S) -di (P-toluoyl) tartaric acid, (2R, 3R) -di (p-toluoyl) tartaric acid, etc.); mandelic acids ((S
- a salt with an optically active acid that can be expected to have a large solubility difference between diastereomeric salts, more preferably a salt with tartaric acids and mandelic acids, and particularly preferably an inexpensive salt.
- salts of N- (1′-phenylethyl) - ⁇ -methylprolinamide with optically active acids and / or achiral acids include (2S, 1 ′S) -N- (1′-phenyl). Ethyl) - ⁇ -methylprolinamide D-tartrate, (2S, 1 ′S) -N- (1′-phenylethyl) - ⁇ -methylprolinamide L-tartrate, (2S, 1′R) -N- (1'-phenylethyl) - ⁇ -methylprolinamide D-tartrate, (2S, 1'R) -N- (1'-phenylethyl) - ⁇ -methylprolinamide L-tartrate , (2R, 1′R) -N- (1′-phenylethyl) - ⁇ -methylprolinamide D-tartrate, (2R, 1′R) -N- (1′-phenylethyl) - ⁇ -methylprolinamide D
- the cyclic nitrogen-containing compound represented by the general formula (2) is at least one selected from the chain ketone compound represented by the general formula (1) selected from ammonia, ammonium salts, primary amines and primary amine salts. It can be synthesized by reacting with a seed and a cyanating agent.
- the chain ketone compound represented by the general formula (1) 5-chloro-2-pentanone, 4-chloro-1-phenyl-1-butanone and the like can be purchased as reagents.
- Other compounds can be optionally produced by methods such as Friedel-Crafts reaction of 3-chloropropionic acid chloride and aromatic compounds, Claisen condensation of ⁇ -butyrolactone and esters, followed by treatment with hydrogen halide (for example, see Chem. Pharm. Bull., 1989, 37, 958.).
- the at least one selected from ammonia, ammonium salt, primary amine and primary amine salt used in step (a) may be any compound that can provide ammonia or primary amine in the reaction system.
- Examples include, but are not limited to, ammonia; benzylamine, 4-methoxybenzylamine, 4-bromobenzylamine, ⁇ -methylbenzylamine, 1- (1-naphthyl) ethylamine, ⁇ -Primary amines such as phenylglycine, ⁇ -phenylglycinamide, ⁇ -phenylglycinol, allylamine, propargylamine; and salts thereof.
- ammonium salts include ammonium salts of mineral acids such as ammonium chloride, ammonium sulfate, ammonium hydrogen sulfate, and ammonium nitrate; inorganics such as ammonium carbonate, ammonium hydrogen carbonate, monoammonium phosphate, and diammonium hydrogen phosphate. Acid ammonium salt; Organic acid ammonium salt such as ammonium acetate, ammonium formate, ammonium citrate and the like can be mentioned. Two or more kinds selected from these ammonia, ammonium salts, primary amines and primary amine salts may be mixed and used.
- ammonia as at least 1 sort (s) chosen from ammonia, an ammonium salt, a primary amine, and the salt of a primary amine
- ammonia such as ammonia water, ammonia methanol solution, ammonia gas
- a primary amine when used as at least one selected from ammonia, ammonium salt, primary amine and primary amine salt, it may be a salt such as hydrochloride, acetate, carbonate, etc. When it has a point, it may be R, S, or racemic.
- a primary amine and / or a salt thereof as at least one selected from ammonia, an ammonium salt, a primary amine, and a primary amine salt results in by-production of the pyrroline represented by the general formula (6).
- the 2-cyanopyrrolidines represented by the general formula (7) can be obtained without any problem.
- an inexpensive benzylamine, (S) - ⁇ -methylbenzylamine and (R) - ⁇ -methylbenzylamine which can be reacted diastereoselectively by having an asymmetric point are preferable. is there.
- ammonia and / or a salt thereof as at least one selected from ammonia, ammonium salts, primary amines and primary amine salts requires a deprotection step in the production of optically active ⁇ -substituted prolines. This is preferable because it requires a shorter process.
- ammonium chloride, ammonium acetate, ammonium formate, and aqueous ammonia which are industrially inexpensive and sufficiently soluble in the reaction solvent, and more preferably acetic acid having a buffer capacity and capable of controlling the reaction solution near neutrality.
- Ammonium and ammonium formate are industrially inexpensive and sufficiently soluble in the reaction solvent, and more preferably acetic acid having a buffer capacity and capable of controlling the reaction solution near neutrality.
- the amount of at least one selected from ammonia, ammonium salt, primary amine and primary amine salt is 0.5 to 10 equivalents, preferably with respect to the chain ketone compound represented by the general formula (1). Is 0.8 to 5 equivalents, more preferably 0.9 to 3 equivalents.
- cyanating agent used in the step (a) examples include inorganic cyanides such as sodium cyanide, potassium cyanide, copper cyanide; trimethylsilyl cyanide, tetrabutyl Organic cyanides such as ammonium cyanide and tributyltin cyanide; cyanic acid; cyanohydrins such as acetone cyanohydrin; aminonitrile compounds such as 2-amino-2-methylpropanenitrile; A plurality of cyanating agents selected from these may be mixed and used.
- the cyanating agent used is an aminonitrile compound, it can also serve as at least one selected from ammonia, ammonium salts, primary amines and primary amine salts.
- ammonia ammonium salts
- primary amines primary amine salts.
- inorganic cyanides that are less likely to generate highly toxic hydrocyanic acid gas by natural decomposition are preferable, and industrially inexpensive sodium cyanide and potassium cyanide are more preferable.
- the excessive use of the cyanating agent is not preferable because it generates a high concentration of cyan waste liquid.
- the amount of the cyanating agent used is the above general formula ( It is 1 to 3 equivalents, preferably 1.0 to 1.5 equivalents, more preferably 1.0 to 1.2 equivalents, with respect to the chain ketone compound represented by 1).
- the amount may be a catalytic amount, and is 0.1 to 3 equivalents, preferably 0.2 to 1.0 equivalent, more preferably 0.2 to 0, relative to the chain ketone compound represented by the general formula (1). .5 equivalents.
- step (a) it is preferable to add an acidic substance for the purpose of making the reaction system weakly acidic to weakly alkaline.
- the addition of the acidic substance is carried out for the purpose of suppressing side reactions such as cyclopropanation that can occur due to strong alkalinity and allowing the reaction to proceed smoothly. Therefore, it may be a compound such as a carboxylic acid ester that generates an acid by hydrolysis or the like in the reaction system even if it is not acidic at the time of addition, or may be a salt of a weak base such as an ammonium salt and an acid.
- mineral acids such as hydrochloric acid, sulfuric acid and nitric acid
- carboxylic acids such as acetic acid, formic acid, trifluoroacetic acid, benzoic acid and oxalic acid
- methanesulfonic acid Sulfonic acids such as toluenesulfonic acid
- phosphoric acids such as phosphoric acid, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and disodium hydrogen phosphate
- carboxylic acid esters such as ethyl acetate, methyl acetate, and methyl benzoate
- Mineral acid ammonium salts such as ammonium chloride, ammonium sulfate, ammonium hydrogen sulfate, ammonium nitrate
- inorganic acid ammonium salts such as ammonium carbonate, ammonium hydrogen carbonate, monoammonium phosphate, diammonium hydrogen phosphate; ammonium acetate, ammonium formate, am
- ammonium salt as at least 1 sort (s) chosen from the ammonia used in process (a), ammonium salt, primary amine, and primary amine
- the ammonium salt used also serves as an acidic substance.
- Ammonia chloride, ammonium acetate, and ammonium formate which are industrially inexpensive and sufficiently soluble in the reaction solvent, are more preferable, and ammonium acetate and ammonium formate are particularly preferable. is there.
- other than ammonium salt as at least 1 sort (s) chosen from the ammonia used in process (a), ammonium salt, primary amine, and primary amine salt, Preferably among these acidic substances, it is chlorinated by reaction.
- weakly acidic carboxylic acids, carboxylic acid esters, or phosphoric acids having a high buffer capacity that can keep the reaction solution weakly acidic even when hydrogen is generated more preferably carboxylic acids, particularly preferably industrial Inexpensive acetic acid and formic acid.
- the amount of the acidic substance used may be such that it can be partially neutralized so as not to become strongly alkaline, and is 0.01 to 10 equivalents, preferably 0.1 to the chain ketone compound represented by the general formula (1). ⁇ 5 equivalents, more preferably 0.3 to 3 equivalents.
- the solvent used in the step (a) is not particularly limited as long as it does not adversely affect the reaction.
- hydrocarbon solvents such as hexane, heptane, benzene, toluene, etc .
- ethyl ether, propyl ether, cyclopentyl methyl ether Ether solvents such as t-butyl methyl ether and tetrahydrofuran
- halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane and chlorobenzene
- ester solvents such as ethyl acetate and butyl acetate
- Amide solvents such as dimethylformamide and N-methylpyrrolidone
- Carbonate ester solvents such as dimethyl carbonate and diethyl carbonate
- Nitrile solvents such as acetonitrile
- a plurality of solvents selected from these may be mixed and used in an arbitrary ratio.
- Preferable solvents include tetrahydrofuran, which dissolves the chain ketone compound represented by the above general formula (1), at least one selected from ammonia, ammonium salt, primary amine and primary amine salt, and a cyanating agent.
- the solvent may be used in any amount, but usually 1 to 50 times volume, preferably 1 with respect to the chain ketone compound represented by the general formula (1). It is ⁇ 20 times volume, more preferably 2 to 10 times volume.
- the reaction temperature in step (a) is not particularly limited as long as it does not adversely affect the reaction, but is usually ⁇ 20 to 120 ° C., preferably 10 to 80 ° C., more preferably 30 to 70 ° C. is there.
- the reaction time in step (a) is not particularly limited as long as it does not adversely affect the reaction, but it is preferably performed in the range of 10 minutes to 24 hours from the viewpoint of suppressing production cost, more preferably 1 to 10 hours.
- the cyclic nitrogen-containing compound represented by the general formula (2) obtained in the step (a) can be purified by a method such as extraction and / or distillation, and can be used in the next step without purification.
- a method such as extraction and / or distillation
- the cyclic nitrogen-containing compound represented by the general formula (2) is a 2-cyanopyrrolidine represented by the general formula (7)
- sufficient purity and water removal can be achieved only by extraction. It is preferable to use it in the next step after performing a concentration operation as necessary without performing any further purification operation in order to simplify the work and increase the productivity.
- the cyclic nitrogen-containing compound represented by the general formula (2) is a pyrroline represented by the general formula (6)
- it is generally a low boiling point compound. If there is no need for purification, it is preferably used for another purpose without purification.
- the pyrroline represented by the general formula (6) can be converted to the 2-cyanopyrrolidine represented by the general formula (7) by reacting with a cyanating agent. After 2-cyanopyrrolidines are generated, they can be used in step (b) without purification. This method is preferable in terms of safety of workers because 2-cyanopyrrolidines that may generate highly toxic hydrocyanic acid gas can be reacted without purification.
- the solvent used for extraction is not particularly limited, but hydrocarbon solvents such as hexane, heptane, benzene and toluene; ether solvents such as ethyl ether, propyl ether, cyclopentyl methyl ether, t-butyl methyl ether and tetrahydrofuran; dichloromethane, chloroform , Halogenated hydrocarbon solvents such as dichloroethane and chlorobenzene; ester solvents such as ethyl acetate and butyl acetate; ketone solvents such as methyl ethyl ketone and methyl isobutyl ketone; carbonate solvents such as dimethyl carbonate and diethyl carbonate; methanol, ethanol And alcohol solvents such as 2-propanol, 1-butanol and t-butanol.
- hydrocarbon solvents such as hexane, heptane, benzene and toluen
- a plurality of solvents selected from these may be mixed and used in an arbitrary ratio, or only the reaction solvent may be used as the extraction solvent without adding the solvent during extraction.
- the extraction may be performed by removing the separated aqueous layer without using an organic solvent.
- Preferable extraction solvents include hexane, heptane, toluene, ethyl acetate, t-butanol, a reaction solvent or a mixed solvent thereof, and it is more preferable to perform extraction without adding an organic solvent in order to increase productivity.
- protective reagents include, but are not limited to, formic acid-acetic anhydride, acetic anhydride, acetyl chloride, chloroacetyl chloride, dichloroacetyl chloride, trichloroacetyl chloride, trifluoroacetic anhydride
- Acylating agents such as propionyl chloride, benzoyl chloride, 4-chlorobenzoyl chloride; methyl chloroformate, ethyl chloroformate, di-t-butyl dicarbonate, benzyl chloroformate (benzyloxycarbonyl chloride), allyl chloroformate (allyl) Alkoxycarbonylating agents such as oxycarbonyl chloride); arylalkylating agents such as benzyl bromide, 4-methoxybenzyl bromide, 4-bromobenzyl
- acylating agents and alkoxycarbonylating agents that suppress decyanodegradation from 2-cyanopyrrolidines represented by the above general formula (7) are preferred, and alkoxycarbonylating agents are more preferred, and they can be easily removed.
- base to be used examples include 3 such as triethylamine, diisopropylethylamine, N-methylmorpholine, quinuclidine, 1,4-diazabicyclo [2.2.2] octane, etc.
- pyridines such as pyridine, 4-dimethylaminopyridine and 2,6-lutidine
- strong organic bases such as 1,8-diazabicyclo [5.4.0] undec-7-ene and tetramethylguanidine
- lithium diisopropyl Metal amides such as amide and sodium hexamethyldisilazide
- Alkyl metals such as n-butyllithium, sec-butyllithium, tert-butyllithium and isopropylmagnesium bromide
- Metal hydrides such as sodium hydride and calcium hydride
- Sodium Methoxide, sodium eth Metal alkoxides such as sid and potassium t-butoxide
- carbonates such as sodium hydrogen carbonate and potassium carbonate
- phosphates such as potassium phosphate and sodium hydrogen phosphate
- hydroxides such as sodium hydroxide and potassium hydroxide
- cyanide And cyanide such as sodium chloride and potassium cyanide.
- the preferred base varies depending on the protecting reagent used, and when the preferred protecting reagent, acetic anhydride, di-t-butyl dicarbonate, is used, preferably a tertiary amine, pyridines, carbonates, hydroxides and cyanides. More preferably, it is a cyanide having an action of converting pyrroline generated by decomposition of 2-cyanopyrrolidine into 2-cyanopyrrolidine again.
- Step (b) The ⁇ -substituted proline amides represented by the general formula (3) are cyclic nitrogen-containing compounds represented by the general formula (2), preferably 2-cyanopyrrolidines represented by the general formula (7). Can be synthesized by hydrating.
- the cyclic nitrogen-containing compound represented by the general formula (2) is a pyrroline represented by the general formula (6) having no cyano group
- the reaction is performed by reacting with a cyanating agent. It is preferably used in the step (b) after being converted to 2-cyanopyrrolidines represented by the general formula (7).
- the 2-cyanopyrrolidines represented by the above general formula (7) can be used in step (b) after being purified by a method such as extraction and then protected if necessary.
- a method such as extraction and then protected if necessary.
- This method can react the 2-cyanopyrrolidines represented by the general formula (7), which may generate highly toxic hydrocyanic acid gas, without purification, and is preferable for the safety of workers.
- the hydration reaction in step (b) can be carried out in the presence of a catalyst that promotes the hydration reaction from nitrile to amide.
- a catalyst that promotes the hydration reaction from nitrile to amide.
- the catalyst used in the hydration reaction include, but are not limited to, hydrogen peroxide; hydroperoxides such as t-butyl hydroperoxide; peracetic acid, metachloroperbenzoic acid Organic peracids such as inorganic acids such as persulfuric acid and periodic acid; inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid; organic acids such as trifluoromethanesulfonic acid, methanesulfonic acid and trifluoroacetic acid; sodium hydroxide, Inorganic base such as potassium carbonate; Complex catalyst such as [ ⁇ Rh (OMe) (cod) ⁇ 2 ] PCy 3 , ⁇ PtH (PMe 2 OH) (PMe 2 O) 2 H ⁇
- a plurality of catalysts selected from these may be mixed and used.
- a preferable catalyst varies depending on a substituent on nitrogen of the 2-cyanopyrrolidine represented by the general formula (7), but R 2 is a hydrogen atom or an optionally substituted alkyl group.
- Inorganic acids, organic acids, complex catalysts, and enzymes that can suppress side reactions such as the decomposition of unstable substrates are preferred, and industrially inexpensive inorganic acids are more preferred.
- R 2 is an acetyl group or a t-butoxycarbonyl group
- a preferred catalyst is a combination of hydrogen peroxide and an inorganic base, a complex catalyst, and an enzyme capable of performing a hydration reaction under mild conditions.
- More preferred is a combination of an industrially inexpensive hydrogen peroxide solution and an inorganic base.
- the preferred amount to be used varies depending on the activity of the catalyst used, but is generally 0.01 to 100 equivalents, preferably 0.02 to 20 equivalents, more preferably 2-cyanopyrrolidines represented by the general formula (7). Is 0.1 to 10 equivalents.
- a solvent may be used as necessary.
- the solvent to be used is not particularly limited as long as it does not adversely affect the reaction, and specifically, hydrocarbon solvents such as hexane, heptane, benzene, toluene, etc .; ethyl ether, propyl ether, cyclopentyl methyl ether, t-butyl methyl Ether solvents such as ether and tetrahydrofuran; Halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane and chlorobenzene; Ester solvents such as ethyl acetate and butyl acetate; Ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone; Amide solvents such as formamide and N-methylpyrrolidone; Carbonate ester solvents such as dimethyl carbonate and diethyl carbonate; Nitrile solvents such as acetrile
- a plurality of solvents selected from these may be mixed and used in an arbitrary ratio.
- Preferred solvents include toluene, ethyl acetate, tetrahydrofuran, acetone, dimethylformamide, acetonitrile, dimethyl sulfoxide, alcohol solvents, water, and mixed solvents thereof, more preferably alcohol solvents, water, and mixtures thereof.
- It is a solvent.
- the solvent can be used in any amount, and is usually 0 to 50 times volume, preferably 2 to 50 times the volume of 2-cyanopyrrolidines represented by the general formula (7).
- the volume is 0 to 20 times, more preferably 0 to 10 times.
- the amount of the solvent used is preferably 0 to 5 times by volume, more preferably 0 to 1 times by volume.
- the reaction temperature in step (b) is not particularly limited as long as it does not adversely affect the reaction, but is usually ⁇ 20 to 120 ° C., preferably 10 to 80 ° C., more preferably 30 to 70 ° C. is there.
- the reaction time in step (b) is not particularly limited as long as it does not adversely affect the reaction, but it is preferably performed in the range of 10 minutes to 24 hours from the viewpoint of suppressing production cost, more preferably 1 to 10 hours.
- the ⁇ -substituted proline amides represented by the above general formula (3) obtained in the step (b) can be purified by a method such as extraction, distillation and / or crystallization, and can be used in the next step without purification. It can also be used. Further, when R 2 is a hydrogen atom, the nitrogen atom on the pyrrolidine ring may be protected before being used in step (c), and when R 2 is an amino protecting group, it is used in step (c). The amino protecting group may be removed in advance.
- Solvents used for extraction and / or crystallization are not particularly limited, but hydrocarbon solvents such as hexane, heptane, cyclohexane, benzene, toluene; ethyl ether, propyl ether, cyclopentyl methyl ether, t-butyl methyl ether, tetrahydrofuran, etc.
- Ether solvents such as: dichloromethane, chloroform, dichloroethane, chlorobenzene and other halogenated hydrocarbon solvents; ethyl acetate, butyl acetate and other ester solvents; methyl ethyl ketone, methyl isobutyl ketone and other ketone solvents; dimethyl carbonate, diethyl carbonate, etc.
- Carbonic acid ester solvents ; alcohol solvents such as 1-butanol, 2-butanol, 1-hexanol and the like. A plurality of solvents selected from these may be mixed and used in an arbitrary ratio.
- Preferable extraction solvents include hexane, heptane, cyclohexane, toluene, ethyl acetate, 1-butanol or a mixed solvent thereof.
- Crystallization here refers to the addition of a poor solvent, acid, base, or the like to the solution, or the normal crystallization of taking out the target product as crystals by lowering the solubility by azeotropic removal of a rich solvent such as water. It also includes recrystallization in which the obtained crude crystals are dissolved in a suitable solvent and then recrystallized.
- the crystals obtained here may be ⁇ -substituted proline amides containing no acid or base component, or ⁇ -substituted proline amides and acid or base salts.
- Step (c) The optically active ⁇ -substituted proline represented by the general formula (4) and / or the optically active ⁇ -substituted proline amide represented by the general formula (5) can be obtained by enzymatic and / or chemical methods.
- the ⁇ -substituted proline amides represented by the general formula (3) can be synthesized by resolution.
- the ⁇ -substituted proline amide represented by the above general formula (3) has no asymmetric point other than the carbon atom to which the carbamoyl group is bonded, it does not have a racemate or sufficient optical purity.
- the ⁇ -substituted proline amides represented by the above general formula (3) can be synthesized by optical resolution.
- the ⁇ -substituted prolinamide represented by the above general formula (3) does not have a sufficient R: S ratio for the stereochemistry at the 2-position of pyrrolidine.
- segmented efficiently Specifically, (d) Asymmetric hydrolysis reaction of the amide group by the enzyme which has amidase activity; (e) Split by diastereomeric salt formation; (f) Examples include separation by column chromatography.
- the dividing step of the present invention may be any one of steps (d) to (f), or may combine two or more steps (d) to (f).
- the enzyme having amidase activity used in step (d) is converted to amino acid by acting stereospecifically on racemic amino acid amide.
- the substance is not particularly limited as long as it is a substance derived from a living body, but the form thereof is, for example, a purified enzyme (and an immobilized product) that retains amidase activity, or a cell containing the same, a preparation of the same cell (broken cell) , Bacterial cell extracts, crudely purified enzymes, and immobilized products thereof), or culture solutions obtained by culturing the same cells.
- amidase and commercially available enzymes produced by the bacterial cells exemplified below are preferred.
- Ocrobacterium anthropi NCIMB 40321 Mycobacterium neoaurum ATCC 25975 ⁇ Rhizopus oryzae for example, an enzyme peptidase R (trade name) manufactured by Amano Enzyme, Inc.
- Rhizopus oryzae for example, an enzyme peptidase R (trade name) manufactured by Amano Enzyme, Inc.
- Rhizopus oryzae for example, an enzyme peptidase R for food addition (trade name) manufactured by Amano Enzyme Co., Ltd.
- the concentration of the enzyme having amidase activity varies depending on the amount of the activity, but is 0.0001 to 5 times by weight, preferably 0.001 to 1 times by weight with respect to the ⁇ -substituted proline amides represented by the general formula (3). More preferably, the weight is 0.001 to 0.1 times the weight. Within this range, the reaction time and the catalyst removal operability are preferable.
- the reactivity can be improved by adding a compound that improves the enzyme activity.
- the additive used is not particularly limited, and specifically, divalent metal ions such as zinc, manganese and magnesium, reducing agents such as mercaptoethanol and dithiothreitol, nonionic surfactants such as Triton X100, and These mixtures are mentioned.
- concentration of the compound that improves the enzyme activity varies depending on the amount of the activity, but it is usually preferably 0.0001% by mass to 1% by mass with respect to the amount of the reaction solution. Within this range, it is preferable from the viewpoint of easy removal of the compound for improving the enzyme activity and the raw material cost.
- step (d) ⁇ -substituted proline amides represented by the above general formula (3) having an arbitrary substituent can be used, and it is preferable that the substituent R 2 is a hydrogen atom. This is preferable because the solubility in water is high.
- ⁇ -substituted proline amides having an arbitrary purity can be used in the step (d). However, depending on impurities, it is preferable to use a raw material purified by a method such as crystallization because the enzyme reaction is inhibited. .
- the ⁇ -substituted proline amides exhibit basicity, and therefore, a salt with an acid generally improves the crystallinity and improves the purification effect. Is preferable because of the increase.
- Specific examples of the acid used here include, but are not limited to, mineral acids such as hydrochloric acid, sulfuric acid, nitric acid; acetic acid, formic acid, trifluoroacetic acid, benzoic acid, oxalic acid, maleic acid And carboxylic acids such as succinic acid; and sulfonic acids such as methanesulfonic acid and toluenesulfonic acid.
- mineral acids and sulfonic acids that are industrially inexpensive and generally have high salt crystallinity are preferable, hydrochloric acid, sulfuric acid, and toluenesulfonic acid are more preferable, and hydrochloric acid is particularly preferable.
- the solvent used in the step (d) is not particularly limited as long as it does not adversely influence the reaction.
- hydrocarbon solvents such as hexane, heptane, benzene, toluene, etc .
- ethyl ether, propyl ether, cyclopentyl methyl ether Ether solvents such as t-butyl methyl ether and tetrahydrofuran
- halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane and chlorobenzene
- ester solvents such as ethyl acetate and butyl acetate
- Amide solvents such as dimethylformamide and N-methylpyrrolidone
- Carbonate ester solvents such as dimethyl carbonate and diethyl carbonate
- Nitrile solvents such as acetonitrile
- a plurality of solvents selected from these may be mixed and used in an arbitrary ratio.
- Preferred solvents include acetone, dimethylformamide, acetonitrile, dimethyl sulfoxide, alcohol solvents, water, and mixed solvents thereof, and more preferred solvents include inexpensive use of water alone and 10 volumes with respect to water.
- the solvent can be used in an arbitrary amount, and is usually 1 to 200 times the volume of the ⁇ -substituted prolineamide represented by the general formula (3). It is preferable to do. Within this range, it is preferable in terms of production efficiency of optically active amino acids.
- the amount of the solvent used is more preferably 1 to 50 times by volume, particularly 1 to 10 times by volume, relative to the ⁇ -substituted proline amides represented by the general formula (3). preferable.
- step (d) it is preferable to adjust the pH of the reaction solution in order to prevent the inactivation of the enzyme having amidase activity and the natural decomposition of ⁇ -substituted proline amides, and to obtain the optimum catalytic activity and reaction yield.
- the appropriate pH range varies depending on the enzyme having amidase activity to be used, but it is usually adjusted so that the measured value at room temperature (specifically, around 20-30 ° C) is 5.0-9.0. Is preferable, and 6.0 to 8.0 is more preferable. Since ⁇ -substituted proline amides represented by the general formula (3) are usually basic in an aqueous solution, an acid is used for pH adjustment.
- the ⁇ -substituted proline amide represented by the general formula (3) when used as a salt such as hydrochloride, it usually shows neutral to weak acidity in an aqueous solution, and therefore an acid or a base is used for pH adjustment. .
- an inorganic acid which is a preferred catalyst in the step (b) when used and an acidic aqueous solution of the ⁇ -substituted proline amides represented by the general formula (3) thus obtained is used for the direct reaction, it usually shows acidity.
- a base is used for pH adjustment.
- an acid or a base may be appropriately added to adjust the pH.
- the pH is preferably adjusted so that the measured value at 20 to 30 ° C. is 5.0 to 9.0, more preferably 6.0 to 8.0.
- Specific examples of the acid or base to be used are listed below, and are not particularly limited as long as the pH can be controlled to an appropriate pH; however, mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid; organics such as methanesulfonic acid, trifluoroacetic acid, acetic acid and formic acid Acids; carbonates such as sodium hydrogen carbonate and potassium carbonate; phosphates such as potassium phosphate and sodium hydrogen phosphate; hydroxides such as sodium hydroxide and potassium hydroxide.
- an inexpensive mineral acid is preferably used as the acid
- an inexpensive hydroxide is preferably used as the base.
- the usage form can be used in the state of compound itself or aqueous solution.
- the reaction temperature in step (d) is not particularly limited as long as it does not adversely affect the reaction, but it is preferably in the range of 5 to 70 ° C. Within this range, it is preferable in terms of reaction time, reaction yield, and the like. 15 to 60 ° C. is more preferable, and 25 to 50 ° C. is particularly preferable.
- the reaction time in step (d) is not particularly limited as long as it does not adversely affect the reaction, and varies depending on the amount of catalyst and the type of ⁇ -substituted proline amides represented by the above general formula (3). 5 to 60 hours. Within this range, the reaction yield, the operation efficiency of the production process and the like are preferable.
- the yield and / or conversion rate is calculated from the quantitative value of ⁇ -substituted prolines by high performance liquid chromatography, and the yield and / or conversion rate is calculated. Is preferably 90% or more of the theoretical value to complete the reaction, more preferably 98% or more of the theoretical value.
- the diastereomeric purity and / or optical purity is calculated from the area ratio and / or quantitative value of ⁇ -substituted prolines and / or ⁇ -substituted proline amides by high performance liquid chromatography, and only on the carbon atom to which the carbamoyl group is bonded.
- it has an asymmetric point, it is preferable to complete the reaction at 80% ee or more, more preferably 95% ee or more.
- high optical purity is required, so 99% It is especially preferable to set it to ee or more.
- the R-form: S-form (molar ratio) 90: 10 to 100: 0 or the R-form: S-form (molar ratio) for the stereochemistry at the 2-position of pyrrolidine
- the reaction is more preferably completed at 97.5 to 0: 100.
- step (d) it is preferable to stop the activity of the enzyme having amidase activity in order to suppress the decrease in optical purity and yield due to excessive reaction progress.
- Specific operations include a method for inactivating an enzyme having an amidase activity by adjusting pH or temperature, an additive for inhibiting the activity of an enzyme having an amidase activity, or for aggregating and removing the activity of an enzyme having an amidase activity. And the like.
- optically active ⁇ -substituted proline represented by the general formula (4) and / or the optically active ⁇ -substituted prolineamide represented by the general formula (5) obtained in the step (d) is filtered and extracted. , Distillation, separation with resin and / or crystallization. Further, when R 2 is a hydrogen atom, the nitrogen atom on the pyrrolidine ring may be protected after step (d), and when R 2 is an amino group protecting group, the amino group is protected after step (d). The group may be removed.
- Filtration includes filtration using a filter such as ultrafiltration membrane, microfiltration membrane, filter cloth, filter paper, and filtration using an adsorbent such as celite or activated carbon.
- a filter such as ultrafiltration membrane, microfiltration membrane, filter cloth, filter paper
- an adsorbent such as celite or activated carbon.
- inorganic flocculants such as aluminum oxide, magnesium chloride and calcium chloride and polymer flocculants such as polyethyleneimine and chitosan
- the enzyme which has amidase activity contained in the fraction concentrated by filtration can also be reused.
- Solvents used for extraction and / or crystallization are not particularly limited, but hydrocarbon solvents such as hexane, heptane, cyclohexane, benzene, toluene; ethyl ether, propyl ether, cyclopentyl methyl ether, t-butyl methyl ether, tetrahydrofuran, etc.
- Ether solvents such as dichloromethane, chloroform, dichloroethane, chlorobenzene and other halogenated hydrocarbon solvents; ethyl acetate, butyl acetate and other ester solvents; acetone, methyl ethyl ketone, methyl isobutyl ketone and other ketone solvents; dimethyl carbonate, diethyl carbonate Carbonate solvents such as nitrile solvents such as acetonitrile; sulfur-containing solvents such as dimethyl sulfoxide and sulfolane; methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, - alcohol solvents such as butanol; water and the like.
- a plurality of solvents selected from these may be mixed and used in an arbitrary ratio.
- Preferable extraction solvents include toluene, ethyl acetate, tetrahydrofuran, methyl ethyl ketone, 1-butanol, 2-butanol, t-butanol or a mixed solvent thereof.
- keeping the aqueous layer basic is that the optically active ⁇ -substituted proline represented by the general formula (5) is added to the optically active ⁇ -substituted proline represented by the general formula (4) in the aqueous layer.
- Amides are preferable because they can be distributed to the organic layer, and it is preferable to add sodium chloride or the like in order to increase the salt concentration of the aqueous layer and increase the extraction efficiency.
- Preferable crystallization solvents include toluene, ethyl acetate, acetone, methanol, ethanol, t-butanol, 2-butanol, 1-butanol, water, or a mixed solvent thereof.
- the optically active ⁇ -substituted prolines represented by the general formula (4) and the optically active ⁇ -substituted proline amides represented by the general formula (5) generally differ greatly in solubility in a solvent. It is preferable to perform crystallization separation by using.
- R 2 of the optically active ⁇ -substituted prolines represented by the general formula (4) is a hydrogen atom
- it is an amino acid having both a carboxyl group and an amino group. It is preferable to crystallize by controlling the isoelectric point to lower the solubility, and further to crystallize by lowering the solubility by adding a salt such as sodium chloride or an organic solvent.
- Resins used for separation by the resin include optically active ⁇ -substituted prolines represented by the above general formula (4), optically active ⁇ -substituted proline amides represented by the above general formula (5) and / or other
- optically active ⁇ -substituted proline amides represented by the above general formula (5) and / or other There is no particular limitation as long as it has the ability to separate impurities, and specific examples thereof include strongly acidic cation exchange resins, strong basic anion exchange resins, weakly acidic cation exchange resins, and weakly basic anion exchange resins. And may be used in combination so as to obtain a sufficient degree of purification.
- the optically active ⁇ -substituted proline represented by the general formula (4) is adsorbed on the resin, and the optically active ⁇ -substituted prolineamide represented by the general formula (5) is used as the resin.
- the means for the purification step is not particularly limited as long as the required degree of purification can be obtained, but it is preferable to use a combination of industrially less burdensome methods in order to increase productivity.
- the reaction solution is limited.
- the filtrate is passed through a strongly basic anion exchange resin, and the optically active ⁇ -substituted proline represented by the general formula (4) and the optically active ⁇ -
- the optically active ⁇ -substituted prolines represented by the above general formula (4) and / or the above general formula (5) are crystallized. And a method for obtaining optically active ⁇ -substituted proline amides.
- the resolution by diastereomeric salt formation in step (e) is optical when the ⁇ -substituted prolineamide represented by the general formula (3) is a racemate.
- an optically active acid or an achiral acid is allowed to act, and the resulting crystalline salt is separated by a method such as filtration. It is a method of dividing by doing.
- the optically active ⁇ -substituted proline amide represented by the general formula (5) is obtained in the crystal and / or filtrate.
- optically active acid used in the step (e) examples include L-tartaric acid, D-tartaric acid, (2S, 3S) -dibenzoyltartaric acid, (2R, Tartaric acids such as (3R) -dibenzoyltartaric acid, (2S, 3S) -di (p-toluoyl) tartaric acid, (2R, 3R) -di (p-toluoyl) tartaric acid; (S) -mandelic acid, (R) -mandel Mandelic acids such as acids; N-acetyl-L-alanine, N-acetyl-L-phenylglycine, N-acetyl-D-phenylglycine, N-benzyl-L-phenylglycine, N-benzyl-D-phenylglycine, Amino acid derivatives such as N-acetyl-L-pheny
- achiral acid used in step (e) include, but are not limited to, mineral acids such as hydrochloric acid, sulfuric acid, nitric acid; acetic acid, formic acid, trifluoroacetic acid, benzoic acid, Examples thereof include carboxylic acids such as oxalic acid, maleic acid, and succinic acid; and sulfonic acids such as methanesulfonic acid and toluenesulfonic acid.
- hydrochloric acid, acetic acid, benzoic acid, oxalic acid, maleic acid, succinic acid, and toluenesulfonic acid are preferable because they are industrially inexpensive and generally have high salt crystallinity.
- the diastereomeric salt to be generated may be a one-to-one salt or a one-to-two or more salt. There may be.
- the amount of the optically active acid and / or achiral acid used is 0.1 to 10 equivalents relative to the ⁇ -substituted proline amides represented by the above general formula (3), and excessive use hinders crystallization. , Preferably 0.2-3 equivalents, more preferably 0.3-1 equivalent. In addition, the usage-amount said here is the equivalent of the acid used for salt formation.
- the solvent used in the step (e) is not particularly limited, but a hydrocarbon solvent such as hexane, heptane, benzene, toluene, etc .; an ether solvent such as ethyl ether, propyl ether, cyclopentyl methyl ether, t-butyl methyl ether, tetrahydrofuran, etc.
- a hydrocarbon solvent such as hexane, heptane, benzene, toluene, etc .
- an ether solvent such as ethyl ether, propyl ether, cyclopentyl methyl ether, t-butyl methyl ether, tetrahydrofuran, etc.
- Halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane and chlorobenzene; ester solvents such as ethyl acetate, isopropyl acetate and butyl acetate; ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone; dimethyl carbonate, diethyl carbonate and the like Carbonate ester solvents; Nitrile solvents such as acetonitrile; Sulfur-containing solvents such as dimethyl sulfoxide and sulfolane; Methanol, ethanol, 2-propanol, 1-butanol, 2-butanol Alcohol solvents such as t- butanol; water and the like.
- ester solvents such as ethyl acetate, isopropyl acetate and butyl acetate
- ketone solvents such as acetone, methyl ethyl ketone and methyl
- a plurality of solvents selected from these may be mixed and used in an arbitrary ratio.
- the ⁇ -substituted proline amides represented by the above general formula (3) and an optically active acid or an achiral acid have sufficient solubility, and the resulting diastereomeric salt has sufficient solubility.
- Low, good ether solvents such as ethyl ether, propyl ether, cyclopentyl methyl ether, t-butyl methyl ether, tetrahydrofuran; ester solvents such as ethyl acetate, isopropyl acetate, butyl acetate; methanol, ethanol, 2-propanol, Alcohol solvents such as 1-butanol, 2-butanol and t-butanol and mixed solvents of these solvents and arbitrary solvents, more preferably ester solvents such as ethyl acetate, isopropyl acetate and butyl acetate and these solvents And a solvent mixture of any solvent.
- the solvent used at this time include hydrocarbon solvents such as hexane, heptane, benzene, and toluene; ester solvents such as ethyl acetate, isopropyl acetate, and butyl acetate.
- the amount of the solvent used is usually 1 to 50 times the volume of the ⁇ -substituted proline amides represented by the above general formula (3), and an amount that can ensure the fluidity of the precipitated diastereomeric salt is required
- the volume is preferably 2 to 20 times volume, more preferably 3 to 10 times volume.
- a seed crystal may be added.
- the diastereomeric salt obtained in step (e) can be used as a seed crystal. Further, after dissolving the optically active ⁇ -substituted proline amides represented by the general formula (5) having high purity and the optically active acid or the achiral acid, concentration, drying, cooling, physical impact, etc. It may be obtained by performing an operation.
- the temperature in the step (e) is not particularly limited, but is usually ⁇ 20 to 120 ° C., preferably ⁇ 10 to 80 ° C., more preferably 0 to 70 ° C.
- step (e) resolution may be achieved by increasing the diastereomeric purity and / or optical purity of the filtrate.
- the diastereoisomers obtained as crystals It is preferred to achieve resolution by increasing the diastereomeric purity of the mer salt.
- the purity is increased by a method such as recrystallization. Is preferred.
- the diastereomeric salt of the optically active ⁇ -substituted proline amides represented by the above general formula (5) obtained in the step (e) is obtained by combining the optically active ⁇ -substituted proline amides with the optically active acid by a method such as extraction. And / or achiral acids can be separated. The separated optically active acid and / or achiral acid may be recovered and reused.
- R 2 of the optically active ⁇ -substituted proline amides represented by the general formula (5) is a hydrogen atom
- the nitrogen atom on the pyrrolidine ring may be protected after step (e), and R 2 is an amino group.
- the amino protecting group may be removed after step (e).
- the optically active ⁇ -substituted proline amides represented by the general formula (5) can be converted to optically active ⁇ -substituted prolines represented by the general formula (4) by hydrolysis. it can.
- the diastereomeric salt may be used as a raw material, and an optical compound represented by the general formula (5) in which an optically active acid and / or an achiral acid is separated Active ⁇ -substituted proline amides may be used as a raw material.
- Hydrolysis catalysts used include, but are not limited to, inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid; organic acids such as trifluoromethanesulfonic acid, methanesulfonic acid and trifluoroacetic acid; water Examples thereof include inorganic bases such as sodium oxide and potassium carbonate; enzymes having amidase and peptidase activity, and the like. A plurality of catalysts selected from these may be mixed and used.
- each diastereomer is separated by passing through a column packed with a packing material.
- optically active ⁇ -substituted proline amides represented by the above general formula (5) are obtained.
- column chromatography used in step (f) examples include, but are not limited to, silica gel column chromatography using spherical silica gel (neutral) and spherical silica gel (acidic); 18, reverse phase column chromatography using silica gel bonded with a linear alkyl group having 8 carbon atoms, etc .; column chromatography using a styrene-divinylbenzene synthetic adsorbent.
- Specific examples of the synthetic adsorbent include HP20, HP21, SP70, SP207, SP700, SP825, and SP850 manufactured by Mitsubishi Chemical Corporation.
- silica gel column chromatography that is inexpensive and easy to use repeatedly
- column chromatography that uses a synthetic adsorbent, more preferably a synthetic adsorbent that can use an inexpensive aqueous solvent as an eluent.
- Column chromatography using The separation method may be batch column chromatography for completely eluting the charged sample each time, or continuous column chromatography using a simulated moving bed.
- the solvent used in the step (f) is not particularly limited, but is a hydrocarbon solvent such as hexane, heptane, benzene or toluene; an ether solvent such as ethyl ether, propyl ether, cyclopentyl methyl ether, t-butyl methyl ether or tetrahydrofuran.
- a hydrocarbon solvent such as hexane, heptane, benzene or toluene
- an ether solvent such as ethyl ether, propyl ether, cyclopentyl methyl ether, t-butyl methyl ether or tetrahydrofuran.
- Halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane and chlorobenzene; ester solvents such as ethyl acetate, isopropyl acetate and butyl acetate; ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone; dimethyl carbonate, diethyl carbonate and the like Carbonate ester solvents; Nitrile solvents such as acetonitrile; Sulfur-containing solvents such as dimethyl sulfoxide and sulfolane; Methanol, ethanol, 2-propanol, 1-butanol, 2-butanol Alcohol solvents such as t- butanol; water and the like.
- ester solvents such as ethyl acetate, isopropyl acetate and butyl acetate
- ketone solvents such as acetone, methyl ethyl ketone and methyl
- a plurality of solvents selected from these may be mixed and used in an arbitrary ratio.
- the preferred solvent varies depending on the type of column chromatography used, but in the case of preferred column chromatography using a synthetic adsorbent, a ketone solvent; a nitrile solvent; an alcohol solvent; water is preferred, and an inexpensive acetone is more preferred. Methanol and water.
- Specific examples of the additive include acids such as acetic acid and formic acid; salts such as ammonium acetate, sodium acetate, and ammonium chloride; bases such as ammonia and sodium hydroxide, and the like. May be.
- the optically active ⁇ -substituted proline amides represented by the above general formula (5) obtained in the step (f) should have an asymmetric point only at the carbon atom to which the carbamoyl group is bonded, and should be 80% ee or more. Is preferable, 90% ee is more preferable, and 95% ee or more is further preferable. In the case of pharmaceuticals and intermediates thereof, high optical purity is required, so 99% ee or more is particularly preferable.
- this oily substance was found to contain 60% by weight (12.5 mmol, 62% yield) of 2-cyano-2-methylpyrrolidine and 7% by weight (2.0 mmol, 2-methyl-1-pyrroline). And a mixture containing 34% by weight of ethyl acetate.
- ⁇ -methylprolinamide hydrochloride obtained according to the method of Example 2 was prepared with 0.2 M Tris buffer (pH 7.0) to a final concentration of 500 g / L, and then 3 The pH was adjusted to 6.8 with aqueous sodium hydroxide.
- 0.2 mL of a peptidase R (trade name, manufactured by Amano Enzyme Co., Ltd., Rhizopus oryzae) aqueous solution prepared at 50 g / L was mixed with 0.8 mL of this mixed solution, and reacted for 40 hours at 40 rpm with a stirring rate of 800 rpm.
- the reaction was performed while adding 28.8 g of 28% aqueous ammonia in portions and adjusting the pH to 7.4-7.6. After 3 hours, 12.2 g (0.25 mol) of sodium cyanide was added, and the reaction was further continued for 3 hours. After cooling to room temperature, the aqueous layer was removed to obtain an ethyl acetate solution of 2-cyano-2-methylpyrrolidine. A separate flask was charged with 40.7 g (0.42 mol) of sulfuric acid, and an ethyl acetate solution of 2-cyano-2-methylpyrrolidine was added dropwise under ice cooling.
- a flask was charged with 38.4 g (0.50 mol) of ammonium acetate, 30 mL of water, 9.8 g (0.20 mol) of sodium cyanide, and 20.0 g (0.17 mol) of 5-chloro-2-pentanone. Reacted for 1 minute. After adding 12.0 g of 28% aqueous ammonia and reacting for 2 hours, the mixture was cooled to room temperature and the aqueous layer was removed.
- the organic layer of the flask was washed with 10 mL of cyclohexane, and 48.8 g (0.50 mol) of concentrated sulfuric acid was added dropwise to the obtained organic layer under ice cooling, and the mixture was reacted at room temperature for 4 hours.
- the reaction solution was ice-cooled, and 72 mL of water and 60.4 g of 28% aqueous ammonia were slowly added. After adding 200 mL of 1-butanol and 3.0 g of 28% ammonia water to the obtained solution, the aqueous layer was removed.
- Peptidase R (trade name, manufactured by Amano Enzyme Co., Ltd., Rhizopus oryzae) 2.3 g of water (15.5 ml) solution was added to the mixed solution, and the mixture was reacted at 40 with stirring at 250 rpm for 60 hours.
- the pure content of (S) - ⁇ -methylproline was 10.5 g (81.0 mmol, yield 342.7%) and the optical purity was 99.0% ee. It was. 50 ml of water and 15 g of activated carbon were added to the reaction solution and shaken at 25 ° C. for 1 hour.
- a flask 0.58 g (19% by weight, 1.0 mmol) of a t-butanol solution of 2-cyano-2-methylpyrrolidine obtained according to the method of Example 5, 49 mg (1 mmol) of sodium cyanide, 0.4 ml of DMSO was charged. Under ice cooling, 0.13 ml (1.5 mmol) of 35% aqueous hydrogen peroxide was added, and the temperature was gradually raised to room temperature.
- a flask was charged with 2.41 g (20 mmol) of 5-chloro-2-pentanone, 1.08 g (22 mmol) of sodium cyanide, 4.62 g (60 mmol) of ammonium acetate, 10 ml of water, and 10 ml of t-butanol, and at 50 ° C. for 6 hours. Reacted. After adding 10 ml of ethyl acetate and 2.4 ml of 50 w / v% NaOH aqueous solution to the reaction solution, the aqueous layer was removed.
- the flask was charged with 0.57 ml (5.0 mmol) of 5-chloro-2-pentanone, 270 mg (5.5 mmol) of sodium cyanide, 1.64 ml (15 mmol) of benzylamine, 0.86 ml (15 mmol) of acetic acid, 2.5 ml of water, 2.5 ml of t-butanol was charged and reacted at 50 ° C. for 2 hours. After adding 10 ml of ethyl acetate and 1.2 ml of 50 w / v% NaOH aqueous solution to the reaction solution, the aqueous layer was removed. The organic layer was concentrated to obtain 2.15 g of a light brown oily substance.
- this oily substance was found to contain 47% by weight (1.01 g, quantitative) of 1-benzyl-2-cyano-2-methylpyrrolidine, 48% by weight of benzylamine, 2% by weight of ethyl acetate, t -A mixture containing 3% by weight of butanol.
- this oily substance was found to contain 78% by weight (3.35 g, 84% yield) of 1-benzyl-2-cyano-2-methylpyrrolidine, 2% by weight of 5-chloro-2-pentanone, chain This was a mixture containing 12% by weight of 2-benzylamino-5-chloro-2-cyanopentane, 6% by weight of benzylamine, and 1% by weight of ethyl acetate.
- the flask was charged with 1.14 ml (10 mmol) of 5-chloro-2-pentanone, 0.54 g (11 mmol) of sodium cyanide, 1.40 ml (11 mmol) of (R) - ⁇ -methylbenzylamine, 0.63 ml (11 mmol) of acetic acid, 2.3 ml of water was charged and reacted at 40 ° C. for 3 hours. After adding 0.80 ml (10 mmol) of a 50 w / v% NaOH aqueous solution to the reaction solution, the mixture was further reacted at 60 ° C. for 1 hour.
- this oily substance was found to contain 83% by weight (1.R, 1′R) and (2S, 1′R) -1- (1′-phenylethyl) -2-cyano-2-methylpyrrolidine.
- the flask was charged with 1.25 ml (11 mmol) of 5-chloro-2-pentanone, 0.54 g (11 mmol) of sodium cyanide, 1.28 ml (10 mmol) of (R) - ⁇ -methylbenzylamine, 0.63 ml (11 mmol) of acetic acid, 2.0 ml of water was charged and reacted at 40 ° C. for 3 hours. After adding 0.80 ml (10 mmol) of a 50 w / v% NaOH aqueous solution to the reaction solution, the reaction solution was further reacted at 60 ° C. for 2 hours. After cooling to room temperature, the aqueous layer was separated to obtain a light brown oily substance.
- the flask was charged with 13.3 g (110 mmol) of 5-chloro-2-pentanone, 5.4 g (110 mmol) of sodium cyanide, 12.1 g (100 mmol) of (S) - ⁇ -methylbenzylamine, 6.3 ml (110 mmol) of acetic acid, 24 ml of water was charged and reacted at 40 ° C. for 3 hours. After adding 8.0 ml (100 mmol) of 50 w / v% NaOH aqueous solution to the reaction solution, the reaction was further allowed to proceed at 60 ° C. for 2 hours. After cooling to room temperature, the aqueous layer was separated to obtain a light brown oily substance.
- the reaction solution was filtered through Celite to obtain a 1-butanol solution of (S) - ⁇ -methylprolinamide.
- the aqueous layer was separated and acetic acid was removed.
- 1 ml of water and 0.49 ml (9.2 mmol) of sulfuric acid were added to the organic layer, (S) - ⁇ -methylprolinamide was extracted into the aqueous layer, and the organic layer was removed. Further, 0.16 ml (3.1 mmol) of sulfuric acid was added and refluxed for 13 hours to hydrolyze the amide.
- reaction mixture was filtered through celite and concentrated to give a crude product of ⁇ -methylprolinamide.
- 1 ml of water and 0.26 ml (4.9 mmol) of sulfuric acid were added and refluxed for 5 hours.
- the reaction mixture was analyzed by chiral HPLC. As a result, racemic ⁇ - Methylproline was produced.
- this oily substance was found to be 45% by weight (0.47 g, 90% yield) of 1-benzyl-2-cyano-2-phenylpyrrolidine, 46% by weight of benzylamine, and 9% by weight of ethyl acetate. It was a mixture containing.
- optically active ⁇ -substituted proline represented by the general formula (4) and the optically active ⁇ -substituted prolineamide represented by the general formula (5) produced by the method of the present invention are useful as pharmaceutical intermediates. is there.
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Abstract
Description
E=ln[(1-c)(1-eeS)]/ln[(1-c)(1+eeS)]
この手法以外のラセミ体のα-メチルプロリンアミドの実用的な製造方法は知られておらず、工業的に優れたラセミ体のα-置換プロリンアミドの製造方法の開発が望まれていた。
[1] 下記工程(a)乃至(c)を含む、一般式(4)
(a)一般式(1)
(b)一般式(2)で表される環状含窒素化合物又はその塩を水和することにより、一般式(3)
(c)一般式(3)で表されるα-置換プロリンアミド類又はその塩を分割することにより、一般式(4)で表される光学活性α-置換プロリン類若しくはその塩、及び/又は、一般式(5)で表される光学活性α-置換プロリンアミド類若しくはその塩を得る。
[2] 下記工程(a)及び(b)を含む、一般式(3)
(a)一般式(1)
(b)一般式(2)で表される環状含窒素化合物又はその塩を水和することにより、一般式(3)で表されるα-置換プロリンアミド類又はその塩を得る。
[3] 下記工程(a)を含む、一般式(2)
(a)一般式(1)
[4] 下記工程(c)を含む、一般式(4)
(c)一般式(3)
当該分割が下記工程(d)ないし(f)のいずれかである。
(d)リゾプス・オリゼー由来のアミダーゼ活性を有する酵素によるアミド基の不斉加水分解反応である。
(e)ジアステレオマー塩形成による分割である。
(f)カラムクロマトグラフィーによる分離である。
[5] 一般式(8)
当該アルキル基が有していてもよい置換基としては、フッ素原子;炭素数2~6のアルケニル基(例、ビニル基等);炭素数1~6のアルコキシ基(例、メトキシ基、エトキシ基等);炭素数1~6のアルキル基(例、メチル基、エチル基、イソプロピル基等)、ハロゲン原子(例、フッ素原子、塩素原子、臭素原子、ヨウ素原子)、炭素数2~6のアルケニル基(例、ビニル基等)、炭素数1~6のアルコキシ基(例、メトキシ基、エトキシ基等)などから選ばれる1~3個の置換基を有していてもよい炭素数6~10のアリール基(例、フェニル基、ナフチル基等)等が挙げられる。当該置換基の数は、特に限定されないが、1~3個が好ましい。置換基が2個以上ある場合は、置換基の種類は同一でも異なっていてもよい。
置換アルキル基としては、具体的には、ベンジル基、4-メトキシベンジル基、アリル基、2-フルオロエチル基等が挙げられる。
当該アリール基が有していてもよい置換基としては、ハロゲン原子(例、フッ素原子、塩素原子、臭素原子、ヨウ素原子);炭素数1~6のアルキル基(例、メチル基、エチル基、イソプロピル基等);炭素数2~6のアルケニル基(例、ビニル基等);炭素数1~6のアルコキシ基(例、メトキシ基、エトキシ基等);ハロゲン原子(例、フッ素原子、塩素原子、臭素原子、ヨウ素原子)、炭素数1~6のアルキル基(例、メチル基、エチル基、イソプロピル基等)、炭素数2~6のアルケニル基(例、ビニル基等)、炭素数1~6のアルコキシ基(例、メトキシ基、エトキシ基等)などから選ばれる1~3個の置換基を有していてもよい炭素数6~10のアリール基(例、フェニル基、ナフチル基等)等が挙げられる。当該置換基の数は、特に限定されないが、1~3個が好ましい。置換基が2個以上ある場合は、置換基の種類は同一でも異なっていてもよい。
当該ヘテロアリール基が有していてもよい置換基としては、ハロゲン原子(例、フッ素原子、塩素原子、臭素原子、ヨウ素原子);炭素数1~6のアルキル基(例、メチル基、エチル基、イソプロピル基等);炭素数2~6のアルケニル基(例、ビニル基等);炭素数1~6のアルコキシ基(例、メトキシ基、エトキシ基等);ハロゲン原子(例、フッ素原子、塩素原子、臭素原子、ヨウ素原子)、炭素数1~6のアルキル基(例、メチル基、エチル基、イソプロピル基等)、炭素数2~6のアルケニル基(例、ビニル基等)、炭素数1~6のアルコキシ基(例、メトキシ基、エトキシ基等)などから選ばれる1~3個の置換基を有していてもよい炭素数6~10のアリール基(例、フェニル基、ナフチル基等)等が挙げられる。当該置換基の数は、特に限定されないが、1~3個が好ましい。置換基が2個以上ある場合は、置換基の種類は同一でも異なっていてもよい。
当該アルキル基が有していてもよい置換基としては、ハロゲン原子(例、フッ素原子、塩素原子、臭素原子、ヨウ素原子);炭素数2~6のアルケニル基(例、ビニル基等);炭素数1~6のアルコキシ基(例、メトキシ基、エトキシ基等);炭素数2~6のアルコキシカルボニル基(例、メトキシカルボニル基、エトキシカルボニル基等);カルバモイル基;カルボキシル基;炭素数1~6のアルキル基(例、メチル基、エチル基、イソプロピル基等)、ハロゲン原子(例、フッ素原子、塩素原子、臭素原子、ヨウ素原子)、炭素数2~6のアルケニル基(例、ビニル基等)、炭素数1~6のアルコキシ基(例、メトキシ基、エトキシ基等)などから選ばれる1~3個の置換基を有していてもよい炭素数6~10のアリール基(例、フェニル基、ナフチル基等)等が挙げられる。当該置換基の数は、特に限定されないが、1~3個が好ましい。置換基が2個以上ある場合は、置換基の種類は同一でも異なっていてもよい。また置換されていてもよいアルキル基が不斉点を有する場合、R体であってもS体であっても、ラセミ体であってもよい。
当該アルキル基が有していてもよい置換基としては、ハロゲン原子(例、フッ素原子、塩素原子、臭素原子、ヨウ素原子);炭素数2~6のアルケニル基(例、ビニル基等);炭素数1~6のアルコキシ基(例、メトキシ基、エトキシ基等);炭素数1~6のアルキル基(例、メチル基、エチル基、イソプロピル基等)、ハロゲン原子(例、フッ素原子、塩素原子、臭素原子、ヨウ素原子)、炭素数2~6のアルケニル基(例、ビニル基等)、炭素数1~6のアルコキシ基(例、メトキシ基、エトキシ基等)などから選ばれる1~3個の置換基を有していてもよい炭素数6~10のアリール基(例、フェニル基、ナフチル基等)等が挙げられる。当該置換基の数は、特に限定されないが、1~3個が好ましい。置換基が2個以上ある場合は、置換基の種類は同一でも異なっていてもよい。
置換アルキル基としては、具体的には、ベンジル基、4-メトキシベンジル基、アリル基、2-クロロエチル基等が挙げられる。
当該アリール基が有していてもよい置換基としては、ハロゲン原子(例、フッ素原子、塩素原子、臭素原子、ヨウ素原子);炭素数1~6のアルキル基(例、メチル基、エチル基、イソプロピル基等);炭素数2~6のアルケニル基(例、ビニル基等);炭素数1~6のアルコキシ基(例、メトキシ基、エトキシ基等);ハロゲン原子(例、フッ素原子、塩素原子、臭素原子、ヨウ素原子)、炭素数1~6のアルキル基(例、メチル基、エチル基、イソプロピル基等)、炭素数2~6のアルケニル基(例、ビニル基等)、炭素数1~6のアルコキシ基(例、メトキシ基、エトキシ基等)などから選ばれる1~3個の置換基を有していてもよい炭素数6~10のアリール基(例、フェニル基、ナフチル基等)等が挙げられる。当該置換基の数は、特に限定されないが、1~3個が好ましい。置換基が2個以上ある場合は、置換基の種類は同一でも異なっていてもよい。
当該ヘテロアリール基が有していてもよい置換基としては、ハロゲン原子(例、フッ素原子、塩素原子、臭素原子、ヨウ素原子);炭素数1~6のアルキル基(例、メチル基、エチル基、イソプロピル基等);炭素数2~6のアルケニル基(例、ビニル基等);炭素数1~6のアルコキシ基(例、メトキシ基、エトキシ基等);ハロゲン原子(例、フッ素原子、塩素原子、臭素原子、ヨウ素原子)、炭素数1~6のアルキル基(例、メチル基、エチル基、イソプロピル基等)、炭素数2~6のアルケニル基(例、ビニル基等)、炭素数1~6のアルコキシ基(例、メトキシ基、エトキシ基等)などから選ばれる1~3個の置換基を有していてもよい炭素数6~10のアリール基(例、フェニル基、ナフチル基等)等が挙げられる。当該置換基の数は、特に限定されないが、1~3個が好ましい。置換基が2個以上ある場合は、置換基の種類は同一でも異なっていてもよい。
また、水酸基の保護体として用いられる保護基は通常の条件で除去可能なものであれば特に限定されないが、その具体例は、ホルミル基、アセチル基、クロロアセチル基、プロピオニル基、ベンゾイル基等のアシル基;ベンジル基、4-メトキシベンジル基、4-ブロモベンジル基、1-フェニルエチル基等の置換されていてもよいアリールアルキル基;メトキシメチル基、エトキシエチル基、ベンジルオキシメチル基等のアセタール型保護基;トリメチルシリル基、t-ブチルジメチルシリル基等のシリル基が挙げられる。
置換基の具体例は以下に挙げられ、これらに限定されるものではないが、炭素数1~6のアルキル基(例、メチル基、エチル基、イソプロピル基等);炭素数2~6のアルケニル基(例、ビニル基、アリル基等);水酸基;炭素数1~6のアルコキシ基(例、メトキシ基、エトキシ基等);アリールアルキル基(例、ベンジル基等)が挙げられる。
保護基の具体例は以下に挙げられ、これらに限定されるものではないが、ホルミル基、アセチル基、クロロアセチル基、ジクロロアセチル基、トリクロロアセチル基、トリフルオロアセチル基、プロピオニル基、ベンゾイル基、4-クロロベンゾイル基等のアシル基;メトキシカルボニル基、エトキシカルボニル基、t-ブトキシカルボニル基、ベンジルオキシカルボニル基、アリルオキシカルボニル基等の置換されていてもよいアルコキシカルボニル基;ベンジル基、4-メトキシベンジル基、4-ブロモベンジル基、1-フェニルエチル基等の置換されていてもよいアリールアルキル基;メタンスルホニル基、p-トルエンスルホニル基、2-ニトロベンゼンスルホニル基等のスルホニル基が挙げられる。
また、チオール基の保護体として用いられる保護基は通常の条件で除去可能なものであれば特に限定されないが、その具体例は、ホルミル基、アセチル基、クロロアセチル基、プロピオニル基、ベンゾイル基等のアシル基;ベンジル基、4-メトキシベンジル基、4-ブロモベンジル基、1-フェニルエチル基等の置換されていてもよいアリールアルキル基;メトキシメチル基、エトキシエチル基、ベンジルオキシメチル基等のアセタール型保護基;トリメチルシリル基、t-ブチルジメチルシリル基等のシリル基が挙げられる。
これらの中で好ましくは、R3は水素原子である。
上記一般式(2)で表される環状含窒素化合物がピロリジン類である場合、当該化合物は、特に下記一般式(7)で表される2-シアノピロリジン類、即ち、ピロリジンの2位に置換基R1とシアノ基を有し、ピロリジンの窒素原子上に置換基R2を有する化合物である。
下記一般式(7)で表される2-シアノピロリジン類は、シアノ基が結合する炭素原子に不斉点を有する。分子内にこれ以外の不斉点を有しない場合、通常はラセミ体である。分子内に複数の不斉点を有する場合、通常はジアステレオマー混合物となる。
また、上記一般式(3)で表されるα-置換プロリンアミド類は、カルバモイル基が結合する炭素原子に不斉点を有する。
カルバモイル基が結合する炭素原子以外に不斉点を有しない場合、ラセミ体であっても、0~99%eeの任意の光学純度を有するS体又はR体のいずれの光学活性体であってもよい。この場合の光学純度は、好ましくは、80%ee以下、より好ましくは60%ee以下、特に好ましくは50%ee以下である。
また、上記一般式(5)で表される光学活性α-置換プロリンアミド類は、カルバモイル基が結合する炭素原子に不斉点を有する光学活性体であり、分子内にこれ以外の不斉点を有しない場合、S体及びR体のいずれでもよい。光学純度は任意の値でよいが、上記一般式(3)で表されるα-置換プロリンアミド類より高い光学純度であり、好ましくは80%ee以上、より好ましくは90%ee以上、更に好ましくは95%ee以上である。医薬品及びその中間体の場合、高い光学純度が要求されるため、特に好ましくは99%ee以上である。
当該α-メチルプロリンアミド類はピロリジンの2位とピロリジン窒素原子上の置換基(1’位)の2つの不斉点を有しており、いずれの立体化学を有するジアステレオマー又はジアステレオマー混合物であってもよい。ピロリジン窒素原子上の置換基(1’位)の不斉炭素は、工程(a)で用いられる1級アミン又はその塩に由来するため、反応中にエピメリ化がない場合は、用いた1級アミンの光学純度が1’位の不斉純度となる。1’位の絶対配置はR体、S体、ラセミ体のいずれであってもよく、その不斉純度は任意の値でよいが、1’位の不斉によってピロリジン2位についての異性体を分割することができるため、高いことが好ましく、1’位についてR体:S体(モル比)=90:10~100:0又はR体:S体(モル比)=10:90~0:100、更に好ましくはR体:S体(モル比)=97.5:2.5~100:0又はR体:S体(モル比)=2.5:97.5~0:100、特に好ましくはR体:S体(モル比)=99.5:0.5~100:0又はR体:S体(モル比)=0.5:99.5~0:100である。
上記一般式(2)で表される環状含窒素化合物は、上記一般式(1)で表される鎖状ケトン化合物をアンモニア、アンモニウム塩、1級アミン及び1級アミンの塩から選ばれる少なくとも1種、及びシアノ化剤と反応させることにより合成できる。
上記一般式(1)で表される鎖状ケトン化合物は、5-クロロ-2-ペンタノン、4-クロロ-1-フェニル-1-ブタノン等が試薬として購入可能である。また、その他の化合物については、3-クロロプロピオン酸クロリドと芳香族化合物のフリーデルクラフツ反応、γ-ブチロラクトンとエステル類のクライゼン縮合と続くハロゲン化水素での処理等の方法で任意に製造できる(例えばChem.Pharm.Bull.,1989,37,958.参照)。
アンモニア、アンモニウム塩、1級アミン及び1級アミンの塩から選ばれる少なくとも1種の使用量は、上記一般式(1)で表される鎖状ケトン化合物に対して0.5~10当量、好ましくは0.8~5当量、さらに好ましくは0.9~3当量である。
シアノ化剤の過剰使用は高濃度のシアン廃液を生じるため好ましくなく、上記一般式(7)で表される2-シアノピロリジン類を製造する目的においてシアノ化剤の使用量は、上記一般式(1)で表される鎖状ケトン化合物に対して1~3当量、好ましくは1.0~1.5当量、さらに好ましくは1.0~1.2当量である。また、上記一般式(6)で表されるピロリン類を製造する目的においては、生成物である上記一般式(6)で表されるピロリン類はシアノ基を含まないため、シアノ化剤の使用量は触媒量でもよく、上記一般式(1)で表される鎖状ケトン化合物に対して0.1~3当量、好ましくは0.2~1.0当量、さらに好ましくは0.2~0.5当量である。
酸性物質の使用量は、強アルカリ性にならないように部分的に中和できればよく、上記一般式(1)で表される鎖状ケトン化合物に対して0.01~10当量、好ましくは0.1~5当量、さらに好ましくは0.3~3当量である。
特に上記一般式(2)で表される環状含窒素化合物が上記一般式(7)で表される2-シアノピロリジン類である場合、抽出のみで十分な純度と水分除去が達成されるため、それ以上の精製操作を行わず、必要に応じて濃縮操作をした後に次工程に用いることが、作業を簡便にし生産性を高めるため好ましい。また、工程(b)に使用する前にピロリジン環上の窒素原子を保護してもよい。
一方、上記一般式(2)で表される環状含窒素化合物が上記一般式(6)で表されるピロリン類の場合、一般に低沸点化合物であるので、精製の必要がある場合は蒸留により精製することが好ましく、精製の必要がない場合は、精製することなく別の用途に使用することが好ましい。なお、上記一般式(6)で表されるピロリン類はシアノ化剤と反応させることで、上記一般式(7)で表される2-シアノピロリジン類へと変換可能であり、反応系中で2-シアノピロリジン類を発生させた後、精製することなく工程(b)に使用することができる。この方法は、猛毒の青酸ガスを発生させる恐れのある2-シアノピロリジン類を精製することなく反応させることができるため、作業員の安全上好ましい。
好ましい塩基は用いる保護試薬によって変わり、好ましい保護試薬である無水酢酸、ジ-t-ブチルジカルボナートを用いた場合、好ましくは、3級アミン、ピリジン類、炭酸塩、水酸化物及びシアン化物であり、さらに好ましくは、2-シアノピロリジン類が分解して生じるピロリン類を再度2-シアノピロリジン類へと変換する作用も併せ持つシアン化物である。
上記一般式(3)で表されるα-置換プロリンアミド類は、上記一般式(2)で表される環状含窒素化合物、好ましくは上記一般式(7)で表される2-シアノピロリジン類を水和させることにより合成できる。
なお、上記一般式(2)で表される環状含窒素化合物が、シアノ基を持たない上記一般式(6)で表されるピロリン類である場合は、シアノ化剤と反応させることで、上記一般式(7)で表される2-シアノピロリジン類へと変換した後に工程(b)に使用することが好ましい。この場合、上記一般式(7)で表される2-シアノピロリジン類を抽出等の方法で精製した後に、必要に応じて保護した後に工程(b)に使用することもできるが、反応系中で2-シアノピロリジン類を発生させた後、精製することなく工程(b)に使用することが操作の単純化のため好ましい。この方法は、猛毒の青酸ガスを発生させる恐れのある上記一般式(7)で表される2-シアノピロリジン類を精製することなく反応させることができ、作業員の安全上好ましい。
これらの中で好ましい触媒は、上記一般式(7)で表される2-シアノピロリジン類の窒素上の置換基によって異なるが、R2が水素原子、又は置換されていてもよいアルキル基の場合、不安定な基質の分解等の副反応を抑制できる無機酸、有機酸、錯体触媒、酵素であり、さらに好ましくは、工業的に安価な無機酸である。
一方、R2がアセチル基又はt-ブトキシカルボニル基の場合、好ましい触媒は、温和な条件で水和反応を行うことのできる、過酸化水素水と無機塩基の組み合わせ、錯体触媒、酵素であり、さらに好ましくは、工業的に安価な過酸化水素水と無機塩基の組み合わせである。
用いる触媒の活性によってその好ましい使用量は変わるが、一般に上記一般式(7)で表される2-シアノピロリジン類に対して0.01~100当量、好ましくは0.02~20当量、さらに好ましくは0.1~10当量である。
上記一般式(4)で表される光学活性α-置換プロリン類及び/又は上記一般式(5)で表される光学活性α-置換プロリンアミド類は、酵素的及び/又は化学的手法により、上記一般式(3)で表されるα-置換プロリンアミド類を分割することで合成できる。ここで、上記一般式(3)で表されるα-置換プロリンアミド類が、カルバモイル基が結合する炭素原子以外に不斉点を有しない場合、ラセミ体又は十分な光学純度を有していない、上記一般式(3)で表されるα-置換プロリンアミド類を光学分割することで合成できる。また、分子内に複数の不斉点を有する場合、ピロリジンの2位の立体化学について、十分なR:S比を有していない、上記一般式(3)で表されるα-置換プロリンアミド類のジアステレオマー混合物を分割することで合成できる。効率的に分割できる手法であれば特に限定されないが、具体的には(d)アミダーゼ活性を有する酵素によるアミド基の不斉加水分解反応;(e)ジアステレオマー塩形成による分割;(f)カラムクロマトグラフィーによる分離が挙げられる。本発明の分割工程は、工程(d)ないし(f)のいずれか単独の工程でもよいし、工程(d)ないし(f)の2以上の工程を組み合わせてもよい。
工程(d)で用いられるアミダーゼ活性を有する酵素とは、ラセミ体アミノ酸アミドに立体特異的に作用してアミノ酸に変換する作用を持つ生体由来の物質であれば特に限定されないが、その形態としては、例えばアミダーゼ活性を保持する精製酵素(及び固定化物)、又はそれを含む細胞、同細胞の調製物(菌体破砕物、菌体抽出物、粗精製酵素、及びこれらの固定化物)、もしくは同細胞を培養して得られた培養液が挙げられる。例えば以下に例示する菌体が産生するアミダーゼや市販酵素が好ましい。
・オクロバクテリウム・アンスロピ(Ochrobactrum anthropi)NCIMB40321
・マイコバクテリウム・ネオオーラム(Mycobacterium neoaurum)ATCC25975
・リゾプス・オリゼー(Rhizopus oryzae)(例えば、天野エンザイム株式会社製の食品添加用酵素ペプチダーゼR(商品名)等)
これらの中で更に好ましくは、α-メチルプロリンアミドの酵素分割において選択性の高いリゾプス・オリゼー由来の酵素(例えば、天野エンザイム株式会社製の食品添加用酵素ペプチダーゼR(商品名)等)である。
アミダーゼ活性を有する酵素の濃度は、その活性量により異なるが上記一般式(3)で表されるα-置換プロリンアミド類に対し0.0001~5倍重量、好ましくは0.001~1倍重量、更に好ましくは0.001~0.1倍重量である。この範囲内であると反応時間や触媒除去操作性が容易であるなどの点で好ましい。
また、工程(d)には、任意の純度のα-置換プロリンアミド類を用いることができるが、不純物によっては酵素反応を阻害するため、晶析等の方法により精製した原料を用いることが好ましい。特に、置換基R2が工程(d)において好ましい水素原子である場合、α-置換プロリンアミド類は塩基性を示すため、酸との塩であることが、一般に結晶性が向上して精製効果が高まるため好ましい。ここで用いられる酸の具体例は以下に挙げられ、これらに限定されるものではないが、塩酸、硫酸、硝酸等の鉱酸;酢酸、ギ酸、トリフルオロ酢酸、安息香酸、シュウ酸、マレイン酸、コハク酸等のカルボン酸類;メタンスルホン酸、トルエンスルホン酸等のスルホン酸類が挙げられる。これらの中で好ましくは、工業的に安価で一般に塩の結晶性が高い鉱酸、スルホン酸類であり、更に好ましくは、塩酸、硫酸、トルエンスルホン酸であり、特に好ましくは塩酸である。
また、溶媒の使用量としては、任意の量の溶媒を用いることができるが、通常は上記一般式(3)で表されるα-置換プロリンアミド類に対して、1~200倍体積量とすることが好ましい。この範囲内であると光学活性アミノ酸の製造効率の点で好ましい。溶媒の使用量は、上記一般式(3)で表されるα-置換プロリンアミド類に対して、1~50倍体積量とすることがより好ましく、1~10倍体積量とすることが特に好ましい。
また、反応中に溶液のpHが変化した場合、pHを調整するため、適宜酸又は塩基を添加しても良い。この場合、pHは、20~30℃での測定値が、5.0~9.0となるように調整することが好ましく、6.0~8.0とすることがより好ましい。
用いられる酸又は塩基の具体例は以下に挙げられ、適切なpHにコントロールできれば特に限定されないが、塩酸、硫酸、リン酸等の鉱酸;メタンスルホン酸、トリフルオロ酢酸、酢酸、ギ酸等の有機酸;炭酸水素ナトリウム、炭酸カリウム等の炭酸塩;リン酸カリウム、リン酸水素ナトリウム等のリン酸塩;水酸化ナトリウム、水酸化カリウム等の水酸化物等が挙げられる。これらの中で、酸としては安価な鉱酸を用いることが好ましく、塩基としては安価な水酸化物を用いることが好ましい。また、使用形態は、化合物そのもの若しくは水溶液の状態で用いることができる。
好ましい抽出溶媒としては、トルエン、酢酸エチル、テトラヒドロフラン、メチルエチルケトン、1-ブタノール、2-ブタノール、t-ブタノール又はこれらの混合溶媒が挙げられる。また、水層を塩基性に保つことが、上記一般式(4)で表される光学活性α-置換プロリン類を水層に、上記一般式(5)で表される光学活性α-置換プロリンアミド類を有機層に分配できるため好ましく、食塩等を添加することが水層の塩濃度を高めて抽出効率を高めるため好ましい。
好ましい晶析溶媒としては、トルエン、酢酸エチル、アセトン、メタノール、エタノール、t-ブタノール、2-ブタノール、1-ブタノール、水又はこれらの混合溶媒が挙げられる。上記一般式(4)で表される光学活性α-置換プロリン類と上記一般式(5)で表される光学活性α-置換プロリンアミド類は、一般に溶媒に対する溶解度が大きく異なるため、溶解度差を利用して晶析分離することが好ましい。また、上記一般式(4)で表される光学活性α-置換プロリン類のR2が水素原子である好ましい態様の場合、カルボキシル基とアミノ基の両方を持つアミノ酸であるので、溶液のpHを等電点にコントロールし、溶解度を下げて結晶化させることが好ましく、さらに食塩等の塩や有機溶媒を添加して溶解度を下げて結晶化させることが好ましい。
工程(e)におけるジアステレオマー塩形成による分割とは、上記一般式(3)で表されるα-置換プロリンアミド類がラセミ体の場合は光学活性な酸、α-置換プロリンアミド類が不斉点を複数持つジアステレオマー混合物の場合は光学活性な酸、又はアキラルな酸を作用させ、生成した結晶性の塩をろ過等の方法により分離することで分割する方法である。この操作により、結晶及び/又はろ液に、上記一般式(5)で表される光学活性α-置換プロリンアミド類が得られる。
工程(e)において用いられるアキラルな酸の具体例は以下に挙げられ、これらに限定されるものではないが、塩酸、硫酸、硝酸等の鉱酸;酢酸、ギ酸、トリフルオロ酢酸、安息香酸、シュウ酸、マレイン酸、コハク酸等のカルボン酸類;メタンスルホン酸、トルエンスルホン酸等のスルホン酸類が挙げられる。これらの中で好ましくは、工業的に安価で一般に塩の結晶性が高い塩酸、酢酸、安息香酸、シュウ酸、マレイン酸、コハク酸、トルエンスルホン酸である。
なお、用いられる光学活性な酸及び/又はアキラルな酸が、酸性基を複数有する2価以上の酸である場合、生成するジアステレオマー塩は1対1の塩でも1対2以上の塩であってもよい。
光学活性な酸及び/又はアキラルな酸の使用量は、上記一般式(3)で表されるα-置換プロリンアミド類に対して0.1~10当量、過剰使用は結晶化を妨げることから、好ましくは0.2~3当量、さらに好ましくは0.3~1当量である。なお、ここで言う使用量とは、塩形成に使用される酸の当量である。
好ましい溶媒としては、上記一般式(3)で表されるα-置換プロリンアミド類及び光学活性な酸、又はアキラルな酸に対して十分な溶解度を持ち、生成するジアステレオマー塩の溶解度が十分低いものが良く、エチルエーテル、プロピルエーテル、シクロペンチルメチルエーテル、t-ブチルメチルエーテル、テトラヒドロフラン等のエーテル系溶媒;酢酸エチル、酢酸イソプロピル、酢酸ブチル等のエステル系溶媒;メタノール、エタノール、2-プロパノール、1-ブタノール、2-ブタノール、t-ブタノール等のアルコール系溶媒及びこれらの溶媒と任意の溶媒の混合溶媒であり、さらに好ましくは酢酸エチル、酢酸イソプロピル、酢酸ブチル等のエステル系溶媒及びこれらの溶媒と任意の溶媒の混合溶媒である。
また、ジアステレオマー塩の溶解度が低い溶媒を反応溶液に添加することで、結晶化を促進してもよい。この時用いられる溶媒としては、ヘキサン、ヘプタン、ベンゼン、トルエン等の炭化水素系溶媒;酢酸エチル、酢酸イソプロピル、酢酸ブチル等のエステル系溶媒が挙げられる。
用いられる溶媒の使用量は、通常上記一般式(3)で表されるα-置換プロリンアミド類に対して1~50倍体積量、析出したジアステレオマー塩の流動性が確保できる量が必要で、かつ使用量が少ない方が生産性が高いため、好ましくは2~20倍体積量、さらに好ましくは3~10倍体積量である。
上記一般式(5)で表される光学活性α-置換プロリンアミド類のR2が水素原子の場合、工程(e)の後にピロリジン環上の窒素原子を保護してもよく、R2がアミノ基の保護基の場合、工程(e)の後にアミノ基の保護基を除去してもよい。また、上記一般式(5)で表される光学活性α-置換プロリンアミド類を加水分解することで、上記一般式(4)で表される光学活性α-置換プロリン類へと変換することもできる。工程(e)の後に続けて反応を行う場合、上記ジアステレオマー塩を原料として用いてもよく、光学活性な酸及び/又はアキラルな酸を分離した上記一般式(5)で表される光学活性α-置換プロリンアミド類を原料として用いてもよい。
用いられる加水分解触媒は以下に挙げられ、これらに限定されるものではないが、塩酸、硫酸、リン酸等の無機酸;トリフルオロメタンスルホン酸、メタンスルホン酸、トリフルオロ酢酸等の有機酸;水酸化ナトリウム、炭酸カリウム等の無機塩基;アミダーゼ、ペプチダーゼ活性を有する酵素等が挙げられる。これらから選ばれる複数の触媒を混合して用いてもよい。
工程(f)におけるカラムクロマトグラフィーによる分離とは、上記一般式(3)で表されるα-置換プロリンアミド類がジアステレオマー混合物の場合に、アキラルな充填剤を詰めたカラムを通すことでそれぞれのジアステレオマーを分離する方法である。この操作により、上記一般式(5)で表される光学活性α-置換プロリンアミド類が得られる。
また、分離の方法としては、毎回チャージしたサンプルを完全溶出させるバッチ式カラムクロマトグラフィーであってもよく、擬似移動床を用いた連続式カラムクロマトグラフィーであってもよい。
好ましい溶媒は用いられるカラムクロマトグラフィーの種類によって異なるが、好ましい合成吸着剤を用いたカラムクロマトグラフィーの場合、ケトン系溶媒;ニトリル系溶媒;アルコール系溶媒;水が好ましく、さらに好ましくは安価なアセトン、メタノール、水である。
また、必要に応じてpH調整のための添加剤を加えても良い。添加剤の具体例としては、酢酸、ギ酸等の酸;酢酸アンモニウム、酢酸ナトリウム、塩化アンモニウム等の塩;アンモニア、水酸化ナトリウム等の塩基等が挙げられ、これらを任意の割合で混合して用いても良い。
2-シアノ-2-メチルピロリジン及び2-メチル-1-ピロリンの製造(上記一般式(2)において、R1=Me、R2=R3=H;工程(a)シアン化ナトリウム、酢酸アンモニウム使用、メタノール-水溶媒での反応)
2-シアノ-2-メチルピロリジン:1H-NMR(400MHz,CDCl3)δ1.58(3H,s),1.72(1H,ddd,J=12.6,9.6,8.3Hz),1.83-2.08(2H,m),2.26(1H,ddd,J=12.6,8.3,4.3Hz),3.12-3.22(2H,m).
α-メチルプロリンアミド塩酸塩の製造(上記一般式(3)において、R1=Me、R2=R3=H;工程(b)塩酸による水和)
1H-NMR(400MHz,CD3OD)δ1.69(3H,s),1.96-2.22(3H,m),2.36-2.44(1H,m),3.34-3.44(2H,m).
(S)-α-メチルプロリン及び(R)-α-メチルプロリンアミドの製造(上記一般式(4)及び(5)において、R1=Me、R2=R3=H;工程(d)ラセミ体の酵素分割)
HPLCでの光学純度分析条件は以下の通りである。
カラム:ASTEC社製CLC-D(4.6mm×150mm)、移動相:2mM CuSO4水溶液、流速:1.0mL/分、カラム温度:45、UV:254nm
また、E値は、反応の転化率(c)と残存する基質の光学純度(eeS)から、次の式により算出した。
E=ln[(1-c)(1-eeS)]/ln[(1-c)(1+eeS)]
2-シアノ-2-メチルピロリジン及び2-メチル-1-ピロリンの製造(上記一般式(2)において、R1=Me、R2=R3=H;工程(a)メタノール溶媒での反応)
フラスコに5-クロロ-2-ペンタノン0.228ml(2.0mmol)、シアン化ナトリウム108mg(2.2mmol)、酢酸アンモニウム462mg(6.0mmol)、メタノール1mlを仕込み、50℃で1時間反応させた。反応液をNMRで解析したところ、5-クロロ-2-ペンタノンは消失しており、2-シアノ-2-メチルピロリジンと2-メチル-1-ピロリンが1:0.4の比率で生成していた。
2-シアノ-2-メチルピロリジン及び2-メチル-1-ピロリンの製造(上記一般式(2)において、R1=Me、R2=R3=H;工程(a)t-ブタノール-水溶媒での反応)
フラスコに5-クロロ-2-ペンタノン4.80g(40mmol)、シアン化ナトリウム2.35g(48mmol)、酢酸アンモニウム6.2g(80mmol)、水10ml、t-ブタノール20mlを仕込み、50℃で2.5時間反応させた後、シアン化ナトリウム1.25g(26mmol)を添加し、さらに2.5時間反応させた。反応液に酢酸エチルと50w/v%NaOH水溶液2.1gを加えた後、分液し、水層を酢酸エチルで再抽出した。有機層を硫酸ナトリウムで乾燥後、溶媒を留去し、黄色油状物質4.2gを得た。NMR解析の結果から、この油状物質は2-シアノ-2-メチルピロリジンを67重量%(2.8g、収率64%)、2-メチル-1-ピロリンを14重量%(0.59g、収率18%)、酢酸エチルを10重量%、t-ブタノールを9重量%含有する混合物であった。
α-メチルプロリンアミド塩酸塩の製造(上記一般式(3)において、R1=Me、R2=R3=H;工程(a)酢酸イソプロピル-水溶媒での反応、工程(b)硫酸による水和)
フラスコに5-クロロ-2-ペンタノン70g(0.58mol)、シアン化ナトリウム34.1g(0.70mmol)、酢酸アンモニウム134g(1.74mol)、水168ml、酢酸イソプロピル280mlを仕込み、60℃で3時間反応させた後、シアン化ナトリウム17.1g(0.35mol)を添加し、さらに6時間反応させた。室温に冷却後、水層を除去し、有機層をセライトろ過し、酢酸イソプロピル20mlで洗浄し、2-シアノ-2-メチルピロリジンの酢酸イソプロピル溶液を得た。
別のフラスコに水25ml、硫酸56.9g(0.58mol)を仕込み、氷冷下に2-シアノ-2-メチルピロリジンの酢酸イソプロピル溶液を滴下した。静置後、酢酸イソプロピル層を除去し、硫酸層を酢酸イソプロピル35mlで洗浄した。さらに硫酸114g(1.39mol)を添加し、25~30℃で1日反応させた。反応液を氷冷し、水140ml、40wt%水酸化ナトリウム水溶液377g、1-ブタノール210mlをゆっくり添加した。生じた硫酸ナトリウムの結晶をろ別し、1-ブタノール200mlとメタノール300mlで洗浄し、ろ液を290gまで濃縮した。水層を除去し、α-メチルプロリンアミドの1-ブタノール溶液を得た。この溶液に濃塩酸41g(0.39mol)、シクロヘキサン28mlを添加し、常圧加熱還流下ディーンスタークで共沸脱水を行った。室温に冷却後、結晶をろ過し、1-ブタノールと酢酸エチルで洗浄し、減圧乾燥し、淡褐色結晶としてα-メチルプロリンアミド塩酸塩46.8gを得た。純度100wt%(HPLC分析)、0.284mol、収率49%。
α-メチルプロリンアミド塩酸塩の製造(上記一般式(3)において、R1=Me、R2=R3=H;工程(a)酢酸エチル-水溶媒での反応、工程(b)硫酸による水和)
フラスコに5-クロロ-2-ペンタノン70g(0.58mol)、シアン化ナトリウム17.1g(0.35mmol)、酢酸アンモニウム134g(1.74mol)、水168ml、酢酸エチル280mlを仕込み、60℃に加熱した。1.5時間後と3.5時間後にシアン化ナトリウム17.1g(0.35mol)を2回添加し、さらに5時間反応させた。室温に冷却後、水層を除去し、2-シアノ-2-メチルピロリジンの酢酸エチル溶液を得た。
別のフラスコに水10ml、硫酸56.9g(0.58mol)を仕込み、氷冷下に2-シアノ-2-メチルピロリジンの酢酸エチル溶液を滴下した。静置後、酢酸エチル層を除去し、硫酸層を酢酸エチル35mlで洗浄した。さらに硫酸114g(1.39mol)を添加し、20~40℃で6時間反応させた。反応液を氷冷し、水140ml、40wt%水酸化ナトリウム水溶液384g、メタノール210mlをゆっくり添加した。生じた硫酸ナトリウムの結晶をろ別し、メタノール350mlで洗浄し、ろ液を300gまで濃縮した。1-ブタノール280mlを添加した後、水層を除去し、水層を1-ブタノール70mlで再抽出し、α-メチルプロリンアミドの1-ブタノール溶液を得た。この溶液に濃塩酸49g(0.47mol)、シクロヘキサン70mlを添加し、常圧加熱還流下ディーンスタークで共沸脱水を行った。室温に冷却後、結晶をろ過し、1-ブタノールと酢酸エチルで洗浄し、減圧乾燥し、淡黄色結晶としてα-メチルプロリンアミド塩酸塩65.6gを得た。純度95wt%(HPLC分析)、0.380mol、収率65%。
α-メチルプロリンアミド塩酸塩の製造(上記一般式(3)において、R1=Me、R2=R3=H;工程(a)酢酸エチル-水溶媒での反応、工程(b)硫酸による水和)
フラスコに、酢酸アンモニウム95.9g(1.25mol)、水100mL、酢酸エチル200mL、5-クロロ-2-ペンタノン50g(0.42mol)、シアン化ナトリウム12.2g(0.25mol)を仕込み、60℃に加熱した。28%アンモニア水28.8gを分割添加し、pHを7.4-7.6に調整しながら反応を行った。3時間後、シアン化ナトリウム12.2g(0.25mol)を添加し、更に3時間反応させた。室温に冷却後、水層を除去し、2-シアノ-2-メチルピロリジンの酢酸エチル溶液を得た。
別なフラスコに硫酸40.7g(0.42mol)を仕込み、氷冷下に2-シアノ-2-メチルピロリジンの酢酸エチル溶液を滴下した。静置後、酢酸エチル層を除去し、硫酸層をシクロヘキサン50mLで2回洗浄した。更に硫酸81.4g(0.83mol)を添加し、40~60℃で4時間反応させた。反応液を氷冷し、水180mL、28%アンモニア水151gをゆっくり添加した。得られた溶液に1-ブタノール330mLを添加した後、水層を除去し、水層を1-ブタノール165mLで再抽出し、α-メチルプロリンアミドの1-ブタノール溶液を得た。この溶液を濃縮して水を除去した後、析出した固形分をろ別した。濃塩酸27.3g(0.26mol)、シクロヘキサン50mLを添加し、常圧加熱還流下ディーンスタークで共沸脱水を行った。室温に冷却後、結晶をろ過し、1-ブタノールと酢酸エチルで洗浄し、減圧乾燥し、淡黄色結晶としてα-メチルプロリンアミド塩酸塩29.7gを得た。純度94wt%(HPLC分析)、0.171mol、収率41%。
2-シアノ-2-メチルピロリジン及び2-メチル-1-ピロリンの製造(上記一般式(2)において、R1=Me、R2=R3=H;工程(a)酢酸、アンモニア水使用、水溶媒での反応)
フラスコに5-クロロ-2-ペンタノン0.57ml(5.0mmol)、シアン化ナトリウム270mg(5.5mmol)、酢酸0.32ml(5.5mmol)、28%アンモニア水0.61ml(10mmol)、水0.57mlを仕込み、40℃で6時間反応させた。50w/v%NaOH水溶液0.4mlを加えた後、さらに60℃で1時間反応させた。反応液を室温に冷却後、有機層と水層を分離した。水層を酢酸エチルで抽出し、あわせた有機層を、トルエンを内部標準としてNMRで定量したところ、2-シアノ-2-メチルピロリジンを2.27mmol(収率45%)、2-メチル-1-ピロリンを0.59mmol(収率12%)含有していた。
2-シアノ-2-メチルピロリジン及び2-メチル-1-ピロリンの製造(上記一般式(2)において、R1=Me、R2=R3=H;工程(a)塩化アンモニウム使用、水溶媒での反応)
フラスコに5-クロロ-2-ペンタノン1.14ml(10mmol)、シアン化ナトリウム540mg(11mmol)、塩化アンモニウム1.07g(20mmol)、水2.3mlを仕込み、40℃で6時間反応させた。28%アンモニア水0.61ml(10mmol)を加えた後、さらに60℃で1時間反応させた。反応液を室温に冷却後、50w/v%NaOH水溶液0.4mlを加えて酢酸エチルで抽出し、有機層をトルエンを内部標準としてNMRで定量したところ、2-シアノ-2-メチルピロリジンを5.7mmol(収率57%)、2-メチル-1-ピロリンを0.60mmol(収率6%)含有していた。
α-メチルプロリンアミド塩酸塩の製造(上記一般式(3)において、R1=Me、R2=R3=H、工程(a)酢酸アンモニウム使用、水溶媒での反応;工程(b)硫酸による水和)
フラスコに酢酸アンモニウム38.4g(0.50mol)、水30mL、シアン化ナトリウム9.8g(0.20mol)、5-クロロ-2-ペンタノン20.0g(0.17mol)を仕込み、50℃で30分間反応させた。28%アンモニア水12.0gを添加して2時間反応させた後、室温に冷却し水層を除去した。シクロヘキサン10mLでフラスコの有機層を洗い込み、得られた有機層に対し、氷冷下で濃硫酸48.8g(0.50mol)を滴下し、室温で4時間反応させた。反応液を氷冷し、水72mL、28%アンモニア水60.4gをゆっくり添加した。得られた溶液に1-ブタノール200mL、28%アンモニア水3.0gを添加した後、水層を除去した。水層に28%アンモニア水4.5gを添加した後、1-ブタノール100mLで再抽出し、α-メチルプロリンアミドの1-ブタノール溶液を得た。この溶液を濃縮して水を除去した後、濃塩酸9.24g(0.089mol)、シクロヘキサン50mLを添加し、常圧加熱還流下ディーンスタークで共沸脱水を行った。室温に冷却後、結晶をろ過し、1-ブタノールと酢酸エチルで洗浄し、減圧乾燥し、淡黄色結晶としてα-メチルプロリンアミド塩酸塩11.3gを得た。純度75wt%(HPLC分析)、0.051mol、収率31%。
(S)-α-メチルプロリン及び(R)-α-メチルプロリンアミドの製造(上記一般式(4)及び(5)において、R1=Me、R2=R3=H;工程(d)ラセミ体の酵素分割)
500ml三角フラスコに、実施例7の方法に準じて得られたα-メチルプロリンアミド塩酸塩32.2g(純度97%、190mmol)と水34.7mlを仕込み、5%水酸化ナトリウム水でpHを7.0にした。混合液にペプチダーゼR(商品名、天野エンザイム株式会社製、リゾプス・オリゼー由来)2.3gの水(15.5ml)溶液を添加し、40、撹拌数250rpmで60時間反応させた。HPLC分析による純度分析及び光学純度分析の結果、(S)-α-メチルプロリンの純分は10.5g(81.0mmol、収率342.7%)で光学純度は99.0%eeであった。反応液に水50mlと活性炭15gを添加し、25℃で1時間振とうさせた。セライトろ過で活性炭を除去し、得られた水溶液をイオン交換樹脂(Amberlyst(登録商標) A-26(OH))に通液し、(R)-α-メチルプロリンアミドを水で、(S)-α-メチルプロリンを1M酢酸水で溶出させた。HPLCで純度分析及び光学純度を分析した結果、(R)-α-メチルプロリンアミド純分は12.6g(98.5mmol、収率52%、87.1%ee)、(S)-α-メチルプロリン純分は11.3g(87.6mmol、収率46%、99.0%ee)であった。
α-メチルプロリンアミドの製造(上記一般式(3)において、R1=Me、R2=R3=H;工程(a)DMSO-水溶媒での反応、工程(b)アルカリ性過酸化水素水による水和)
この反応液にシアン化ナトリウム250mg(5.0mmol)、50w/v%NaOH水溶液1.0ml(13mmol)、35%過酸化水素水1.3ml(15mmol)を添加し、室温で1時間反応させた。チオ硫酸ナトリウム0.79g(5.0mmol)を添加して、過剰の酸化剤を分解した後、酢酸エチルで2回抽出した。HPLCにより分析したところ、α-メチルプロリンアミドが有機層に235mg(1.83mmol、収率37%)、水層に149mg(1.16mmol、収率23%)含まれていた。
α-メチルプロリンアミドの製造(上記一般式(3)において、R1=Me、R2=R3=H;工程(b)アルカリ性過酸化水素水による水和)
フラスコに実施例5の方法に準じて得られた2-シアノ-2-メチルピロリジンのt-ブタノール溶液0.58g(19重量%、1.0mmol)、シアン化ナトリウム49mg(1mmol)、DMSO0.4mlを仕込んだ。氷冷下、35%過酸化水素水0.13ml(1.5mmol)を添加し、徐々に室温に昇温した。21時間後、シアン化ナトリウム49mg(1mmol)と35%過酸化水素水0.13ml(1.5mmol)を15℃にて添加し、3時間反応させた。氷冷下、亜硫酸水素ナトリウム53mg(0.5mmol)を添加して、過剰の酸化剤を分解した後、沈殿をろ別した。ろ液を濃縮し、橙色油状物質608mgを得た。HPLCにより分析したところ、α-メチルプロリンアミドが94mg(0.73mmol、収率73%)含まれていた。
1-(t-ブトキシカルボニル)-2-シアノ-2-メチルピロリジンの製造(上記一般式(7)において、R1=Me、R2=Boc、R3=H;工程(a)t-ブタノール-水溶媒での反応、Boc保護)
1H-NMR(400MHz,CDCl3)δ1.53(9H,brs),1.70(3H,brs),1.86-2.23(3H,m),2.46-2.58(1H,m),3.36-3.48(1H,m),3.50-3.66(1H,m).
N-(t-ブトキシカルボニル)-α-メチルプロリンアミドの製造(上記一般式(3)において、R1=Me、R2=Boc、R3=H;工程(b)アルカリ性過酸化水素水による水和)
1H-NMR(400MHz,CDCl3,1:1の回転異性体混合物)δ1.47(9H,brs),1.55(1.5H,brs),1.65(1.5H,brs),1.60-2.05(3H,m),2.24-2.36(0.5H,m),2.57-2.69(0.5H,m),3.36-3.66(2H,m),5.23-5.41(1H,m),5.82-5.98(0.5H,m),7.12-7.28(0.5H,m).
α-メチルプロリンアミド塩酸塩の製造(上記一般式(3)において、R1=Me、R2=R3=H;Boc基の除去)
フラスコに実施例14で得られたN-(t-ブトキシカルボニル)-α-メチルプロリンアミド0.76g(3.33mmol)、メタノール0.76ml、4N塩酸-酢酸エチル溶液1.7mlを加え、室温で3時間、40℃で3時間反応させた。反応液を氷冷し、酢酸エチル0.76mlを添加した後、結晶をろ過し、減圧乾燥し、白色結晶としてα-メチルプロリンアミド塩酸塩0.50g(3.04mmol、収率91%)を得た。
1-ベンジル-2-シアノ-2-メチルピロリジンの製造(上記一般式(7)において、R1=Me、R2=Bn、R3=H;工程(a)ベンジルアミン、酢酸使用、t-ブタノール-水溶媒での反応)
1H-NMR(400MHz,CDCl3)δ1.56(3H,s),1.74-1.95(3H,m),2.30-2.45(2H,m),2.99(1H,ddd,J=9.8,8.3,3.3Hz),3.35(1H,d,J=13.1Hz),4.02(1H,d,J=13.1Hz),7.24-7.37(5H,m).
1-ベンジル-2-シアノ-2-メチルピロリジンの製造(上記一般式(7)において、R1=Me、R2=Bn、R3=H;工程(a)酢酸エチル-水溶媒での反応)
フラスコに5-クロロ-2-ペンタノン2.28ml(20mmol)、シアン化ナトリウム1.08g(22mmol)、ベンジルアミン2.40ml(22mmol)、酢酸1.26ml(22mmol)、水4.6ml、酢酸エチル9.1mlを仕込み、50℃で3時間反応させた。反応液に50w/v%NaOH水溶液0.8ml(10mmol)とシアン化ナトリウム0.50g(10mmol)を加えた後、さらに50℃で2時間反応させた。室温に冷却後、水層を除去し、有機層を濃縮し、淡褐色油状物質4.30gを得た。NMR解析の結果から、この油状物質は1-ベンジル-2-シアノ-2-メチルピロリジンを78重量%(3.35g、収率84%)、5-クロロ-2-ペンタノンを2重量%、鎖状中間体である2-ベンジルアミノ-5-クロロ-2-シアノペンタンを12重量%、ベンジルアミンを6重量%、酢酸エチルを1重量%含有する混合物であった。
1-ベンジル-2-シアノ-2-メチルピロリジンの製造(上記一般式(7)において、R1=Me、R2=Bn、R3=H;工程(a)トルエン-水溶媒での反応)
フラスコに5-クロロ-2-ペンタノン0.57ml(5.0mmol)、シアン化ナトリウム270mg(5.5mmol)、ベンジルアミン0.60ml(5.5mmol)、酢酸0.32ml(5.5mmol)、水1.1ml、トルエン2.3mlを仕込み、50℃で2時間反応させた。反応液にシアン化ナトリウム0.17g(3.5mmol)を加えた後、さらに50℃で4時間反応させた。反応液をNMRで解析したところ、原料である5-クロロ-2-ペンタノン、目的物である1-ベンジル-2-シアノ-2-メチルピロリジン、及び鎖状中間体である2-ベンジルアミノ-5-クロロ-2-シアノペンタンが0.04:1:0.27の比率で存在していた。
N-ベンジル-α-メチルプロリンアミドの製造(上記一般式(3)において、R1=Me、R2=Bn、R3=H;工程(a)エタノール-水溶媒での反応、工程(b)硫酸による水和)
別のフラスコに水0.09ml、硫酸1.47g(15mmol)を仕込み、氷冷下に上記橙色油状物質1.44gを添加し、トルエンで洗いいれた。60℃で3時間反応させた後、氷冷下、水0.57ml、28%アンモニア水2.4mlをゆっくり添加した。酢酸エチルで抽出し、有機層を濃縮し、橙色油状物質2.00gを得た。HPLCにより分析したところ、N-ベンジル-α-メチルプロリンアミドが770mg(3.52mmol、収率70%)含まれていた。
1H-NMR(400MHz,CDCl3)δ1.34(3H,s),1.68-1.89(3H,m),2.13-2.22(1H,m),2.40(1H,td,J=9.1,7.3Hz),2.97-3.03(1H,m),3.35(1H,d,J=13.1Hz),3.88(1H,d,J=13.1Hz),5.36(1H,brs),7.24-7.37(5H,m),7.55(1H,brs).
N-ベンジル-α-メチルプロリンアミドの製造(上記一般式(3)において、R1=Me、R2=Bn、R3=H;工程(a)水溶媒での反応、工程(b)硫酸による水和)
フラスコに5-クロロ-2-ペンタノン6.03g(50mmol)、シアン化ナトリウム2.7g(55mmol)、ベンジルアミン6.0ml(55mmol)、酢酸3.2ml(55mmol)、水11.4mlを仕込み、40℃で3時間反応させた。反応液に50w/v%NaOH水溶液4.0ml(50mmol)を加えた後、さらに60℃で1時間反応させた。反応液をNMRで解析したところ、ほぼ目的物である1-ベンジル-2-シアノ-2-メチルピロリジンであった。水層を分離し、淡褐色油状物質を得た。
別のフラスコに硫酸14.7g(150mmol)を仕込み、氷冷下に上記淡褐色油状物質を添加し、トルエンで洗いいれた。60℃で7時間、70℃で2時間反応させた後、水浴上で水50ml、トルエン6ml、50w/v%NaOH水溶液32mlをゆっくり添加し、pHを10とした。生じた結晶をろ過し、水で洗浄し、減圧乾燥し、淡褐色固体としてN-ベンジル-α-メチルプロリンアミド8.67gを得た。純度98wt%(HPLC分析)、39.0mmol、収率78%。
1-ベンジル-2-シアノ-2-メチルピロリジンの製造(上記一般式(7)において、R1=Me、R2=Bn、R3=H;工程(a)酢酸添加なし、エタノール-水溶媒での反応)
フラスコに5-クロロ-2-ペンタノン0.57ml(5.0mmol)、シアン化ナトリウム270mg(5.5mmol)、ベンジルアミン0.60ml(5.5mmol)、水1.1ml、エタノール1.1mlを仕込み、50℃で1.5時間反応させた。反応液をNMRで解析したところ、原料である5-クロロ-2-ペンタノン、目的物である1-ベンジル-2-シアノ-2-メチルピロリジン、及び原料から副生したシクロペンチルメチルケトンが0.02:1:0.32の比率で存在していた。酢酸を添加した実施例20と比較して系内が強い塩基性となったためシクロペンチルメチルケトンが副生したが、目的物である1-ベンジル-2-シアノ-2-メチルピロリジンを主生成物として得た。
1-ベンジル-2-シアノ-2-メチルピロリジンの製造(上記一般式(7)において、R1=Me、R2=Bn、R3=H;工程(a)酢酸添加なし、酢酸エチル-水溶媒での反応)
フラスコに5-クロロ-2-ペンタノン0.57ml(5.0mmol)、シアン化ナトリウム270mg(5.5mmol)、ベンジルアミン0.60ml(5.5mmol)、水1.1ml、酢酸エチル2.3mlを仕込み、50℃で4.5時間反応させた。反応液をNMRで解析したところ、原料である5-クロロ-2-ペンタノン、目的物である1-ベンジル-2-シアノ-2-メチルピロリジン、及び鎖状中間体である2-ベンジルアミノ-5-クロロ-2-シアノペンタンが0.02:1:0.06の比率で存在しており、シクロペンチルメチルケトンは観測されなかった。実施例22と同様に酸を添加していないが、酢酸エチルが加水分解を受けて酢酸が生じたため、系内が強い塩基性とならず、シクロペンチルメチルケトンの副生が抑制されたと考えられる。
α-メチルプロリンアミド塩酸塩の製造(上記一般式(3)において、R1=Me、R2=R3=H;Bn基の除去)
フラスコに実施例20で得られたN-ベンジル-α-メチルプロリンアミド6.62g(30.3mmol)、エタノール33ml、10%パラジウム炭素(NEケムキャット社製 PE-type、55%含水)1.43g(0.61mmol)を添加した。常圧水素雰囲気下、室温で2時間、40℃で4時間反応させた。反応液をセライトろ過し、ろ液を濃縮し、淡黄色油状物質としてα-メチルプロリンアミド4.12gを得た。純度92wt%(HPLC分析)、29.5mmol、収率97%。
フラスコに上記黄色油状物質2.38g(17.1mmol)、エタノール2ml、酢酸エチル5mlを仕込んだ。水浴上で4N塩酸-酢酸エチル溶液4.5mlを添加し、生じた結晶をろ過し、酢酸エチルで洗浄し、減圧乾燥した。白色結晶としてα-メチルプロリンアミド塩酸塩2.42g(14.7mmol、収率86%)を得た。
α-メチルプロリンアミドの製造(上記一般式(3)において、R1=Me、R2=R3=H;Bn基の除去)
フラスコに実施例20で得られたN-ベンジル-α-メチルプロリンアミド1.01g(4.6mmol)、酢酸0.53ml(9.2mmol)、メタノール5ml、10%パラジウム炭素(NEケムキャット社製 PE-type、55%含水)54mg(0.023mmol)を添加した。常圧水素雰囲気下、60℃で2時間反応させた。反応液をセライトろ過し、ろ液を濃縮し、淡黄色油状物質1.20gを得た。HPLC分析の結果、α-メチルプロリンアミド0.60g(収率定量的)が含まれていた。
(2R,1’R)及び(2S,1’R)-1-(1’-フェニルエチル)-2-シアノ-2-メチルピロリジンの製造(上記一般式(7)において、R1=Me、R2=(R)-1-フェニルエチル、R3=H;工程(a)(R)-α-メチルベンジルアミン使用、水溶媒での反応)
(2R,1’R)-1-(1’-フェニルエチル)-2-シアノ-2-メチルピロリジン
1H-NMR(400MHz,CDCl3)δ1.02(3H,s),1.48(3H,d,J=6.8Hz),1.79-1.92(3H,m),2.22-2.32(1H,m),2.75-2.83(1H,m),3.18-3.25(1H,m),3.92(1H,q,J=6.8Hz),7.21-7.39(5H,m).
(2S,1’R)-1-(1’-フェニルエチル)-2-シアノ-2-メチルピロリジン
1H-NMR(400MHz,CDCl3)δ1.48(3H,d,J=6.8Hz),1.67(3H,s),1.69-1.78(2H,m),1.92-1.99(1H,m),2.32-2.39(1H,m),2.47(1H,dt,J=9.6,8.1Hz),2.84-2.91(1H,m),3.84(1H,q,J=6.8Hz),7.21-7.39(5H,m).
(2R,1’R)及び(2S,1’R)-N-(1’-フェニルエチル)-α-メチルプロリンアミドの製造(上記一般式(5)において、R1=Me、R2=(R)-1-フェニルエチル、R3=H;工程(a)(R)-α-メチルベンジルアミン使用、水溶媒での反応、工程(b)硫酸による水和、工程(f)シリカゲルカラムクロマトグラフィーによる分離)
別のフラスコに硫酸3.9g(40mmol)を仕込み、水浴上で上記淡褐色油状物質を添加し、トルエンで洗い入れた。60℃で6時間反応させた後、水浴上で水2ml、50w/v%NaOH水溶液6.4mlをゆっくり添加し、pHを10とした。酢酸エチルで抽出し、有機層を硫酸マグネシウムで乾燥し、有機層を濃縮した。残渣をシリカゲルカラムクロマトグラフィーにて精製し、(2R,1’R)及び(2S,1’R)-N-(1’-フェニルエチル)-α-メチルプロリンアミドの2つの分画を得た。2位の立体化学は、光学活性α-メチルプロリンに誘導し決定した(参考例5参照)。
分画1:(2R,1’R):(2S,1’R)=96:4、0.48g、純度85%(NMR)、1.75mmol、収率18%。
分画2:(2R,1’R):(2S,1’R)=60:40、1.52g、純度88%(NMR)、5.80mmol、収率58%。
(2R,1’R)-N-(1’-フェニルエチル)-α-メチルプロリンアミド
1H-NMR(400MHz,CDCl3)δ1.30(3H,d,J=6.6Hz),1.37(3H,s),1.64-1.73(2H,m),1.80-1.88(1H,m),2.16-2.32(2H,m),2.69-2.75(1H,m),3.62(1H,q,J=6.6Hz),5.45(1H,brs),7.22-7.28(1H,m),7.28-7.35(4H,m),7.45(1H,brs).
(2S,1’R)-N-(1’-フェニルエチル)-α-メチルプロリンアミド
1H-NMR(400MHz,CDCl3)δ1.41(3H,s),1.42(3H,d,J=6.8Hz),1.66-1.89(3H,m),2.12-2.22(1H,m),2.90-3.00(1H,m),3.09-3.15(1H,m),4.04(1H,q,J=6.8Hz),5.17(1H,brs),7.02(1H,brs),7.20-7.27(1H,m),7.29-7.35(4H,m).
(R)-α-メチルプロリンアミドの製造(上記一般式(5)において、R1=Me、R2=R3=H;1-フェニルエチル基の除去)
(R)-α-メチルプロリンの製造(上記一般式(4)において、R1=Me、R2=R3=H;アミド加水分解、α-メチルプロリンの絶対配置決定)
(2S,1’S)及び(2R,1’S)-N-(1’-フェニルエチル)-α-メチルプロリンアミドの製造(上記一般式(3)において、R1=Me、R2=(S)-1-フェニルエチル、R3=H;工程(a)(S)-α-メチルベンジルアミン使用、水溶媒での反応、工程(b)硫酸による水和)
別のフラスコに硫酸39g(400mmol)を仕込み、水浴上で上記淡褐色油状物質を添加し、トルエンで洗い入れた。60℃で3時間、70℃で3時間反応させた後、水浴上で水36ml、28%アンモニア水60ml、酢酸エチルをゆっくり添加し、pHを9とした。酢酸エチルで抽出し、有機層を水で3回、飽和食塩水で1回洗浄し、有機層を濃縮し、淡褐色油状物質として(2S,1’S)及び(2R,1’S)-N-(1’-フェニルエチル)-α-メチルプロリンアミド23.8g(純度80wt%(HPLC分析)、81.4mmol、収率81%、(2S,1’S):(2R,1’S)=1:0.4)を得た。
(2S,1’S)及び(2R,1’S)-N-(1’-フェニルエチル)-α-メチルプロリンアミドの製造(上記一般式(5)において、R1=Me、R2=(S)-1-フェニルエチル、R3=H;工程(f)シリカゲルカラムクロマトグラフィーによる分離)
酢酸(1当量以上)を含有する、実施例26の方法に準じて得られた(2S,1’S)及び(2R,1’S)-N-(1’-フェニルエチル)-α-メチルプロリンアミド(純量9.80g、42.2mmol)をシリカゲル100g(関東化学製シリカゲル60N(球状、中性)63-210μm)を用いたカラムクロマトグラフィーにて精製し、(2S,1’S)及び(2R,1’S)-N-(1’-フェニルエチル)-α-メチルプロリンアミドの2つの分画を得た。溶離液:ヘキサン:酢酸エチル=2:1~1:1。
分画1:6.71g。NMR分析の結果、(2S,1’S):(2R,1’S)=100:0、純度72%、20.8mmol、収率49%。酢酸20wt%、酢酸エチル8wt%含む。
分画2:3.11g。NMR分析の結果、(2R,1’S):(2S,1’S)=87:13、純度82%、11.0mmol、収率25%。酢酸13wt%、酢酸エチル5wt%含む。
α-メチルプロリンアミド塩酸塩の製造(上記一般式(3)において、R1=Me、R2=R3=H;1-フェニルエチル基の除去、塩酸塩化)
フラスコに実施例26で得られた(2S,1’S)及び(2R,1’S)-N-(1’-フェニルエチル)-α-メチルプロリンアミド5.94g(純度80%、20.4mmol)、酢酸エチル25ml、活性炭2.5gを仕込み、室温で1時間攪拌し、着色成分及び不純物を吸着させた。セライトろ過した後、ろ液を濃縮し、さらにメタノール24ml、酢酸1.4ml(25mmol)、10%パラジウム炭素(NEケムキャット社製 PE-type、55%含水)0.24g(0.10mmol)を添加した。常圧水素雰囲気下、60℃で4.5時間反応させた後、反応液をセライトろ過し、ろ液を濃縮し、淡黄色油状物質5.14gを得た。
フラスコに上記黄色油状物質、メタノール1.6ml、酢酸エチル6mlを仕込んだ。水浴上で4N塩酸-酢酸エチル溶液6mlを添加し、生じた結晶をろ過し、酢酸エチルで洗浄し、減圧乾燥した。白色結晶としてα-メチルプロリンアミド塩酸塩2.46g(14.9mmol、収率73%)を得た。
(S)-α-メチルプロリン及び(R)-α-メチルプロリンアミドの製造(上記一般式(4)及び(5)において、R1=Me、R2=R3=H;工程(d)α-メチルプロリンアミド((S):(R)=7:3)の酵素分割)
50mlサンプルチューブに、参考例6で得られたα-メチルプロリンアミド塩酸塩2.0g(12.2mmol)と水2.0mlを仕込み、5%水酸化ナトリウム水でpHを7.0にした。混合液にペプチダーゼR(商品名、天野エンザイム株式会社、リゾプス・オリゼー由来)0.15gの水(0.9ml)溶液を添加し、40℃、撹拌数250rpmで162時間反応させた。反応液に水2.5mlと活性炭0.75gを添加し、25℃で1時間振とうさせた。セライトろ過で活性炭を除去し、得られた水溶液をイオン交換樹脂(ダイヤイオン(登録商標)PA312LOH)に通液し、(R)-α-メチルプロリンアミドを水で、(S)-α-メチルプロリンを1M酢酸水で溶出させた。HPLCで純度分析及び光学純度を分析した結果、(R)-α-メチルプロリンアミド純分は454mg(3.54mmol、収率29%、93.5%ee)、(S)-α-メチルプロリン純分は799mg(6.19mmol、収率51%、99.1%ee)であった。
(2S,1’R)-N-(1’-フェニルエチル)-α-メチルプロリンアミド・D-酒石酸塩の製造(上記一般式(5)において、R1=Me、R2=(R)-1-フェニルエチル、R3=H;工程(e)D-酒石酸によるジアステレオマー塩分割)
1H-NMR(400MHz,DMSO-d6)δ1.28(3H,s),1.35(3H,d,J=6.8Hz),1.62-1.79(3H,m),1.95-2.03(1H,m),2.83-2.91(1H,m),3.05-3.12(1H,m),3.99-4.06(1H,m),4.26(2H,s),6.96(2H,brs),7.19-7.24(1H,m),7.28-7.34(2H,m),7.35-7.39(2H,m).
(2R,1’S)-N-(1’-フェニルエチル)-α-メチルプロリンアミド・L-酒石酸塩及び(2S,1’S)-N-(1’-フェニルエチル)-α-メチルプロリンアミドの製造(上記一般式(5)において、R1=Me、R2=(S)-1-フェニルエチル、R3=H;工程(e)L-酒石酸によるジアステレオマー塩分割)
(2S,1’S)-N-(1’-フェニルエチル)-α-メチルプロリンアミド・(S)-マンデル酸塩の製造(上記一般式(5)において、R1=Me、R2=(S)-1-フェニルエチル、R3=H;工程(e)(S)-マンデル酸塩種結晶の取得)
1H-NMR(400MHz,acetone-d6)δ1.28(3H,s),1.28(3H,d,J=6.6Hz),1.65-1.81(3H,m),2.07-2.18(1H,m),2.29(1H,q,J=8.5Hz),2.68-2.75(1H,m),3.66(1H,q,J=6.6Hz),5.20(1H,s),7.20-7.25(1H,m),7.27-7.34(3H,m),7.34-7.39(2H,m),7.42-7.47(2H,m),7.49-7.53(2H,m).
(2S,1’S)-N-(1’-フェニルエチル)-α-メチルプロリンアミド・(S)-マンデル酸塩の製造(上記一般式(5)において、R1=Me、R2=(S)-1-フェニルエチル、R3=H;工程(e)(S)-マンデル酸によるジアステレオマー塩分割)
フラスコに実施例26の方法に準じて得られた(2S,1’S)及び(2R,1’S)-N-(1’-フェニルエチル)-α-メチルプロリンアミドの酢酸エチル溶液2.23g(純度32wt%、3.0mmol、(2S,1’S):(2R,1’S)=7:3)、(S)-マンデル酸456mg(3.0mmol)を添加し、40℃で加熱溶解させた。30℃に冷却後、実施例31の方法に準じて得られた(2S,1’S)-N-(1’-フェニルエチル)-α-メチルプロリンアミド・(S)-マンデル酸塩の種結晶を極少量添加したところ、結晶が析出した。20℃に冷却した後、結晶をろ過し、酢酸エチルで洗浄し、減圧乾燥し、白色結晶として(2S,1’S)-N-(1’-フェニルエチル)-α-メチルプロリンアミド・(S)-マンデル酸塩753mg(1.96mmol、収率64%、94.2%de)を得た。
(2S,1’S)-N-(1’-フェニルエチル)-α-メチルプロリンアミド・(S)-マンデル酸塩の製造(上記一般式(5)において、R1=Me、R2=(S)-1-フェニルエチル、R3=H;工程(e)(S)-マンデル酸によるジアステレオマー塩分割)
フラスコに実施例26の方法に準じて得られた(2S,1’S)及び(2R,1’S)-N-(1’-フェニルエチル)-α-メチルプロリンアミドの酢酸エチル溶液7.26g(純度32wt%、10.0mmol、(2S,1’S):(2R,1’S)=7:3)、(S)-マンデル酸1.22g(8.0mmol)を添加し、40℃で加熱溶解させた。40℃で実施例31の方法に準じてより得られた(2S,1’S)-N-(1’-フェニルエチル)-α-メチルプロリンアミド・(S)-マンデル酸塩の種結晶を極少量添加したところ、結晶が析出した。徐々に氷冷まで冷却した後、結晶をろ過し、酢酸エチルで洗浄し、減圧乾燥し、白色結晶として(2S,1’S)-N-(1’-フェニルエチル)-α-メチルプロリンアミド・(S)-マンデル酸塩2.36g(6.13mmol、収率61%、96.6%de)を得た。
(S)-α-メチルプロリンの製造(上記一般式(4)において、R1=Me、R2=R3=H;1-フェニルエチル基の除去、アミド加水分解)
フラスコに実施例33で得られた(2S,1’S)-N-(1’-フェニルエチル)-α-メチルプロリンアミド・(S)-マンデル酸塩2.36g(6.13mmol、96.6%de)、1-ブタノール7ml、50w/v%NaOH水0.54ml、水2.8ml、飽和食塩水1mlを添加し攪拌した後、水層を除去し、さらに有機層を飽和食塩水1mlで洗浄し、(S)-マンデル酸を除去した。得られた有機層に、酢酸0.39ml(6.7mmol)、10%パラジウム炭素(NEケムキャット社製 PE-type、55%含水)72mg(0.031mmol)を添加し、常圧水素雰囲気下、60℃で2時間反応させた。反応液をセライトろ過し、(S)-α-メチルプロリンアミドの1-ブタノール溶液を得た。この溶液に50w/v%NaOH水0.59ml、水0.59mlを添加した後、水層を分離し、酢酸を除去した。有機層に水1ml、硫酸0.49ml(9.2mmol)を添加し、(S)-α-メチルプロリンアミドを水層に抽出し、有機層を除去した。さらに硫酸0.16ml(3.1mmol)を添加し、13時間還流し、アミドの加水分解を行った。室温に冷却後、50w/v%NaOH水1.47mlを添加し、生じたスラリーを減圧濃縮し、加水分解により生じたアンモニアを除去した。硫酸と50w/v%NaOH水を用い、pHを約8とした後、アセトン5mlを添加して硫酸ナトリウムを析出させた。生じた結晶をろ別し、ろ液を濃縮した後、1-ブタノールとシクロヘキサンを添加し、常圧加熱還流下ディーンスタークで共沸脱水を行った。室温に冷却後、生じた結晶をろ過し、酢酸エチルで洗浄し、減圧乾燥し、白色結晶として(S)-α-メチルプロリン531mg(HPLC純度分析:93wt%、3.84mmol、収率63%)。(S)-α-メチルプロリンの光学純度は99.8%eeであった。
(2S,1’S)及び(2R,1’S)-N-(1’-フェニルエチル)-α-メチルプロリンアミドの逆相HPLC分離(工程(f)逆相HPLCによる分離)
実施例26で得られた(2S,1’S)及び(2R,1’S)-N-(1’-フェニルエチル)-α-メチルプロリンアミド((2S,1’S):(2R,1’S)=7:3)を以下の逆相HPLC条件で分析したところ、保持時間の大きな差が認められた。このことより、擬似移動床を含む逆相カラム分取クロマトグラフィーが効率的に適応可能であると言える。
逆相HPLC条件
カラム:化学物質評価研究機構製L-column(4.6mm×250mm)、移動相:20mM酢酸-20mM酢酸アンモニウム水溶液/メタノール=40/60、流速:1.0ml/分、カラム温度:40℃、UV:220nm、保持時間:(2R,1’S)-N-(1’-フェニルエチル)-α-メチルプロリンアミド5.8分、(2S,1’S)-N-(1’-フェニルエチル)-α-メチルプロリンアミド9.3分
(2S,1’S)及び(2R,1’S)-N-(1’-フェニルエチル)-α-メチルプロリンアミドの合成吸着剤カラムクロマトグラフィー分離(工程(f)合成吸着剤カラムクロマトグラフィーによる分離)
実施例26で得られた(2S,1’S)及び(2R,1’S)-N-(1’-フェニルエチル)-α-メチルプロリンアミド((2S,1’S):(2R,1’S)=7:3)を以下の合成吸着剤カラムを用いたHPLC条件で分析したところ、保持時間の大きな差が認められた。このことより、擬似移動床を含む逆相カラム分取クロマトグラフィーが効率的に適応可能であると言える。
合成吸着剤カラムを用いたHPLC条件
カラム:三菱化学社製MCI(登録商標)-GEL CHP10M(4.6mm×150mm)、移動相:20mM酢酸-20mM酢酸アンモニウム水溶液/アセトニトリル=50/50、流速:1.0ml/分、カラム温度:40℃、UV:220nm、保持時間:(2R,1’S)-N-(1’-フェニルエチル)-α-メチルプロリンアミド3.7分、(2S,1’S)-N-(1’-フェニルエチル)-α-メチルプロリンアミド5.1分
1-(カルバモイルフェニルメチル)-2-シアノ-2-メチルピロリジンの製造(上記一般式(7)において、R1=Me、R2=カルバモイルフェニルメチル、R3=H;工程(a)D-フェニルグリシンアミド塩酸塩使用、酢酸エチル-水溶媒での反応)
1H-NMRでは7:3のジアステレオマー混合物を観測、主生成物:1H-NMR(400MHz,CDCl3)δ1.62(3H,s),1.74-1.99(3H,m),2.29-2.41(2H,m),2.78-2.84(1H,m),4.51(1H,s),5.81(1H,brs),6.97(1H,brs),7.31-7.44(5H,m).
副生成物:1H-NMR(400MHz,CDCl3)δ0.85(3H,s),1.74-1.99(3H,m),2.29-2.41(1H,m),2.70-2.78(1H,m),3.43-3.50(1H,m),4.19(1H,s),5.58(1H,brs),6.15(1H,brs),7.31-7.44(3H,m),7.52-7.58(2H,m).
N-(カルバモイルフェニルメチル)-α-メチルプロリンアミドの製造(上記一般式(3)において、R1=Me、R2=カルバモイルフェニルメチル、R3=H;工程(b)硫酸による水和)
1H-NMR(400MHz,CDCl3)δ1.45(3H,s),1.63-1.72(1H,m),1.80-1.94(2H,m),2.19-2.27(1H,m),2.99-3.05(1H,m),3.42-3.49(1H,m),4.48(1H,s),5.31(1H,brs),5.38(1H,brs),5.58(1H,brs),6.97(1H,brs),7.29-7.47(5H,m).
α-メチルプロリンの製造(上記一般式(4)において、R1=Me、R2=R3=H;カルバモイルフェニルメチル基の除去、アミド加水分解)
フラスコに実施例37で得られたN-(カルバモイルフェニルメチル)-α-メチルプロリンアミドの粗生成物0.50g、酢酸0.070ml(1.2mmol)、10%パラジウム炭素(NEケムキャット社製 PE-type、55%含水)29mg(0.012mmol)、メタノール2mlを添加し、常圧水素雰囲気下、60℃で2時間反応させた。反応液をセライトろ過後、濃縮し、α-メチルプロリンアミドの粗生成物を得た。この粗生成物に水1ml、硫酸0.26ml(4.9mmol)を添加し、5時間還流し、アミドの加水分解を行った後、反応液をキラルHPLCで分析したところ、ラセミ体のα-メチルプロリンが生成していた。
1-(カルバモイルフェニルメチル)-2-シアノ-2-メチルピロリジンの製造(上記一般式(7)において、R1=Me、R2=カルバモイルフェニルメチル、R3=H;工程(a)D-フェニルグリシンアミド塩酸塩使用、DMSO溶媒での反応)
フラスコに5-クロロ-2-ペンタノン0.25ml(2.2mmol)、シアン化ナトリウム0.29g(6mmol)、D-フェニルグリシンアミド塩酸塩0.37g(2mmol)、酢酸0.34ml(6mmol)、DMSO1ml、水0.2mlを仕込み、室温で6時間反応させた。反応液に水3.8mlを加えた後、結晶をろ過し、水で洗浄し、減圧乾燥した。淡褐色結晶として1-(カルバモイルフェニルメチル)-2-シアノ-2-メチルピロリジン0.32g(1.3mmol、収率67%)を得た。なお、実施例37、参考例8と同様にしてα-メチルプロリンへと誘導したところラセミ体であったことから、本反応中にカルバモイルフェニルメチル基のエピメリ化が進行したものと考えられる。
2-フェニルピロリンの製造(上記一般式(6)において、R1=Ph、R2=R3=H;工程(a)4-クロロ-1-フェニル-1-ブタノン、酢酸アンモニウム使用、t-ブタノール-水溶媒での反応)
1H-NMR(400MHz,CDCl3)δ2.00-2.09(2H,m),2.92-2.99(2H,m),4.04-4.10(2H,m),7.38-7.44(3H,m),7.81-7.87(2H,m).
1-ベンジル-2-シアノ-2-フェニルピロリジンの製造(上記一般式(7)において、R1=Ph、R2=Bn、R3=H;工程(a)4-クロロ-1-フェニル-1-ブタノン、ベンジルアミン、酢酸使用、t-ブタノール-水溶媒での反応)
NMR解析の結果から、この油状物質は1-ベンジル-2-シアノ-2-フェニルピロリジンを45重量%(0.47g、収率90%)、ベンジルアミンを46重量%、酢酸エチルを9重量%含有する混合物であった。
1H-NMR(400MHz,CDCl3)δ1.91-2.28(4H,m),2.52-2.60(1H,m),3.16-3.23(1H,m),3.28(1H,d,J=12.9Hz),3.74(1H,d,J=13.1Hz),7.23-7.39(6H,m),7.41-7.46(2H,m),7.73-7.77(2H,m).
2-メチル-1-ピロリンの製造(上記一般式(6)において、R1=Me、R2=R3=H;工程(a)シアン化ナトリウム添加せず、アンモニア水使用、メタノール溶媒での反応)
2-メチル-1-ピロリンの製造(上記一般式(6)において、R1=Me、R2=R3=H;工程(a)シアン化ナトリウム添加せず、酢酸アンモニウム使用、t-ブタノール-水溶媒での反応)
フラスコに5-クロロ-2-ペンタノン0.114ml(1.0mmol)、酢酸アンモニウム231mg(3.0mmol)、水0.5ml、t-ブタノール0.5mlを仕込み、50℃で4時間反応させた。反応液をNMRで解析したところ、5-クロロ-2-ペンタノンのみが観測され、2-シアノ-2-メチルピロリジンは生成していなかった。
Claims (5)
- 下記工程(a)乃至(c)を含む、一般式(4)
(式中、R1は置換されていてもよいアルキル基、置換されていてもよいアリール基、又は置換されていてもよいヘテロアリール基を示し、R2は水素原子、置換されていてもよいアルキル基、又はアミノ基の保護基を示し、R3はそれぞれ独立して、水素原子、置換されていてもよいアルキル基、置換されていてもよいアリール基、置換されていてもよいヘテロアリール基、置換されていてもよい水酸基、置換されていてもよいアミノ基、置換されていてもよいチオール基、又はハロゲン原子を示し、2つ以上のR3が1つ又は複数の環構造を形成していてもよく、*は不斉炭素を示す。)で表される光学活性α-置換プロリン類若しくはその塩、及び/又は、一般式(5)
(式中、各記号は前述と同義である。)で表される光学活性α-置換プロリンアミド類若しくはその塩の製造方法;
(a)一般式(1)
(式中、R1及びR3は前述と同義であり、Xはハロゲン原子、又はスルホニルオキシ基を示す。)で表される鎖状ケトン化合物をアンモニア、アンモニウム塩、1級アミン及び1級アミンの塩から選ばれる少なくとも1種、及びシアノ化剤と反応させ、必要によりピロリジン環上の窒素原子を保護することにより、一般式(2)
(式中、R1及びR3は前述と同義であり、Yは窒素原子又はR2で置換された窒素原子、Zは炭素原子又はシアノ基で置換された炭素原子を示す。Yが窒素原子、Zが炭素原子を示すとき、YとZの間の結合は二重結合であり、YがR2で置換された窒素原子、Zがシアノ基で置換された炭素原子を示すとき、YとZの間の結合は単結合である。R2は前述と同義である。)で表される環状含窒素化合物又はその塩を得る;及び
(b)一般式(2)で表される環状含窒素化合物又はその塩を水和することにより、一般式(3)
(式中、各記号は前述と同義である。)で表されるα-置換プロリンアミド類又はその塩を得る;及び
(c)一般式(3)で表されるα-置換プロリンアミド類又はその塩を分割することにより、一般式(4)で表される光学活性α-置換プロリン類若しくはその塩、及び/又は、一般式(5)で表される光学活性α-置換プロリンアミド類若しくはその塩を得る。 - 下記工程(a)及び(b)を含む、一般式(3)
(式中、各記号は請求項1と同義である。)で表される2-置換プロリンアミド類又はその塩の製造方法;
(a)一般式(1)
(式中、各記号は請求項1と同義である。)で表される鎖状ケトン化合物をアンモニア、アンモニウム塩、1級アミン及び1級アミノの塩から選ばれる少なくとも1種、及びシアノ化剤と反応させ、必要によりピロリジン環上の窒素原子を保護することにより、一般式(2)
(式中、各記号は請求項1と同義である。)で表される環状含窒素化合物又はその塩を得る;及び
(b)一般式(2)で表される環状含窒素化合物又はその塩を水和することにより、一般式(3)で表されるα-置換プロリンアミド類又はその塩を得る。 - 下記工程(c)を含む、一般式(4)
(式中、各記号は請求項1と同義である。)で表される光学活性α-置換プロリン類若しくはその塩、及び/又は、一般式(5)
(式中、各記号は請求項1と同義である。)で表される光学活性α-置換プロリンアミド類又はその塩の製造方法;
(c)一般式(3)
(式中、各記号は請求項1と同義である。)で表されるα-置換プロリンアミド類又はその塩を分割することにより、一般式(4)で表される光学活性α-置換プロリン類若しくはその塩、及び/又は、一般式(5)で表される光学活性α-置換プロリンアミド類若しくはその塩を得る;
当該分割が下記工程(d)ないし(f)のいずれか1以上の工程である。
(d)リゾプス・オリゼー由来のアミダーゼ活性を有する酵素によるアミド基の不斉加水分解反応である。
(e)ジアステレオマー塩形成による分割である。
(f)カラムクロマトグラフィーによる分離である。
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CN201280025219.6A CN103596924A (zh) | 2011-05-31 | 2012-03-29 | 光学活性的α-取代的脯氨酸的制造方法 |
US14/122,365 US20140127762A1 (en) | 2011-05-31 | 2012-03-29 | Method for producing optically active alpha-substituted proline |
SG2013088455A SG195224A1 (en) | 2011-05-31 | 2012-03-29 | Method for producing optically active #-substituted proline |
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