WO2012057093A1 - 3,4-二置換ピロリジン誘導体の製造方法 - Google Patents
3,4-二置換ピロリジン誘導体の製造方法 Download PDFInfo
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- WO2012057093A1 WO2012057093A1 PCT/JP2011/074463 JP2011074463W WO2012057093A1 WO 2012057093 A1 WO2012057093 A1 WO 2012057093A1 JP 2011074463 W JP2011074463 W JP 2011074463W WO 2012057093 A1 WO2012057093 A1 WO 2012057093A1
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- 0 CCC(CC1CCCC(C*)=C)CC1*(C)(C)CC Chemical compound CCC(CC1CCCC(C*)=C)CC1*(C)(C)CC 0.000 description 3
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- 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
- C07D207/22—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 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
- C07D207/24—Oxygen or sulfur atoms
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B61/00—Other general methods
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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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
- C07D207/22—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 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones 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 other ring carbon atoms
- C07D207/277—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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention relates to a novel method for producing a 3,4-disubstituted pyrrolidine derivative, which is an intermediate for producing an antibacterial agent effective against resistant bacteria.
- Patent Documents 1 and 2 disclose 10- (3-cyclopropylaminomethyl-4-substituted-1-pyrrolidinyl) pyridobenzoxazinecarboxylic acid as an antibacterial agent exhibiting excellent antibacterial activity against resistant bacteria and having high safety. Derivatives, 7- (3-cyclopropylaminomethyl-4-substituted-1-pyrrolidinyl) quinolone carboxylic acid derivatives are disclosed.
- Patent Documents 1 and 2 have a (3R, 4S) -3-alkylaminomethyl-4-fluoropyrrolidyl group at the 7-position, but the synthesis raw material (3R, 4S)- In order to synthesize 3-alkylaminomethyl-4-fluoropyrrolidine, there are problems such as a large number of steps (Patent Documents 1 and 2) and purification not easy (Patent Document 3).
- Patent Document 4 discloses an improved production method using an asymmetric hydrogenation reaction of an ⁇ -substituted- ⁇ -ketoester derivative. That is, anti- (3S, 4R) -3-alkoxycarbonyl-4-hydroxypyrrolidine is obtained by subjecting the racemic 3-alkoxycarbonyl-4-oxopyrrolidine derivative to asymmetric hydrogenation using an optically active catalyst. It is disclosed that an optically active derivative or its enantiomer can be obtained with high stereoselectivity.
- anti- (3S, 4R) -3-alkoxycarbonyl-4-hydroxypyrrolidine derivative into an alkylamide group
- anti- (3S, 4R) -3 It is disclosed that an optically active form of an alkylcarbamoyl-4-hydroxypyrrolidine derivative can be obtained.
- the compound has very good crystallinity, and the target enantiomer [(3R, 4S) -form] and its diastereomer, which are slightly produced in the asymmetric hydrogenation step, are recrystallized and the like. Can be removed. Thereafter, it can be led to an optically active substance of (3R, 4S) -3-alkylaminomethyl-4-fluoropyrrolidine through a process such as fluorination of a hydroxy group (Patent Document 4).
- Non-Patent Document 1 describes an example of catalytic asymmetric hydrogenation using ⁇ -alkyl- ⁇ -ketoamide.
- Patent Document 4 The production method described in International Publication No. 2007/102567 (Patent Document 4) is very useful in that the number of steps is short and purification is easy. However, when the asymmetric hydrogenation reaction is performed, a high pressure is used. There was a problem that conditions were necessary and a large amount of catalyst was used. Also, Organic Letters, 2010, 12 (3), 512-515.
- the main product obtained as a target product in (Non-patent Document 1) is a syn- ⁇ -hydroxyamide form, and does not give an anti-form as a main product.
- the present invention is a key intermediate for producing an optically active form of (3R, 4S) -3-alkylaminomethyl-4-fluoropyrrolidine or an enantiomer thereof useful as a pharmaceutical production intermediate.
- An inexpensive and industrially advantageous production method of an optically active substance of an anti- (3S, 4R) -3-alkylcarbamoyl-4-hydroxypyrrolidine derivative or its enantiomer is provided.
- the 4-oxopyrrolidine-3-carboxylic acid amide derivative which is a raw material for asymmetric hydrogenation, uses a 3-[(alkoxycarbonylmethyl) amino] propionic acid ester derivative as a starting material and selects one of the ester groups.
- Efficient synthesis step D
- step C step C
- step B step B
- Step A An optical compound represented by general formula (II) is obtained by asymmetric hydrogenation of a 4-oxopyrrolidine-3-carboxylic acid amide derivative represented by general formula (I) using an optically active catalyst.
- PG 1 represents an amino-protecting group
- R 1 represents hydrogen, an optionally substituted C1-C6 alkyl group or an optionally substituted C3-C8 cycloalkyl group. . ]
- Step B By treating the compound represented by the general formula (III) with at least one base selected from alkali metal carbonates, alkali metal amides, alkali metal hydrides and alkali metal alkoxides, Step for obtaining a 4-oxopyrrolidine-3-carboxylic acid amide derivative represented by (I)
- Step A A compound represented by the general formula (I) obtained in Step B is asymmetrically hydrogenated using an optically active catalyst.
- PG 1 represents an amino-protecting group
- R 1 represents hydrogen, an optionally substituted C1-C6 alkyl group or an optionally substituted C3-C8 cycloalkyl group
- R 2 represents a C1-C6 alkyl group.
- Step D Step of obtaining a compound represented by the general formula (V) by treating the compound represented by the general formula (IV) with an acid
- Step C In the general formula (V) obtained in the step D Step of obtaining a compound represented by the general formula (III) by condensing the compound represented by the amine represented by the general formula (VI)
- Step B Compound represented by the general formula (III) obtained in Step C Is treated with at least one base selected from alkali metal carbonates, alkali metal amides, alkali metal hydrides and alkali metal alkoxides to give 4-oxopyrrolidine-3- Step of obtaining a carboxylic acid amide derivative
- the compound represented by the general formula (I) obtained in Step B is represented by the general formula (II) by asymmetric hydrogenation using an optically active catalyst.
- PG 1 represents an amino-protecting group
- R 2 represents a C1-C6 alkyl group.
- R 1 represents hydrogen, an optionally substituted C1-C6 alkyl group or an optionally substituted C3-C8 cycloalkyl group.
- step A The production method according to any one of [1] to [3], wherein in step A, the optically active catalyst is an optically active ruthenium catalyst having an asymmetric ligand.
- the asymmetric ligand in the optically active catalyst is optically active 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP) or an analog thereof, '-Bis (diphenylphosphino) -4,4'-bi-1,3-benzodioxole (SEGPHOS) or its analog, or (2,2'-bisdiphenylphosphino) -6,6'-
- BINAP 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl
- SEGPHOS '-Bis (diphenylphosphino) -4,4'-bi-1,3-benzodioxole
- 2,2'-bisdiphenylphosphino) -6,6'- The production method according to any one of [1] to [4], which is dimethoxy-1,1′-biphenyl (MeO
- the asymmetric ligand in the optically active catalyst is 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP) or 5,5′-bis (diphenylphosphino)
- BINAP 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl
- SEGPHOS 5,5′-bis (diphenylphosphino)
- SEGPHOS ⁇ 4,4′-bi-1,3-benzodioxole
- PG 1 is an aralkoxycarbonyl group or an alkoxycarbonyl group.
- step A The process according to any one of [1] to [11], wherein in step A, an optically active catalyst is used in an amount of 0.01 to 2 mol% relative to the general formula (I).
- step A The production method according to any one of [1] to [12], wherein in step A, an optically active catalyst is used in an amount of 0.01 to 1 mol% relative to the general formula (I).
- a method for producing a compound represented by the general formula (I) for asymmetric hydrogenation using an optically active catalyst (Step B) By treating the compound represented by the general formula (III) with a base selected from an alkali metal carbonate, an alkali metal amide, an alkali metal hydride and an alkali metal alkoxide, Process for producing the indicated 4-oxopyrrolidine-3-carboxylic acid amide derivative.
- PG 1 represents an amino-protecting group
- R 1 represents hydrogen, an optionally substituted C1-C6 alkyl group or an optionally substituted C3-C8 cycloalkyl group. It represents, R 2 represents an alkyl group of C1 ⁇ C6.
- Step D A process for producing a compound represented by the general formula (V) by treating a compound represented by the general formula (IV) with an acid.
- PG 1 represents an amino-protecting group
- R 2 represents a C1-C6 alkyl group.
- PG 1 and R 2 are as defined above.
- [20] The production method according to any one of [3] to [13] and [19], wherein in step D, the acid is trifluoroacetic acid or formic acid.
- [21] The production method according to any one of [3] to [13] and [19] to [20], wherein in step D, the acid is formic acid.
- [22] The production according to any one of [2] to [21], wherein the amino-protecting group represented by PG 1 is an aralkoxycarbonyl group, and R 2 is a C1-C4 lower alkyl group.
- a racemate of the 4-oxopyrrolidine-3-carboxylic acid amide derivative represented by the general formula (I) can be obtained with high yield.
- a racemic form of a 4-oxopyrrolidine-3-carboxylic acid amide derivative is subjected to asymmetric hydrogenation using an optically active catalyst, whereby anti- (3S, 4R) -4-hydroxy is obtained.
- An optically active form of a pyrrolidine-3-carboxylic acid amide derivative or an enantiomer thereof can be obtained with high optical purity.
- optically active form of the anti- (3S, 4R) -4-hydroxypyrrolidine-3-carboxylic acid amide derivative or its enantiomer obtained by the method of the present invention is obtained by a known method (International Publication No. 2007/102567). It can be converted into an optically active form of (3R, 4S) -3-alkylaminomethyl-4-fluoropyrrolidine useful as a pharmaceutical production intermediate or an enantiomer thereof.
- an industrial production method of an optically active substance of (3R, 4S) -3-alkylaminomethyl-4-fluoropyrrolidine or its enantiomer is provided.
- PG 1 represents an amino-protecting group.
- R 1 represents hydrogen, an optionally substituted C1-C6 alkyl group or an optionally substituted C3-C8 cycloalkyl group.
- R 2 represents a C1 to C6 alkyl group, and preferably a C1 to C4 lower alkyl group.
- amino-protecting group shown in the present specification is not particularly limited as long as it is a protecting group commonly known as an amino-protecting group.
- an aralkyl such as a benzyl group or a paramethoxybenzyl group is used.
- alkoxycarbonyl group such as methoxycarbonyl group, ethoxycarbonyl group, propyloxycarbonyl group, isopropyloxycarbonyl group, butyloxycarbonyl group, isobutyloxycarbonyl group or tert-butyloxycarbonyl group, benzyloxycarbonyl group, p-methoxy group
- Aralkoxycarbonyl groups such as benzyloxycarbonyl group or p-nitrobenzyloxycarbonyl group, or 1- (such as methoxymethyl group, methoxyethoxymethyl group, 1- (ethoxy) ethyl group, methoxyisopropyl group, etc.
- Alkoxy) alkyl group an acetyl group, trifluoroacetyl group, a propionyl group, a butyryl group, pivaloyl group, etc.
- acyl group such as benzoyl group or a methyl benzoyl group.
- an aralkoxycarbonyl group or an alkoxycarbonyl group is preferable, an aralkoxycarbonyl group is more preferable, and a benzyloxycarbonyl group is still more preferable.
- the “optionally substituted C1-C6 alkyl group” shown in the present specification means a halogen atom, a hydroxyl group, a cyano group, a C1-C6 alkoxy group, an optionally substituted aryloxy group, C1 C1-C6 alkylcarbonyl group, C1-C6 alkoxycarbonyl group, C1-C6 alkylthio group, amino group, mono- or di-substituted C1-C6 alkylamino group, 1 to 3 heteroatoms Good C4 to C9 cyclic amino group, formylamino group, C1 to C6 alkylcarbonylamino group, C1 to C6 alkoxycarbonylamino group, C1 to C6 alkylsulfonylamino group and optionally substituted arylsulfonylamino group Means a C1-C6 alkyl group optionally having 1 to 5 substituents selected from the group consisting of To.
- the “C1-C6 alkyl group” means a linear or branched alkyl group.
- Examples of the C1-C6 alkyl group include a methyl group, an ethyl group, a propyl group, a 1-methylethyl group, a 1-methylpropyl group, a 2-methylpropan-1-yl group, a tert-butyl group, and 1-ethyl.
- Examples thereof include a propyl group, a 2-ethylpropyl group, a butyl group, and a hexyl group. Among these, an ethyl group or a tert-butyl group is preferable.
- the “optionally substituted C3-C8 cycloalkyl group” shown in the present specification refers to a halogen atom, a hydroxyl group, a cyano group, a C1-C6 alkoxy group, and an optionally substituted aryloxy group.
- the “C3-C8 cycloalkyl group” means an alkyl group having a cycloalkyl ring.
- Examples of the C3-C8 cycloalkyl group include a cyclopropyl group, a cyclopropylmethyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group. is there.
- C1-C6 alkoxy group examples include a methoxy group, an ethoxy group, a butoxy group, and a hexyloxy group.
- the “optionally substituted aryloxy group” is a group consisting of a halogen atom, a hydroxyl group, a cyano group, a nitro group, a C1-C6 alkyl group, a C1-C6 alkoxy group, and a C1-C6 alkylthio group.
- aryloxy group examples include a phenoxy group and a naphthyloxy group.
- C1-C6 alkylcarbonyl group examples include acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, hexanoyl group and the like.
- C1-C6 alkoxycarbonyl group examples include a methoxycarbonyl group, an ethoxycarbonyl group, and a tert-butoxycarbonyl group.
- C1-C6 alkylthio group examples include a methylthio group, an ethylthio group, a propylthio group, and an isopropylthio group.
- the “mono- or di-substituted C1-C6 alkylamino group” means a halogen atom, hydroxyl group, cyano group, C1-C6 alkoxy group, C1-C6 alkylthio group, amino group, 1 to 3 heteroatoms
- a group consisting of a C4 to C9 cyclic amino group, a formylamino group, a C1 to C6 alkylcarbonylamino group, a C1 to C6 alkylsulfonylamino group, an optionally substituted arylsulfonylamino group, and the like Means a C1-C6 alkylamino group optionally having 1 to 2 substituents selected from
- C1-C6 alkylamino group examples include, for example, methylamino group, ethylamino group, n-propylamino group, n-butylamino group, sec-butylamino group, n-pentylamino group or n-hexyl. An amino group etc. are mentioned.
- the “C4 to C9 cyclic amino group” means a cyclic amino group containing one or more nitrogen atoms in the ring and optionally having an oxygen atom or a sulfur atom in the ring.
- Examples of the C4 to C9 cyclic amino group include an aziridyl group, a pyrrolidyl group, a piperidyl group, a morpholyl group, an oxazolyl group, an azabicycloheptyl group, and an azabicyclooctyl group.
- C1-C6 alkylcarbonylamino group examples include an acetylamino group, a propionylamino group, and a butyrylamino group.
- C1-C6 alkoxycarbonylamino group examples include a methoxycarbonylamino group, an ethoxycarbonylamino group, a tert-butoxycarbonylamino group, and a hexyloxycarbonylamino group.
- C1-C6 alkylsulfonylamino group examples include a methylsulfonylamino group and an ethylsulfonylamino group.
- the “optionally substituted arylsulfonylamino group” includes a halogen atom, a hydroxyl group, a cyano group, a nitro group, a C1-C6 alkyl group, a C1-C6 alkoxy group, and a C1-C6 alkylthio group. It means an arylsulfonylamino group optionally having 1 to 5 substituents selected from the group.
- arylsulfonylamino group examples include a phenylsulfonylamino group, a 4-methylphenylsulfonylamino group, and a naphthylsulfonylamino group.
- the “C1-C4 lower alkyl group” means a linear or branched alkyl group.
- Examples of the “C1-C4 lower alkyl group” include a methyl group, an ethyl group, a propyl group, a 1-methylethyl group, a 1-methylpropyl group, a 2-methylpropan-1-yl group, a tert-butyl group, A butyl group etc. are mentioned. Among these, a methyl group or an ethyl group is preferable, and an ethyl group is more preferable.
- alkali metal examples include lithium, sodium, and potassium.
- Step D is a step in which one ester group (tert-butyl ester group) of the diester compound represented by the general formula (IV) is subjected to ester cleavage by adding an acid to obtain a monocarboxylic acid compound (V).
- the “acid” used in the reaction of Step D means an organic acid or an inorganic acid, and an organic acid is preferable.
- Organic acid used in the reaction of Step D means an organic compound having an acidic functional group such as carboxylic acid, sulfonic acid, sulfinic acid, and phenol.
- examples of the organic acid include formic acid, acetic acid, trifluoroacetic acid (TFA), p-toluenesulfonic acid (p-TsOH), and methanesulfonic acid.
- trifluoroacetic acid or formic acid is preferable from the viewpoint of yield, and formic acid is more preferable.
- formic acid there is an advantage that the calorific value is easily controlled or isolated.
- “Inorganic acid” used in the reaction of step D means an acid obtained by a chemical reaction of an inorganic compound.
- examples of the inorganic acid include hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrofluoric acid, boric acid, hydrogen chloride, and the like. Among these, hydrochloric acid is preferable.
- the amount of trifluoroacetic acid or formic acid used is usually preferably 10 to 100 equivalents, more preferably 10 to 60 equivalents, relative to the compound represented by the general formula (IV). is there.
- the amount of p-toluenesulfonic acid used with respect to the compound represented by formula (IV) is preferably 0.1 to 2 equivalents, more preferably 0. .1 to 0.5 equivalents.
- the amount of hydrochloric acid used with respect to the compound represented by formula (IV) is usually preferably 1 to 100 equivalents, more preferably 50 to 60 equivalents.
- the amount of the hydrogen chloride / ethyl acetate solution to be used with respect to the compound represented by the general formula (IV) is usually preferably 1 to 5 equivalents, more preferably 1. 5 to 2.5 equivalents.
- the reaction temperature in step D is usually preferably in the range of 0 ° C. to the boiling point of the solvent, more preferably 25 ° C. to the boiling point of the solvent, and further preferably 40 to 50 ° C.
- the reaction solvent in Step D is not particularly limited as long as it is solventless or is a solvent that is stable under the reaction conditions and is inert and does not hinder the reaction.
- solvents include hydrocarbons such as hexane, cyclohexane or heptane, aromatic hydrocarbons such as benzene, toluene or xylene, 1,2-dimethoxyethane (DME), tetrahydrofuran (THF), diisopropyl ether, 2 -Ethers such as methyltetrahydrofuran, tetrahydropyran, diglyme or cyclopentylmethyl ether, esters such as methyl acetate, ethyl acetate, isopropyl acetate or butyl acetate, nitriles such as acetonitrile and propionitrile, methanol, ethanol, 2-propanol , Tert-butyl alcohol, 2-methoxyethanol, alcohols such as
- solvents are appropriately selected according to the ease of reaction, and are used alone or in combination.
- a suitable dehydrating agent or desiccant is used as a non-aqueous solvent.
- step D when formic acid is used as the acid, the reaction is preferably carried out without a solvent.
- the solvent is preferably acetonitrile or toluene, more preferably toluene.
- Step C is a step of condensing an amine represented by general formula (VI) to a monocarboxylic acid compound represented by general formula (V) to obtain an amide compound represented by general formula (III).
- condensation reaction commonly used condensation conditions can be used.
- R 1 has the same meaning as described above.
- the amount of the amine represented by the general formula (VI) is not particularly limited, but it is usually preferably 1 to 3 equivalents, more preferably 1.0 to 1.5, relative to the compound represented by the general formula (V). Is equivalent.
- the condensing agent is not particularly limited as long as it can produce an amide bond from a carboxylic acid and an amine.
- condensing agent examples include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) or its hydrochloride, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), diphenylphosphoryl azide (DPPA), cyanophosphoric acid Diethyl (DEPC), benzotriazol-1-yl-oxytrisdimethylaminophosphonium hexafluorophosphate (BOP), 2- (1-hydrobenzotriazol-1-yl) -1,1,3,3-tetramethyluronium Hexafluorophosphate (HBTU), 2- (1-hydrobenzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-chloro-N, N, 2- Trimethyl Lopenylamine, 2-chloro-4,6-dimethoxy-1,3,5-triflu
- 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) or its hydrochloride is preferable, and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI ⁇ HCl) is preferable. More preferred.
- the amount of the condensing agent used is not particularly limited, but is usually preferably 1 to 5 equivalents, more preferably 1.0 to 1.5 equivalents, relative to the compound represented by the general formula (V).
- Step C it is preferable to use an additive because the reaction yield is improved by using the additive together with the condensing agent.
- additives examples include 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), 1-hydroxysuccinimide (HOSu), or 3,4-dihydro-3-hydroxy-4-oxo.
- HOOBt 1-hydroxybenzotriazole
- 1-hydroxy-7-azabenzotriazole HOAt
- 1-hydroxysuccinimide HSu
- 3,4-dihydro-3-hydroxy-4-oxo 3,4-dihydro-3-hydroxy-4-oxo.
- HOOBt 1-hydroxybenzotriazole
- 1-hydroxysuccinimide (HOSu) or 1-hydroxybenzotriazole (HOBt) is preferable, and 1-hydroxybenzotriazole (HOBt) is more preferable.
- an additive is not specifically limited, Even when it reduces to 0.01 equivalent with respect to the compound shown by general formula (V), reaction yield can be maintained.
- the amount of the additive used is preferably 0.01 to 5 equivalents, and more preferably 0.01 to 1.2 equivalents.
- step C the reaction proceeds without using a base, but using a base together with a condensing agent is preferable because the reaction conversion rate is improved.
- Any base may be used as long as it does not inhibit the reaction, such as triethylamine, trimethylamine, tripropylamine, diisopropylethylamine, pyridine, dimethylaniline, N-methylmorpholine, N-methylpyrrolidine, or 4-dimethylaminopyridine.
- Organic bases such as triethylamine, trimethylamine, tripropylamine, diisopropylethylamine, pyridine, dimethylaniline, N-methylmorpholine, N-methylpyrrolidine, or 4-dimethylaminopyridine.
- N-methylmorpholine, N-methylpyrrolidine or triethylamine is preferable, and triethylamine is more preferable.
- a solvent examples include esters such as ethyl acetate, butyl acetate and isopropyl acetate, aromatic compounds such as benzene, toluene and xylene, hydrocarbons such as hexane, heptane and cyclohexane, dioxane, tetrahydrofuran (THF), 2 -Ethers such as methyltetrahydrofuran (2-MeTHF), tert-butyl methyl ether (TBME), dimethoxyethane (DME) or diglyme, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride or 1,2-dichloroethane Nitriles such as acetonitrile, amides such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide or N-methylpyrrolidon
- tetrahydrofuran a mixed solvent of tetrahydrofuran and N, N-dimethylformamide, or a mixed solvent of 2-methyltetrahydrofuran and N, N-dimethylformamide are preferable, and tetrahydrofuran is more preferable.
- the reaction temperature in Step C is usually preferably in the range of ⁇ 20 ° C. to the boiling point of the solvent used, more preferably 0 ° C. to the boiling point of the solvent, and further preferably 30 to 50 ° C.
- Step B is a step of obtaining a 4-oxopyrrolidine-3-carboxylic acid amide derivative represented by the general formula (I) by treating the amide compound represented by the general formula (III) with a base.
- Examples of the base include alkali metal carbonates, alkali metal amides, alkali metal alkoxides, and alkali metal hydrides. Among these, alkali metal alkoxide is preferable.
- Alkali metal carbonate means an alkali metal carbonate.
- Examples of the alkali metal carbonate include lithium carbonate, sodium carbonate, and potassium carbonate, and potassium carbonate is preferable.
- Alkali metal amide is a compound in which a hydrogen atom of an amine is replaced with a metal atom.
- alkali metal amide examples include lithium amide, sodium amide, potassium amide, lithium diethylamide, lithium diisopropylamide, lithium cyclohexylisopropylamide, lithium tetramethylpiperidide, lithium hexamethyldisilazide (LHMDS), sodium hexamethyldi Examples include silazide (NaHMDS) or potassium hexamethyldisilazide (KHMDS). Among these, potassium hexamethyldisilazide is preferable.
- Alkali metal alkoxide is a compound in which a hydroxyl group of an alcohol is substituted with an alkali metal.
- alkali metal alkoxide examples include sodium methoxide (NaOMe), sodium ethoxide (NaOEt), potassium ethoxide (KOEt), sodium tert-butoxide (tBuONa), potassium tert-butoxide (tBuOK), lithium tert-butoxide ( tBuOLi), sodium tert-pentoxide (C 2 H 5 C (CH 3 ) 2 ONa) or potassium tert-pentoxide (C 2 H 5 C (CH 3 ) 2 OK).
- potassium tert-butoxide sodium tert-pentoxide or potassium tert-pentoxide is preferable, and potassium tert-pentoxide is more preferable.
- alkali metal hydride examples include lithium hydride, sodium hydride, potassium hydride and the like.
- the amount of the base used is not particularly limited, it is usually preferably 1 to 4 equivalents relative to the compound represented by the general formula (III), and the by-product represented by the general formula (VII) is formed. From the viewpoint of suppression, it is more preferably 1 to 1.5 equivalents.
- the reaction temperature in step B is usually preferably in the range of ⁇ 20 to 100 ° C., more preferably 35 to 55 ° C., and still more preferably in terms of suppressing the formation of by-products of the general formula (VII). 40 to 50 ° C.
- a solvent for the reaction in Step B It is usually preferable to use a solvent for the reaction in Step B.
- the solvent include alcohols such as methanol, ethanol, 2-propanol, tert-butyl alcohol, 2-methoxyethanol, ethylene glycol and diethylene glycol, esters such as ethyl acetate and butyl acetate, benzene, toluene and xylene.
- Aromatic compounds such as hexane, heptane or cyclohexane, ethers such as dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane or diglyme, halogens such as dichloromethane, chloroform, carbon tetrachloride or 1,2-dichloroethane Hydrocarbons, nitriles such as acetonitrile, N, N-dimethylformamide (DMF) or N, N-dimethylacetamide or N-methylpyrrole Amides or mixtures thereof, such as emissions and the like.
- DMF N-dimethylformamide
- N-methylpyrrole Amides or mixtures thereof such as emissions and the like.
- N, N-dimethylformamide, tetrahydrofuran or toluene is preferable, and toluene is more preferable.
- step A the racemic form (I) of a 4-oxopyrrolidine-3-carboxylic acid amide derivative is asymmetrically hydrogenated using an optically active catalyst to produce anti- (3S, 4R) -4-hydroxypyrrolidine-
- step A the racemic form (I) of a 4-oxopyrrolidine-3-carboxylic acid amide derivative is asymmetrically hydrogenated using an optically active catalyst to produce anti- (3S, 4R) -4-hydroxypyrrolidine-
- This is a step for obtaining an optically active substance (II) of a 3-carboxylic acid amide derivative or an enantiomer thereof.
- the “optically active catalyst” is an optically active transition metal compound obtained by mixing a transition metal compound and an optically active asymmetric ligand in an organic solvent.
- transition metal compound examples include a ruthenium compound, a rhodium compound, an iridium compound, a nickel compound, a palladium compound, or a platinum compound, and a ruthenium compound is preferable.
- Examples of the ruthenium compound include dichloro (p-cymene) ruthenium (II) dimer, dibromo (p-cymene) ruthenium (II) dimer or diiodo (p-cymene) ruthenium (II) dimer, dichloro (1,5-cyclohexane).
- Examples include octadiene) ruthenium (II) polymer, dichlorobenzene ruthenium (II) dimer, dibromobenzene ruthenium (II) dimer, diiodobenzene ruthenium (II) dimer, and the like. Of these, dichlorobenzene ruthenium (II) dimer is preferred.
- asymmetric ligand As the asymmetric ligand, a conventionally used asymmetric ligand can be used. For example, the ligands described in Catalytic Asymmetric Synthesis, 2nd edition, 2000, paragraphs 2-6 (CATALYTIC ASYMMETRIC SYNTHESIS Second Edition, 2000, WILEY-VCH, p2-6) can be mentioned.
- Examples of the asymmetric ligand include (S) -BINAP, (S) -TolBINAP, (S) -XylBINAP, (S) -Cy-BINAP, (S) -H8-BINAP, (S) -MeO.
- (S) -BINAP, (S) -TolBINAP, (S) -MeO-BIPHEP, (S) -SEGPHOS or (S) -DM-SEGPHOS or their enantiomers are preferred, and (S)- BINAP or its enantiomers are preferred.
- BINAP means 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl.
- SEGPHOS means 5,5'-bis (diphenylphosphino) -4,4'-bi-1,3-benzodioxole.
- DM-SEGPHOS means 5,5'-bis (di (3,5-xylyl) phosphino) -4,4'-bi-1,3-benzodioxole.
- TolBINAP means 2,2'-bis (di-p-tolylphosphino) -1,1'-binaphthyl.
- MeO-BIPHEP means (6,6'-dimethoxybiphenyl-2,2'-diyl) bis (diphenylphosphine).
- the BINAP analog is a compound having 1 to 5 substituents such as an alkyl group on each of four benzene rings on the phosphorus atom of BINAP, and a substituent such as an alkyl group or an aryl group on the naphthyl ring of BINAP. Or a compound in which the naphthyl ring is partially hydrogenated.
- Examples of the BINAP analog include (S) -TolBINAP, (S) -XylBINAP, (S) -Cy-BINAP, (S) -H8-BINAP, and the like.
- the SEGHOPS analog means a compound having 1 to 5 substituents such as an alkyl group or an alkoxy group on four benzene rings on the phosphorus atom of SEGHOPS.
- SEGHOPS analogs include (S) -DM-SEGPHOS or (S) -DTBM-SEGPHOS.
- the MeO-BIPHEP analog means a compound having 1 to 5 substituents such as alkyl groups on four benzene rings on the phosphorus atom of MeO-BIPHEP.
- Examples of the MeO-BIPHEP analog include (S) -p-Tol-MeO-BIPHEP or di-tert-Bu-MeO-BIPHEP.
- the optically active catalyst may be an optically active transition metal compound obtained by mixing a transition metal compound and an optically active asymmetric ligand in an organic solvent.
- the optically active catalyst include a ruthenium- (S) -BINAP catalyst prepared from a ruthenium compound and (S) -BINAP, and a ruthenium- (S) -SEGPHOS prepared from a ruthenium compound and (S) -SEGPHOS.
- ruthenium- (S) -MeO-BIPHEP catalyst prepared from ruthenium compound and (S) -MeO-BIPHEP, or ruthenium- (S)-prepared from ruthenium compound and (S) -DM-SEGPHOS DM-SEGPHOS catalyst may be mentioned.
- a ruthenium- (S) -BINAP catalyst is preferable.
- the amount of the optically active catalyst to be used is not particularly limited, but it is preferably 0.01 to 20 mol%, more preferably 0.01 to 2 mol% with respect to the compound represented by the general formula (I). More preferably, it is 0.01 to 1 mol%. In the reaction of Step A, even when the amount of the optically active catalyst used is reduced to 0.1 mol%, the reaction proceeds without affecting the yield and the stereoselectivity of the target product.
- the amount of the optically active catalyst used is large, the transition metal compound or the like remains in the compound represented by the general formula (II) as the target product, and the purification is not easy, and the optically active catalyst is expensive. A smaller amount of the optically active catalyst is preferable.
- Examples of the hydrogen source include hydrogen or formic acid / triethylamine system, formic acid / ⁇ -phenethylamine system, formic acid / triphenylamine system, ammonium formate, cyclohexenes, 2-propanol and the like, and hydrogen is preferable.
- a solvent in the reaction of Step A.
- the solvent include water, organic acids such as formic acid and acetic acid, esters such as ethyl acetate and butyl acetate, aromatic compounds such as benzene, toluene, chlorobenzene and xylene, and hydrocarbons such as hexane, heptane and cyclohexane.
- alcohols such as ethylene glycol or diethylene glycol, dioxane, tetrahydrofuran, dimethoxy Ethers such as ethane or diglyme, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride or 1,2-dichloroethane,
- dichloromethane tetrahydrofuran, ethyl acetate, toluene, xylene, or chlorobenzene is preferable, and dichloromethane or chlorobenzene is more preferable.
- the reaction temperature is usually preferably in the range of ⁇ 20 ° C. to 200 ° C., more preferably in the range of 25 ° C. to 120 ° C., further preferably in the range of 60 ° C. to 100 ° C., particularly preferably in the range of 60 to 80 ° C. It is a range.
- the reaction pressure is not particularly limited, but can usually be performed under normal pressure to 10 MPa.
- the reaction of Step A even when the reaction is performed under a low pressure condition of 0.1 to 1 MPa, the reaction proceeds without affecting the yield or the stereoselectivity of the target product.
- the reaction under high pressure conditions is unsuitable industrially and the risk of explosion is high, so the reaction pressure is preferably low.
- a preferable reaction pressure is 0.1 to 1 MPa.
- the compound of the general formula (II) can be isolated by purification by using an ordinary separation means (for example, extraction, recrystallization, chromatography, etc.) if desired.
- the reaction in Step A is expensive compared to the conventional method using an asymmetric hydrogenation reaction of an ⁇ -substituted- ⁇ -ketoester derivative (International Publication No. 2007/102567), and is expensive.
- This is an excellent production method in that the amount of the optically active catalyst used can be reduced, and that the amount of the optically active catalyst used can be reduced to facilitate purification.
- the reaction in Step A is an example of catalytic asymmetric hydrogenation using an ⁇ -substituted- ⁇ -ketoamide derivative as a substrate, but an anti- ⁇ -hydroxyamide derivative is obtained as a main product as a main product. come. Organic Letters, 2010, 12 (3), 512-515.
- catalytic asymmetric hydrogenation using ⁇ -substituted- ⁇ -ketoamide but syn- ⁇ -hydroxyamide is given as the main product, and anti- ⁇ -hydroxyamide is This reaction is completely different from this reaction in which is given as the main product.
- double amount means the amount of solvent (mL) relative to the mass (g) of the substrate.
- tert-butyl acrylate (50.0 g, 0.390 mol) was added dropwise to the mixed solution at an internal temperature of 62 ° C. to 63 ° C., and the mixture was stirred at an internal temperature of 60 ° C. to 62 ° C. for 5 hours.
- the reaction was cooled to room temperature and allowed to stand overnight.
- the reaction solution was diluted with ethyl acetate (1 L), and extracted with 3% sodium hydrogen carbonate (1 L).
- the organic layer was separated to obtain an ethyl acetate solution of tert-butyl 3- (ethoxycarbonylmethylamino) propionate. A part of the solution was concentrated and 1 H NMR was measured.
- a sodium bicarbonate solution (72.1 g (0.860 mol) of sodium bicarbonate dissolved in 1.3 L of water) was added at room temperature.
- Benzyl chloroformate (133 g, 0.780 mol) was added dropwise at an internal temperature of 26 ° C. to 33 ° C., and the mixture was stirred at an internal temperature of 28 ° C. to 33 ° C. for 2 hours.
- reaction solution was cooled to room temperature and allowed to stand overnight, and then extracted.
- the organic layer was separated, and the organic layer was washed successively with 0.5 mol / L hydrochloric acid (0.5 L) and 5% brine (0.5 L) and dried over anhydrous sodium sulfate.
- Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give 265 g of the title compound as a yellow oil.
- Reaction conversion rate (%) target product / (substrate + target product) ⁇ 100
- the substrate is tert-butyl 3- ⁇ N-benzyloxycarbonyl-N- (ethoxycarbonylmethyl) amino ⁇ propionate
- the target is 3- ⁇ N-benzyloxycarbonyl-N- (ethoxycarbonylmethyl) amino ⁇
- Reaction conversion rate (%) target product / (substrate + target product) ⁇ 100
- the substrate is tert-butyl 3- ⁇ N-benzyloxycarbonyl-N- (ethoxycarbonylmethyl) amino ⁇ propionate
- the target is 3- ⁇ N-benzyloxycarbonyl-N- (ethoxycarbonylmethyl) amino ⁇
- Example 1 3- ⁇ N-benzyloxycarbonyl-N- (ethoxycarbonylmethyl) amino ⁇ propionic acid tert-butyl 3- ⁇ N-benzyloxycarbonyl-N- (ethoxycarbonylmethyl) amino ⁇ propionic acid (500 mg, 1.37 mmol) was added with formic acid (2.5 mL, 66.3 mmol), and the mixture was stirred at an external temperature setting of 40 ° C. for 3 hours. After allowing to cool, ethyl acetate (10 mL) and water (10 mL) were added to the reaction solution, and the organic layer was separated. Ethyl acetate (10 mL) was added to the aqueous layer, and the organic layer was separated.
- the reaction conversion rate is calculated as follows, with HPLC measurement under the following measurement condition C, and the obtained area percentages (%) of the substrate and target product are 100% in total. It is the value.
- Reaction conversion rate (%) target product / (substrate + target product) ⁇ 100
- the substrate is 3- ⁇ N-benzyloxycarbonyl-N- (ethoxycarbonylmethyl) amino ⁇ propionic acid
- the target is N-benzyloxycarbonyl-N- ⁇ (2-cyclopropylaminocarbonyl) ethyl ⁇ aminoacetic acid
- Example 9 to Example 16 In the same manner as in Example 8, the amount of cyclopropylamine (1.1 to 2.5 equivalents), HOBt ⁇ H 2 O (0 to 1.2 equivalents) shown in Table 2, and the reaction solvent was THF / DMF or The reaction was carried out at room temperature using a 2: 1 mixed solvent of 2-MeTHF / DMF (20 times volume).
- the reaction in Step C proceeded (Examples 17 to 20).
- the reaction in Step C proceeds even when no base is added (Example 20), but when the base is added, the reaction conversion rate is improved (Examples 17 to 19). In particular, when triethylamine was used as the base, the reaction conversion rate was the highest (Example 17).
- HPLC (%) refers to HPLC measurement using the following measurement condition D, and the obtained substrate, target product and hydrolyzate area percentages (%) are 100% in total. It is a value calculated as follows.
- the substrate is N-benzyloxycarbonyl-N- ⁇ (2-cyclopropylaminocarbonyl) ethyl ⁇ aminoacetate ethyl
- the target is benzyl 3- (cyclopropylcarbamoyl) -4-oxopyrrolidine-1-carboxylate
- the hydrolyzed product refers to N-benzyloxycarbonyl-N- ⁇ (2-cyclopropylaminocarbonyl) ethyl ⁇ aminoacetic acid, respectively.
- Example 30 Benzyl 3- (cyclopropylcarbamoyl) -4-oxopyrrolidine-1-carboxylate N-benzyloxycarbonyl-N- ⁇ (2-cyclopropylaminocarbonyl) ethyl ⁇ aminoethyl acetate (200 mg, 0.574 mmol) in toluene ( 2.0 mL) was added potassium tert-butoxide (136 mg, 1.21 mmol) as a base at an external temperature setting of 40 ° C., and the mixture was stirred for 2 hours. Subsequently, HPLC measurement of this reaction liquid was performed. The results are shown in Table 5.
- Example 31 to Example 40 In the same manner as in Example 30, the mixture was stirred at an external temperature setting of 40 ° C. for 0.5 to 7 hours using the base described in Table 5 (2.1 equivalents) and the solvent (10 times the amount). Subsequently, HPLC measurement of this reaction liquid was performed. The results are shown in Table 5.
- the target product could be obtained by the reaction in Step B (Examples 30 to 40).
- the base potassium tert-butoxide, sodium tert-butoxide, potassium hexamethyldisilazide, sodium hexamethyldisilazide, lithium hexamethyldisilazide, sodium hydride or sodium tert-pentoxide is used as the base.
- disassembly was a by-product, the reaction could be completed (Examples 30, 31, 33 to 36, 40).
- Example 41 Benzyl 3- (cyclopropylcarbamoyl) -4-oxopyrrolidine-1-carboxylate N-benzyloxycarbonyl-N- ⁇ (2-cyclopropylaminocarbonyl) ethyl ⁇ aminoethyl acetate (500 mg, 1.44 mmol) in toluene ( To the 5.0 mL) solution, a 1.7 mol / L toluene solution (2.6 mL, 4.46 mmol) of potassium tert-pentoxide was added at an external temperature setting of 40 ° C., and the mixture was stirred for 2 hours.
- reaction solution was ice-cooled, 2 mol / L hydrochloric acid (10 mL) and ethyl acetate (20 mL) were added, and the organic layer was separated. Ethyl acetate (20 mL) was added to the aqueous layer, the organic layer was separated, the organic layers were combined, and washed with saturated brine (20 mL).
- the extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
- Example 42 to Example 45 In the same manner as in Example 41, the reaction was carried out for 0.5 to 1 hour at the equivalent (1.1 to 3.1 equivalent) potassium tert-pentoxide listed in Table 6 and the reaction temperature (30 to 60 ° C). The reaction was evaluated using HPLC. The results are shown in Table 6.
- Reaction conversion rate (%) syn body + anti body / (substrate + syn body + anti body) ⁇ 100
- the substrate is benzyl 3- (cyclopropylcarbamoyl) -4-oxopyrrolidine-1-carboxylate, and the syn form is benzyl (3R, 4R) -3- (cyclopropylcarbamoyl) -4-hydroxypyrrolidine-1-carboxylate , Its enantiomers and mixtures thereof, and anti isomer refer to benzyl (3S, 4R) -3- (cyclopropylcarbamoyl) -4-hydroxypyrrolidine-1-carboxylate, its enantiomers and mixtures thereof, respectively .
- (3R, 4S) form is (3R, 4S) -3- (cyclopropylcarbamoyl) -4-hydroxypyrrolidine-1-carboxylate benzyl
- (3R, 4R) form is (3R, 4R) -3- ( Cyclopropylcarbamoyl) -4-hydroxypyrrolidine-1-carboxylate
- (3S, 4S) form is (3S, 4S) -3- (cyclopropylcarbamoyl) -4-hydroxypyrrolidine-1-carboxylate
- 3S, 4R) refers to benzyl (3S, 4R) -3- (cyclopropylcarbamoyl) -4-hydroxypyrrolidine-1-carboxylate, respectively.
- Example 46 Catalyst (dichlorobenzene ruthenium (II) dimer, 0.5 mol%), benzyl 3- (cyclopropylcarbamoyl) -4-oxopyrrolidine-1-carboxylate, asymmetric ligand [(S)-( ⁇ )-BINAP 1.0 mol%] and solvent (dichloromethane, 7.5 volumes).
- the mixture was replaced with hydrogen, hydrogen pressure (0.5-0.6 MPa) was added, and the mixture was stirred at an external temperature of about 60 ° C. for 8 hours.
- the reaction solution was subjected to HPLC measurement. The results are shown in Table 7.
- Example 47 to 55 Comparative Examples 1 and 2
- the reaction was carried out for 6 to 10 hours using the solvents described in Table 7 (7.5 times the amount). The results are shown in Table 7.
- Example 56 In the same manner as in Example 46, the reaction was carried out for 6 to 10 hours at the hydrogen pressure and catalyst amount shown in Table 8. The results are shown in Table 8.
- Example 63 to 66 In the same manner as in Example 46, the reaction was carried out for 6 to 10 hours using the asymmetric ligands shown in Table 9. The results are shown in Table 9.
- Example 67 Catalyst (dichlorobenzene ruthenium (II) dimer, 0.5 mol%), benzyl 3- (cyclopropylcarbamoyl) -4-oxopyrrolidine-1-carboxylate, asymmetric ligand [(S)-( ⁇ )-BINAP 1.0 mol%] and a solvent (toluene, 7.5 times amount).
- the mixture was replaced with hydrogen, hydrogen pressure (0.5-0.6 MPa) was added, and the mixture was stirred at an external temperature of about 55 ° C. for 8 hours.
- the reaction solution was subjected to HPLC measurement. The results are shown in Table 10.
- Example 68 to 70 The reaction was conducted in the same manner as in Example 68 at the temperature shown in Table 10 for 6 to 10 hours. The results are shown in Table 10.
- tert-butyl acrylate 250 g, 1.95 mol was added dropwise to the mixture at an internal temperature of 63 ° C. to 64 ° C., and the mixture was stirred at an internal temperature of 63 ° C. to 64 ° C. for 1 hour.
- the mixture was cooled to an internal temperature of 30 ° C. and allowed to stand overnight.
- the mixture was reheated and stirred at an internal temperature of 55 ° C. to 64 ° C. for 2 hours.
- the mixture was cooled to an internal temperature of 30 ° C., 3% sodium hydrogen carbonate (5 L) was added, and the mixture was extracted with ethyl acetate (5 L), and the organic layer was separated.
- a sodium hydrogen carbonate solution (sodium hydrogen carbonate 328 g (3.90 mol) dissolved in 6.5 L of water) was added at an internal temperature of 25 ° C. to 30 ° C., and benzyl chloroformate (557 mL, 3.90 mol). was added dropwise at an internal temperature of 29 ° C. to 36 ° C. and stirred at an internal temperature of 30 ° C. to 33 ° C. for 2 hours.
- the reaction solution was cooled to an internal temperature of 24 ° C., and the organic layer was separated. The organic layer was washed successively with 0.5 mol / L hydrochloric acid (2.5 L) and 5% brine (2.5 L), and concentrated under reduced pressure to give 1329 g of the title compound as a reddish brown oil.
- reaction solution was cooled and 5% saline (10 L) was added, followed by extraction with a toluene / DME (4: 1) mixture (10 L). 20% potassium hydrogen carbonate (5 L) was added to the organic layer, and the aqueous layer was separated. To the aqueous layer was added 6 mol / L hydrochloric acid (2 L) at an internal temperature of 10 ° C. to 11 ° C. to adjust the pH to around 1, and the mixture was extracted with a toluene / DME (4: 1) mixture (7 L). The organic layer was separated, washed with water (3.5 L), and concentrated under reduced pressure. Toluene (1.5 L) was added to the concentrated residue and concentrated under reduced pressure to obtain 796 g of the title compound as a brown oil.
- the reaction liquid was cooled to an internal temperature of 17 ° C., water (8 L) and toluene (8 L) were added and extracted by stirring, and the organic layer was separated.
- the organic layer was washed successively with 1 mol / L hydrochloric acid (4 L) and water (2 L), and concentrated under reduced pressure.
- Toluene (1.5 L) was added to the concentrated residue and concentrated under reduced pressure.
- Acetone (0.5 L) and diisopropyl ether (14.5 L) were added to the concentrated residue, the mixture was heated, crystallized at an internal temperature of 35 ° C., and then stirred at an internal temperature of 30 ° C. to 33 ° C. for 0.5 hour.
- the mixture was gradually cooled and then stirred at an internal temperature of 5 ° C. to 9 ° C. for 0.5 hour.
- the precipitated crystals were collected by filtration and washed with diisopropyl ether (2.5 L).
- the wet crystals were dried under reduced pressure overnight at 40 ° C. to obtain 689 g (yield 51%, 4 steps) of the title compound as fine yellowish white crystals.
- Toluene (6 L) was added to ethyl N-benzyloxycarbonyl-N- ⁇ (2-cyclopropylaminocarbonyl) ethyl ⁇ aminoacetate (600 g, 1.72 mol) synthesized by the method of Example 72, and then the mixture was mixed.
- a 1.7 mol / L toluene solution (1.11 L, 1.89 mol) of potassium tert-pentoxide was added dropwise at an internal temperature of 46 ° C. to 48 ° C., and the mixture was stirred at an internal temperature of 48 ° C. to 49 ° C. for 2 hours.
- 1 mol / L hydrochloric acid (2.1 L) was added dropwise at an internal temperature of 4 ° C. to 7 ° C. to adjust the pH to 1.2 (pH meter).
- the reaction conversion rate is measured by HPLC measurement using the following measurement condition G, and the obtained area percentages (%) of the substrate, syn isomer and anti isomer are 100% in total, as follows: This is the calculated value.
- Reaction conversion rate (%) syn body + anti body / (substrate + syn body + anti body) ⁇ 100
- the substrate is 4-oxopyrrolidine-1,3-dicarboxylic acid-1-benzyl-3-ethyl ester
- the target is anti- (3R, 4S) -4-hydroxypyrrolidine-1,3-dicarboxylic acid-1. -Refers to benzyl-3-ethyl ester, respectively.
- (3R, 4S) is (3R, 4S) -4-hydroxypyrrolidine-1,3-dicarboxylic acid-1-benzyl-3-ethyl ester
- (3R, 4R) is (3R, 4R) -4 -Hydroxypyrrolidine-1,3-dicarboxylic acid-1-benzyl-3-ethyl ester
- (3S, 4S) form is (3S, 4S) -4-hydroxypyrrolidine-1,3-dicarboxylic acid-1-benzyl-
- Reference Examples 3 to 7 are conventional techniques described in International Publication No. 2007/102567, which are asymmetric hydrogenation reactions of 4-oxopyrrolidine-1,3-dicarboxylic acid-1-benzyl-3-ethyl ester. . It can be seen that when the hydrogen pressure is lowered to 0.5 to 0.6 MPa, the reaction conversion rate decreases (Reference Example 3).
- the reaction proceeds without decreasing the reaction conversion rate even at a pressure of 0.5 to 0.6 MPa or lower.
- the reaction under high-pressure conditions is industrially unsuitable and has a high risk of explosion, so the present invention can be said to be more useful than the conventional technology.
- Reference Examples 8 to 10 are conventional techniques described in International Publication No. 2007/102567 and are asymmetric hydrogenation reactions of 4-oxopyrrolidine-1,3-dicarboxylic acid 1-benzyl 3-ethyl ester. . It can be seen that when the amount of the catalyst is reduced to 1 mol%, the reaction conversion rate decreases (Reference Example 10).
- the present invention is a key intermediate for producing a high-quality (3R, 4S) -3-alkylaminomethyl-4-fluoropyrrolidine optically active substance or enantiomer thereof useful as a pharmaceutical production intermediate.
- An optically active form of an anti- (3S, 4R) -3-alkylcarbamoyl-4-hydroxypyrrolidine derivative or an enantiomer thereof can be advantageously produced industrially and is useful.
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Abstract
Description
[1](工程A)一般式(I)で示される4-オキソピロリジン-3-カルボン酸アミド誘導体を、光学活性触媒を用いて不斉水素化することにより一般式(II)で示される光学活性なanti-4-ヒドロキシピロリジン-3-カルボン酸アミド誘導体またはその鏡像異性体を製造する方法。
[2]以下の工程Bおよび工程Aを含む一般式(II)で示される光学活性なanti-4-ヒドロキシピロリジン-3-カルボン酸アミド誘導体またはその鏡像異性体の製造方法。
(工程B)一般式(III)で示される化合物を、アルカリ金属の炭酸塩、アルカリ金属アミド、アルカリ金属の水素化物およびアルカリ金属アルコキシドから選ばれる少なくとも1種の塩基で処理することにより、一般式(I)で示される4-オキソピロリジン-3-カルボン酸アミド誘導体を得る工程
(工程A)工程Bで得られた一般式(I)で示される化合物を、光学活性触媒を用いて不斉水素化することにより一般式(II)で示される化合物またはその鏡像異性体を得る工程
[3]以下の工程D~Aを含む、一般式(II)で示される光学活性なanti-4-ヒドロキシピロリジン-3-カルボン酸アミド誘導体またはその鏡像異性体の製造方法。
(工程D)一般式(IV)で示される化合物を、酸で処理することにより、一般式(V)で示される化合物を得る工程
(工程C)工程Dで得られた一般式(V)で示される化合物と、一般式(VI)で示されるアミンを縮合することにより一般式(III)で示される化合物を得る工程
(工程B)工程Cで得られた一般式(III)で示される化合物を、アルカリ金属の炭酸塩、アルカリ金属アミド、アルカリ金属の水素化物およびアルカリ金属アルコキシドから選ばれる少なくとも1種の塩基で処理することにより、一般式(I)で示される4-オキソピロリジン-3-カルボン酸アミド誘導体を得る工程
(工程A)工程Bで得られた一般式(I)で示される化合物を、光学活性触媒を用いて不斉水素化することにより一般式(II)で示される化合物またはその鏡像異性体を得る工程
[4]工程Aにおいて、光学活性触媒が不斉配位子を有する光学活性ルテニウム触媒である、[1]~[3]のいずれか1に記載の製造方法。
[5]工程Aにおいて、光学活性触媒における不斉配位子が、光学活性な2,2’-ビス(ジフェニルホスフィノ)-1,1’-ビナフチル(BINAP)若しくはその類縁体、5,5’-ビス(ジフェニルホスフィノ)-4,4’-ビ-1,3-ベンゾジオキソール(SEGPHOS)若しくはその類縁体、または(2,2’-ビスジフェニルフォスフィノ)-6,6’-ジメトキシ-1,1’-ビフェニル(MeO-BIPHEP)若しくはその類縁体である、[1]~[4]のいずれか1に記載の製造方法。
[6]工程Aにおいて、光学活性触媒における不斉配位子が2,2’-ビス(ジフェニルホスフィノ)-1,1’-ビナフチル(BINAP)または5,5’-ビス(ジフェニルホスフィノ)-4,4’-ビ-1,3-ベンゾジオキソール(SEGPHOS)である、[1]~[5]のいずれか1に記載の製造方法。
[7]PG1で示されるアミノ基の保護基がアラルコキシカルボニル基またはアルコキシカルボニル基である[1]~[6]のいずれか1に記載の製造方法。
[8]PG1で示されるアミノ基の保護基がアラルコキシカルボニル基である[1]~[7]のいずれか1に記載の製造方法。
[9]PG1で示されるアミノ基の保護基がベンジルオキシカルボニル基である[1]~[8]のいずれか1に記載の製造方法。
[10]R1がシクロプロピル基である、[1]~[9]のいずれか1に記載の製造方法。
[11]工程Aにおいて、水素圧が常圧~1MPa未満の条件下で反応を行うことを特徴とする[1]~[10]のいずれか1に記載の製造方法。
[12]工程Aにおいて、一般式(I)に対し、光学活性触媒を0.01~2mol%用いることを特徴とする、[1]~[11]のいずれか1に記載の製造方法。
[13]工程Aにおいて、一般式(I)に対し、光学活性触媒を0.01~1mol%用いることを特徴とする、[1]~[12]のいずれか1に記載の製造方法。
[14]光学活性触媒を用いて不斉水素化するための一般式(I)で示される化合物の製造方法であり、
(工程B)一般式(III)で示される化合物を、アルカリ金属の炭酸塩、アルカリ金属アミド、アルカリ金属の水素化物およびアルカリ金属アルコキシドから選ばれる塩基で処理することにより、一般式(I)で示される4-オキソピロリジン-3-カルボン酸アミド誘導体を製造する方法。
[15]工程Bにおいて、塩基がアルカリ金属アルコキシドであることを特徴とする[2]~[14]のいずれか1に記載の製造方法。
[16]工程Bにおいて、塩基がカリウムtert-ペントキシドであることを特徴とする[2]~[15]のいずれか1に記載の製造方法。
[17]工程Bにおいて、一般式(III)で示される化合物に対し、塩基を1~1.5当量用いることをと特徴とする[2]~[16]のいずれか1に記載の製造方法。
[18]PG1で示されるアミノ基の保護基がアラルコキシカルボニル基であり、R1がシクロプロピル基である、[1]~[17]のいずれか1に記載の製造方法。
[19](工程D)一般式(IV)で示される化合物を、酸で処理することにより、一般式(V)で示される化合物を得る製造方法。
[20]工程Dにおいて、酸がトリフルオロ酢酸またはギ酸であることを特徴とする[3]~[13]および[19]のいずれか1に記載の製造方法。
[21]工程Dにおいて、酸がギ酸であることを特徴とする[3]~[13]および[19]~[20]のいずれか1に記載の製造方法。
[22]PG1で示されるアミノ基の保護基がアラルコキシカルボニル基であり、R2がC1~C4の低級アルキル基である、[2]~[21]のいずれか1に記載の製造方法。
工程Dは一般式(IV)で示されるジエステル化合物の片方のエステル基(tert-ブチルエステル基)を、酸を加えることによりエステル開裂を行い、モノカルボン酸化合物(V)を得る工程である。
工程Cは一般式(V)で示されるモノカルボン酸化合物に、一般式(VI)で示されるアミンを縮合し、一般式(III)で示されるアミド化合物を得る工程である。縮合反応は一般的に用いられる縮合条件を用いることができる。
工程Bは、一般式(III)で示されるアミド化合物を、塩基で処理することにより、一般式(I)で示される4-オキソピロリジン-3-カルボン酸アミド誘導体を得る工程である。
工程Aは、4-オキソピロリジン-3-カルボン酸アミド誘導体のラセミ体(I)を、光学活性触媒を用いて不斉水素化することにより、anti-(3S,4R)-4-ヒドロキシピロリジン-3-カルボン酸アミド誘導体の光学活性体(II)またはその鏡像異性体を得る工程である。
3-{N-ベンジルオキシカルボニル-N-(エトキシカルボニルメチル)アミノ}プロピオン酸tert-ブチル
グリシンエチルエステル塩酸塩(163g,1.17mol)に、2-プロパノールと水の3:1混合溶媒(600mL)を投入した後加温し、内温59℃でトリエチルアミン(174mL,1.25mol)を加えた。混合液にアクリル酸tert-ブチル(50.0g,0.390mol)を内温60℃~62℃で滴下し、内温60℃~62℃で2時間撹拌した。さらに、混合液にアクリル酸tert-ブチル(50.0g,0.390mol)を内温62℃~63℃で滴下し、内温60℃~62℃で5時間撹拌した。
カラム;化学物質評価研究機構 CERI L-column2 ODS,4.6φ×150mm、3μm)、プレカラム:化学物質評価研究機構 CERI L-column2 ODS,4.0φ×10mm、移動相:A液 メタノール、B液 リン酸塩緩衝液(pH6.9)、0~5分;A:B=53:47(アイソクラティック)、5~15分;A:B=53:47→75:25(リニアグラジエント)、15~40分;A:B=75:25(アイソクラティック)、測定波長:210nm、カラム温度:40℃、流量:0.80mL/min.
保持時間:基質;32分付近、目的物;6分付近
カラム;ジーエルサイエンス Inertsil ODS-3(4.6φ×150mm)、プレカラム;ジーエルサイエンス Inertsil ODS-3(4.0φ×10mm)、移動相;A液 アセトニトリル、B液 薄めたリン酸(1→1000)溶液、0~25分;A:B=60:40(アイソクラティック)、測定波長:210nm、カラム温度:40℃、流量:1.0mL/min.
保持時間:基質;3分付近、目的物;14分付近
3-{N-ベンジルオキシカルボニル-N-(エトキシカルボニルメチル)アミノ}プロピオン酸
3-{N-ベンジルオキシカルボニル-N-(エトキシカルボニルメチル)アミノ}プロピオン酸tert-ブチル(500mg,1.37mmol)にギ酸(2.5mL,66.3mmol)を加え、外温設定40℃で3時間撹拌した。放冷後、反応液に酢酸エチル(10mL)および水(10mL)を加え、有機層を分取した。水層に酢酸エチル(10mL)を加え有機層を分取後、有機層を合一し、飽和食塩水(10mL)で洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。得られた濃縮残渣を減圧下、室温で乾燥することで無色油状物の表題化合物を421mg(収率99%)得た。
3-{N-ベンジルオキシカルボニル-N-(エトキシカルボニルメチル)アミノ}プロピオン酸tert-ブチルを用いて、表1に記載の条件で反応を実施し、この反応液のHPLC測定を行った。その結果を表1に示す。
カラム;ジーエルサイエンス Inertsil ODS-3(4.6φ×150mm)、プレカラム;ジーエルサイエンス Inertsil ODS-3(4.0φ×10mm)、移動相;A液 アセトニトリル、B液 薄めたリン酸(1→1000)溶液、0~25分; A:B=60:40(アイソクラティック)、測定波長:210nm、カラム温度:40℃、流量:1.0mL/min.
保持時間:基質;22分付近、目的物;25分付近
N-ベンジルオキシカルボニル-N-{(2-シクロプロピルアミノカルボニル)エチル}アミノ酢酸エチル
3-{N-ベンジルオキシカルボニル-N-(エトキシカルボニルメチル)アミノ}プロピオン酸(866mg,2.83mmol相当)にTHF(17mL)を加えて溶解した。HOBt・H2O(521mg,3.40mmol)、シクロプロピルアミン(0.49mL,7.08mmol)およびEDCI・HCl(652mg,3.40mmol)を順次加え、室温で1時間撹拌した。
実施例8と同様の方法で、表2に示す量のシクロプロピルアミン(1.1~2.5当量)、HOBt・H2O(0~1.2当量)、反応溶媒はTHF/DMFまたは2-MeTHF/DMFの2:1混合溶媒(20倍量)を使用して反応を室温で行った。
3-{N-ベンジルオキシカルボニル-N-(エトキシカルボニルメチル)アミノ}プロピオン酸(100mg,0.311mmol相当)にTHF(0.5mL)を加えて溶解した。HOBt・H2O(2.39mg,0.0156mmol)、表3に示す塩基(1.1当量)、シクロプロピルアミン(23.7μL,0.342mmol)およびEDCI・HCl(71.5mg,0.373mmol)を順次加え、外温設定40℃で1時間撹拌した。次いで、この反応液のHPLC測定を行った。その結果を表3に示す。
3-{N-ベンジルオキシカルボニル-N-(エトキシカルボニルメチル)アミノ}プロピオン酸(100mg,0.311mmol相当)に表4に示す溶媒(0.5mL)を加えて溶解した。HOBt・H2O(2.39mg,0.0156mmol)、トリエチルアミン(47.4μL,0.342mmol)、シクロプロピルアミン(23.7μL,0.342mmol)およびEDCI・HCl(71.5mg,0.373mmol)を順次加え、外温設定40℃で1~4.5時間撹拌した。この反応液のHPLC測定を行った。その結果を表4に示す。
カラム;ジーエルサイエンス Inertsil ODS-3(4.6φ×150mm)、プレカラム;ジーエルサイエンス Inertsil ODS-3(4.0φ×10mm)、移動相;A液 アセトニトリル、B液 薄めたリン酸(1→1000)溶液、0~25分; A:B=38:62(アイソクラティック)、測定波長:210nm、カラム温度:40℃、流量:1.0mL/min.
保持時間:基質;21分付近、目的物;13分付近、加水分解体;6分付近
3-(シクロプロピルカルバモイル)-4-オキソピロリジン-1-カルボン酸ベンジル
N-ベンジルオキシカルボニル-N-{(2-シクロプロピルアミノカルボニル)エチル}アミノ酢酸エチル(200mg,0.574mmol)のトルエン(2.0mL)溶液に、外温設定40℃で、塩基としてカリウムtert-ブトキシド(136mg,1.21mmol)を加え2時間撹拌した。次いで、この反応液のHPLC測定を行った。その結果を表5に示す。
実施例30と同様の方法で、表5に記載の塩基(2.1当量)、溶媒(10倍量)を使用して外温設定40℃で0.5~7時間撹拌した。次いで、この反応液のHPLC測定を行った。その結果を表5に示す。
3-(シクロプロピルカルバモイル)-4-オキソピロリジン-1-カルボン酸ベンジル
N-ベンジルオキシカルボニル-N-{(2-シクロプロピルアミノカルボニル)エチル}アミノ酢酸エチル(500mg,1.44mmol)のトルエン(5.0mL)溶液に、外温設定40℃でカリウムtert-ペントキシドの1.7mol/Lトルエン溶液(2.6mL,4.46mmol)を加え2時間撹拌した。
実施例41と同様の方法で,表6に記載のカリウムtert-ペントキシドの当量(1.1~3.1当量)、反応温度(30℃~60℃)で0.5~1時間反応を行い、HPLCを用いて反応評価を行った。その結果を表6に示す。
カラム;ジーエルサイエンス Inertsil ODS-3(4.6φ×150mm、3μm)、プレカラム;ジーエルサイエンス Inertsil ODS-3(4.0φ×10mm)、移動相;A液 メタノール、B液 5mmol 1-オクタンスルホン酸ナトリウム含有薄めたリン酸(1→1000)溶液、0~30分; A:B=42:58(アイソクラティック)、測定波長:215nm、カラム温度:40℃、流量:0.80mL/min.
保持時間:基質;22分付近、syn体;15分付近、anti体;16分付近.
カラム;ダイセル化学工業 Chiralpak AD-RH(4.6φ×150mm)およびダイセル化学工業 Chiralpak AD-3R(4.6φ×150mm)を連結、プレカラム;ジーエルサイエンス Inertsil ODS-3(4.0φ×10mm)、移動相;A液 アセトニトリル、B液 薄めたリン酸(1→1000)溶液、0~30分;A:B=25:75(アイソクラティック)、測定波長:215nm、カラム温度:40℃、流量:1.0mL/min.
保持時間:(3R,4S)体;12分付近、(3S,4S)体;16分付近、(3R,4R)体;20分付近、(3S,4R)体;20分付近.
3-(シクロプロピルカルバモイル)-4-オキソピロリジン-1-カルボン酸ベンジルに触媒(ジクロロベンゼンルテニウム(II)ダイマー、0.5mol%)、不斉配位子[(S)-(-)-BINAP、1.0mol%]および溶媒(ジクロロメタン、7.5倍量)を加えた。混合物を水素置換し、水素圧(0.5-0.6MPa)を加え、外温60℃付近で8時間撹拌した。この反応液のHPLC測定を行った。その結果を表7に示す。
実施例46と同様の方法で、表7に記載の溶媒(7.5倍量)を使用して反応を6~10時間行った。その結果を表7に示す。
実施例46と同様の方法で、表8に記載の水素圧および触媒量で反応を6~10時間行った。その結果を表8に示す。
実施例46と同様の方法で、表9に記載の不斉配位子を用いて反応を6~10時間行った。その結果を表9に示す。
3-(シクロプロピルカルバモイル)-4-オキソピロリジン-1-カルボン酸ベンジルに触媒(ジクロロベンゼンルテニウム(II)ダイマー、0.5mol%)、不斉配位子[(S)-(-)-BINAP、1.0mol%]および溶媒(トルエン、7.5倍量)を加えた。混合物を水素置換し、水素圧(0.5-0.6MPa)を加え、外温55℃付近で8時間撹拌した。この反応液のHPLC測定を行った。その結果を表10に示す。
実施例68と同様の方法で、表10に記載の温度で反応を6~10時間行った。その結果を表10に示す。
3-{N-ベンジルオキシカルボニル-N-(エトキシカルボニルメチル)アミノ}プロピオン酸tert-ブチル
3-{N-ベンジルオキシカルボニル-N-(エトキシカルボニルメチル)アミノ}プロピオン酸
N-ベンジルオキシカルボニル-N-{(2-シクロプロピルアミノカルボニル)エチル}アミノ酢酸エチル
3-(シクロプロピルカルバモイル)-4-オキソピロリジン-1-カルボン酸ベンジル
(3S,4R)-3-(シクロプロピルカルバモイル)-4-ヒドロキシピロリジン-1-カルボン酸ベンジル
1H NMR(CDCl3,400MHz) δ: 0.45-0.77(2H,m),0.69-0.77(2H,m),2.63-2.82(2H,m),3.19-3.29(1H,m),3.49-3.85(3H,m),3.91-4.15(1H,m),4.35-4.49(1H,m),5.10(2H,s),6.57(1H,d,J=15.9Hz),7.26-7.37(5H,m).
カラム;ジーエルサイエンス Inertsil ODS-3(4.6 φ×150mm)、プレカラム;ジーエルサイエンス Inertsil ODS-3(4.0φ×10mm)、移動相;A液 薄めたリン酸(1→1000)溶液、B液 アセトニトリル、0~30分;A:B=50:50(アイソクラティック)、測定波長:210nm、カラム温度:30℃、流量:1.0mL/min.保持時間:目的物;4分付近、原料;7分付近
カラム;ダイセル化学工業 Chiralcel AD-RH(4.6 φ×150mm)、プレカラム;ジーエルサイエンス Inertsil ODS-3(4.0φ×10mm)、移動相;A液 薄めたリン酸(1→1000)溶液、B液 アセトニトリル、0~30分;A:B=80:20(アイソクラティック)、測定波長:210nm、カラム温度:50℃、流量:1.0mL/min.保持時間:目的物;23分付近、鏡像体;18分付近,ジアステレオマー;23分および28分付近.
ジクロロベンゼンルテニウム(II)ダイマー(172mg,0.34mmol)、(S)-(-)-BINAP(428mg,0.69mmol)およびジクロロメタン(3.7mL)を加え、外温60℃~65℃で0.5時間撹拌し、その後室温付近の温度まで冷却した。
ジクロロベンゼンルテニウム(II)ダイマー、(S)-(-)-BINAPおよびジクロロメタン(3.7mL)を加え、外温60℃~65℃で0.5時間撹拌し、その後室温付近の温度まで冷却した。混合物に、4-オキソピロリジン-1,3-ジカルボン酸-1-ベンジル-3-エチルエステル(5.0g,17.2mmol)およびジクロロメタン(15mL)をアルゴン雰囲気下で加え、2.0-2.5MPaの水素加圧下、内温60℃~65℃で8時間撹拌した。この反応液のHPLC測定を行った。その結果を表12に示す。
本出願は、2010年10月25日出願の日本特許出願2010-238077に基づくものであり、その内容はここに参照として取り込まれる。
Claims (22)
- 以下の工程Bおよび工程Aを含む一般式(II)で示される光学活性なanti-4-ヒドロキシピロリジン-3-カルボン酸アミド誘導体またはその鏡像異性体の製造方法。
(工程B)一般式(III)で示される化合物を、アルカリ金属の炭酸塩、アルカリ金属アミド、アルカリ金属の水素化物およびアルカリ金属アルコキシドから選ばれる少なくとも1種の塩基で処理することにより、一般式(I)で示される4-オキソピロリジン-3-カルボン酸アミド誘導体を得る工程
(工程A)工程Bで得られた一般式(I)で示される化合物を、不斉配位子を有する光学活性触媒を用いて不斉水素化することにより一般式(II)で示される化合物またはその鏡像異性体を得る工程
- 以下の工程D~Aを含む、一般式(II)で示される光学活性なanti-4-ヒドロキシピロリジン-3-カルボン酸アミド誘導体またはその鏡像異性体の製造方法。
(工程D)一般式(IV)で示される化合物を、酸で処理することにより、一般式(V)で示される化合物を得る工程
(工程C)工程Dで得られた一般式(V)で示される化合物と、一般式(VI)で示されるアミンを縮合することにより一般式(III)で示される化合物を得る工程
(工程B)工程Cで得られた一般式(III)で示される化合物を、アルカリ金属の炭酸塩、アルカリ金属アミド、アルカリ金属の水素化物およびアルカリ金属アルコキシドから選ばれる少なくとも1種の塩基で処理することにより、一般式(I)で示される4-オキソピロリジン-3-カルボン酸アミド誘導体を得る工程
(工程A)工程Bで得られた一般式(I)で示される化合物を、不斉配位子を有する光学活性触媒を用いて不斉水素化することにより一般式(II)で示される化合物またはその鏡像異性体を得る工程
- 工程Aにおいて、光学活性触媒が不斉配位子を有する光学活性ルテニウム触媒である、請求項1~3のいずれか一項に記載の製造方法。
- 工程Aにおいて、光学活性触媒における不斉配位子が、光学活性な2,2’-ビス(ジフェニルホスフィノ)-1,1’-ビナフチル(BINAP)若しくはその類縁体、5,5’-ビス(ジフェニルホスフィノ)-4,4’-ビ-1,3-ベンゾジオキソール(SEGPHOS)若しくはその類縁体、または(2,2’-ビスジフェニルフォスフィノ)-6,6’-ジメトキシ-1,1’-ビフェニル(MeO-BIPHEP)若しくはその類縁体である、請求項1~4のいずれか一項に記載の製造方法。
- 工程Aにおいて、光学活性触媒における不斉配位子が2,2’-ビス(ジフェニルホスフィノ)-1,1’-ビナフチル(BINAP)または5,5’-ビス(ジフェニルホスフィノ)-4,4’-ビ-1,3-ベンゾジオキソール(SEGPHOS)である、請求項1~5のいずれか一項に記載の製造方法。
- PG1で示されるアミノ基の保護基がアラルコキシカルボニル基またはアルコキシカルボニル基である請求項1~6のいずれか一項に記載の製造方法。
- PG1で示されるアミノ基の保護基がアラルコキシカルボニル基である請求項1~7のいずれか一項に記載の製造方法。
- PG1で示されるアミノ基の保護基がベンジルオキシカルボニル基である請求項1~8のいずれか一項に記載の製造方法。
- R1がシクロプロピル基である、請求項1~9のいずれか一項に記載の製造方法。
- 工程Aにおいて、水素圧が常圧~1MPa未満の条件下で反応を行うことを特徴とする請求項1~10のいずれか一項に記載の製造方法。
- 工程Aにおいて、一般式(I)に対し、光学活性触媒を0.01~2mol%用いることを特徴とする、請求項1~11のいずれか一項に記載の製造方法。
- 工程Aにおいて、一般式(I)に対し、光学活性触媒を0.01~1mol%用いることを特徴とする、請求項1~12のいずれか一項に記載の製造方法。
- 工程Bにおいて、塩基がアルカリ金属アルコキシドであることを特徴とする請求項2~14のいずれか一項に記載の製造方法。
- 工程Bにおいて、塩基がカリウムtert-ペントキシドであることを特徴とする請求項2~15のいずれか一項に記載の製造方法。
- 工程Bにおいて、一般式(III)で示される化合物に対し、塩基を1~1.5当量用いることをと特徴とする請求項2~16のいずれか一項に記載の製造方法。
- PG1で示されるアミノ基の保護基がアラルコキシカルボニル基であり、R1がシクロプロピル基である、請求項1~17のいずれか一項に記載の製造方法。
- 工程Dにおいて、酸がトリフルオロ酢酸またはギ酸であることを特徴とする請求項3~13および請求項19のいずれか一項に記載の製造方法。
- 工程Dにおいて、酸がギ酸であることを特徴とする請求項3~13および請求項19~20のいずれか一項に記載の製造方法。
- PG1で示されるアミノ基の保護基がアラルコキシカルボニル基であり、R2がC1~C4の低級アルキル基である、請求項2~21のいずれか一項に記載の製造方法。
Priority Applications (11)
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JP2012540851A JP5844739B2 (ja) | 2010-10-25 | 2011-10-24 | 3,4−二置換ピロリジン誘導体の製造方法 |
AU2011321551A AU2011321551A1 (en) | 2010-10-25 | 2011-10-24 | Method for producing 3,4-disubstituted pyrrolidine derivative |
US13/880,207 US9108915B2 (en) | 2010-10-25 | 2011-10-24 | Method for producing 3,4-disubstituted pyrrolidine derivative |
EP11836226.8A EP2634172A4 (en) | 2010-10-25 | 2011-10-24 | METHOD FOR MANUFACTURING DISUBSTITUTED DERIVED DERIVATIVE 3, 4 |
SG2013029707A SG189469A1 (en) | 2010-10-25 | 2011-10-24 | Method for producing 3,4-disubstituted pyrrolidine derivative |
NZ609505A NZ609505A (en) | 2010-10-25 | 2011-10-24 | Method for producing 3,4-disubstituted pyrrolidine derivative |
BR112013010164A BR112013010164A2 (pt) | 2010-10-25 | 2011-10-24 | método para a produção de derivado de pirrolidina 3,4-dissubstituída |
KR1020137010603A KR20130143041A (ko) | 2010-10-25 | 2011-10-24 | 3,4-이치환 피롤리딘 유도체의 제조 방법 |
MX2013004403A MX2013004403A (es) | 2010-10-25 | 2011-10-24 | Metodo para producir derivados de pirrolidina 3,4-bisustituida. |
CN201180051578.4A CN103228628B (zh) | 2010-10-25 | 2011-10-24 | 制备3,4-双取代的吡咯烷衍生物的方法 |
CA2815952A CA2815952A1 (en) | 2010-10-25 | 2011-10-24 | Method for producing 3,4-disubstituted pyrrolidine derivative |
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US (1) | US9108915B2 (ja) |
EP (1) | EP2634172A4 (ja) |
JP (1) | JP5844739B2 (ja) |
KR (1) | KR20130143041A (ja) |
CN (1) | CN103228628B (ja) |
AU (1) | AU2011321551A1 (ja) |
BR (1) | BR112013010164A2 (ja) |
CA (1) | CA2815952A1 (ja) |
MX (1) | MX2013004403A (ja) |
NZ (1) | NZ609505A (ja) |
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WO2020230802A1 (ja) * | 2019-05-14 | 2020-11-19 | 杏林製薬株式会社 | 4-オキソピロリジン-3-カルボン酸アミド誘導体の製造方法 |
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2011
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- 2011-10-24 KR KR1020137010603A patent/KR20130143041A/ko not_active Application Discontinuation
- 2011-10-24 EP EP11836226.8A patent/EP2634172A4/en not_active Withdrawn
- 2011-10-24 NZ NZ609505A patent/NZ609505A/en not_active IP Right Cessation
- 2011-10-24 US US13/880,207 patent/US9108915B2/en not_active Expired - Fee Related
- 2011-10-24 MX MX2013004403A patent/MX2013004403A/es not_active Application Discontinuation
- 2011-10-24 WO PCT/JP2011/074463 patent/WO2012057093A1/ja active Application Filing
- 2011-10-24 SG SG2013029707A patent/SG189469A1/en unknown
- 2011-10-24 AU AU2011321551A patent/AU2011321551A1/en not_active Abandoned
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Cited By (1)
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WO2020230802A1 (ja) * | 2019-05-14 | 2020-11-19 | 杏林製薬株式会社 | 4-オキソピロリジン-3-カルボン酸アミド誘導体の製造方法 |
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AU2011321551A1 (en) | 2013-05-09 |
EP2634172A1 (en) | 2013-09-04 |
US9108915B2 (en) | 2015-08-18 |
EP2634172A4 (en) | 2014-01-29 |
KR20130143041A (ko) | 2013-12-30 |
JP5844739B2 (ja) | 2016-01-20 |
MX2013004403A (es) | 2013-05-22 |
NZ609505A (en) | 2014-11-28 |
BR112013010164A2 (pt) | 2016-07-05 |
CN103228628A (zh) | 2013-07-31 |
US20130217893A1 (en) | 2013-08-22 |
SG189469A1 (en) | 2013-05-31 |
CN103228628B (zh) | 2016-06-29 |
JPWO2012057093A1 (ja) | 2014-05-12 |
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