WO2014157653A1 - 光学活性ジアミン誘導体の製造方法 - Google Patents
光学活性ジアミン誘導体の製造方法 Download PDFInfo
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- WO2014157653A1 WO2014157653A1 PCT/JP2014/059247 JP2014059247W WO2014157653A1 WO 2014157653 A1 WO2014157653 A1 WO 2014157653A1 JP 2014059247 W JP2014059247 W JP 2014059247W WO 2014157653 A1 WO2014157653 A1 WO 2014157653A1
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- 0 C*C(C1CCCCC1)=O Chemical compound C*C(C1CCCCC1)=O 0.000 description 7
- KOPLGNIORBIYJV-CGTJXYLNSA-N CC(C)(C)OC(NS(N[C@H](C[C@H](CC1)C(N(C)C)=O)[C@@H]1OS(c1ccc(C)cc1)(=O)=O)(=O)=O)=O Chemical compound CC(C)(C)OC(NS(N[C@H](C[C@H](CC1)C(N(C)C)=O)[C@@H]1OS(c1ccc(C)cc1)(=O)=O)(=O)=O)=O KOPLGNIORBIYJV-CGTJXYLNSA-N 0.000 description 1
- HGVDHZBSSITLCT-JLJPHGGASA-N CN(C)C([C@@H](CC[C@@H]1NC(C(Nc(cc2)ncc2Cl)=O)=O)C[C@H]1NC(c1nc(CCN(C)C2)c2[s]1)=O)=O Chemical compound CN(C)C([C@@H](CC[C@@H]1NC(C(Nc(cc2)ncc2Cl)=O)=O)C[C@H]1NC(c1nc(CCN(C)C2)c2[s]1)=O)=O HGVDHZBSSITLCT-JLJPHGGASA-N 0.000 description 1
- HOTFAXDOHRWVLO-FHNOGEEDSA-N CN(C)C([C@@H](CC[C@H]12)C[C@@H]1N2S(NC(OCc1ccccc1)=O)(=O)=O)=O Chemical compound CN(C)C([C@@H](CC[C@H]12)C[C@@H]1N2S(NC(OCc1ccccc1)=O)(=O)=O)=O HOTFAXDOHRWVLO-FHNOGEEDSA-N 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- C07B53/00—Asymmetric syntheses
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- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/24—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/34—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfuric acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C307/00—Amides of sulfuric acids, i.e. compounds having singly-bound oxygen atoms of sulfate groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C307/04—Diamides of sulfuric acids
- C07C307/08—Diamides of sulfuric acids having nitrogen atoms of the sulfamide groups bound to carbon atoms of rings other than six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
- C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
- C07C309/66—Methanesulfonates
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/14—Thiadiazoles; Hydrogenated thiadiazoles condensed with carbocyclic rings or ring systems
Definitions
- the present invention relates to a method for producing an intermediate of a compound that exhibits an inhibitory action on activated blood coagulation factor X (FXa) and is useful as a preventive and / or therapeutic agent for thrombotic diseases.
- FXa activated blood coagulation factor X
- activated blood coagulation factor X (sometimes referred to as FXa (activated Factor X)] and is useful as a prophylactic and / or therapeutic agent for thrombotic diseases, for example, the following formula (X)
- a p-toluenesulfonic acid monohydrate of compound (X) represented by the formula is known (for example, see Patent Documents 1 to 4).
- Patent Document 6 discloses a method for producing a compound (X) that is an FXa inhibitor, a pharmacologically acceptable salt thereof, or a hydrate thereof.
- the production method of the compounds (X and Xa) disclosed in Patent Document 6 is obtained by converting a compound (A-6) that is a mesyloxy form from a compound (A-5).
- compound (A-7) which is an azide compound
- compound (A-7) to compound (1a) which is an amino compound, and then treat compound (1a) with oxalic acid.
- Patent Document 6 discloses that in the production of compound (X) which is an FXa inhibitor, compound (1a) and compound (1) which is an oxalate thereof are important as production intermediates.
- a compound (A-7) having an azide group with inherent danger is used as an intermediate.
- a hazardous reagent azide in large quantities as a reaction reagent, and the amino compound (1)
- Patent Document 6 a mixture of an amino compound (1a) and a trans-isomer compound (1a-trans) is treated with oxalic acid to give an acid addition salt with oxalic acid ( With 1), it is substantially obtained as a single cis-isomer.
- compound (1) and compound (1a) which are important intermediates in the production of compounds (X) and (Xa), which are FXa inhibitors. Only a method involving the point [(a) and (b)] via the compound (A-7) which is an azide form has been known (see, for example, Patent Documents 1 to 6).
- An object of the present invention is to provide an efficient production method of compound (1) or compound (1a), which is an important intermediate in the production of FXa inhibitors (X) and (Xa).
- the present invention can be used as a novel industrial production method for FXa inhibitors (X) and (Xa).
- R 1a represents a di (C1-C6 alkyl) amino group
- R 4 represents a C1-C6 alkyl group, a benzyl group (the benzene ring of the benzyl group has 1 to 2 selected from the group consisting of a C1-C6 alkyl group, a C1-C6 alkoxy group, a nitro group, and a halogen atom) May have one group as a substituent.
- a solution A is prepared by treating the compound represented by formula (II) with chlorosulfonyl isocyanate and a tertiary amine; [Reagent B] Following formula (II)
- R 4 is a C1-C6 alkyl group, a benzyl group (the benzene ring of the benzyl group is selected from the group consisting of a C1-C6 alkyl group, a C1-C6 alkoxy group, a nitro group, and a halogen atom) 1 to 2 groups which may be substituted as substituents);
- R 21 and R 22 represent the following (a), (b) or (c).
- A the same or different, a C1-C6 alkyl group
- R 22 represents a C1-C6 alkyl group, and two R 21 together with the nitrogen atom to which R 21 is bonded form a piperidine ring, a pyrrolidine ring or a 1,4-morpholine ring
- C Together with two R 21 and R 22 , and the nitrogen atom to which R 22 and R 21 are bonded, a 1,4-diazabicyclo [2.2.2] octane ring and a quinuclidine ring are formed.
- R 6 SO 2 X (III) [Wherein R 6 is a C1-C6 alkyl group, a halo C1-C6 alkyl group, a phenyl group (the phenyl group is composed of a C1-C6 alkyl group, a C1-C6 alkoxy group, a nitro group, and a halogen atom) 1 to 2 groups selected from the group may optionally be substituted); X represents a halogen atom. ]
- R 1a represents a di (C1-C6 alkyl) amino group.
- R 4 is a C1-C6 alkyl group, a benzyl group (the benzene ring of the benzyl group is selected from the group consisting of a C1-C6 alkyl group, a C1-C6 alkoxy group, a nitro group, and a halogen atom) 1 to 2 groups which may be substituted as substituents); R 1a has the same meaning as above.
- R 1a represents a di (C1-C6 alkyl) amino group.
- a compound represented by the following formula (5) is characterized by treating with the following [reagent B]:
- R 4 is a C1-C6 alkyl group, a benzyl group (the benzene ring of the benzyl group is selected from the group consisting of a C1-C6 alkyl group, a C1-C6 alkoxy group, a nitro group, and a halogen atom) 1 to 2 groups which may be substituted as substituents);
- R 21 and R 22 represent the following (a), (b) or (c).
- A the same or different, a C1-C6 alkyl group
- R 22 represents a C1-C6 alkyl group, and two R 21 together with the nitrogen atom to which R 21 is bonded form a piperidine ring, a pyrrolidine ring or a 1,4-morpholine ring
- C Together with two R 21 and R 22 , and the nitrogen atom to which R 22 and R 21 are bonded, a 1,4-diazabicyclo [2.2.2] octane ring and a quinuclidine ring are formed.
- a compound represented by [6] The production method according to [1] or [5], wherein R 21 and R 22 are ethyl groups. [7] The following formula (5)
- R 1a represents a di (C1-C6 alkyl) amino group
- R 4 represents a C1-C6 alkyl group, a benzyl group (the benzene ring of the benzyl group has 1 to 2 selected from the group consisting of a C1-C6 alkyl group, a C1-C6 alkoxy group, a nitro group, and a halogen atom) May have one group as a substituent.
- R 6 is a C1-C6 alkyl group, a halo C1-C6 alkyl group, a phenyl group (the phenyl group is composed of a C1-C6 alkyl group, a C1-C6 alkoxy group, a nitro group, and a halogen atom). 1 to 2 groups selected from the group may optionally be substituted); X represents a halogen atom.
- R 1a , R 4 and R 6 are as defined above.
- R 1a represents a di (C1-C6 alkyl) amino group
- R 4 represents a C1-C6 alkyl group, a benzyl group (the benzene ring of the benzyl group has 1 to 2 selected from the group consisting of a C1-C6 alkyl group, a C1-C6 alkoxy group, a nitro group, and a halogen atom)
- R 6 is a C1-C6 alkyl group, a halo C1-C6 alkyl group, a phenyl group (the phenyl group is selected from the group consisting of a C1-C6 alkyl group, a C1-C6 alkoxy group, a nitro group, and a halogen atom) It may have 1 to 2 groups as substituents).
- the compound represented by formula (8c) is characterized by treating with a base:
- R 1a represents a di (C1-C6 alkyl) amino group
- R 4 represents a C1-C6 alkyl group, a benzyl group (the benzene ring of the benzyl group has 1 to 2 selected from the group consisting of a C1-C6 alkyl group, a C1-C6 alkoxy group, a nitro group, and a halogen atom) May have one group as a substituent.
- the compound represented by formula (1d) is desulfonylated:
- R 1 represents a C1-C6 alkoxy group or a di (C1-C6 alkyl) amino group
- R 2 and R 3 are each independently a hydrogen atom, a C1-C6 alkoxycarbonyl group, a benzyloxycarbonyl group (the benzene ring of the benzyl group includes a C1-C6 alkyl group, a C1-C6 alkoxy group, a nitro group
- And 1 to 2 groups selected from the group consisting of halogen atoms may be substituted.
- R 1 represents a C1-C6 alkoxy group or a di (C1-C6 alkyl) amino group
- R 4 represents a C1-C6 alkyl group, a benzyl group (the benzene ring of the benzyl group has 1 to 2 selected from the group consisting of a C1-C6 alkyl group, a C1-C6 alkoxy group, a nitro group, and a halogen atom) May have one group as a substituent.
- R 1a represents a di (C1-C6 alkyl) amino group
- R 4 represents a C1-C6 alkyl group, a benzyl group (the benzene ring of the benzyl group has 1 to 2 selected from the group consisting of a C1-C6 alkyl group, a C1-C6 alkoxy group, a nitro group, and a halogen atom) May have one group as a substituent.
- R 1a represents a di (C1-C6 alkyl) amino group
- R 4 represents a C1-C6 alkyl group, a benzyl group (the benzene ring of the benzyl group has 1 to 2 selected from the group consisting of a C1-C6 alkyl group, a C1-C6 alkoxy group, a nitro group, and a halogen atom) An optionally substituted group
- R 6 is a C1-C6 alkyl group, a halo C1-C6 alkyl group, a phenyl group (the phenyl group is selected from the group consisting of a C1-C6 alkyl group, a C1-C6 alkoxy group, a nitro group, and a halogen atom) It may have 1 to 2 groups as substituents).
- R 1a represents a di (C1-C6 alkyl) amino group
- R 4 represents a C1-C6 alkyl group, a benzyl group (the benzene ring of the benzyl group has 1 to 2 selected from the group consisting of a C1-C6 alkyl group, a C1-C6 alkoxy group, a nitro group, and a halogen atom) May have one group as a substituent.
- R 4 is a tert-butyl group or a benzyl group.
- R 4a is a C1-C6 alkyl group, a benzyl group (the benzene ring of the benzyl group is selected from the group consisting of a C1-C6 alkyl group, a C1-C6 alkoxy group, a nitro group, and a halogen atom) 1 to 2 groups may be substituted as a substituent).
- halogen atom means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
- C1-C6 alkyl group means a monovalent group composed of a linear or branched saturated hydrocarbon having 1 to 6 carbon atoms.
- Examples of C1-C6 alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl and the like.
- halo C1-C6 alkyl group means 1 to 5 identical or different C1-C6 alkyl groups substituted with the above halogen atoms.
- halo C1-C6 alkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, fluoroethyl (meaning both 1-fluoroethyl and 2-fluoroethyl), 2 , 2-difluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentapururoethyl, fluoropropyl (3-fluoropropyl, 2-fluoropropyl, 1-fluoropropyl all And the like.
- C1-C6 alkoxy group in the present specification means a C1-C6 alkyloxy group formed from a C1-C6 alkyl group and an oxygen atom, and the C1-C6 alkyl is as described above.
- Examples of C1-C6 alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy and the like.
- di (C1-C6 alkyl) amino group means an amino group substituted by two identical C1-C6 alkyl groups, and the C1-C6 alkyl group is as described above.
- di (C1-C6 alkyl) amino include di (methyl) amino, di (ethyl) amino, di (n-propyl) amino and the like.
- examples of the “C1-C6 alkoxycarbonyl group” include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl and the like.
- the “phenyl group” means a monovalent group which may have a substituent on the benzene ring, and the benzene ring of the phenyl group has the same or different C1-C6 alkyl group.
- a C1-C6 alkoxy group, a nitro group, and one or two groups selected from the group consisting of halogen atoms may be substituted.
- Examples of the phenyl group in this specification include phenyl, p- (or o-) methylphenyl, p- (or o-) methoxyphenyl, 3,4-dimethoxyphenyl, p- (or o-) nitrophenyl. Chlorophenyl, 2,4-dichlorophenyl and the like.
- the “benzyl group” in the present specification means a monovalent group formed from a methyl group substituted with an optionally substituted phenyl group, and the benzene ring of the phenyl group is the same or different, It means that it may have 1 to 2 groups selected from the group consisting of a C1-C6 alkyl group, a C1-C6 alkoxy group, a nitro group, and a halogen atom as a substituent.
- benzyl group in the present specification examples include benzyl, p- (or o-) methylbenzyl, p- (or o-) methoxybenzyl, 3,4-dimethoxybenzyl, p- (or o-) nitrobenzyl. , Chlorobenzyl, 2,4-dichlorobenzyl and the like.
- the “benzyloxycarbonyl group” in the present specification means a monovalent group formed from a methoxy group substituted with a phenyl group which may be substituted and a carbonyl group, and the benzene ring of the phenyl group includes Means 1 to 2 groups selected from the group consisting of a C1-C6 alkyl group, a C1-C6 alkoxy group, a nitro group, and a halogen atom, which may be the same or different, as a substituent. .
- the benzyloxycarbonyl group in the present specification is not particularly limited as long as it is widely used as a protective group for an amino group.
- benzyloxycarbonyl group examples include benzyloxycarbonyl, p- (or o-) methylbenzyloxycarbonyl, p- (or o-) methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, p- (or o-) Nitrobenzyloxycarbonyl, chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl and the like.
- C1-C6 alkylsulfonyloxy group means a monovalent group formed from a C1-C6 alkyl group and a sulfonyloxy group, and the C1-C6 alkyl group is as described above.
- Examples of the C1-C6 alkylsulfonyloxy group include methanesulfonyloxy, ethanesulfonyloxy, n-propylsulfonyloxy and the like.
- halo C1-C6 alkylsulfonyloxy group means a monovalent group formed from a haloC1-C6 alkyl group and a sulfonyloxy group, and the haloC1-C6 alkyl group is as described above. It is.
- Examples of the halo C1-C6 alkylsulfonyloxy group in the present specification include chloromethanesulfonyloxy, trifluoromethanesulfonyloxy, (2,2,2-trifluoroethane) sulfonyloxy and the like.
- phenylsulfonyloxy group in the present specification means a monovalent group formed from a phenyl group which may be substituted and a sulfonyloxy group, and the benzene rings of the phenyl group are the same or different, This means that it may have 1 to 2 groups selected from the group consisting of a C1-C6 alkyl group, a C1-C6 alkoxy group, a nitro group, and a halogen atom as a substituent.
- phenylsulfonyloxy group examples include benzenesulfonyloxy, o- (m- or p-) chlorobenzenesulfonyloxy, 3,5-dichlorobenzenesulfonyloxy, o- (m- or p-) nitrobenzenesulfonyloxy, o- (M- or p-) methylbenzenesulfonyloxy (o- (m- or p-) toluenesulfonyloxy), o- (m- or p-) methoxybenzenesulfonyloxy and the like can be mentioned.
- N 1- (5-chloropyridin-2-yl) -N 2 -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2- ⁇ [(5-methyl- 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino ⁇ cyclohexyl) ethanediamide
- N 1- (5-Chloropyridin-2-yl) -N 2 -(( 1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2- ⁇ [(5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c] pyridine-2-yl) carbonyl] amino ⁇ cyclohexyl) ethanediamide
- N 1- (5-Chloropyridin-2-yl) -N 2 -(( 1S, 2R, 4S) -4-[
- the above compound (X) may be a pharmacologically acceptable salt thereof or a hydrate thereof.
- One embodiment of the production method of the present invention is an octahydro-2,1,3-benzothiadiazol skeleton represented by the following formula (8a), which is a cis-configuration bicyclic compound as shown in [Scheme 1] below.
- a method for producing a compound represented by the following formula (1b) having a cis-diamino skeleton by performing a deprotection reaction (desulfonylation) for removing a sulfonyl group from the sulfamoyl partial structure. Since desulfonylation which is such a deprotection reaction proceeds in a stepwise manner, the compound represented by the following formula (9) can be isolated as a salt if desired.
- R 1 represents a C1-C6 alkoxy group or a di (C1-C6 alkyl) amino group
- R 2 and R 3 are each independently a hydrogen atom, a C1-C6 alkoxycarbonyl group, a benzyloxycarbonyl group (the benzene ring of the benzyl group includes a C1-C6 alkyl group, a C1-C6 alkoxy group, a nitro group
- 1 to 2 groups selected from the group consisting of halogen atoms may be substituted.
- the above-described reaction step that is, the deprotection reaction (desulfonylation reaction) for removing the “sulfonyl group (—S (O) 2 —)”, which is a protecting group for two amino groups, is a known method (for example, Organic Letters, 9 (24), 4943-4945 (2007), Synlett, No.
- the sulfamic acid derivative (9) in which only one of the S—N bonds is cleaved is formed as an intermediate from the compound (8a) to the compound (1b), and can be isolated as desired as described above. Is possible. However, by treating compound (8a) with heating in water and a base, it is possible to convert compound (1b), which is the target product, at once without isolation of intermediate (9). it can.
- an organic base or an inorganic base can be used, but an organic base is preferable; for example, ethylenediamine, N, N, N ′, N Ethylenediamines such as'-(tetra C1-C6 alkyl) ethylenediamine, pyridine, picoline (the picoline includes any isomer of ⁇ -picoline, ⁇ -picoline and ⁇ -picoline), lutidine (the lutidine is 2,3-lutidine, 2,4-lutidine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine and 3,5-lutidine isomers), collidine (the collidine is 2,3,4-collidine, 2,3,5-collidine, 2,3,6-collidine, 2,4,5-collidine, 2,4,6-collidine, 3,4,5-collidine Any isomer of Gin also including), and 4-pyridines of dimethyl
- the addition ratio of water and base can be 1: 1 to 10 (V / V) as water: base.
- the reaction temperature may be in the range of 50 ° C. to the boiling point of the solvent, but is preferably in the range of 70 to 85 ° C.
- an organic solvent may be used as a reaction auxiliary solvent.
- the organic solvent is not particularly limited as long as it does not inhibit the reaction.
- ether solvents such as tetrahydrofuran and dioxane, halogenated hydrocarbon solvents, aromatic hydrocarbon solvents, acetonitrile, N, N-dimethylformamide, N , N-dimethylacetamide, N-methylpyrrolidone and the like nitrogen-containing solvents, ketone solvents, and mixed solvents thereof.
- this invention provides the method of manufacturing a compound (1c) from a compound (8b) shown to the following [Scheme2].
- R 1 represents a C1-C6 alkoxy group or a di (C1-C6 alkyl) amino group
- R 4 represents a C1-C6 alkyl group, a benzyl group (the benzene ring of the benzyl group has 1 to 2 selected from the group consisting of a C1-C6 alkyl group, a C1-C6 alkoxy group, a nitro group, and a halogen atom) May have one group as a substituent.
- R 1 is preferably a di (C1-C6 alkyl) amino group
- R 4 is preferably a C1-C6 alkyl group or a benzyl group.
- the reaction step shown in [Scheme 2] the production method described in [Scheme 1] can be applied mutatis mutandis.
- the intermediate compound (9b) can also be isolated as a salt as described above.
- R 1a is a di (C1-C6 alkyl) amino group shown in [Scheme 3] below. The route which manufactures the compound (8c) which is is shown.
- R 1a represents a di (C1-C6 alkyl) amino group
- R 4 represents a C1-C6 alkyl group, a benzyl group (the benzene ring of the benzyl group has 1 to 2 selected from the group consisting of a C1-C6 alkyl group, a C1-C6 alkoxy group, a nitro group, and a halogen atom)
- R 6 is a C1-C6 alkyl group, a halo C1-C6 alkyl group, a phenyl group (the phenyl group is selected from the group consisting of a C1-C6 alkyl group, a C1-C6 alkoxy group, a nitro group, and a halogen atom) It may have 1 to 2 groups as substituents).
- R 1a represents a di (C1-C6 alkyl) amino group
- R 4 represents a C1-C6
- Step a) is a step of producing a compound (5) by sulfonylating the amino group of the compound (4) (described later for a general production method) with the compound (II).
- Compound (II) [Reagent B]) may be a commercially available one, or [Solution A] containing Compound (II) is prepared and used as described below. Also good.
- R 1a and R 4 in the compound (4), the compound (5) and the compound (I) will be described.
- R 1a represents a di (C1-C6 alkyl) amino group, preferably a di (methyl) amino group.
- R 4 represents a C1-C6 alkyl group, a benzyl group (the benzene ring of the benzyl group has 1 to 2 selected from the group consisting of a C1-C6 alkyl group, a C1-C6 alkoxy group, a nitro group, and a halogen atom)
- R 4 may be a C1-C6 alkyl group and a benzyl group, more preferably a tert-butyl group and a benzyl group.
- Solution A is prepared by removing a commercially available chlorosulfonyl isocyanate, known as a reagent for dehydration reaction or converting a carboxy group into a cyano group, in a solvent in the following formula (I): R 4 —OH (I) (Wherein R 4 has the same meaning as described above.) It can prepare by processing with alcohol (I) represented by these, and a tertiary amine.
- solution A for example, triethylamine, diisopropylethylamine, 4-methylmorpholine, piperidine, pyrrolidine, tributylamine, 1,4-diazabicyclo [2.2.2] octane, Quinuclidine and the like are preferable, and triethylamine is particularly preferable.
- Solution A is prepared using alcohol (I) and a tertiary amine as a base in a solvent and has the following formula (II)
- R 21 and R 22 are (A) the same or different, a C1-C6 alkyl group; (B) R 22 represents a C1-C6 alkyl group, and two R 21 together with the nitrogen atom to which R 21 is bonded form a pyrrolidine ring, piperidine ring or 1,4-morpholine ring. Or (c) together with two R 21 and R 22 , and the nitrogen atom to which R 22 and R 21 are bonded, forms a 1,4-diazabicyclo [2.2.2] octane or quinuclidine ring Show; R 4 has the same meaning as described above. ) Is contained as a main component.
- Solvents used when preparing the solution A include ether solvents such as diethyl ether, di-n-propyl ether, diisopropyl ether, tetrahydrofuran, methyl tert-butyl ether or cyclopentyl methyl ether; methyl acetate, ethyl acetate, propyl acetate, acetic acid Ester solvents such as butyl or phenyl acetate; halogenated hydrocarbon solvents such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane or tetrachloroethane; aromatic hydrocarbon solvents such as benzene, chlorobenzene, toluene or xylene; acetonitrile, N, N— Nitrogen-containing solvents such as dimethylformamide, N, N-dimethylacetamide or N-methylpyrrolidone; ketone solvents such as acetone and methyl iso
- the amount of CSI, alcohol (I) and base tertiary amine used in preparing solution A is stoichiometrically CSI: alcohol (I): tertiary amine is 1: 0.95 to 1 .05: A molar equivalent ratio of about 2 to 4 is preferred.
- the reaction temperature when preparing the solution A is preferably a room temperature or lower.
- the reaction time for preparing [Solution A] is completed in about 0.5 to 5 hours.
- a compound (5) can be produced by reacting an aqueous solution of the compound (4) (here, a production method using an aqueous solution is exemplified) with the above [solution A] at about 0 ° C. .
- a base may be added, and as the base to be used, either an inorganic base or an organic base can be used, but an inorganic base is preferable.
- the inorganic base include alkali metal or alkaline earth metal hydroxides and carbonates, and lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate are preferable. It is preferably used as an aqueous solution.
- the addition amount of the base is preferably an amount that can maintain the neutrality to basicity of the reaction solution even after the addition of [Solution A].
- the reaction temperature after the addition of [Solution A] is preferably 0 ° C. to room temperature, and the reaction time is completed in about 0.5 to 5 hours.
- a mineral acid such as hydrochloric acid is added to the reaction solution to make the pH weakly acidic, followed by extraction with an organic solvent such as ethyl acetate to obtain compound (5).
- R 6 is a C1-C6 alkyl group, a halo C1-C6 alkyl group, a phenyl group (the phenyl group is composed of a C1-C6 alkyl group, a C1-C6 alkoxy group, a nitro group, and a halogen atom).
- 1 to 2 groups selected from the group may optionally be substituted);
- R 1a and R 4 are as defined above.
- Step b is a reaction of compound (5) with the following formula (III) in the presence of a base.
- R 6 is as defined above.
- R 1 is particularly preferably a di (methyl) amino group as described above
- R 4 is preferably a C1-C6 alkyl group and a benzyl group, and a tert-butyl group
- R 6 is particularly preferably R 6 is preferably a methyl group, an ethyl group, a phenyl group or a 4-methylphenyl group (p-tolyl group), particularly preferably a methyl group.
- an organic solvent as a reaction solvent.
- the organic solvent include ether solvents such as diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), tetrahydrofuran (THF), cyclopentyl methyl ether, dimethoxyethane, 1,4-dioxane; methyl acetate, ethyl acetate, Ester solvents such as propyl acetate, butyl acetate or phenyl acetate; Halogenated hydrocarbon solvents such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane or tetrachloroethane; Aromatic hydrocarbon solvents such as benzene, chlorobenzene, toluene or xylene; Acetonitrile, etc.
- ether solvents such as diethyl ether, diisopropyl ether, methyl tert-butyl
- an organic base or an inorganic base can be used, but an organic base is preferable, a tertiary amine such as triethylamine, tributylamine, N, N-diisopropylethylamine, and the like, 1,8 Use diazabicyclo [5.4.0] undec-7-ene (DBU), 1,8-diazabicyclo [4.3.0] non-5-ene (DBN), dimethylaniline, N-methylmorpholine, etc. Can do.
- DBU diazabicyclo [5.4.0] undec-7-ene
- DBN 1,8-diazabicyclo [4.3.0] non-5-ene
- dimethylaniline dimethylmorpholine
- N-methylmorpholine etc.
- tertiary amines such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine, 2,6-lutidine, N-methylimidazole are preferable, and triethylamine, N -Methylmorpholine and 2,6-lutidine are particularly preferred.
- the amount of base used is usually in the range of 0.8 to 5 molar equivalents relative to compound (5), preferably about 1 to 1.5 molar equivalents.
- methanesulfonyl chloride methanesulfonyl chloride, ethanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride and the like are preferable, and methanesulfonyl chloride is more preferable.
- the amount of compound (III) used is usually in the range of 0.8 to 3 molar equivalents, preferably about 1 to 1.5 molar equivalents, relative to compound (5).
- the reaction temperature in (Step b) is preferably 40 ° C. or less, more preferably about 0 ° C.
- the reaction time is usually completed in about 0.5 to 5 hours.
- R 1a represents a di (C1-C6 alkyl) amino group
- R 4 represents a C1-C6 alkyl group, a benzyl group (the benzene ring of the benzyl group has 1 to 2 selected from the group consisting of a C1-C6 alkyl group, a C1-C6 alkoxy group, a nitro group, and a halogen atom) An optionally substituted group
- R 6 represents a C1-C6 alkyl group, a halo C1-C6 alkyl group, a phenyl group (the phenyl group is a C1-C6 alkyl group, a halo C1-C6 alkyl group, a C1-C6 alkoxy group, a nitro group, and a halogen group). It may have one or more groups selected from the group consisting of atoms as a substituent. ]
- Step c is characterized in that the compound (6a) is treated with a base, and (3aR, 7aS) -octahydro-2,1,3- is obtained by stereoselective and regioselective intramolecular cyclization reaction.
- a compound (8c) having a benzothiadiazol ring is produced.
- step c) high regioselectivity in (step c) is obtained by treating compound (6a) with a base, via compound (7), which is considered to be superior in reaction kinetics, as a reaction intermediate, followed by an aziridine ring. It was inferred that after regioselective ring opening, compound (8c) was selectively produced by reclosing to form a thermodynamically stable 5-membered ring.
- Step c) is an intramolecular reaction, it is preferably carried out in an organic solvent under dilution.
- R 1a is preferably a di (methyl) amino group;
- R 4 is preferably a C1-C6 alkyl group and a benzyl group, particularly preferably a tert-butyl group and a benzyl group;
- R 6 is a methyl group, an ethyl group, a phenyl group Group, a 4-methylphenyl group (p-tolyl group) is preferable, and a methyl group is particularly preferable.
- Examples of the organic solvent used in (Step c) include ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), tetrahydrofuran (THF), cyclopentyl methyl ether, dimethoxyethane, and 1,4-dioxane.
- ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), tetrahydrofuran (THF), cyclopentyl methyl ether, dimethoxyethane, and 1,4-dioxane.
- Ester solvent such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate or phenyl acetate; halogenated hydrocarbon solvent such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane or tetrachloroethane; benzene, chlorobenzene, toluene or xylene Aromatic hydrocarbon solvents; nitrogen-containing solvents such as acetonitrile; ketone solvents such as acetone and methyl isobutyl ketone; and mixed solvents thereof; preferably tetrahydrofuran, chloro Lum, dichloromethane, toluene, include acetonitrile or a mixed solvent thereof; particularly preferably, and the like acetonitrile.
- ester solvent such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate or phenyl
- an organic base or an inorganic base can be used, but an organic base is preferable, a tertiary amine such as triethylamine, N, N-diisopropylethylamine, and the like, 1,8-diazabicyclo [ 5.4.0] Undec-7-ene (DBU), 1,8-diazabicyclo [4.3.0] non-5-ene (DBN), (N, N-dimethyl) aniline, N-methylmorpholine, etc. Can be used.
- DBU Undec-7-ene
- DBN 1,8-diazabicyclo [4.3.0] non-5-ene
- DBN non-5-ene
- aniline N-methylmorpholine, etc.
- tertiary amines such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine and pyridine are preferable, and triethylamine is particularly preferable.
- the amount of base used is usually in the range of 0.8 to 2 molar equivalents, preferably about 1 to 1.2 molar equivalents, relative to compound (6a).
- the reaction temperature may be from room temperature to the boiling point of the solvent, but is preferably in the range of 70 ° C. to the boiling point of the solvent.
- the reaction time is about 1 to 10 hours.
- the present invention provides a method for selectively producing a compound represented by formula (8c) from an aziridine derivative represented by formula (7) as shown in the following scheme.
- R 1a and R 4 have the same meanings as described above.
- R 1a is preferably a di (methyl) amino group
- R 4 is preferably a tert-butyl group or a benzyl group.
- R 1a represents a di (C1-C6 alkyl) amino group
- R 4 represents a C1-C6 alkyl group, a benzyl group (the benzene ring of the benzyl group has 1 to 2 selected from the group consisting of a C1-C6 alkyl group, a C1-C6 alkoxy group, a nitro group, and a halogen atom) May have one group as a substituent.
- Step d is a step of producing compound (1d) by cleaving two nitrogen-sulfur bonds of the thiadiazole ring.
- the “sulfonyl group (—S (O) 2 —)” to be removed can be regarded as a protecting group for two amino groups. Therefore, as described above, it can be carried out by referring to the deprotection reaction conditions relating to the “protecting group” of the 1,2-diamino group (for example, Organic Letters, 9 (24), 4943-4945 (2007), Synlett, (6), 623-624 (1998), JP 2012-036181 etc.).
- compound (8c) is produced by heating in a mixed solvent of water and a base.
- a base either an organic base or an inorganic base can be used, but an organic base is preferable; pyridines such as pyridine, lutidine and collidine are more preferable; pyridine is particularly preferable.
- the addition ratio of water and base may be 1: 1 to 10 (V / V), but is preferably about 1: 1.5 to 5 (V / V).
- the reaction temperature may be in the range of 50 ° C. to the boiling point of the solvent, but is preferably in the range of 70 to 100 ° C.
- the reaction time is about 1 to 10 hours.
- an organic solvent can be used as a reaction auxiliary solvent.
- the organic solvent include ether solvents such as dipropyl ether, diisopropyl ether, tetrahydrofuran, methyl tert-butyl ether, and cyclopentyl methyl ether; halogenated hydrocarbon solvents such as chloroform, carbon tetrachloride, dichloroethane, and tetrachloroethane; benzene, chlorobenzene Aromatic hydrocarbon solvents such as toluene or xylene; nitrogen-containing solvents such as acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide or N-methylpyrrolidone; ketone solvents such as acetone and methyl isobutyl ketone and the like A mixed solvent is mentioned; Preferably, tetrahydrofuran, chloroform, toluene, acetonit
- the reaction mixture is preferably made alkaline and then extracted with an organic solvent.
- an alkali metal or alkaline earth metal hydroxide and carbonate aqueous solution may be added, and lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, It is preferred to use potassium carbonate as an aqueous solution.
- extraction solvents include diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), tetrahydrofuran (THF), cyclopentyl methyl ether, dimethoxyethane, 1,4-dioxane, and other ether solvents; methyl acetate, ethyl acetate, propyl acetate, Examples include ester solvents such as butyl acetate and phenyl acetate; halogenated hydrocarbon solvents such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, and tetrachloroethane; aromatic hydrocarbon solvents such as benzene, chlorobenzene, toluene, and xylene.
- ester solvents such as butyl acetate and phenyl acetate
- halogenated hydrocarbon solvents such as dichloromethane, chloroform, carbon te
- the compound (1d) sulfate precipitated from the reaction solution is filtered and washed as an acid addition salt with sulfuric acid produced by desulfonylation, so that isolation and purification can be performed without performing the above extraction operation.
- R 1a and R 4 have the same meanings as described above.
- Step e is a step of treating compound (1d) produced in (step d) with oxalic acid to produce compound (1e) which is an oxalate salt of compound (1d) or a hydrate thereof.
- oxalic acid for example, a known method disclosed in Document 6 or WO2012 / 002538 can be used.
- step d by filtering and washing the sulfate of compound (1d) precipitated from the reaction solution as an acid addition salt with sulfuric acid generated by desulfonylation, Isolation and purification can also be performed without performing the above extraction operation.
- the sulfate of compound (1d) can be used for the production of compound (A-9) shown below in the same manner as compound (1e).
- step a The compound (4) [or the aqueous solution of the compound (4)] used in the above (step a) is converted from the compound (A-1) to the compound (A-2) and the compound ((5) as shown in the following [Scheme 5]. It can be manufactured by a known method via A-3).
- R 1a represents a di (C1-C6 alkyl) amino group
- X represents an iodine atom or a bromine atom.
- Boc represents a tert-butoxycarbonyl group.
- the present invention relates to a novel intermediate compound obtained in the following steps simultaneously with the above production method.
- the present invention provides the following formula (5)
- R 1a represents a di (C1-C6 alkyl) amino group
- R 4 represents a C1-C6 alkyl group, a benzyl group (the benzene ring of the benzyl group has 1 to 2 selected from the group consisting of a C1-C6 alkyl group, a C1-C6 alkoxy group, a nitro group, and a halogen atom) May have one group as a substituent.
- R 1a is preferably a di (methyl) amino group
- R 4 is preferably a C1-C6 alkyl group or a benzyl group; more preferably a tert-butyl group or a benzyl group.
- R 1a represents a di (C1-C6 alkyl) amino group
- R 4 represents a C1-C6 alkyl group, a benzyl group (the benzene ring of the benzyl group has 1 to 2 selected from the group consisting of a C1-C6 alkyl group, a C1-C6 alkoxy group, a nitro group, and a halogen atom)
- R 6 is a C1-C6 alkyl group, a halo C1-C6 alkyl group, a phenyl group (the phenyl group is selected from the group consisting of a C1-C6 alkyl group, a C1-C6 alkoxy group, a nitro group, and a halogen atom) It may have 1 to 2 groups as substituents).
- R 1a is preferably a di (methyl) amino group
- R 4 is preferably a C1-C6 alkyl group or a benzyl group; tert-butyl group Or a benzyl group is particularly preferable.
- R 6 is preferably a C1-C6 alkyl group or a 4-methylphenyl group; a methyl group is particularly preferred.
- R 1a represents a di (C1-C6 alkyl) amino group
- R 4 represents a C1-C6 alkyl group, a benzyl group (the benzene ring of the benzyl group has 1 to 2 selected from the group consisting of a C1-C6 alkyl group, a C1-C6 alkoxy group, a nitro group, and a halogen atom) May have one group as a substituent.
- R 1a is preferably a di (methyl) amino group
- R 4 is preferably a C1-C6 alkyl group or a benzyl group
- tert-butyl group Or a benzyl group is particularly preferable.
- a 28% aqueous ammonia solution (1563 ml) was added to an aqueous solution (500 ml) of (1S, 3S, 4S) -3-hydroxy-4-bromo-N, N-dimethylcyclohexanecarboxamide (274.5 g) and heated to 40 ° C. The mixture was stirred for 8 hours, and further stirred at room temperature for 6 hours. 48% sodium hydroxide (67.3 ml) was added to the reaction mixture, and the mixture was concentrated to 500 ml to give the title compound (184.0 g, yield 81%) as an aqueous solution (572 g).
- Boc represents a tert-butoxycarbonyl group.
- Boc represents a tert-butoxycarbonyl group.
- the reaction mixture was triethylamine (155 ml), 5-methyl-4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridine-2-carboxylic acid / hydrochloride (52. 5 g), 1-hydroxybenzotriazole (33.0 g) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (46.8 g) were added, and the mixture was stirred at room temperature for 16 hours. Triethylamine and water were added, and the mixture was stirred for 1 hour under ice cooling. The crystals were collected by filtration to give the title compound (X) (103.2 g).
- Aqueous solution (11.2 mL) was added and stirred for about 30 minutes.
- the Burgess reagent prepared by the above method was added to the reaction mixture over about 5 minutes, and the adjusted solution was washed with methylene chloride (5 mL), dropped, and stirred for 2 hours.
- 6 mol / L aqueous hydrochloric acid was added to adjust the pH to 1.5, and the organic layer was separated. Again, the aqueous layer was extracted with methylene chloride (100 mL). The organic layers were matched, washed with 20% brine (50 mL), concentrated to dryness, ethyl acetate (300 mL) was added to the resulting residue, and the mixture was concentrated to about 100 mL.
- the obtained concentrated liquid was cooled to about 0 ° C. and stirred for about 30 minutes, and then the precipitated crystals were collected by filtration and dried under reduced pressure.
- the obtained crude crystals were added to water (30 mL) and stirred, and the mixture was filtered and washed with water. The obtained crystals were dried under reduced pressure to give 13.26 g (yield 68%) of the title compound as crystals.
- Example 2 ⁇ [(1R, 2R, 5S) -5- (Dimethylcarbamoyl) -2-hydroxycyclohexyl] sulfamoyl ⁇ tert-butyl carbamate tert-butyl alcohol (51 ml) was added to acetonitrile (600 ml), After cooling to about 0 ° C. and chlorosulfonyl isocyanate (46.3 ml) was added dropwise over about 20 minutes, the mixture was stirred for about 15 minutes. Triethylamine (156.3 ml) was added dropwise to the reaction mixture over about 30 minutes, and the mixture was further stirred for about 30 minutes to prepare a Burgess type reagent.
- Example 3 ⁇ [(1R, 2R, 5S) -5- (Dimethylcarbamoyl) -2-hydroxycyclohexyl] sulfamoyl ⁇ carbamate tert-butyl tert-butyl alcohol (5.56 ml) in acetonitrile (60 ml) The mixture was cooled to about 0 ° C., and chlorosulfonyl isocyanate (5.06 ml) was added dropwise over about 10 minutes, followed by stirring for about 15 minutes. Triethylamine (17.1 ml) was added dropwise to the reaction mixture over about 15 minutes, and then stirred for about 30 minutes to prepare a Burgess type reagent.
- Chlorosulfonyl isocyanate (1.36 ml) was added to methylene chloride (15 ml), cooled to about 0 ° C., benzyl alcohol (1.36 ml) was added dropwise over about 15 minutes, and the mixture was stirred for 5 minutes. .
- Triethylamine (4.42 ml) was added dropwise to the reaction mixture over about 20 minutes to prepare a Burgess type reagent.
- N-methylmorpholine (6.81 ml) was added dropwise to the reaction mixture, and the mixture was stirred for about 3 hours.
- Water (61 ml) was added to the reaction mixture, 6 mol / l hydrochloric acid was added to adjust to pH 3, water (93 ml) was further added, and the mixture was stirred for about 15 hours.
- the precipitated solid was collected by filtration and washed with a 27.5% aqueous acetonitrile solution (30 ml). The obtained solid was dried under reduced pressure to obtain the title compound (13.0 g, yield 89%).
- the instrumental spectra of the finished product were consistent with those produced in Example 5.
- reaction solution was dropped into a mixed solution of acetonitrile (650 ml) and triethylamine (480 ml) over about 4 hours to prepare an acetonitrile solution of a Burgess reagent.
- This solution was dropped into the acetonitrile solution of the above Burgess reagent over about 30 minutes, water (100 ml) was added, and the mixture was stirred at about 5 ° C. for about 5 hours.
- the obtained reaction solution was concentrated to about 1400 ml, ethyl acetate (1500 ml), citric acid (74.96 g) and water (100 ml) were added, heated to about 40 ° C., stirred, allowed to stand, and then the organic layer was separated. separated. The aqueous layer was re-extracted with ethyl acetate (1500 ml), the organic layers were matched, washed with 20% brine (760 ml), and concentrated to about 1000 ml.
- Acetonitrile (1500 ml) was added to the concentrated solution thus obtained, and the mixture was concentrated to about 600 ml.
- Acetonitrile (1500 ml) was added and concentrated, and ⁇ [(1R, 2R, 5S) -5- (dimethylcarbamoyl) -2- Hydroxycyclohexyl] sulfamoyl ⁇ tert-butyl carbamate in acetonitrile (about 600 ml) was obtained.
- Acetonitrile (600 ml) was added to this acetonitrile solution (about 600 ml), cooled to about 5 ° C., methanesulfonyl chloride (77 ml) was added, and N-methylmorpholine (136 ml) was added dropwise over about 15 minutes. After the mixture was stirred for about 3 hours, water (100 ml) and concentrated hydrochloric acid (49.39 g) were added. The reaction mixture was slowly added to water (2980 ml) cooled to about 5 ° C., and then stirred for about 12 hours, and the precipitated crystals were collected by filtration. The crystal cake was washed with 27% acetonitrile aqueous solution (600 ml) and toluene (400 ml), and then dried under reduced pressure to obtain the title compound (284.44 g).
- Example 12 (3aS, 6S, 7aR) -6- (Dimethylcarbamoyl) -2,2-dioxohexahydro-2,1,3-benzothiadiazol-1 (3H) -benzyl carboxylate ⁇ [(1R, 2R, 5S) -5- (Dimethylcarbamoyl) -2-hydroxycyclohexyl] sulfamoyl ⁇ benzyl carbamate (1.00 g) was added to methylene chloride (10 ml) and triethylamine (1.76 ml) was added. Thereafter, methanesulfonyl chloride (0.28 ml) was added dropwise and stirred for about 1 hour.
- Triethylamine (2.00 ml) was added to the reaction mixture, and the mixture was heated to about 80 ° C. and stirred for about 4 hours.
- the reaction mixture was purified by thin layer chromatography to give 545 mg (57% yield) of the title compound as an oil.
- the reaction mixture was cooled to about 50 ° C., 10% brine (200 ml), toluene (1000 ml) and 48% aqueous sodium hydroxide solution (80 ml) were added, and the mixture was stirred at about 50 ° C. for about 15 minutes, and then the organic layer was separated. .
- 22% brine (500 ml) and 48% aqueous sodium hydroxide solution (80 ml) were added to the aqueous layer and stirred at about 50 ° C. for about 15 minutes, and the organic layer was separated.
- the organic layers were combined and concentrated to about 150 ml, then acetonitrile (500 ml) was added, and the mixture was further concentrated to about 100 ml.
- Example 15 (1R, 2S, 5S) -2-Amino-5-[(dimethylamino) carbonyl] cyclohexylcarbamic acid tert-butyl oxalate (1)
- the mixture was heated to about 70 ° C.
- the reaction solution was cooled to about 50 ° C., water (80 ml), toluene (800 ml), 20% brine (80 ml), 25% sodium hydroxide solution (120 ml) were added, and the mixture was allowed to stand to separate the organic layer. .
- the obtained organic layer was washed successively with 20% brine (80 ml) and 25% sodium hydroxide solution (16 ml), and then the obtained organic layer was concentrated to about 240 ml.
- the precipitated crystals were filtered, washed with 7% aqueous acetonitrile (300 ml), and the monohydrate ((1R, 2S, 5S) -2-amino-5-[(dimethylamino) carbonyl] cyclohexylcarbamine of the title compound. Acid tert-butyl oxalate monohydrate) was obtained. Acetonitrile (560 ml) was added to the monohydrate of the title compound, and the mixture was heated to about 70 ° C. After stirring at the same temperature for about 5 hours, the mixture was concentrated to about 320 ml, acetonitrile (320 ml) was added to the concentrated solution, and the mixture was cooled to about 25 ° C. The precipitated crystals were filtered, washed with acetonitrile (80 ml), and dried under reduced pressure to give the title compound anhydride (55.74 g, yield 82%).
- the production method of the present invention can be used as an industrial production method for compound (X) and compound (Xa), which are inhibitors of FXa.
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Abstract
Description
しかしながら、特許文献6における化合物(1又は1a)の製造方法の問題点として、以下の(a)及び(b)を挙げることができる。
しかしながら、これまでにFXa阻害薬である化合物(X)及び(X-a)の製造における重要中間体である化合物(1)及び化合物(1a)の製造方法としては、上述のように多くの問題点[(a)及び(b)]がある、アジド体である化合物(A-7)を経由する方法しか知られていなかった(例えば、特許文献1~6参照)。
[1]下記式(1d)
R4は、C1-C6アルキル基、ベンジル基(該ベンジル基のベンゼン環には、C1-C6アルキル基、C1-C6アルコキシ基、ニトロ基、及び、ハロゲン原子からなる群より選ばれる1~2個の基を置換基として有していてもよい)を示す。]
で表される化合物、その塩又はそれらの水和物の製造方法であって、下記式(4)
で表される化合物を、下記の[溶液A]
[溶液A]
溶媒中、下記式(I)
R4-OH (I)
で表される化合物を、クロロスルホニルイソシアナート及び三級アミンと処理して溶液Aを調製する;若しくは、下記の[試薬B]
[試薬B]
下記式(II)
R21及びR22は、次の(a)、(b)又は(c)を示す。
(a)同一又は異なって、C1-C6アルキル基;
(b)R22はC1-C6アルキル基を示し、2つのR21は、R21の結合する窒素原子と一緒になってピペリジン環、ピロリジン環又は1,4-モルホリン環を形成する;
(c)2つのR21及びR22、及び、R22、R21の結合する窒素原子と一緒になって1,4-ジアザビシクロ[2.2.2]オクタン環及びキヌクリジン環を形成する。]
で示される化合物;
と処理して得られる、下記式(5)
で表される化合物を、塩基の存在下、下記式(III)
R6SO2X (III)
[式中、R6は、C1-C6アルキル基、ハロC1-C6アルキル基、フェニル基(該フェニル基は、C1-C6アルキル基、C1-C6アルコキシ基、ニトロ基、及び、ハロゲン原子からなる群より選ばれる1~2個の基を置換基として有していてもよい)を示し;
Xはハロゲン原子を示す。]
で表される化合物と処理して得られる、下記式(6a)
で表される化合物を、塩基と処理して得られる、下記式(8c)
で表される化合物を、脱スルホニル化を行うことを特徴とする、式(1d)で表される化合物、その塩又はそれらの水和物の製造方法。
[2]脱スルホニル化が、水及び塩基と処理するものである、[1]に記載の製造方法。
[3]塩基がピリジン類である、[2]に記載の製造方法。
[4]下記式(4)
で表される化合物を、下記の[溶液A]と処理することを特徴とする、下記式(5)
R1aは上記と同義を示す。]
で表される化合物の製造方法。
[溶液A]
溶媒中、下記式(I)
R4-OH (I)
(式中、R4は前記と同義を示す。)
で表される化合物を、クロロスルホニルイソシアナート及び三級アミンと処理して溶液Aを調製する。
[5]下記式(4)
で表される化合物を、下記の[試薬B]と処理することを特徴とする、下記式(5)
で表される化合物の製造方法。
[試薬B]
下記式(II)
R21及びR22は、次の(a)、(b)又は(c)を示す。
(a)同一又は異なって、C1-C6アルキル基;
(b)R22はC1-C6アルキル基を示し、2つのR21は、R21の結合する窒素原子と一緒になってピペリジン環、ピロリジン環又は1,4-モルホリン環を形成する;
(c)2つのR21及びR22、及び、R22、R21の結合する窒素原子と一緒になって1,4-ジアザビシクロ[2.2.2]オクタン環及びキヌクリジン環を形成する。]
で表される化合物。
[6]R21及びR22が、エチル基である、[1]又は[5]に記載の製造方法。
[7]下記式(5)
R4は、C1-C6アルキル基、ベンジル基(該ベンジル基のベンゼン環には、C1-C6アルキル基、C1-C6アルコキシ基、ニトロ基、及び、ハロゲン原子からなる群より選ばれる1~2個の基を置換基として有していてもよい)を示す。]
で表される化合物を、塩基の存在下、下記式(III)
R6SO2X (III)
Xはハロゲン原子を示す。]
で表される化合物と処理することを特徴とする、下記式(6a)
で表される化合物の製造方法。
[8]R6がC1-C6アルキル基である、[1]又は[7]に記載の製造方法。
[9]R6が、メチル基である、[1]又は[7]に記載の製造方法。
[10]下記式(6a)
R4は、C1-C6アルキル基、ベンジル基(該ベンジル基のベンゼン環には、C1-C6アルキル基、C1-C6アルコキシ基、ニトロ基、及び、ハロゲン原子からなる群より選ばれる1~2個の基を置換基として有していてもよい)を示し;
R6は、C1-C6アルキル基、ハロC1-C6アルキル基、フェニル基(該フェニル基は、C1-C6アルキル基、C1-C6アルコキシ基、ニトロ基、及び、ハロゲン原子からなる群より選ばれる1~2個の基を置換基として有していてもよい)を示す。]
で表される化合物を、塩基と処理することを特徴とする、下記式(8c)
で表される化合物の製造方法。
[11]下記式(8c)
R4は、C1-C6アルキル基、ベンジル基(該ベンジル基のベンゼン環には、C1-C6アルキル基、C1-C6アルコキシ基、ニトロ基、及び、ハロゲン原子からなる群より選ばれる1~2個の基を置換基として有していてもよい)を示す。]
で表される化合物を、脱スルホニル化を行うことを特徴とする、下記式(1d)
で表される化合物、その水和物又はそれらの水和物の製造方法。
[12]脱スルホニル化が、水及び塩基と処理するものである、[11]に記載の製造方法。
[13]塩基がピリジン類である、[12]に記載の製造方法。
[14]R1aがジ(メチル)アミノ基である、[1]~[13]のいずれか1に記載の製造方法。
[15]R4が、tert-ブチル基又はベンジル基である、[1]~14のいずれか1項に記載の製造方法。
[16]式(1d)で表される化合物、その水和物又はそれらの水和物が、式(1d)で表される化合物の硫酸塩、式(1d)で表される化合物のシュウ酸塩・1水和物、又は、式(1d)で表される化合物のシュウ酸塩である、[14]~[15]のいずれか1に記載の製造方法。
[17]下記式(1b)
R2及びR3は、それぞれ独立して、水素原子、C1-C6アルコキシカルボニル基、ベンジルオキシカルボニル基(該ベンジル基のベンゼン環には、C1-C6アルキル基、C1-C6アルコキシ基、ニトロ基、及び、ハロゲン原子からなる群より選ばれる1~2個の基を置換基として有していてもよい)を示す。]
で表される化合物、その塩又はそれらの水和物の製造方法であって、下記式(8a)
で表される化合物を、脱スルホニル化を行うことを特徴とする、式(1b)で表される化合物、その塩又はそれらの水和物の製造方法。
[18]下記式(1c)
R4は、C1-C6アルキル基、ベンジル基(該ベンジル基のベンゼン環には、C1-C6アルキル基、C1-C6アルコキシ基、ニトロ基、及び、ハロゲン原子からなる群より選ばれる1~2個の基を置換基として有していてもよい)を示す。]
で表される化合物、その塩又はそれらの水和物の製造方法であって、
下記式(8b)
で表される化合物を、脱スルホニル化を行うことを特徴とする、式(1c)で表される化合物、その塩又はそれらの水和物の製造方法。
[19]下記式(5)
R4は、C1-C6アルキル基、ベンジル基(該ベンジル基のベンゼン環には、C1-C6アルキル基、C1-C6アルコキシ基、ニトロ基、及び、ハロゲン原子からなる群より選ばれる1~2個の基を置換基として有していてもよい)を示す。]
で表される化合物。
[20]下記式(6a)
R4は、C1-C6アルキル基、ベンジル基(該ベンジル基のベンゼン環には、C1-C6アルキル基、C1-C6アルコキシ基、ニトロ基、及び、ハロゲン原子からなる群より選ばれる1~2個の基を置換基として有していてもよい)を示し;
R6は、C1-C6アルキル基、ハロC1-C6アルキル基、フェニル基(該フェニル基は、C1-C6アルキル基、C1-C6アルコキシ基、ニトロ基、及び、ハロゲン原子からなる群より選ばれる1~2個の基を置換基として有していてもよい)を示す。]
で表される化合物。
[21]R6がC1-C6アルキル基である、[20]に記載の化合物。
[22]R6がメチル基である、[20]に記載の化合物。
[23]下記式(8c)
R4は、C1-C6アルキル基、ベンジル基(該ベンジル基のベンゼン環には、C1-C6アルキル基、C1-C6アルコキシ基、ニトロ基、及び、ハロゲン原子からなる群より選ばれる1~2個の基を置換基として有していてもよい)を示す。]
で表される化合物。
[24]R1aがジ(メチル)アミノ基である、[19]~[23]のいずれか1に記載の化合物。
[25]R4が、tert-ブチル基又はベンジル基である、[19]~[23]のいずれか1に記載の化合物。
[26]下記式(X-a)
で表される化合物を、水及び塩基と処理して得られる、下記式(1f)
で表される化合物を、脱保護し、得られる下記式(A-10)
からなる、式(X-a)で表される化合物の製造方法。
[27]R4aがtert-ブチル基である、[26]に記載の製造方法。
R2及びR3は、それぞれ独立して、水素原子、C1-C6アルコキシカルボニル基、ベンジルオキシカルボニル基(該ベンジル基のベンゼン環には、C1-C6アルキル基、C1-C6アルコキシ基、ニトロ基、及び、ハロゲン原子からなる群より選ばれる1~2個の基を置換基として有していてもよい)を示す。]
R4は、C1-C6アルキル基、ベンジル基(該ベンジル基のベンゼン環には、C1-C6アルキル基、C1-C6アルコキシ基、ニトロ基、及び、ハロゲン原子からなる群より選ばれる1~2個の基を置換基として有していてもよい)を示す。]
[Scheme2]に示した反応工程においては、上記[Scheme1]で説明した製造方法が準用できる。また、中間体である化合物(9b)は、上述のようにを塩として単離することもできる。
上述の、(3aR,7aS)-オクタヒドロ-2,1,3-ベンゾチアジアゾ-ル誘導体の具体的な製造例として、下記の[Scheme3]に示した、R1aがジ(C1-C6アルキル)アミノ基である化合物(8c)を製造するルートを示す。
R4は、C1-C6アルキル基、ベンジル基(該ベンジル基のベンゼン環には、C1-C6アルキル基、C1-C6アルコキシ基、ニトロ基、及び、ハロゲン原子からなる群より選ばれる1~2個の基を置換基として有していてもよい)を示し;
R6は、C1-C6アルキル基、ハロC1-C6アルキル基、フェニル基(該フェニル基は、C1-C6アルキル基、C1-C6アルコキシ基、ニトロ基、及び、ハロゲン原子からなる群より選ばれる1~2個の基を置換基として有していてもよい)を示す。]
溶媒中、下記式(I)
R4-OH (I)
(式中、R4は上記と同義を示す。)
で表される化合物を、クロロスルホニルイソシアナート(イソシアン酸クロロスルホニル,以下、CSIと略す場合がある)及び三級アミンと処理して溶液Aを調製する。
R1aは、ジ(C1-C6アルキル)アミノ基を示し、ジ(メチル)アミノ基が好ましい。
R4は、C1-C6アルキル基、ベンジル基(該ベンジル基のベンゼン環には、C1-C6アルキル基、C1-C6アルコキシ基、ニトロ基、及び、ハロゲン原子からなる群より選ばれる1~2個の基を置換基として有していてもよい)を示し;R4は、C1-C6アルキル基、及びベンジル基が好ましく、tert-ブチル基、及びベンジル基がより好ましい。
R4-OH (I)
(式中、R4は前記と同義を示す。)
で表されるアルコール(I)、及び三級アミンと処理して調製できる。ここで、溶液Aを調製する時に使用する三級アミンとしては、例えば、トリエチルアミン、ジイソプロピルエチルアミン、4-メチルモルホリン、ピペリジン、ピロリジン、トリブチルアミン、1,4-ジアザビシクロ[2.2.2]オクタン、キヌクリジン等が好ましく、トリエチルアミンが特に好ましい。溶液Aは、溶媒中、アルコール(I)及び塩基として三級アミンを使用して調製されるものであり、下記式(II)
(a)同一又は異なって、C1-C6アルキル基;を示すか、
(b)R22はC1-C6アルキル基を示し、2つのR21は、R21の結合する窒素原子と一緒になってピロリジン環、ピペリジン環又は1,4-モルホリン環を形成する;を示すか、又は
(c)2つのR21及びR22、及び、R22、R21の結合する窒素原子と一緒になって1,4-ジアザビシクロ[2.2.2]オクタン環又はキヌクリジン環を形成する;を示し;
R4は前記と同義を示す。)
で表される反応試薬を主成分として含有する。ここで、化合物(II)においてR21及びR22がエチル基で、R4がメチル基であるものは、バ-ジェス試薬(例えば、J. Indian Inst. Sci., 2001, 81, 461-476等を参照)として市販されている。
溶液Aを調製するときの反応温度は、室温以下の温度が好ましい。[溶液A]を調製するときの反応時間は0.5~5時間程度で完結する。
反応終了後、反応液に塩酸などの鉱酸を加えて、pHを弱酸性にした後、例えば酢酸エチル等の有機溶媒で抽出し、化合物(5)が得られる。
R1a及びR4は、上記と同義を示す。)
で表される化合物と処理して化合物(6a)を製造する工程である。化合物(5)及び化合物(6a)の、R1は、上記のように、ジ(メチル)アミノ基が特に好ましく;R4は、C1-C6アルキル基、及びベンジル基が好ましく、tert-ブチル基及びベンジル基が特に好ましく;R6は、メチル基、エチル基、フェニル基、4-メチルフェニル基(p-トリル基)が好ましく、メチル基が特に好ましい。
これらの塩基のうち、(工程b)においては、トリエチルアミン、N,N-ジイソプロピルエチルアミン、N-メチルモルホリン、ピリジン、2,6-ルチジン、N-メチルイミダゾール等の三級アミンが好ましく、トリエチルアミン、N-メチルモルホリン及び2,6-ルチジンが特に好ましい。
塩基の使用量は、通常、化合物(5)に対して、化学量論的に0.8~5モル当量の範囲でよく、好ましくは1~1.5モル当量程度である。
化合物(III)の使用量は、通常、化合物(5)に対して、化学量論的に0.8~3モル当量の範囲でよく、好ましくは1~1.5モル当量程度である。
R4は、C1-C6アルキル基、ベンジル基(該ベンジル基のベンゼン環には、C1-C6アルキル基、C1-C6アルコキシ基、ニトロ基、及び、ハロゲン原子からなる群より選ばれる1~2個の基を置換基として有していてもよい)を示し;
R6は、C1-C6アルキル基、ハロC1-C6アルキル基、フェニル基(該フェニル基は、C1-C6アルキル基、ハロC1-C6アルキル基、C1-C6アルコキシ基、ニトロ基、及び、ハロゲン原子からなる群より選ばれる1以上の基を置換基として有していてもよい)を示す。]
R1aはジ(メチル)アミノ基が好ましく;R4は、C1-C6アルキル基、及びベンジル基が好ましく、tert-ブチル基及びベンジル基が特に好ましく;R6は、メチル基、エチル基、フェニル基、4-メチルフェニル基(p-トリル基)が好ましく、メチル基が特に好ましい。
本工程においては、これらの塩基のうち、トリエチルアミン、N,N-ジイソプロピルエチルアミン、N-メチルモルホリン、ピリジン等の三級アミンが好ましく、トリエチルアミンが特に好ましい。
塩基の使用量は、通常、化合物(6a)に対して、化学量論的に0.8~2モル当量の範囲でよく、好ましくは1~1.2モル当量程度である。
反応温度としては、室温から溶媒の沸点で実施できるが、70℃~溶媒の沸点の範囲が好ましい。反応時間としては、1~10時間程度で完結する。
ここで、R1aは、ジ(メチル)アミノ基が好ましく;R4は、tert-ブチル基及びベンジル基が好ましい。
R4は、C1-C6アルキル基、ベンジル基(該ベンジル基のベンゼン環には、C1-C6アルキル基、C1-C6アルコキシ基、ニトロ基、及び、ハロゲン原子からなる群より選ばれる1~2個の基を置換基として有していてもよい)を示す。]
使用する塩基としては、有機塩基又は無機塩基のいずれも使用できるが、有機塩基が好ましく;ピリジン、ルチジン、コリジン等のピリジン類がより好ましく;ピリジンが特に好ましい。
水及び塩基の添加比率としては、1:1~10(V/V)で実施できるが、1:1.5~5(V/V)程度が好ましい。
反応温度としては、50℃~溶媒の沸点の範囲で実施できるが、70~100℃の範囲が好ましい。
反応時間としては、1~10時間程度で完結する。
一方、反応終了後、脱スルホニルにより生成する硫酸との酸付加塩として、反応液から析出する化合物(1d)の硫酸塩をろ過、洗浄することにより、上記の抽出操作を行わずに単離精製することもできる。
Xは、ヨウ素原子又は臭素原子を示す。]
本発明の化合物(1)から製造した化合物(A-9)を用いて、高純度のFXa阻害薬の化合物(X)、及び化合物(X)のモノp-トルエンスルホン酸塩・1水和物である化合物(X-a)を製造する方法としては、特許文献1又は特許文献3に開示されている公知の方法を用いればよく、具体的には下記のスキーム及び後述の参考例に示すとおりである。
R4は、C1-C6アルキル基、ベンジル基(該ベンジル基のベンゼン環には、C1-C6アルキル基、C1-C6アルコキシ基、ニトロ基、及び、ハロゲン原子からなる群より選ばれる1~2個の基を置換基として有していてもよい)を示す。]
で表される化合物に関する。
R4は、C1-C6アルキル基又はベンジル基が好ましく;tert-ブチル基又はベンジル基がより好ましい。
R4は、C1-C6アルキル基、ベンジル基(該ベンジル基のベンゼン環には、C1-C6アルキル基、C1-C6アルコキシ基、ニトロ基、及び、ハロゲン原子からなる群より選ばれる1~2個の基を置換基として有していてもよい)を示し;
R6は、C1-C6アルキル基、ハロC1-C6アルキル基、フェニル基(該フェニル基は、C1-C6アルキル基、C1-C6アルコキシ基、ニトロ基、及び、ハロゲン原子からなる群より選ばれる1~2個の基を置換基として有していてもよい)を示す。]
で表される化合物に関する。
R6は、C1-C6アルキル基又は4-メチルフェニル基が好ましく;メチル基が特に好ましい。
R4は、C1-C6アルキル基、ベンジル基(該ベンジル基のベンゼン環には、C1-C6アルキル基、C1-C6アルコキシ基、ニトロ基、及び、ハロゲン原子からなる群より選ばれる1~2個の基を置換基として有していてもよい)を示す。]
で表される化合物に関する。
磁気共鳴スペクトル(NMR)における内部標準物質としては、テトラメチルシランを使用し、多重度を示す略語は、s=singlet、d=doublet、t=triplet、q=quartet、m=multiplet、及びbr s=broad singletを示す。
各種スペクトルデータは、文献記載[M. Chini, et al., Tetrahedron, 48(3), 539-544, 1992]のものと一致した。
また、本化合物は上記の酢酸エチル濃縮液から析出した結晶をろ過することにより単離することもできる。
HRMS: calculated for C9H16BrNO2,[M+H]+:m/z 249.0364; found: m/z 249.0437.
HRMS(ESI+): calculated for C9H16BrNO2,[M+H]+:m/z 250.0443; Found:m/z 250.0437.
(1S,3S,4S)-3-ヒドロキシ-4-ブロモ-N,N-ジメチルシクロヘキサンカルボキサミド(21.84g)の水溶液(50mL)に28%アンモニア水溶液(125mL)を加え、40℃に加温し、8時間攪拌し、室温で6時間攪拌した。反応混合物を50mLまで濃縮し、標題化合物14.33g(収率79%)を水溶液(49g)として得た。
(1R,2R,4S)-2-[(tert-ブトキシカルボニル)アミノ]-4-[(ジメチルアミノ)カルボニル]シクロヘキシルメタンスルホナート(A-6)(20.0g)のトルエン溶液(100ml)に、室温でアジ化ナトリウム(7.14g)及びドデシルピリジニウム クロリド(7.80g)を加えた。混合液を60℃で72時間攪拌後、室温に放冷した。反応液に水を加え、有機層を分取した。有機層を飽和重層水、水にて洗浄後、溶媒を留去した。
残渣にメタノールを加え、7.5%Pd-C及びギ酸アンモニウムを加えて40℃で1時間攪拌した。Pd-Cをろ過にて除去後、溶媒を減圧濃縮し、これに含水アセトニトリル(200ml)及び無水シュウ酸(4.94g)を加え、室温で17時間攪拌した。析出した結晶をろ取した。得られた結晶をアセトニトリル(200ml)に添加し、40℃で24時間攪拌した。析出した結晶をろ取・乾燥して標題化合物(1)(12.7g)を得た。
元素分析:C16H29N3O7.
理論値:C;50.70%、H;7.75%、N;10.96%.
実測値:C;51.19%、H;7.79%、N;11.19%.
tert-ブチル (1R,2S,5S)-2-アミノ-5-(ジメチルアミノカルボニル)シクロヘキシルカルバマート 1・シュウ酸塩(1)(100.1g)のアセトニトリル懸濁液(550ml)に、60℃にてトリエチルアミン(169ml)を加えた。そのままの温度にて、2-[(5-クロロピリジン-2-イル)アミノ]-2-オキソアセタート エチルエステル 1・塩酸塩(A-8)(84.2g)を加え、6時間攪拌後、室温にて16時間攪拌した。反応液に水を加え、10℃にて1時間30分攪拌後、結晶をろ取して標題化合物(A-9)(106.6g)を得た。
MS(ESI)m/z:548(M+H)+.
MS(ESI)m/z:548(M+H)+.
元素分析:C24H30ClN7O4S・C7H8O3S・H2O
理論値:C;50.43,H;5.46,N;13.28,Cl;4.80,S;8.69.
実測値:C;50.25,H;5.36,N;13.32,Cl;4.93,S;8.79.
mp(分解):245~248℃.
参考例5と同様の方法により調製した(1S,3R,4R)-3-アミノ-4-ヒドロキシ-N,N-ジメチルシクロヘキサンカルボキサミド(10.0g)の水溶液(34g)に、48%水酸化ナトリウム水溶液(11.2mL)を加え、約30分間攪拌した。反応混合物に、上記の方法により調製したバ-ジェス型試薬を約5分かけて添加し、調整液を塩化メチレン(5mL)で洗浄、滴下後、2時間攪拌した。反応混合物に、6mol/L塩酸水を加えてpH1.5に調整し、有機層を分離した。再度、水層を塩化メチレン(100mL)で抽出した。有機層を合致し、20%食塩水(50mL)で洗浄後、濃縮乾固し、得られた残渣に酢酸エチル(300mL)を加え、約100mLまで濃縮した。得られた濃縮液を約0℃に冷却し、約30分攪拌後、析出した結晶をろ取し、減圧乾燥した。得られた粗結晶を水(30mL)に添加して攪拌し、混合物をろ過し、水で洗浄した。得られた結晶を減圧乾燥し、標題化合物13.26g(収率68%)を結晶として得た。
HRMS(ESI-):calculated for C14H27N3O6S,[M-H]-: m/z 364.1542. Found m/z 364.1549.
tert-ブチルアルコ-ル(51ml)をアセトニトリル(600ml)に加え、約0℃に冷却し、クロロスルホニルイソシアナ-ト(46.3ml)を約20分かけて滴下した後、約15分間攪拌した。反応混合物にトリエチルアミン(156.3ml)を約30分かけて滴下後、さらに約30分間攪拌してバ-ジェス型試薬を調製した。
参考例4と同様の方法により調製した(1S,3R,4R)-3-アミノ-4-ヒドロキシ-N,N-ジメチルシクロヘキサンカルボキサミド(73.6g)の水溶液(229g)を約0℃に冷却し、48%水酸化ナトリウム水溶液(40.4ml)を加え、約30分間攪拌した。反応混合物に上記の方法により調製したバ-ジェス型試薬を滴下し、調製液をアセトニトリル(75ml)で洗浄、滴下後、約1時間攪拌した。反応混合物に6mol/l塩酸水(211ml)を加えてpH4に調整した後、アセトニトリルを留去した。濃縮した反応混合物に酢酸エチル(750ml)と水(75ml)を加え、激しく攪拌し、有機層を分離した。再度、水層を酢酸エチル(750ml)で抽出した。合わせた有機層を、22%食塩水(380ml)で洗浄後、濃縮した。得られた残渣にアセトニトリル(750ml)を加え、濃縮した。再度、残渣にアセトニトリル(750ml)を加え、濃縮して標題化合物(138.5g,収率96%)をアセトニトリルスラリー液(300ml)として得た。本液から一部単離した成績物の各種機器スペクトルは実施例1のものと一致した。
tert-ブチルアルコ-ル(5.56ml)をアセトニトリル(60ml)に加え、約0℃に冷却し、クロロスルホニルイソシアナ-ト(5.06ml)を約10分かけて滴下した後、約15分間攪拌した。反応混合物にトリエチルアミン(17.1ml)を約15分かけて滴下後、約30分間攪拌してバ-ジェス型試薬を調製した。
参考例4と同様の方法により調製した(1S,3R,4R)-3-アミノ-4-ヒドロキシ-N,N-ジメチルシクロヘキサンカルボキサミド(6.43g)の水溶液(46.5g)に25%水酸化ナトリウム水溶液(9.14ml)を加え、約30分間攪拌した。この混合物を、上記の方法により調製したバ-ジェス型試薬の中に約10分間かけて滴下し、滴下後3時間攪拌した。反応混合物からにアセトニトリルを留去し、酢酸エチル(75ml)、クエン酸(4.21g)を加えてpH4に調整した後、激しく攪拌し、有機層を分離した。再度、水層を酢酸エチル(75ml)で抽出した。合わせた有機層を、20%食塩水(38ml)で洗浄後、濃縮した。得られた残渣にアセトニトリル(75ml)を加え、濃縮した。再度、残渣にアセトニトリル(75ml)を加え、濃縮して標題化合物(12.1g,収率96%)をアセトニトリル溶液(30ml)として得た。本液から一部単離した成績物の各種機器スペクトルは実施例1のものと一致した。
tert-ブチル {(1R,2R,5S)-5-[(ジメチルアミノ)カルボニル]-2-ヒドロキシシクロヘキシル}カルバメート(国際公開第2007/032498号)の実施例12)(3.00g)に6mol/l-塩酸水(15.00mL)を加えて約30分攪拌した。反応混合物に48%水酸化ナトリウム水溶液(9.7ml)を加え、引き続き調製したバ-ジェス型試薬を塩化メチレン(5mL)を用いて約5分かけて添加し、さらに室温で約2時間攪拌した。
反応終了を確認後、6mol/l-塩酸水を加えてpH1.5に調整し、有機層を分離した。再度、水層を塩化メチレン(100mL)で抽出した。有機層を合わせ、シリカゲルクロマトグラフィーにて精製し、標題化合物2.22g(収率53%)を油状化合物として得た。
HRMS(ESI-): calculated for C15H29N3O8S2,M-H- m/z 442.1318. Found m/z 442.1326.
{[(1R,2R,5S)-5-(ジメチルカルバモイル)-2-ヒドロキシシクロヘキシル]スルファモイル}カルバミン酸tert-ブチル(12.1g)のアセトニトリル溶液(30ml)に、アセトニトリル(30ml)を加え、約0℃に冷却した後、メタンスルホニルクロリド(3.77ml)を加えた。反応混合物にN-メチルモルホリン(6.81ml)を滴下し、約3時間攪拌した。反応混合物に水(61ml)を加えた後、6mol/l塩酸水を加えてpH3に調整し、さらに水(93ml)を加えて約15時間攪拌した。析出固形物をろ取し、27.5%アセトニトリル水溶液(30ml)で洗浄した。得られた固形物を減圧乾燥し、標題化合物(13.0g,収率89%)を得た。成績物の各種機器スペクトルは、実施例5で製造したものと一致した。
tert-ブチルアルコ-ル(117ml)、アセトニトリル(550ml)を混合し、約0℃に冷却した後、クロロスルホニルイソシアナ-ト(101ml)を3時間かけて滴下した。得られた反応液をアセトニトリル(650ml)とトリエチルアミン(480ml)の混合液に約4時間かけて滴下し、バ-ジェス型試薬のアセトニトリル溶液を調製した。
参考例6と同様の方法により調製した(1S,3R,4R)-3-アミノ-4-ヒドロキシ-N,N-ジメチルシクロヘキサンカルボキサミド(147.52g)の水溶液を約5℃に冷却し、25%水酸化ナトリウム水溶液(184ml)を加えた。この溶液を上記のバ-ジェス型試薬のアセトニトリル溶液の中へ約30分間かけて滴下し、水(100ml)を加えた後、約5℃で約5時間攪拌した。得られた反応液を約1400mlまで濃縮し、酢酸エチル(1500ml)、クエン酸(74.96g)、水(100ml)を加え、約40℃に加温、攪拌し、静置後、有機層を分離した。水層を酢酸エチル(1500ml)にて再抽出し、有機層を合致した後、20%食塩水(760ml)で洗浄し、約1000mlまで濃縮した。得られた濃縮液にアセトニトリル(1500ml)を加え、約600mlまで濃縮した後、アセトニトリル(1500ml)を加えて、濃縮し、{[(1R,2R,5S)-5-(ジメチルカルバモイル)-2-ヒドロキシシクロヘキシル]スルファモイル}カルバミン酸tert-ブチルのアセトニトリル溶液(約600ml)を得た。このアセトニトリル溶液(約600ml)にアセトニトリル(600ml)を加え、約5℃に冷却し、メタンスルホニルクロリド(77ml)を添加した後、N-メチルモルホリン(136ml)を約15分かけて滴下した。混合液を約3時間攪拌した後、水(100ml)と濃塩酸(49.39g)を添加した。この反応混合液を約5℃に冷却した水(2980ml)にゆっくりと添加後、約12時間攪拌し、析出した結晶をろ取した。結晶ケーキを27%アセトニトリル水溶液(600ml)及びトルエン(400ml)にて洗浄した後、減圧乾燥し、標題化合物(284.44g)を得た。
HRMS(ESI-): calculated for C14H25N3O5S,M-H- m/z 346.1437. Found m/z 346.1446.
{[(1R,2R,5S)-5-(ジメチルカルバモイル)-2-ヒドロキシシクロヘキシル]スルファモイル}カルバミン酸ベンジル(1.00g)を塩化メチレン(10ml)に加え、トリエチルアミン(1.76ml)を添加した後、メタンスルホニルクロリド(0.28ml)を滴下し、約1時間攪拌した。反応混合物にトリエチルアミン(2.00ml)を加え、約80℃に加温し、約4時間攪拌した。反応混合物を薄層クロマトグラフィーにて精製して標題化合物545mg(収率57%)を油状物として得た。
HPLC条件
検出:210nm
カラム:L-Colunm ODS(4.6mmID×250mm,5μm)
流速:1.0ml/分
移動相:A液:10mM酢酸アンモニウム水溶液、B液:MeCN
グラジエント条件(B液の濃度):10→80%(0-15分)、80%(15-17分)、10%(17.01-23分)
(実施例12と同じHPLC条件にて分析)
得られた化合物(1)の各種スペクトルデータは、国際公開第2007/032498号に記載のものと一致した。
(1R,2R,4S)-2-{[(tert-ブトキシカルボニル)スルファモイル]アミノ}-4-(ジメチルカルバモイル)シクロヘキシル=メタンスルホネ-ト(80g)にアセトニトリル(360ml)、トリエチルアミン(26.6ml)を加え、約70℃に加温し、約2時間攪拌し(3aS,6S,7aR)-6-(ジメチルカルバモイル)-2,2-ジオキソヘキサヒドロ-2,1,3-ベンゾチアジアゾ-ル-1(3H)-カルボン酸tert-ブチルのアセトニトリル溶液(467ml)を得た。
上記のアセトニトリル溶液(467ml)に水(20ml)、ピリジン(80ml)を添加し、約75℃まで加温した後、約6時間攪拌した。反応液を約50℃まで冷却し、水(80ml)、トルエン(800ml)、20%食塩水(80ml)、25%水酸化ナトリウム溶液(120ml)を添加後、静置し、有機層を分離した。得られた有機層を20%食塩水(80ml)、25%水酸化ナトリウム溶液(16ml)で順次洗浄した後、得られた有機層を約240mlまで濃縮した。濃縮液にトルエン(320ml)を加え約240mlまで濃縮を行う操作を2回行い、濃縮液にアセトニトリル(400ml)を添加し、不溶物をろ過により除去し、(1R,2S,5S)-2-アミノ-5-[(ジメチルアミノ)カルボニル]シクロヘキシルカルバミン酸tert-ブチルのアセトニトリル溶液(溶液量約640ml)を得た。
シュウ酸(16.24g)をアセトニトリル(640ml)、水(40ml)に添加し、約35℃に加温した。この溶液に、上記の方法により調製した(1R,2S,5S)-2-アミノ-5-[(ジメチルアミノ)カルボニル]シクロヘキシルカルバミン酸tert-ブチルのアセトニトリル溶液(約640ml)を滴下し、約35℃で約1時間攪拌した後、約25℃まで冷却し約1時間攪拌した。析出した結晶をろ過し、7%含水アセトニトリル(300ml)にて洗浄し、標題化合物の一水和物((1R,2S,5S)-2-アミノ-5-[(ジメチルアミノ)カルボニル]シクロヘキシルカルバミン酸tert-ブチル シュウ酸塩一水和物)を得た。この標題化合物の一水和物にアセトニトリル(560ml)を添加後、約70℃に加温した。同温度にて約5時間攪拌した後、約320mlまで濃縮を行い、濃縮液にアセトニトリル(320ml)を加え、約25℃まで冷却した。析出した結晶をろ過し、アセトニトリル(80ml)で洗浄後、減圧乾燥し、標題化合物の無水物(55.74g,収率82%)を得た。
Claims (27)
- 下記式(1d)
[式中、R1aは、ジ(C1-C6アルキル)アミノ基を示し;
R4は、C1-C6アルキル基、ベンジル基(該ベンジル基のベンゼン環には、C1-C6アルキル基、C1-C6アルコキシ基、ニトロ基、及び、ハロゲン原子からなる群より選ばれる1~2個の基を置換基として有していてもよい)を示す。]
で表される化合物、その塩又はそれらの水和物の製造方法であって、下記式(4)
(式中、R1aは上記と同義を示す。)
で表される化合物を、下記の[溶液A]
[溶液A]
溶媒中、下記式(I)
R4-OH (I)
(式中、R4は前記と同義を示す。)
で表される化合物を、クロロスルホニルイソシアナート及び三級アミンと処理して溶液Aを調製する;若しくは、下記の[試薬B]
[試薬B]
下記式(II)
[式中、R4は、C1-C6アルキル基、ベンジル基(該ベンジル基のベンゼン環には、C1-C6アルキル基、C1-C6アルコキシ基、ニトロ基、及び、ハロゲン原子からなる群より選ばれる1~2個の基を置換基として有していてもよい)を示し;
R21及びR22は、次の(a)、(b)又は(c)を示す。
(a)同一又は異なって、C1-C6アルキル基;
(b)R22はC1-C6アルキル基を示し、2つのR21は、R21の結合する窒素原子と一緒になってピペリジン環、ピロリジン環又は1,4-モルホリン環を形成する;
(c)2つのR21及びR22、及び、R22、R21の結合する窒素原子と一緒になって1,4-ジアザビシクロ[2.2.2]オクタン環及びキヌクリジン環を形成する。]
で示される化合物;
と処理して得られる、下記式(5)
(式中、R1a及びR4は、上記と同義を示す。)
で表される化合物を、塩基の存在下、下記式(III)
R6SO2X (III)
[式中、R6は、C1-C6アルキル基、ハロC1-C6アルキル基、フェニル基(該フェニル基は、C1-C6アルキル基、C1-C6アルコキシ基、ニトロ基、及び、ハロゲン原子からなる群より選ばれる1~2個の基を置換基として有していてもよい)を示し;
Xはハロゲン原子を示す。]
で表される化合物と処理して得られる、下記式(6a)
(式中、R1a、R4及びR6は上記と同義を示す。)
で表される化合物を、塩基と処理して得られる、下記式(8c)
(式中、R1a及びR4は上記と同義を示す。)
で表される化合物を、脱スルホニル化を行うことを特徴とする、式(1d)で表される化合物、その塩又はそれらの水和物の製造方法。 - 脱スルホニル化が、水及び塩基と処理するものである、請求項1に記載の製造方法。
- 塩基がピリジン類である、請求項2に記載の製造方法。
- 下記式(4)
[式中、R1aは、ジ(C1-C6アルキル)アミノ基を示す。]
で表される化合物を、下記の[溶液A]と処理することを特徴とする、下記式(5)
[式中、R4は、C1-C6アルキル基、ベンジル基(該ベンジル基のベンゼン環には、C1-C6アルキル基、C1-C6アルコキシ基、ニトロ基、及び、ハロゲン原子からなる群より選ばれる1~2個の基を置換基として有していてもよい)を示し;
R1aは上記と同義を示す。]
で表される化合物の製造方法。
[溶液A]
溶媒中、下記式(I)
R4-OH (I)
(式中、R4は前記と同義を示す。)
で表される化合物を、クロロスルホニルイソシアナート及び三級アミンと処理して溶液Aを調製する。 - 下記式(4)
[式中、R1aは、ジ(C1-C6アルキル)アミノ基を示す。]
で表される化合物を、下記の[試薬B]と処理することを特徴とする、下記式(5)
(式中、R1a及びR4は、上記と同義を示す。)
で表される化合物の製造方法。
[試薬B]
下記式(II)
[式中、R4は、C1-C6アルキル基、ベンジル基(該ベンジル基のベンゼン環には、C1-C6アルキル基、C1-C6アルコキシ基、ニトロ基、及び、ハロゲン原子からなる群より選ばれる1~2個の基を置換基として有していてもよい)を示し;
R21及びR22は、次の(a)、(b)又は(c)を示す。
(a)同一又は異なって、C1-C6アルキル基;
(b)R22はC1-C6アルキル基を示し、2つのR21は、R21の結合する窒素原子と一緒になってピペリジン環、ピロリジン環又は1,4-モルホリン環を形成する;
(c)2つのR21及びR22、及び、R22、R21の結合する窒素原子と一緒になって1,4-ジアザビシクロ[2.2.2]オクタン環及びキヌクリジン環を形成する。]
で表される化合物。 - R21及びR22が、エチル基である、請求項1又は5に記載の製造方法。
- 下記式(5)
[式中、R1aは、ジ(C1-C6アルキル)アミノ基を示し;
R4は、C1-C6アルキル基、ベンジル基(該ベンジル基のベンゼン環には、C1-C6アルキル基、C1-C6アルコキシ基、ニトロ基、及び、ハロゲン原子からなる群より選ばれる1~2個の基を置換基として有していてもよい)を示す。]
で表される化合物を、塩基の存在下、下記式(III)
R6SO2X (III)
(式中、R6は、C1-C6アルキル基、ハロC1-C6アルキル基、フェニル基(該フェニル基は、C1-C6アルキル基、C1-C6アルコキシ基、ニトロ基、及び、ハロゲン原子からなる群より選ばれる1~2個の基を置換基として有していてもよい)を示し;
Xはハロゲン原子を示す。]
で表される化合物と処理することを特徴とする、下記式(6a)
(式中、R1a、R4及びR6は上記と同義を示す。)
で表される化合物の製造方法。 - R6がC1-C6アルキル基である、請求項1又は7に記載の製造方法。
- R6が、メチル基である、請求項1又は7に記載の製造方法。
- 下記式(6a)
[式中、R1aは、ジ(C1-C6アルキル)アミノ基を示し;
R4は、C1-C6アルキル基、ベンジル基(該ベンジル基のベンゼン環には、C1-C6アルキル基、C1-C6アルコキシ基、ニトロ基、及び、ハロゲン原子からなる群より選ばれる1~2個の基を置換基として有していてもよい)を示し;
R6は、C1-C6アルキル基、ハロC1-C6アルキル基、フェニル基(該フェニル基は、C1-C6アルキル基、C1-C6アルコキシ基、ニトロ基、及び、ハロゲン原子からなる群より選ばれる1~2個の基を置換基として有していてもよい)を示す。]
で表される化合物を、塩基と処理することを特徴とする、下記式(8c)
(式中、R1a及びR4は前記と同義を示す。)
で表される化合物の製造方法。 - 脱スルホニル化が、水及び塩基と処理するものである、請求項11に記載の製造方法。
- 塩基がピリジン類である、請求項12に記載の製造方法。
- R1aがジ(メチル)アミノ基である、請求項1~13のいずれか1項に記載の製造方法。
- R4が、tert-ブチル基又はベンジル基である、請求項1~14のいずれか1項に記載の製造方法。
- 式(1d)で表される化合物、その水和物又はそれらの水和物が、式(1d)で表される化合物の硫酸塩、式(1d)で表される化合物のシュウ酸塩・1水和物、又は、式(1d)で表される化合物のシュウ酸塩である、請求項14~15のいずれか1項に記載の製造方法。
- 下記式(1b)
[式中、R1は、C1-C6アルコキシ基又はジ(C1-C6アルキル)アミノ基を示し;
R2及びR3は、それぞれ独立して、水素原子、C1-C6アルコキシカルボニル基、ベンジルオキシカルボニル基(該ベンジル基のベンゼン環には、C1-C6アルキル基、C1-C6アルコキシ基、ニトロ基、及び、ハロゲン原子からなる群より選ばれる1~2個の基を置換基として有していてもよい)を示す。]
で表される化合物、その塩又はそれらの水和物の製造方法であって、下記式(8a)
(式中、R1、R2及びR3は上記と同義を示す。)
で表される化合物を、脱スルホニル化を行うことを特徴とする、式(1b)で表される化合物、その塩又はそれらの水和物の製造方法。 - R6がC1-C6アルキル基である、請求項20に記載の化合物。
- R6がメチル基である、請求項20に記載の化合物。
- R1aがジ(メチル)アミノ基である、請求項19~23のいずれか1項に記載の化合物。
- R4が、tert-ブチル基又はベンジル基である、請求項19~23のいずれか1項に記載の化合物。
- 下記式(X-a)
で表される化合物を、水及び塩基と処理して得られる、下記式(1f)
で表される化合物のシュウ酸塩又は硫酸塩を、塩基の存在下に、下記式(A-8)
で表される化合物を、脱保護し、得られる下記式(A-10)
からなる、式(X-a)で表される化合物の製造方法。 - R4aがtert-ブチル基である、請求項26に記載の製造方法。
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CN201480010561.8A CN105008325B (zh) | 2013-03-29 | 2014-03-28 | 光学活性二胺化合物的制备方法 |
US14/805,123 US9447118B2 (en) | 2013-03-29 | 2015-07-21 | Preparation method of optically active diamine compound |
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CN104761571A (zh) * | 2015-03-10 | 2015-07-08 | 山东科兴生物制品有限公司 | 一种依度沙班的合成方法 |
CN106316889A (zh) * | 2015-06-15 | 2017-01-11 | 上海阳帆医药科技有限公司 | 依度沙班中间体的制备方法 |
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KR20210066404A (ko) | 2019-11-28 | 2021-06-07 | 동방에프티엘(주) | 광학 활성 다이아민 유도체 및 티아졸 유도체의 생산을 위한 새로운 합성경로 |
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EP2980067A4 (en) | 2016-10-26 |
US9447118B2 (en) | 2016-09-20 |
KR20150134345A (ko) | 2015-12-01 |
US20160016974A1 (en) | 2016-01-21 |
CA2897731A1 (en) | 2014-10-02 |
IL241771B (en) | 2018-03-29 |
BR112015019667A2 (pt) | 2017-07-18 |
KR102084413B1 (ko) | 2020-03-04 |
TWI602803B (zh) | 2017-10-21 |
CA2897731C (en) | 2017-11-07 |
ES2637272T3 (es) | 2017-10-11 |
EP2980067A1 (en) | 2016-02-03 |
CN105008325B (zh) | 2016-10-19 |
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EP2980067B1 (en) | 2017-05-17 |
HK1220964A1 (zh) | 2017-05-19 |
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