WO2019004114A1 - Production method for diamine derivative by flow synthesis - Google Patents

Production method for diamine derivative by flow synthesis Download PDF

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WO2019004114A1
WO2019004114A1 PCT/JP2018/023984 JP2018023984W WO2019004114A1 WO 2019004114 A1 WO2019004114 A1 WO 2019004114A1 JP 2018023984 W JP2018023984 W JP 2018023984W WO 2019004114 A1 WO2019004114 A1 WO 2019004114A1
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compound represented
group
following formula
formula
solution
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PCT/JP2018/023984
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Japanese (ja)
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誠 道田
秀明 石河
伸也 立壁
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第一三共株式会社
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    • C—CHEMISTRY; METALLURGY
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • 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
    • 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
    • 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
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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

Definitions

  • the present invention relates to a method for producing useful synthetic intermediates for efficiently synthesizing edoxaban which is a direct oral anticoagulant (DOAC: Direct Oral AntiCoagulant).
  • DOAC Direct Oral AntiCoagulant
  • Edoxaban selectively and reversibly activates Activated Blood Coagulation Factor X or FXa, which has the function of forming thrombin from prothrombin in the blood coagulation cascade and promoting thrombus formation to form a thrombus. And it is DOAC which expresses thrombus formation inhibitory effect by inhibiting directly.
  • Edoxaban has the following formula (X)
  • Edoxaban may be a solvate (including a hydrate) or a pharmacologically acceptable salt or a solvate (including a hydrate) thereof.
  • a pharmacologically acceptable salt or a solvate thereof preferably, the following formula (Xa):
  • Examples of methods for producing edoxaban, pharmaceutically acceptable salts thereof, and solvates thereof include the methods described in Patent Documents 5 and 6, for example. That is, the compound (1-1) was converted to the compound (1-2) by treating the compound (1-1) with a Burgess-type reagent prepared from chlorosulfonyl isocyanate, tert-butyl alcohol, and triethylamine as shown in the following formula. After that, methanesulfonylation reaction, treatment with a base, and then reaction with oxalic acid to obtain an intermediate compound (1-5), and further performing an appropriate conversion from compound (1-5) to edoxaban (X) and its tosylate hydrate (Xa) are obtained.
  • a Burgess-type reagent prepared from chlorosulfonyl isocyanate, tert-butyl alcohol, and triethylamine as shown in the following formula. After that, methanesulfonylation reaction, treatment with a base,
  • Boc represents a tert-butoxycarbonyl group
  • Ms represents a methanesulfonyl group
  • the compound (2-) which is an intermediate in preparing the Burgess-type reagent (2-3) from chlorosulfonyl isocyanate (2-1) by tert-butyl alcohol and triethylamine by a conventional batch method, It was found that the yield and the purity of the compound (1-2) were lowered because 2) was easily decomposed and the decomposition product was reacted with the compound (1-1) as the raw material.
  • the object of the present invention is to suppress the decomposition of the compound (2-2) and to suppress the decrease in the yield and the purity of the compound (1-2), whereby the compound (1-3) and edoxaban, which are important intermediates of edoxaban, To provide an efficient and high purity method.
  • the present invention relates to the following [1] to [14].
  • R 1 is a C1-C6 alkyl group or a benzyl group (the benzene ring of the benzyl group is independently 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 a substituent))
  • R 2 represents a C 1 -C 6 alkyl group, a halo C 1 -C 6 alkyl group, or a phenyl group (wherein the phenyl group represents a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a nitro group and a halogen atom More preferably selected from 1 to 2 groups as substituents);
  • X represents a halogen atom
  • a process for producing the compound represented by and comprising the following steps 1 to 6 Process 1) Following formula (5) manufactured using the manufacturing method as described in [3] or [4]
  • Step 2 The compound represented by Formula 7 obtained in Step 1) is treated with water and pyridines to obtain the following Formula (6)
  • Step 6 A compound represented by the formula (Xa) by treating a compound represented by the formula (X) obtained in the step 5) with p-sulenesulfonic acid monohydrate in water-containing ethanol To get [7] The process according to any one of [1] to [6], wherein R 1 is a tert-butyl group or a benzyl group. [8] The process according to any one of [3] to [7], wherein R 2 is a methyl group. [9] The process according to any one of [1] to [8], wherein the flow rate of the flow reactor is 0.1 ml / min to 10 L / min.
  • edoxaban important intermediates in producing edoxaban can be synthesized in high yield and high purity.
  • BRIEF DESCRIPTION OF THE DRAWINGS The schematic diagram of the flow reaction apparatus used for the Example of this invention.
  • a and B are respectively reagent inlets (feed A and feed B) equipped with pumps capable of controlling the flow rate, C indicates a reactor portion (tube reactor) as a reaction field, and D indicates a reaction vessel .
  • BRIEF DESCRIPTION OF THE DRAWINGS The reaction by the flow synthesis apparatus of Example 1 of this invention is illustrated typically.
  • Fig. 6 schematically shows a reaction by the flow synthesis apparatus of Example 2 of the present invention.
  • halogen atom in the present specification means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • C1-C6 alkyl group means a monovalent group consisting 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 in the present specification means 1 to 5 identical or different C1-C6 alkyl groups substituted with the above-mentioned halogen atom.
  • halo C1-C6 alkyl for example, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, fluoroethyl (meaning both 1-fluoroethyl and 2-fluoroethyl), 2, Includes all of 2-difluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoroethyl, fluoropropyl (3-fluoropropyl, 2-fluoropropyl, 1-fluoropropyl Can be mentioned.
  • 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.
  • phenyl group in the present specification means a monovalent group which may have a substituent on the benzene ring, and the phenyl group is the same or different and is a C1-C6 alkyl group, C1-C6. It may have 1 to 2 groups independently selected from the group consisting of an alkoxy group, a nitro group and a halogen atom as a substituent.
  • phenyl examples include phenyl, p- (or o-) methylphenyl, p- (or o-) methoxyphenyl, 3,4-dimethoxyphenyl, p- (or o-) nitrophenyl, Chlorophenyl, 2,4-dichlorophenyl and the like can be mentioned.
  • benzyl group as used herein means a monovalent group formed from a methyl group substituted with a phenyl group which may be substituted, and the benzene rings of the benzyl group may be the same or different, C1 It may have 1 to 2 groups independently selected from the group consisting of —C 6 alkyl group, C 1 -C 6 alkoxy group, nitro group and halogen atom as a substituent.
  • examples of benzyl include benzyl, p- (or o-) methylbenzyl, p- (or o-) methoxybenzyl, 3,4-dimethoxybenzyl, p- (or o-) nitrobenzyl, Chlorobenzyl, 2,4-dichlorobenzyl and the like can be mentioned.
  • pyridines are pyridine, and picoline (the picoline includes any isomer of ⁇ -picoline, ⁇ -picoline and ⁇ -picoline), lutidine (the lutidine is 2,3 -Collidine (which includes all isomers of lutidine, 2,4-lutidine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine and 3,5-lutidine), collidine (the collidine is 3,4-collidine, 2,3,5-collidine, 2,3,6-collidine, 2,4,5-collidine, 2,4,6-collidine, or any isomer of 3,4,5-collidine And also includes pyridine derivatives in which hydrogen on the pyridine ring is substituted with another group such as 4-dimethylaminopyridine and the like.
  • 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-Chloropyridine-2-yl) -N 2 -(( lS, 2R, 4S) -4-[(dimethylamino) carbonyl] -2- ⁇ [(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-yl) carbonyl] amino (Cyclohexyl) ethanolideamide) is a free form of the compound represented by the formula (Xa), and in the World Health Organization (WHO), International Nonproprietary Names (INN):
  • the above compound (X) may be a pharmacologically acceptable salt thereof, or may be a hydrate of them, but the following formula (Xa):
  • 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 p-toluenesulfonic acid salt monohydrate is preferred.
  • the flow reaction apparatus used in the present invention is a reaction apparatus in which a reaction is performed in a pipe while continuously sending a solution containing two or more kinds of liquid compounds or compounds in the pipe.
  • the flow reactor generally comprises a pump portion for delivering the compounds and reagents into the device, a mixer portion for mixing two or more compounds and reagents, and a reactor portion for reaction.
  • the pump is not particularly limited, but a common syringe pump or plunger pump can be used.
  • various types of basic Y-shaped, V-shaped or T-shaped can be used in the present invention.
  • a tube type tube reactor is preferable, and what the temperature control apparatus was attached is more preferable.
  • various materials can be used according to the type of reaction, reaction conditions, etc., and stainless steel, glass, aluminum, copper, fluorine resin, etc. can be used appropriately.
  • a pump When performing a flow reaction, a pump is generally used to deliver a liquid reagent or a solution containing the reagent to the mixer part and the subsequent reactor part.
  • the liquid transfer rate varies depending on the type of reaction, reaction conditions and the like, but in the present invention is selected from 0.1 ml / min to 10 L / min, preferably 0.1 ml / min to 6 L / min.
  • the mixing time of the liquids is proportional to the square of the inner diameter of the flow passage, and the smaller inner diameter of the flow passage is advantageous for mixing, and the heat exchange efficiency is also increased.
  • the inner diameter of the flow path is preferably in the range of 0.1 to 50 mm, more preferably 0.5 to 25 mm.
  • the flow path length of the reactor portion is different.
  • the residence time may be within 10 to 120 seconds, preferably 15 to 90 seconds.
  • the reaction temperature can be controlled using a temperature controller.
  • the reaction temperature is not particularly limited in the present invention, but the reaction temperature is preferably room temperature or less, more preferably about 0 ° C.
  • R 1 represents a C1-C6 alkyl group or a benzyl group (wherein the benzene ring of the benzyl group is independently selected from the group consisting of a C1-C6 alkyl group, a C1-C6 alkoxy group, a nitro group and a halogen atom
  • R 2 represents a C 1 -C 6 alkyl group, a halo C 1 -C 6 alkyl group, or a phenyl group (the phenyl group is a C 1 -C 6 alkyl group).
  • X represents a halogen, which may have 1 to 2 groups independently selected from the group consisting of a C6 alkyl group, a C1 to C6 alkoxy group, a dibasic group and a halogen atom; Indicates an atom]
  • Step a-1 Step of Synthesizing Compound (A-2)
  • R 1 represents the same as the above
  • Step a-1 is a step of sulfonylating the amino group of compound (A-1) to obtain compound (A-2).
  • the sulfonylation reagent [solution A] is prepared as follows using a flow reactor.
  • R 1 in R 1 -OH is C 1 -C 6 alkyl group or benzyl group (the benzene ring of the benzyl group is independently selected from the group consisting of C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, nitro group and halogen atom It may have 1 to 2 groups selected as a substituent), preferably a tert-butyl group or a benzyl group.
  • reaction solvents used in preparation of solution A include diethyl ether, di-n-propyl ether, diisopropyl ether, ethereal solvents such as tetrahydrofuran hydrofuran, methyl tert-butyl ether or cyclopentyl methyl ether; 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; Nitrogen-containing solvents such as acetonitrile, N, N-dimethylformamide, N, N-dimethylacetoamide or N-methylpyrrolidone; ketone solvents such as acetone
  • tertiary amines used in preparation of solution A include, for example, triethylamine, diisopropylethylamine, N-methylmorpholine, piperidine, pyrrolidine, tributylamine, 1,4-diazabicyclo [2.2.2] octane, quinuclidine, etc. Is preferred, and triethylamine is particularly preferred.
  • the reaction temperature (including both the reaction temperature in the flow reactor and the reaction temperature when added dropwise to the tertiary amine) when preparing the solution A is preferably a temperature below room temperature, and more preferably about 0 ° C.
  • the inner diameter of the flow path of the tube reactor at that time is preferably in the range of 0.1 to 50 mm, more preferably 0.5 to 25 mm.
  • the compound (A-2) can be produced by adding the compound (A-1) separately synthesized to the solution A dropwise and reacting at about 0 ° C.
  • a base may be added, and as a base to be used, any of an inorganic base and an organic base can be used, but an inorganic base is preferable.
  • the inorganic base hydroxides and carbonates of alkali metals or alkaline earth metals can be mentioned as preferable, and lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate are preferable, and It is preferred to use an aqueous solution.
  • the amount of the base added is preferably such that the reaction mixture can maintain its neutrality to basicity.
  • the temperature at which the compound (A-1) is added to the [solution A] and the reaction temperature after the addition are preferably 0 ° C. to room temperature, and the reaction time is about 0.5 to 5 hours.
  • an aqueous solution of a mineral acid such as hydrochloric acid or an organic acid such as citric acid is added to the reaction solution to make the pH weakly acidic, and then extracted with an organic solvent such as ethyl acetate to obtain a compound (A-2) Is obtained.
  • Step a-2 Step of Synthesizing Compound (A-3)
  • R 2 represents a C 1 -C 6 alkyl group, a halo C 1 -C 6 alkyl group, or a phenyl group (wherein the phenyl group represents a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a nitro group and a halogen atom
  • X 1 represents a halogen atom; and R 1 represents the same as the above].
  • step (a-2) the alcohol moiety of the compound (A-2) is reduced to the following formula (4) in the presence of a base:
  • a methyl group, an ethyl group, a phenyl group or a 4-methylphenyl group (p-tolyl group) is preferable, and a methyl group is particularly preferable.
  • 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, etc .; methyl acetate, acetic acid Ester solvents such as ethyl acetate, propyl acetate, butyl acetate or phenyl acetate; halogenated hydrocarbon solvents such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane or tetrachloroethane; aromatic hydrocarbons such as benzene, chlorobenzene, toluene or xylene Solvents; nitrogen-containing solvents such as acetonitrile; ketone solvents; nitrogen-containing solvents such as acetonit
  • an organic base or an inorganic base can be used, but an organic base is preferred, and a tertiary amine such as triethylamine, tributylamine or N, N-diisopropylethylamine, 1,1, 8-Diazabicyclo [5.4.0] undec-7-ene (DBU), 1,8-diazabicyclo [4.3.0] non-5-ene (DBN), dimethylaniline, pyridine, 2,6-lutidine, N-methyl Imidazole or N-methyl morpholine etc. can be used.
  • a tertiary amine such as triethylamine, tributylamine or N, N-diisopropylethylamine, 1,1, 8-Diazabicyclo [5.4.0] undec-7-ene (DBU), 1,8-diazabicyclo [4.3.0] non-5-ene (DBN), dimethylaniline, pyridine, 2,6-lutidine, N-methyl I
  • tertiary amines such as triethylamine or N, N-diisopropylethylamine, N-methylmorpholine, pyridine, 2,6-lutidine or N-methylimidazole are preferable. Particular preference is given to triethylamine, N-methylmorpholine or 2,6-lutidine.
  • the amount of the base to be used is generally in the range of 0.8 to 5 molar equivalents stoichiometrically to the compound (A-2), preferably about 1 to 2 molar equivalents.
  • methanesulfonyl chloride, ethanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride and the like are preferable, and methanesulfonyl chloride is more preferable.
  • the amount of the compound (4) to be used is generally in the range of 0.8 to 3 molar equivalents stoichiometrically to the compound (A-2), preferably about 1 to 1.5 molar equivalents.
  • the reaction temperature of (Step a-2) is preferably 40 ° C. or less, and more preferably about 0 ° C.
  • the reaction time is usually about 0.5 to 15 hours.
  • the compound (A-1) [or the aqueous solution of the compound (A-1)] used in the above (Step a-1) can be prepared from the compound (B-1) to the compound (B-) as shown in Scheme B below. 2) and the compound (B-3), it can be produced by known methods.
  • Boc represents a tert-butoxycarbonyl group.
  • the compound (A-2) [compound (3)] and the compound (A-3) [compound (5)] obtained by the present invention are the compound (C-4), which is an important synthetic intermediate, and FXa It is useful as a synthetic intermediate of compounds (X) and (Xa) which are inhibitors.
  • the combined solution was concentrated under reduced pressure to a volume of 550 mL.
  • tap water 220 mL
  • concentrated under reduced pressure to a volume of 275 mL.
  • tap water 1450 mL
  • aqueous ammonia 688 mL, 28%)
  • aqueous sodium hydroxide 68 mL, 25%
  • the stirred solution was concentrated under reduced pressure to a volume of 550 mL.
  • the obtained solution contained 70.81 g of the title compound (HPLC quantitative value, 86.5% yield).
  • Boc represents a tert-butoxycarbonyl group.
  • the stirred solution was concentrated under reduced pressure to a volume of 140 mL.
  • Citric acid (7.50 g) and ethyl acetate (220 mL) were added to the obtained solution, and a liquid separation operation was performed.
  • the aqueous layer was extracted with ethyl acetate (80 mL) added.
  • brine (76 mL, 20%) was added to the organic layer obtained by the separation operation.
  • the aqueous layer was mixed with the organic layer obtained by the extraction operation, and a liquid separation operation was performed.
  • the two obtained organic layers were combined and concentrated under reduced pressure to a volume of 100 mL.
  • Acetonitrile (50 mL) was added to the obtained solution, and the solution was concentrated under reduced pressure to a volume of 60 mL. This operation was repeated 5 times.
  • Acetonitrile (60 mL), methanesulfonyl chloride (11.17 g, 98 mmol) and N-methylmorpholine (12.53 g, 124 mmol) were added to the obtained solution, and the mixture was stirred at 5 ° C. for 13 hours.
  • Aqueous sulfuric acid solution 13 mL, 5% was added to the resulting solution.
  • the obtained aqueous solution was added to tap water (246 mL), tap water (40 mL) and acetonitrile (8 mL) were added, and the mixture was stirred at 5 ° C. for 3 hours and filtered through a Kiriyama funnel.
  • the crystals were washed with a mixture of acetonitrile (17 mL) and tap water (44 mL), toluene (40 mL).
  • the crystals obtained were dried at 50 ° C. under reduced pressure, and 28.5 g of the title crystals (content 97.2%, yield 64.2% from (1S, 4S, 5S) -4-bromo-6-oxabicyclo [3.2.1] octan-7 -one) got.
  • Boc represents a tert-butoxycarbonyl group.
  • Boc represents a tert-butoxycarbonyl group.
  • the reaction solution was cooled to about 50 ° C., water (80 ml), toluene (800 ml), 20% saline solution (80 ml) and 25% aqueous sodium hydroxide solution (120 ml) were added and allowed to stand to separate the organic layer.
  • the obtained organic layer was washed successively with 20% brine (80 ml) and 25% aqueous sodium hydroxide solution (16 ml), and the obtained organic layer was concentrated to about 240 ml.
  • Toluene (320 ml) is added to the concentrate, and the operation of concentration to about 240 ml is performed twice, acetonitrile (400 ml) is added to the concentrate, insolubles are removed by filtration, and (1R, 2S, 5S) -2
  • An acetonitrile solution (about 640 ml) of tert-butyl (amino acid 3) [amino-5-[(dimethylamino) carbonyl] cyclohexylcarbamate (C-3) was obtained.
  • Oxalic acid (16.24 g) was added to acetonitrile (640 ml), water (40 ml) and warmed to about 35 ° C.
  • the precipitated crystals are filtered, washed with 7% aqueous acetonitrile (300 ml), and the monohydrate of the title compound ((1R, 2S, 5S) -2-amino-5-[(dimethylamino) carbonyl] cyclohexylcarbamine Acid tert-butyl oxalate monohydrate was obtained.
  • Acetonitrile (560 ml) was added to the monohydrate of the title compound and warmed to about 70 ° C. After stirring for about 5 hours at the same temperature, concentration was performed to about 320 ml, acetonitrile (320 ml) was added to the concentrate, 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 as an anhydride (55. 74 g, yield 82%).
  • Boc represents a tert-butoxycarbonyl group
  • Example 1 (1R, 2R, 4S) -2- ⁇ [(tert-butoxycarbonyl) sulfamoyl] amino ⁇ -4- (dimethylcarbamoyl) cyclohexyl methacrylate sulfonate (1R, 2R, 4S) -2- ⁇ [(tert-butoxycarbonyl) sulfamoyl] amino ⁇ -4- (dimethylcarbamoyl) cyclohexyl methanesulfonate
  • the Feed A was flowed at 7.939 mL / h, Feed B at 72.06 mL / h, and as shown in the figure, the tube reactor ( ⁇ 0.5 mm, volume: 0.4 mL) cooled was passed through to give triethylamine (48 To the mixed solution of mL (341 mmol) and acetonitrile (33 mL) was added dropwise. The aqueous solution (100 mL, 99.05 g) obtained by the method of Reference Example 1 was added dropwise to the solution obtained by operation for 1.27 hours, and after the aqueous sodium hydroxide solution (18 mL, 25%) was poured, the solution was obtained at 5 ° C. Stir for 3 hours.
  • the stirred solution was concentrated under reduced pressure to a volume of 140 mL.
  • Citric acid (7.50 g) and ethyl acetate (220 mL) were added to the obtained solution, and a liquid separation operation was performed.
  • the aqueous layer was extracted with ethyl acetate (80 mL) added.
  • brine (76 mL, 20%) was added to the organic layer obtained by the separation operation.
  • the aqueous layer was mixed with the organic layer obtained by the extraction operation, and a liquid separation operation was performed.
  • the two obtained organic layers were combined and concentrated under reduced pressure to a volume of 100 mL.
  • Acetonitrile (50 mL) was added to the obtained solution, and the solution was concentrated under reduced pressure to a volume of 60 mL. This operation was repeated 5 times.
  • Acetonitrile (60 mL), methanesulfonyl chloride (11.17 g, 97.51 mmol) and N-methylmorpholine (12.53 g, 124 mmol) were added to the resulting solution, and the mixture was stirred at 5 ° C. for 5 hours.
  • Aqueous sulfuric acid solution 13 mL, 5% was added to the resulting solution.
  • the obtained aqueous solution was added to tap water (246 mL), tap water (40 mL) and acetonitrile (8 mL) were added, and the mixture was stirred at 5 ° C. for 3 hours and filtered through a Kiriyama funnel.
  • the crystals were washed with a mixture of acetonitrile (17 mL) and tap water (44 mL), toluene (40 mL).
  • the crystals obtained were dried at 50 ° C. under reduced pressure, and the title compound was obtained in 29.79 g (content 99.0%, yield 68.2% from (1S, 4S, 5S) -4-bromo-6-oxabicyclo [3.2.1] octan-7 -one) got.
  • the Feed A was flowed at 12.66 mL / min and the Feed B was flowed at 109.81 mL / min, and a tube reactor ( ⁇ 5 mm, volume: 112 mL) was passed through it as shown in the figure, and triethylamine (3569 mL, 25.6 mol) and acetonitrile (2490 mL) were added dropwise to the mixed solution.
  • An aqueous solution (6.68 kg, 92.4% from (1S, 4S, 5S) -4-bromo-6-oxabicyclo [3.2.1] octan-7- obtained by the method of Reference Example 1 in a solution obtained by operating for 51 minutes.
  • aqueous solution is added to tap water (15695 mL), tap water (2550 mL) and acetonitrile (510 mL) are added, and the mixture is stirred at 5 ° C. for 0.5 hours, and then an aqueous sulfuric acid solution (32.0 mL, 5%) is added. The pH was adjusted to 3.11. After further stirring for 3 hours at 5 ° C., an aqueous sulfuric acid solution (11.2 mL, 5%) was added to adjust the pH to 2.9. The slurry solution was filtered through a Nutche.

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Abstract

Provided is a production method for efficiently synthesizing a compound (1-2) which is an important intermediate in production of edoxaban. The method comprises dripping a compound (1-1) into a solution A that is obtained by causing a reaction between chlorosulfonyl isocyanate and an alcohol (2) with use of a flow reaction device, and by dripping the resultant mixture into a tertiary amine, whereby a compound (1-2) is obtained.

Description

フロー合成によるジアミン誘導体の製造方法Process for producing diamine derivative by flow synthesis
　本発明は直接経口抗凝固薬(DOAC：Direct Oral AntiCoagulant)であるエドキサバンを効率的に合成するための有用な合成中間体の製造方法に関する。 The present invention relates to a method for producing useful synthetic intermediates for efficiently synthesizing edoxaban which is a direct oral anticoagulant (DOAC: Direct Oral AntiCoagulant).
 エドキサバンは、血液凝固カスケードにおいてプロトロンビンからトロンビンを生成し、フィブリン形成を促進することにより血栓を形成する作用のある活性化血液凝固第X因子(Activated Blood Coagulation Factor XまたはFXa)を選択的、可逆的かつ直接的に阻害することにより、血栓形成抑制作用を発現するDOACである。 Edoxaban selectively and reversibly activates Activated Blood Coagulation Factor X or FXa, which has the function of forming thrombin from prothrombin in the blood coagulation cascade and promoting thrombus formation to form a thrombus. And it is DOAC which expresses thrombus formation inhibitory effect by inhibiting directly.
 エドキサバンは下記式(X) Edoxaban has the following formula (X)
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
で表される、N1-(5-クロロピリジン-2-イル)-N2-((1S，2R，4S)-4-［(ジメチルアミノ)カルボニル］-2-｛［(5-メチル-4，5，6，7-テトラヒドロチアゾロ［5，4-c］ピリジン-2-イル)カルボニル］アミノ｝シクロヘキシル)エタンジアミド(以下、化合物Xと記載することがある)である。 And 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 (hereinafter sometimes referred to as compound X).
　エドキサバンは溶媒和物(水和物を含む)であってもよく、薬理上許容される塩又はそれらの溶媒和物(水和物を含む)であってもよい。その薬理上許容される塩又はそれらの溶媒和物としては、好適には、下記式(X-a) Edoxaban may be a solvate (including a hydrate) or a pharmacologically acceptable salt or a solvate (including a hydrate) thereof. As the pharmacologically acceptable salt or a solvate thereof, preferably, the following formula (Xa):
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
で表される、N1-(5-クロロピリジン-2-イル)-N2-((1S，2R，4S)-4-［(ジメチルアミノ)カルボニル］-2-｛［(5-メチル-4，5，6，7-テトラヒドロチアゾロ［5，4-c］ピリジン-2-イル)カルボニル］アミノ｝シクロヘキシル)エタンジアミド p-トルエンスルホン酸塩1水和物(エドキサバントシル酸塩水和物)である。(特許文献1～4参照) And 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 p-toluenesulfonate monohydrate (edoxaban tosylate hydrate) ). (Refer to patent documents 1-4)
　エドキサバン、その薬理上許容される塩、およびそれらの溶媒和物の製造方法としては、例えば特許文献5及び6に記載される方法が挙げられる。すなわち、下式に示すように化合物(1-1)をクロロスルホニルイソシアナート、tert-ブチルアルコール、及びトリエチルアミンから調製されるバージェス型試薬で処理することにより、化合物(1-2)へと変換した後、メタンスルホニル化反応、塩基による処理、その後、シュウ酸と反応させることによって中間体である化合物(1-5)を得て、さらに化合物(1-5)から適切な変換を行うことによってエドキサバン(X)及びそのトシル酸塩水和物(X-a)を得るというものである。 Examples of methods for producing edoxaban, pharmaceutically acceptable salts thereof, and solvates thereof include the methods described in Patent Documents 5 and 6, for example. That is, the compound (1-1) was converted to the compound (1-2) by treating the compound (1-1) with a Burgess-type reagent prepared from chlorosulfonyl isocyanate, tert-butyl alcohol, and triethylamine as shown in the following formula. After that, methanesulfonylation reaction, treatment with a base, and then reaction with oxalic acid to obtain an intermediate compound (1-5), and further performing an appropriate conversion from compound (1-5) to edoxaban (X) and its tosylate hydrate (Xa) are obtained.
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000021
［式中、Bocはtert-ブトキシカルボニル基を、Msはメタンスルホニル基を示す。］ [Wherein, Boc represents a tert-butoxycarbonyl group, and Ms represents a methanesulfonyl group. ]
　しかしながら、上記方法ではクロロスルホニルイソシアナート(2-1)からtert-ブチルアルコール及びトリエチルアミンを用いて従来のバッチ法によってバージェス型試薬(2-3)を調製する際、中間体である化合物(2-2)が容易に分解し、その分解物が原料である化合物(1-1)と反応するため、化合物（1-2）の収率及び純度が低下することがわかった。 However, in the above method, the compound (2-), which is an intermediate in preparing the Burgess-type reagent (2-3) from chlorosulfonyl isocyanate (2-1) by tert-butyl alcohol and triethylamine by a conventional batch method, It was found that the yield and the purity of the compound (1-2) were lowered because 2) was easily decomposed and the decomposition product was reacted with the compound (1-1) as the raw material.
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000022
米国特許第7365205号明細書U.S. Pat. No. 7,365,205 米国特許出願公開2005/0245565号明細書U.S. Patent Application Publication No. 2005/0245565 米国特許第7342014号明細書U.S. Patent No. 7342014 米国特許第7576135号明細書U.S. Pat. No. 7,576,135 米国特許第8686189号明細書U.S. Patent No. 8686189 米国特許第9447118号明細書U.S. Pat. No. 9,447,118
　本発明の課題は化合物(2-2)の分解を抑え、化合物（1-2）の収率及び純度の低下を抑制することにより、エドキサバンの重要中間体である化合物(1-3)およびエドキサバンを効率的に及び高純度で得る方法を提供することにある。 The object of the present invention is to suppress the decomposition of the compound (2-2) and to suppress the decrease in the yield and the purity of the compound (1-2), whereby the compound (1-3) and edoxaban, which are important intermediates of edoxaban, To provide an efficient and high purity method.
　本発明者らは上記課題を解決するために鋭意検討を行った結果、適切な溶媒に溶解したtert-ブチルアルコール (tert-BuOH)をフロー反応装置中でクロロスルホニルイソシアナートと反応させると化合物(2-2)の分解を抑えることができ、その結果、化合物(1-2)および化合物(1-3)を効率的に及び高純度で得ることに成功した。 As a result of intensive studies to solve the above problems, the present inventors have found that when tert-butyl alcohol (tert-BuOH) dissolved in an appropriate solvent is reacted with chlorosulfonyl isocyanate in a flow reactor, the compound ( The decomposition of 2-2) can be suppressed, and as a result, compound (1-2) and compound (1-3) were successfully obtained efficiently and with high purity.
 すなわち、本発明は以下の［1］～［14］に関する。 That is, the present invention relates to the following [1] to [14].
［1］下記式(1) [1] The following formula (1)
Figure JPOXMLDOC01-appb-C000023
で表される化合物を、下記の溶液A
［溶液A：
フロー反応装置を用い、クロロスルホニルイソシアナートと下記式(2)
Figure JPOXMLDOC01-appb-C000023
The compound represented by the following solution A
[Solution A:
Using a flow reactor, chlorosulfonyl isocyanate and the following formula (2)
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000024
（式中、R1はC1-C6アルキル基、又はベンジル基（該ベンジル基のベンゼン環は、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独立して選ばれる1～2個の基を置換基として有していてもよい）を示す）
で表される化合物の溶液をチューブリアクター内で反応させることによって得られた溶液を三級アミンの溶液に滴下することによって調製される］
と処理することを特徴とする、下記式(3) (Wherein, R 1 is a C1-C6 alkyl group or a benzyl group (the benzene ring of the benzyl group is independently 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 a substituent))
Prepared by reacting a solution of a compound represented by the following formula in a tube reactor into a solution of a tertiary amine]
And characterized by the following equation (3)
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000025
（式中R1は上記と同義を示す）
で表される化合物の製造方法。
［2］三級アミンがトリエチルアミンである［1］に記載の製造方法。
［3］［1］又は［2］に記載の製造方法を用いて製造した下記式(3) (Wherein, R 1 represents the same as the above)
Process for producing a compound represented by
[2] The process according to [1], wherein the tertiary amine is triethylamine.
The following formula (3) manufactured using the manufacturing method as described in [3] [1] or [2]
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026
（式中R1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(4) (Wherein, R 1 represents the same as the above)
In the presence of a base, the compound of the following formula (4)
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000027
（式中、R2は、C1-C6アルキル基、ハロC1-C6アルキル基、又はフェニル基（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独立して選ばれる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）
で表される化合物で処理することを特徴とする、下記式(5) (Wherein R 2 represents a C 1 -C 6 alkyl group, a halo C 1 -C 6 alkyl group, or a phenyl group (wherein the phenyl group represents a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a nitro group and a halogen atom More preferably selected from 1 to 2 groups as substituents); X represents a halogen atom)
Treated with a compound represented by the following formula (5):
Figure JPOXMLDOC01-appb-C000028
Figure JPOXMLDOC01-appb-C000028
（式中、R1及びR2は上記と同義を示す）
で表される化合物の製造方法。
［4］塩基がトリエチルアミン又はN-メチルモルホリンである［3］に記載の製造方法。
［5］下記式(6) (Wherein, R 1 and R 2 are as defined above)
Process for producing a compound represented by
[4] The process according to [3], wherein the base is triethylamine or N-methylmorpholine.
[5] The following formula (6)
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000029
で表される化合物を製造する方法であって、以下の工程1及び2を含む方法：
工程1）　［3］又は［4］に記載の製造方法を用いて製造した下記式(5) A process for producing a compound represented by and comprising the following steps 1 and 2:
Process 1) Following formula (5) manufactured using the manufacturing method as described in [3] or [4]
Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000030
（式中、R1及びR2は上記と同義を示す）
で表される化合物をトリエチルアミンで処理することによって下記式(7) (Wherein, R 1 and R 2 are as defined above)
Is treated with triethylamine to give the following formula (7)
Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000031
（式中、R1は上記と同義を示す）
で表される化合物を得る工程；及び、
工程2）　工程1）で得られた式(7)で表される化合物を水及びピリジン類と処理して式(6)で表される化合物を得る工程。
［6］下記式（X-a） (Wherein, R 1 represents the same as the above)
Obtaining a compound represented by
Step 2) A step of treating the compound represented by Formula (7) obtained in Step 1) with water and pyridines to obtain a compound represented by Formula (6).
[6] The following formula (Xa)
Figure JPOXMLDOC01-appb-C000032
Figure JPOXMLDOC01-appb-C000032
で表される化合物を製造する方法であって、以下の工程1から6を含む方法：
工程1）　［3］又は［4］に記載の製造方法を用いて製造した下記式(5) A process for producing the compound represented by and comprising the following steps 1 to 6:
Process 1) Following formula (5) manufactured using the manufacturing method as described in [3] or [4]
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000033
（式中、R1及びR2は上記と同義を示す）
で表される化合物をトリエチルアミンで処理することによって下記式(7) (Wherein, R 1 and R 2 are as defined above)
Is treated with triethylamine to give the following formula (7)
Figure JPOXMLDOC01-appb-C000034
Figure JPOXMLDOC01-appb-C000034
（式中、R1は上記と同義を示す）
で表される化合物を得る工程；
工程2）　工程1）で得られた式7で表される化合物を水及びピリジン類と処理して下記式(6) (Wherein, R 1 represents the same as the above)
Obtaining a compound represented by
Step 2) The compound represented by Formula 7 obtained in Step 1) is treated with water and pyridines to obtain the following Formula (6)
Figure JPOXMLDOC01-appb-C000035
Figure JPOXMLDOC01-appb-C000035
（式中、R1は上記と同義を示す）
で表される化合物を得る工程；
工程3）　工程2）で得られた式(6)で表される化合物をシュウ酸塩又は硫酸塩とした後に、そのシュウ酸塩又は硫酸塩を塩基の存在下、下記式(8) (Wherein, R 1 represents the same as the above)
Obtaining a compound represented by
Step 3) After converting the compound represented by the formula (6) obtained in the step 2) into an oxalate salt or a sulfate, the oxalate salt or the sulfate in the presence of a base gives the following formula (8)
Figure JPOXMLDOC01-appb-C000036
Figure JPOXMLDOC01-appb-C000036
で表される化合物と処理し、下記式(9) And the compound represented by formula (9)
Figure JPOXMLDOC01-appb-C000037
Figure JPOXMLDOC01-appb-C000037
（式中、R1は上記と同義を示す）
で表される化合物を得る工程；
工程4）　工程3）で得られた式(9)で表される化合物の保護基R1の除去を行って下記式(10) (Wherein, R 1 represents the same as the above)
Obtaining a compound represented by
Step 4) Removal of the protecting group R 1 of the compound represented by the formula (9) obtained in the step 3) is carried out to obtain a compound represented by the following formula (10)
Figure JPOXMLDOC01-appb-C000038
Figure JPOXMLDOC01-appb-C000038
で表される化合物を得る工程；
工程5）　工程4）で得られた式(10)で表される化合物又はその塩を、下記式(11) Obtaining a compound represented by
Step 5) The compound represented by the formula (10) obtained in the step 4) or a salt thereof is converted to the following formula (11)
Figure JPOXMLDOC01-appb-C000039
Figure JPOXMLDOC01-appb-C000039
で表される化合物と縮合して、下記式（X） By condensation with a compound represented by formula (X)
Figure JPOXMLDOC01-appb-C000040
Figure JPOXMLDOC01-appb-C000040
で表される化合物を得る工程；及び、
工程6）　工程5）で得られた式（X）で表される化合物を、含水エタノール中、p-卜ルエンスルホン酸・1水和物と処理することによって式（X-a）で表される化合物を得る工程。
［7］R1がtert-ブチル基又はベンジル基である［1］～［6］のいずれか1項に記載の製造方法。
［8］R2がメチル基である［3］～［7］のいずれか1項に記載の製造方法。
［9］フロー反応装置の流速が0.1 ml/min～10 L／minである［1］～［8］のいずれか１項に記載の製造方法。
［10］フロー反応装置の流速が0.1 ml/min～6 L／minである［9］に記載の製造方法。
［11］フロー反応装置の流路の内径が0.1～50mmである［1］～［10］のいずれか1項に記載の製造方法。
［12］フロー反応装置の流路の内径が0.5～25mmである［11］に記載の製造方法。
［13］フロー反応装置の滞留時間が10～120秒である［1］～［12］のいずれか１項に記載の製造方法。
［14］フロー反応装置の滞留時間が15～90秒である［13］に記載の製造方法。 Obtaining a compound represented by
Step 6) A compound represented by the formula (Xa) by treating a compound represented by the formula (X) obtained in the step 5) with p-sulenesulfonic acid monohydrate in water-containing ethanol To get
[7] The process according to any one of [1] to [6], wherein R 1 is a tert-butyl group or a benzyl group.
[8] The process according to any one of [3] to [7], wherein R 2 is a methyl group.
[9] The process according to any one of [1] to [8], wherein the flow rate of the flow reactor is 0.1 ml / min to 10 L / min.
[10] The production method according to [9], wherein the flow rate of the flow reactor is 0.1 ml / min to 6 L / min.
[11] The production method according to any one of [1] to [10], wherein the inner diameter of the flow path of the flow reactor is 0.1 to 50 mm.
[12] The production method according to [11], wherein the inner diameter of the flow channel of the flow reactor is 0.5 to 25 mm.
[13] The process according to any one of [1] to [12], wherein the residence time of the flow reactor is 10 to 120 seconds.
[14] The process according to [13], wherein the residence time of the flow reactor is 15 to 90 seconds.
　本発明により、エドキサバンを製造する際の重要中間体を高収率及び高純度で合成することができる。 According to the present invention, important intermediates in producing edoxaban can be synthesized in high yield and high purity.
[規則91に基づく訂正 28.08.2018]　
本発明の実施例に用いたフロー反応装置の模式図。A、Bはそれぞれ流速を制御可能なポンプを備えた試薬の取込口(feed Aおよびfeed B)であり、Cは反応の場となるリアクター部分(チューブリアクター)を、Dは反応容器を示す。 本発明の実施例１のフロー合成装置による反応を模式的に図示したものである。 本発明の実施例２のフロー合成装置による反応を模式的に図示したものである。
[Correction based on rule 91 28.08.218]
BRIEF DESCRIPTION OF THE DRAWINGS The schematic diagram of the flow reaction apparatus used for the Example of this invention. A and B are respectively reagent inlets (feed A and feed B) equipped with pumps capable of controlling the flow rate, C indicates a reactor portion (tube reactor) as a reaction field, and D indicates a reaction vessel . BRIEF DESCRIPTION OF THE DRAWINGS The reaction by the flow synthesis apparatus of Example 1 of this invention is illustrated typically. Fig. 6 schematically shows a reaction by the flow synthesis apparatus of Example 2 of the present invention.
　本明細書における「ハロゲン原子」とは、フッ素原子、塩素原子、臭素原子、ヨウ素原子を意味する。 The "halogen atom" in the present specification means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
　本明細書における「C1-C6アルキル基」とは、炭素数1-6の直鎖又は分岐鎖の飽和炭化水素からなる一価の基を意味する。C1-C6アルキルとしては、例えば、メチル、エチル、n-プロピル、イソプロピル、n-ブチル、tert-ブチル、n-ペンチル、n-ヘキシル等を挙げることができる。 The term "C1-C6 alkyl group" as used herein means a monovalent group consisting 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.
　本明細書における「ハロC1-C6アルキル基」とは、1～5個の、同一又は異なった、上記ハロゲン原子が置換したC1-C6アルキル基を意味する。ハロC1-C6アルキルとしては、例えば、フルオロメチル、ジフルオロメチル、トリフルオロメチル、クロロメチル、ジクロロメチル、トリクロロメチル、フルオロエチル(1 -フルオロエチル、2-フルオロエチルの両方を意味する)、2，2-ジフルオロエチル、2，2，2-トリフルオロエチル、2，2，3，3，3-ペンタフルオロエチル、フルオロプロピル(3-フルオロプロピル、2-フルオロプロピル、1-フルオロプロピルの全てを包含する)等を挙げることができる。 The "halo C1-C6 alkyl group" in the present specification means 1 to 5 identical or different C1-C6 alkyl groups substituted with the above-mentioned halogen atom. As halo C1-C6 alkyl, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, fluoroethyl (meaning both 1-fluoroethyl and 2-fluoroethyl), 2, Includes all of 2-difluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoroethyl, fluoropropyl (3-fluoropropyl, 2-fluoropropyl, 1-fluoropropyl Can be mentioned.
　本明細書における「C1-C6アルコキシ基」とは、C1-C6アルキル基と酸素原子から形成されるC1-C6アルキルオキシ基を意味し、C1-C6アルキルは上記の通りである。C1-C6アルコキシとしては、例えば、メトキシ、エトキシ、n-プロポキシ、イソプロポキシ、n-ブトキシ、tert-ブトキシ、n-ペンチルオキシ、n-ヘキシルオキシ等を挙げることができる。 The "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.
　本明細書における「フェニル基」とは、ベンゼン環上に置換基を有してもよい一価の基を意味し、該フェニル基は、同一又は異なった、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独立して選ばれる1～2個の基を置換基として有していてもよい。本明細書中におけるフェニルとしては、例えば、フェニル、p-(又はo-) メチルフェニル、p-(又はo-) メトキシフェニル、3，4-ジメトキシフェニル、p-(又はo-) ニトロフェニル、クロロフェニル、2，4-ジクロロフェニル等を挙げることができる。 The "phenyl group" in the present specification means a monovalent group which may have a substituent on the benzene ring, and the phenyl group is the same or different and is a C1-C6 alkyl group, C1-C6. It may have 1 to 2 groups independently selected from the group consisting of an alkoxy group, a nitro group and a halogen atom as a substituent. In the present specification, examples of phenyl include phenyl, p- (or o-) methylphenyl, p- (or o-) methoxyphenyl, 3,4-dimethoxyphenyl, p- (or o-) nitrophenyl, Chlorophenyl, 2,4-dichlorophenyl and the like can be mentioned.
　本明細書における「ベンジル基」とは、置換されてもよいフェニル基が置換されたメチル基から形成される一価の基を意味し、該ベンジル基のベンゼン環は、同一又は異なった、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独立して選ばれる1～2個の基を置換基として有していてもよい。本明細書中におけるベンジルとしては、例えば、ベンジル、p-(又はo-)メチルベンジル、p-(又はo-)メトキシベンジル、3，4-ジメトキシベンジル、p-(又はo-)ニトロベンジル、クロロベンジル、2，4-ジクロロベンジル等を挙げることができる。 The term "benzyl group" as used herein means a monovalent group formed from a methyl group substituted with a phenyl group which may be substituted, and the benzene rings of the benzyl group may be the same or different, C1 It may have 1 to 2 groups independently selected from the group consisting of —C 6 alkyl group, C 1 -C 6 alkoxy group, nitro group and halogen atom as a substituent. In the present specification, examples of benzyl include benzyl, p- (or o-) methylbenzyl, p- (or o-) methoxybenzyl, 3,4-dimethoxybenzyl, p- (or o-) nitrobenzyl, Chlorobenzyl, 2,4-dichlorobenzyl and the like can be mentioned.
　本明細書における「ピリジン類」とは、ピリジン、並びにピコリン(該ピコリンは、α-ピコリン、β-ピコリン及びγ-ピコリンのいずれの異性体も包含する)、ルチジン(該ルチジンは、2，3-ルチジン、2，4-ルチジン、2，5-ルチジン、2，6-ルチジン、3，4-ルチジン及び3，5-ルチジンのいずれの異性体も包含する)、コリジン(該コリジンは、2，3，4-コリジン、2，3，5-コリジン、2，3，6-コリジン、2，4，5-コリジン、2，4，6-コリジン、3，4，5-コリジンのいずれの異性体も包含する)及び4-ジメチルアミノピリジン等のピリジン環上の水素が他の基で置換されたピリジン誘導体を意味する。 In the present specification, “pyridines” are pyridine, and picoline (the picoline includes any isomer of α-picoline, β-picoline and γ-picoline), lutidine (the lutidine is 2,3 -Collidine (which includes all isomers of lutidine, 2,4-lutidine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine and 3,5-lutidine), collidine (the collidine is 3,4-collidine, 2,3,5-collidine, 2,3,6-collidine, 2,4,5-collidine, 2,4,6-collidine, or any isomer of 3,4,5-collidine And also includes pyridine derivatives in which hydrogen on the pyridine ring is substituted with another group such as 4-dimethylaminopyridine and the like.
　本明細書における下記式(X) The following formula (X) in the present specification
Figure JPOXMLDOC01-appb-C000041
Figure JPOXMLDOC01-appb-C000041
で表される、N1-(5-クロロピリジン-2-イル)-N2-((1S，2R，4S)-4-［(ジメチルアミノ)カルボニル］-2-｛［(5-メチル-4，5，6，7-テトラヒドロチアゾロ［5，4-c］ピリジン-2-イル)カルボニル］アミノ｝シクロヘキシル)エタンジアミド(N1-(5-Chloropyridin-2-yl)-N2-((lS，2R，4S)-4-［(dimethylamino)carbonyl］-2-｛［(5-methyl-4，5，6，7-tetrahydrothiazolo［5，4-c］ pyridine-2-yl)carbonyl］amino｝cyclohexyl) ethanediamide)は、式(X-a) で表される化合物のフリー体であり、世界保健機構(WHO) には、国際一般名称(International Nonproprietary Names、INN)：エドキサバン(edoxaban)、N-(5-クロロピリジン-2-イル)-N’-［(1S，2R，4S)-4-(N，N-ジメチルカルバモイル)-2-(5-メチル-4，5，6，7-テ卜ラヒドロ［1，3］チアゾロ［5，4-c］ピリジン-2-カルボキサミド)シクロヘキシル］オキサミド(N-(5-chloropyridin-2-yl)-N’-［(1S，2R，4S)-4-(N，N-dimethylcarbamoyl)-2-(5-methyl-4，5，6，7-tetrahydro［1，3］thiazolo［5，4-c］pyridine-2-carboxamido)cyclohexyl］oxamide) として登録されている。 And 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-Chloropyridine-2-yl) -N 2 -(( lS, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-yl) carbonyl] amino (Cyclohexyl) ethanolideamide) is a free form of the compound represented by the formula (Xa), and in the World Health Organization (WHO), International Nonproprietary Names (INN): edoxaban, N- ( 5-chloropyridin-2-yl) -N '-[(1S, 2R, 4S) -4- (N, N-dimethylcarbamoyl) -2- (5-methyl-4,5,6,7-tetra) Rahydro [1,3] thiazolo [5,4-c] pyridine-2-carboxamido) cyclohexyl] oxamide (N- (5-chloropyridin-2-yl) -N '-[(1S, 2R, 4S) -4- (N, N-dimethylcarbamoyl) -2- (5-methyl-4,5,6,7-tetrahydro [1,3] thiazolo [5,4-c] pyridine-2-carboxamido) cyclohexyl] oxamide) Registered as.
　上記の化合物(X)は、その薬理学上許容される塩であってもよく、またそれらの水和物であってもよいが、下記式(X-a) The above compound (X) may be a pharmacologically acceptable salt thereof, or may be a hydrate of them, but the following formula (Xa):
Figure JPOXMLDOC01-appb-C000042
Figure JPOXMLDOC01-appb-C000042
で表されるN1-(5-クロロピリジン-2-イル)-N2-((1S，2R，4S)-4-［(ジメチルアミノ)カルボニル］-2-｛［(5-メチル-4，5，6，7-テトラヒドロチアゾロ［5，4-c］ピリジン-2-イル)カルボニル］アミノ｝シクロヘキシル)エタンジアミド p-トルエンスルホン酸塩1水和物が好ましい。 Or 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 p-toluenesulfonic acid salt monohydrate is preferred.
　本発明に用いられるフロー反応装置とは2種以上の液体化合物又は化合物を含む溶液を管内に連続して送液しながら管内にて反応させる反応装置である。さまざまなメーカーのものが市販されており、例えば、Vapourtec社、Syrris社などが挙げられる。フロー反応装置は一般に化合物および試薬を装置内に送液するポンプ部分、2種以上の化合物および試薬を混合するミキサー部分及び反応の場となるリアクター部分から構成される。ポンプとしては特に制限されないが、一般的なシリンジポンプ又はプランジャーポンプなどが利用できる。ミキサー部分に関しては基本的なY字型、V字型又はT字型などさまざまなタイプのものが本発明には利用できる。また、本発明におけるリアクター部分としてはチューブ型のチューブリアクターが好ましく、温度制御装置が付属したものがより好ましい。 The flow reaction apparatus used in the present invention is a reaction apparatus in which a reaction is performed in a pipe while continuously sending a solution containing two or more kinds of liquid compounds or compounds in the pipe. Various manufacturers are commercially available, such as Vapourtec, Syrris and the like. The flow reactor generally comprises a pump portion for delivering the compounds and reagents into the device, a mixer portion for mixing two or more compounds and reagents, and a reactor portion for reaction. The pump is not particularly limited, but a common syringe pump or plunger pump can be used. With respect to the mixer section, various types of basic Y-shaped, V-shaped or T-shaped can be used in the present invention. Moreover, as a reactor part in this invention, a tube type tube reactor is preferable, and what the temperature control apparatus was attached is more preferable.
　上記フロー反応装置の流路としては反応の種類及び反応条件等に応じてさまざまな材質のものを用いることができ、ステンレス、ガラス、アルミニウム、銅、フッ素樹脂などを適宜用いることができる。 As the flow path of the flow reaction device, various materials can be used according to the type of reaction, reaction conditions, etc., and stainless steel, glass, aluminum, copper, fluorine resin, etc. can be used appropriately.
　フロー反応を行う際は一般にポンプを用いて液体試薬又は試薬を含む溶液をミキサー部分、それに続くリアクター部分へと送液する。その送液速度は反応の種類、反応条件等によって異なるが、本発明においては0.1 ml/min～10 L／minから選択され、好ましくは0.1 ml/min～6 L/minである。 When performing a flow reaction, a pump is generally used to deliver a liquid reagent or a solution containing the reagent to the mixer part and the subsequent reactor part. The liquid transfer rate varies depending on the type of reaction, reaction conditions and the like, but in the present invention is selected from 0.1 ml / min to 10 L / min, preferably 0.1 ml / min to 6 L / min.
　フロー反応においては2種以上の化合物および試薬はミキサー部分で混合され、リアクター部分を通過して反応が進行する。液体同士の混合時間は流路の内径の2乗に比例することが知られており、流路の内径はより小さい方が混合には有利であり、また熱交換効率も上がる。しかしながら、内径が小さくなると送液するために必要な圧力が上昇することから反応の種類、反応条件、反応スケールなどによって流路の内径は異なる。流路の内径は本発明においては好ましくは0.1～50mmの範囲であり、より好ましくは0.5～25mmである。 In the flow reaction, two or more compounds and reagents are mixed in the mixer portion, and the reaction proceeds through the reactor portion. It is known that the mixing time of the liquids is proportional to the square of the inner diameter of the flow passage, and the smaller inner diameter of the flow passage is advantageous for mixing, and the heat exchange efficiency is also increased. However, if the inner diameter is smaller, the pressure required to transfer the liquid increases, so the inner diameter of the flow path differs depending on the type of reaction, reaction conditions, reaction scale, and the like. In the present invention, the inner diameter of the flow path is preferably in the range of 0.1 to 50 mm, more preferably 0.5 to 25 mm.
　フロー反応においては流路内で一定の反応時間（滞留時間）を得るためにそのリアクター部分の流路長は異なる。本発明においては滞留時間が10～120秒以内であればよく、好ましくは15～90秒である。また、リアクター部分においては温度制御装置を用いて反応温度は制御することができる。本発明においては特に制限されないが、反応温度は室温以下が好ましく、さらに好ましくは0℃程度である。 In the flow reaction, in order to obtain a constant reaction time (residence time) in the flow path, the flow path length of the reactor portion is different. In the present invention, the residence time may be within 10 to 120 seconds, preferably 15 to 90 seconds. Also, in the reactor section, the reaction temperature can be controlled using a temperature controller. The reaction temperature is not particularly limited in the present invention, but the reaction temperature is preferably room temperature or less, more preferably about 0 ° C.
　以下のScheme Aに本発明の製造方法を示し、各工程について詳述する。 The production method of the present invention is shown in Scheme A below, and each step is described in detail.
Figure JPOXMLDOC01-appb-C000043
Figure JPOXMLDOC01-appb-C000043
［式中、R1は、C1-C6アルキル基、又はベンジル基(該ベンジル基のベンゼン環は、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独立して選ばれる1～2個の基を置換基として有していてもよい)を示し；R2は、C1-C6アルキル基、ハロC1-C6アルキル基、又はフェニル基(該フェニル基は、C1-C6アルキル基、C1-C6アルコキシ基、二卜ロ基及びハロゲン原子からなる群より独立して選ばれる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］ [Wherein, R 1 represents a C1-C6 alkyl group or a benzyl group (wherein the benzene ring of the benzyl group is independently selected from the group consisting of a C1-C6 alkyl group, a C1-C6 alkoxy group, a nitro group and a halogen atom And R 2 represents a C 1 -C 6 alkyl group, a halo C 1 -C 6 alkyl group, or a phenyl group (the phenyl group is a C 1 -C 6 alkyl group). And X represents a halogen, which may have 1 to 2 groups independently selected from the group consisting of a C6 alkyl group, a C1 to C6 alkoxy group, a dibasic group and a halogen atom; Indicates an atom]
(工程a-1)：化合物(A-2)を合成する工程 (Step a-1): Step of Synthesizing Compound (A-2)
Figure JPOXMLDOC01-appb-C000044
Figure JPOXMLDOC01-appb-C000044
［式中、R1は上記と同義を示す］ [Wherein, R 1 represents the same as the above]
(工程a-1)は化合物(A-1)のアミノ基をスルホニル化し、化合物(A-2)を得る工程である。スルホニル化試薬である［溶液A］はフロー反応装置を用いて以下のように調製される。 (Step a-1) is a step of sulfonylating the amino group of compound (A-1) to obtain compound (A-2). The sulfonylation reagent [solution A] is prepared as follows using a flow reactor.
［溶液A］
　フロー反応装置は図1のように設置する。試薬の取込口A(Feed A)よりクロロスルホニルイソシアナートを、取込口B(Feed B)よりアルコールR1-OHの溶液を送液し、リアクター部分(チューブリアクター)にて反応を行った後、三級アミンの溶液に滴下することによって溶液Aが得られる。クロロスルホニルイソシアナートおよびアルコールR1-OHの溶液の流速は0.1 ml/min～10 L/minから選択され、好ましくは0.1 ml/min～6 L/minである。 [Solution A]
The flow reactor is installed as shown in FIG. Chlorosulfonyl isocyanate was fed from the inlet A (Feed A) of the reagent, and a solution of alcohol R 1 -OH was sent from the inlet B (Feed B), and the reaction was carried out in the reactor part (tube reactor) Thereafter, solution A is obtained by dropping it into a solution of tertiary amine. The flow rate of the solution of chlorosulfonyl isocyanate and alcohol R 1 -OH is selected from 0.1 ml / min to 10 L / min, preferably 0.1 ml / min to 6 L / min.
　R1-OHにおけるR1はC1-C6アルキル基、又はベンジル基(該ベンジル基のベンゼン環は、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独立して選ばれる1～2個の基を置換基として有していてもよい)を示し、好ましくはtert-ブチル基又はベンジル基である。 R 1 in R 1 -OH is C 1 -C 6 alkyl group or benzyl group (the benzene ring of the benzyl group is independently selected from the group consisting of C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, nitro group and halogen atom It may have 1 to 2 groups selected as a substituent), preferably a tert-butyl group or a benzyl group.
　溶液Aを調製する際に用いる反応溶媒の例としてはジエチルエーテル、ジ-n-プロピルエーテル、ジイソプロピルエーテル、テ卜ラヒドロフラン、メチルtert-ブチルエーテル若しくはシクロペンチルメチルエーテル等のエーテル溶媒；酢酸メチル、酢酸エチル、酢酸プロピル、酢酸ブチル若しくは酢酸フェニル等のエステル溶媒；ジクロロメタン、クロロホルム、四塩化炭素、ジクロロエタン若しくはテ卜ラクロロエタン等のハロゲン化炭化水素溶媒；ベンゼン、クロロベンゼン、トルエン若しくはキシレン等の芳香族炭化水素溶媒；アセトニトリル、N，N-ジメチルホルムアミド、N，N-ジメチルアセ卜アミド若しくはN-メチルピロリドン等の含窒素溶媒；アセトン、メチルイソブチルケトン等のケトン溶媒；又はこれらの混合溶媒が挙げられ；好ましくは、シクロペンチルメチルエーテル、テ卜ラヒドロフラン、酢酸エチル、クロロホルム、ジクロロメタン、トルエン、アセトニトリル、メチルイソブチルケトン又はこれらの混合溶媒が挙げられ；特に好ましくは、アセトニトリルなどを挙げることができる。 Examples of reaction solvents used in preparation of solution A include diethyl ether, di-n-propyl ether, diisopropyl ether, ethereal solvents such as tetrahydrofuran hydrofuran, methyl tert-butyl ether or cyclopentyl methyl ether; 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; Nitrogen-containing solvents such as acetonitrile, N, N-dimethylformamide, N, N-dimethylacetoamide or N-methylpyrrolidone; ketone solvents such as acetone and methyl isobutyl ketone; or mixed solvents thereof; Mashiku is cyclopentyl methyl ether, Te Bok Rahidorofuran, ethyl acetate, chloroform, dichloromethane, toluene, acetonitrile, can be mentioned methyl isobutyl ketone or mixed solvent thereof; particularly preferably, and the like acetonitrile.
　溶液Aを調製する際に用いられる三級アミンの例としては、例えば、トリエチルアミン、ジイソプロピルエチルアミン、N-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。 Examples of tertiary amines used in preparation of solution A include, for example, triethylamine, diisopropylethylamine, N-methylmorpholine, piperidine, pyrrolidine, tributylamine, 1,4-diazabicyclo [2.2.2] octane, quinuclidine, etc. Is preferred, and triethylamine is particularly preferred.
　溶液Aを調製する際の、クロロスルホニルイソシアナート、及びR1-OHの使用量は、クロロスルホニルイソシアナート：R1-OH＝1：0.95～1.20程度のモル当量の割合が好ましい。また、使用する三級アミンの使用量は、クロロスルホニルイソシアナート：三級アミン＝1：2～4程度のモル当量の割合が好ましい。 The amount of chlorosulfonyl isocyanate and R 1 -OH used in preparation of solution A is preferably a molar equivalent ratio of chlorosulfonyl isocyanate: R 1 -OH = 1: 0.95 to 1.20. The amount of tertiary amine to be used is preferably a molar equivalent ratio of chlorosulfonyl isocyanate: tertiary amine = 1: 2-4.
　溶液Aを調製するときの反応温度(フロー反応装置における反応温度及び三級アミンに滴下する際の反応温度の両方を含む)は、室温以下の温度が好ましく、0℃程度がより好ましい。また、［溶液A］を調製する際のフロー合成装置における滞留時間は15～90秒程度になるようにチューブリアクターの長さを選択することが好ましい。その際のチューブリアクターの流路の内径は好ましくは0.1～50mmの範囲であり、より好ましくは0.5～25mmである。 The reaction temperature (including both the reaction temperature in the flow reactor and the reaction temperature when added dropwise to the tertiary amine) when preparing the solution A is preferably a temperature below room temperature, and more preferably about 0 ° C. In addition, it is preferable to select the length of the tube reactor so that the residence time in the flow synthesis apparatus when preparing [solution A] is about 15 to 90 seconds. The inner diameter of the flow path of the tube reactor at that time is preferably in the range of 0.1 to 50 mm, more preferably 0.5 to 25 mm.
　別途合成した化合物(A-1)を、溶液Aに滴下し、0℃程度で反応させることにより、化合物(A-2)を製造することができる。この際、塩基を添加してもよく、用いる塩基としては、無機塩基及び有機塩基の何れも使用できるが、無機塩基が好ましい。無機塩基としては、アルカリ金属又はアルカリ土類金属の水酸化物及び炭酸塩を好ましいものとして挙げることができ、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウムが好ましく、これらの水溶液を使用するのが好ましい。 The compound (A-2) can be produced by adding the compound (A-1) separately synthesized to the solution A dropwise and reacting at about 0 ° C. At this time, a base may be added, and as a base to be used, any of an inorganic base and an organic base can be used, but an inorganic base is preferable. As the inorganic base, hydroxides and carbonates of alkali metals or alkaline earth metals can be mentioned as preferable, and lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate are preferable, and It is preferred to use an aqueous solution.
　上記塩基の添加量は、反応液の液性が中性から塩基性を保てる量を添加するのが好ましい。 The amount of the base added is preferably such that the reaction mixture can maintain its neutrality to basicity.
　化合物（A-1）を［溶液A］に添加する際の温度、及び添加した後の反応温度は、0℃～室温が好ましく、反応時間は0.5～5時間程度である。反応終了後、反応液に塩酸などの鉱酸又はクエン酸などの有機酸の水溶液を加えて、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(A-2)が得られる。 The temperature at which the compound (A-1) is added to the [solution A] and the reaction temperature after the addition are preferably 0 ° C. to room temperature, and the reaction time is about 0.5 to 5 hours. After completion of the reaction, an aqueous solution of a mineral acid such as hydrochloric acid or an organic acid such as citric acid is added to the reaction solution to make the pH weakly acidic, and then extracted with an organic solvent such as ethyl acetate to obtain a compound (A-2) Is obtained.
(工程a-2)：化合物(A-3)を合成する工程 (Step a-2): Step of Synthesizing Compound (A-3)
Figure JPOXMLDOC01-appb-C000045
Figure JPOXMLDOC01-appb-C000045
［式中、R2は、C1-C6アルキル基、ハロC1-C6アルキル基、又はフェニル基(該フェニル基は、C1-C6アルキル基、C1-C6アルコキシ基、ニ卜ロ基及びハロゲン原子からなる群より独立して選ばれる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、ハロゲン原子を示し；R1は、上記と同義を示す］ [Wherein, R 2 represents a C 1 -C 6 alkyl group, a halo C 1 -C 6 alkyl group, or a phenyl group (wherein the phenyl group represents a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a nitro group and a halogen atom And X 1 represents a halogen atom; and R 1 represents the same as the above].
(工程а-2)は、化合物(A-2)のアルコール部分を塩基の存在下、下記式(4) In the step (a-2), the alcohol moiety of the compound (A-2) is reduced to the following formula (4) in the presence of a base:
Figure JPOXMLDOC01-appb-C000046
Figure JPOXMLDOC01-appb-C000046
［式中、R2、及びXは上記と同義を示す］
で表される化合物で処理して化合物(A-3)を得る工程である。 [Wherein, R 2 and X are as defined above]
And the step of obtaining the compound (A-3).
　化合物(4)中のR2は、メチル基、エチル基、フェニル基、又は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。 As R 2 in the compound (4), a methyl group, an ethyl group, a phenyl group or a 4-methylphenyl group (p-tolyl group) is preferable, and a methyl group is particularly preferable.
　(工程a-2)では反応溶媒として有機系溶媒を使用するのが好ましい。有機系溶媒としては、例えば、ジエチルエーテル、ジイソプロピルエーテル、メチルtert-ブチルエーテル(MTBE)、テ卜ラヒドロフラン(THF)、シクロペンチルメチルエーテル、ジメトキシエタン、1，4-ジオキサン等のエーテル溶媒；酢酸メチル、酢酸エチル、酢酸プロピル、酢酸ブチル若しくは酢酸フェニル等のエステル溶媒；ジクロロメタン、クロロホルム、四塩化炭素、ジクロロエタン若しくはテ卜ラクロロエタン等のハロゲン化炭化水素溶媒；ベンゼン、クロロベンゼン、トルエン若しくはキシレン等の芳香族炭化水素溶媒；アセトニトリル等の含窒素溶媒；アセトン、メチルイソブチルケトン等のケトン溶媒；又はこれらの混合溶媒が挙げられ；好ましくは、テトラヒドロフラン、酢酸エチル、クロロホルム、ジクロロメタン、トルエン、アセトニトリル、メチルイソブチルケトン又はこれらの混合溶媒が挙げられ；特に好ましくは、アセトニトリルなどを挙げることができる。 In (Step a-2), it is preferable to use an organic solvent as a reaction solvent. Examples of 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, etc .; methyl acetate, acetic acid Ester solvents such as ethyl acetate, propyl acetate, butyl acetate or phenyl acetate; halogenated hydrocarbon solvents such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane or tetrachloroethane; aromatic hydrocarbons such as benzene, chlorobenzene, toluene or xylene Solvents; nitrogen-containing solvents such as acetonitrile; ketone solvents such as acetone and methyl isobutyl ketone; or mixed solvents thereof; preferably tetrahydrofuran, ethyl acetate, chloroform, dichloromethane, toluene, Acetonitrile, methyl isobutyl ketone or a mixed solvent thereof can be mentioned; Particularly preferably, acetonitrile and the like can be mentioned.
　(工程a-2)で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、トリエチルアミン、トリブチルアミン、若しくはN，N-ジイソプロピルエチルアミンなどの三級アミン、1，8-ジアザビシクロ［5.4.0］ウンデク-7-エン(DBU)、1，8-ジアザビシクロ［4.3.0］ノン-5-エン(DBN)、ジメチルアニリン、ピリジン、2,6-ルチジン、N-メチルイミダゾール、又はN-メチルモルホリン等を用いることができる。これらの塩基のうち、(工程a-2)においては、トリエチルアミン若しくはN，N-ジイソプロピルエチルアミンなどの三級アミン、N-メチルモルホリン、ピリジン、2，6-ルチジン、又はN-メチルイミダゾール等が好ましく、トリエチルアミン、N-メチルモルホリン又は2，6-ルチジンが特に好ましい。 As the base used in (Step a-2), either an organic base or an inorganic base can be used, but an organic base is preferred, and a tertiary amine such as triethylamine, tributylamine or N, N-diisopropylethylamine, 1,1, 8-Diazabicyclo [5.4.0] undec-7-ene (DBU), 1,8-diazabicyclo [4.3.0] non-5-ene (DBN), dimethylaniline, pyridine, 2,6-lutidine, N-methyl Imidazole or N-methyl morpholine etc. can be used. Among these bases (in step a-2), tertiary amines such as triethylamine or N, N-diisopropylethylamine, N-methylmorpholine, pyridine, 2,6-lutidine or N-methylimidazole are preferable. Particular preference is given to triethylamine, N-methylmorpholine or 2,6-lutidine.
　塩基の使用量は、通常、化合物(A-2)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1-2モル当量程度である。 The amount of the base to be used is generally in the range of 0.8 to 5 molar equivalents stoichiometrically to the compound (A-2), preferably about 1 to 2 molar equivalents.
　化合物(4)としては、メタンスルホニルクロリド、エタンスルホニルクロリド、ベンゼンスルホニルクロリド、p-トルエンスルホニルクロリド等が好ましく、メタンスルホニルクロリドがより好ましい。化合物(4)の使用量は、通常、化合物(A-2)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。 As the compound (4), methanesulfonyl chloride, ethanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride and the like are preferable, and methanesulfonyl chloride is more preferable. The amount of the compound (4) to be used is generally in the range of 0.8 to 3 molar equivalents stoichiometrically to the compound (A-2), preferably about 1 to 1.5 molar equivalents.
　(工程a-2)の反応温度は40℃以下が好ましく、0℃程度がより好ましい。反応時間は、通常0.5～15時間程度である。 The reaction temperature of (Step a-2) is preferably 40 ° C. or less, and more preferably about 0 ° C. The reaction time is usually about 0.5 to 15 hours.
　上記の(工程a-1)に用いる化合物(A-1)［又は化合物(A-1)の水溶液］は、下記のScheme Bに示すように、化合物(B-1)から、化合物(B-2)及び化合物(B-3)を経由して、公知の方法で製造できる。 The compound (A-1) [or the aqueous solution of the compound (A-1)] used in the above (Step a-1) can be prepared from the compound (B-1) to the compound (B-) as shown in Scheme B below. 2) and the compound (B-3), it can be produced by known methods.
Figure JPOXMLDOC01-appb-C000047
Figure JPOXMLDOC01-appb-C000047
［式中、Xは、臭素又はヨウ素を示す。］ [Wherein, X represents bromine or iodine. ]
(工程c)～(工程e)での具体的な製造例については、参考例として後述する。 Specific production examples in (Step c) to (Step e) will be described later as reference examples.
　本発明の化合物(A-1)から製造した化合物(A-3)を用いて、高純度の化合物(X)及び化合物(X)のp-トルエンスルホン酸塩1水和物(X-a)を製造する方法としては、特許文献5に開示されている公知の方法を用いればよく、化合物(A-3)においてR1がtert-ブチル、R2がメチルである化合物（C-1）を用いた具体例を下記のScheme C及び後述の参考例に示す。 Production of Compound (X) of high purity and p-toluenesulfonate monohydrate (Xa) of Compound (X) using Compound (A-3) produced from Compound (A-1) of the present invention As a method for the formation, a known method disclosed in Patent Document 5 may be used, and in the compound (A-3), a compound (C-1) in which R 1 is tert-butyl and R 2 is methyl was used. A specific example is shown in the following Scheme C and a reference example described later.
Figure JPOXMLDOC01-appb-C000048
Figure JPOXMLDOC01-appb-C000048
［式中、Bocはtert-ブトキシカルボニル基を示す。］ [Wherein, Boc represents a tert-butoxycarbonyl group. ]
　以上のように本発明によって得られる化合物（A-2）[化合物(3)]および化合物(A-3)[化合物(5)]は重要合成中間体である化合物（C-4）、並びにFXa阻害剤である化合物(X)及び(X-a)の合成中間体として有用である。 As described above, the compound (A-2) [compound (3)] and the compound (A-3) [compound (5)] obtained by the present invention are the compound (C-4), which is an important synthetic intermediate, and FXa It is useful as a synthetic intermediate of compounds (X) and (Xa) which are inhibitors.
　次に、参考例及び実施例を挙げて本発明を詳細に説明するが、本発明は、何らこれに限定されるものではない。核磁気共鳴スペク卜ル(NMR) における内部標準物質としては、テ卜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。 Next, the present invention will be described in detail by way of Reference Examples and Examples, but the present invention is not limited thereto. As an internal standard substance in nuclear magnetic resonance spectrum (NMR), tetramethylsilane is used, and an abbreviation indicating multiplicity is s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, And br s = broad singlet.
(参考例1)
 (1S,3R,4R)-3-amino-4-hydroxy-N,N-dimethyl-cyclohexanecarboxamide
(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（A-1） (Reference Example 1)
(1S, 3R, 4R) -3-amino-4-hydroxy-N, N-dimethyl-cyclohexanecarboxamide
(1S, 3R, 4R) -3-Amino-4-hydroxy-N, N-dimethyl-cyclohexanecarboxamide (A-1)
Figure JPOXMLDOC01-appb-C000049
Figure JPOXMLDOC01-appb-C000049
(1S,4S,5S)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one (110 g, 536 mmol)、酢酸エチル (550 mL)、ジメチルアミン水溶液 (168 mL, 50%)を添加し、5 ℃で14時間攪拌した。食塩 (50.6 g)、クエン酸 (72.1 g)、水道水 (190 mL)を得られた溶液に滴下し、水道水(44 mL)、酢酸エチル (44 mL)を添加し、分液操作を行った。水層を酢酸エチル (220 mL)で2回抽出し、得られた有機層を混合した。混合した溶液を容量が550 mLになるまで減圧濃縮した。濃縮後の溶液に水道水 (220 mL)を添加し、容量が275 mLになるまで減圧濃縮した。濃縮後の溶液に水道水(147 mL)、アンモニア水 (688 mL, 28%)、水酸化ナトリウム水溶液 (68 mL, 25%)を添加し、40 ℃で5時間攪拌した。攪拌した溶液を容量が550 mLになるまで減圧濃縮した。得られた溶液には表記化合物が70.81 g含まれていた (HPLC定量値、収率86.5%)。 (1S, 4S, 5S) -4-bromo-6-oxabicyclo [3.2.1] octan-7-one (110 g, 536 mmol), ethyl acetate (550 mL), aqueous dimethylamine solution (168 mL, 50%) Was added and stirred at 5 ° C. for 14 hours. Add sodium chloride (50.6 g), citric acid (72.1 g), tap water (190 mL) dropwise to the obtained solution, add tap water (44 mL), ethyl acetate (44 mL), and perform liquid separation operation. The The aqueous layer was extracted twice with ethyl acetate (220 mL), and the obtained organic layers were combined. The combined solution was concentrated under reduced pressure to a volume of 550 mL. To the concentrated solution was added tap water (220 mL), and concentrated under reduced pressure to a volume of 275 mL. To the solution after concentration, tap water (147 mL), aqueous ammonia (688 mL, 28%) and aqueous sodium hydroxide (68 mL, 25%) were added, and the mixture was stirred at 40 ° C. for 5 hours. The stirred solution was concentrated under reduced pressure to a volume of 550 mL. The obtained solution contained 70.81 g of the title compound (HPLC quantitative value, 86.5% yield).
(参考例2)
(1R,2R,4S)-2-{[(tert-butoxycarbonyl)sulfamoyl]amino}-4-(dimethylcarbamoyl)cyclohexyl methanesulfonate
(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(C-1) (Reference Example 2)
(1R, 2R, 4S) -2-{[(tert-butoxycarbonyl) sulfamoyl] amino} -4- (dimethylcarbamoyl) cyclohexyl methacrylate sulfonate
(1R, 2R, 4S) -2-{[(tert-butoxycarbonyl) sulfamoyl] amino} -4- (dimethylcarbamoyl) cyclohexyl methanesulfonate (C-1)
Figure JPOXMLDOC01-appb-C000050
Figure JPOXMLDOC01-appb-C000050
［式中、Bocはtert-ブトキシカルボニル基を示す。］ [Wherein, Boc represents a tert-butoxycarbonyl group. ]
　t-ブチルアルコール (9.11 g, 123 mmol)をアセトニトリル (57 mL)に溶解し、5 ℃以下に冷却した。クロロスルホニルイソシアネート (16.57 g, 117 mmol)を5時間かけて滴下した。得られた溶液をトリエチルアミン (48 mL, 344 mmol)とアセトニトリル (57 mL)を混合した溶液に滴下した。参考例1にて取得した水溶液 (100 mL, 99.05 g)を滴下し、水酸化ナトリウム水溶液 (18 mL, 25%)を注下した後、5 ℃で3時間攪拌した。攪拌した溶液を容量が140 mLになるまで減圧濃縮した。得られた溶液にクエン酸 (7.50 g)、酢酸エチル (220 mL)を添加し、分液操作を行った。水層に酢酸エチル (80 mL)を添加し抽出操作を行った。分液操作で得られた有機層に食塩水 (76 mL, 20%)を添加し分液操作を行った。水層に抽出操作で得られた有機層を混合し分液操作を行った。得られた2つの有機層を混合し、容量が100 mLになるまで減圧濃縮した。得られた溶液にアセトニトリル (50 mL)を添加し容量が60 mLになるまで減圧濃縮した、この操作を5回繰り返した。得られた溶液にアセトニトリル (60 mL)、メタンスルホニルクロリド (11.17 g, 98 mmol)、N-メチルモルホリン (12.53 g, 124 mmol)を添加し、5 ℃で13時間攪拌した。得られた溶液に硫酸水溶液 (13 mL, 5%)を添加した。得られた水溶液を水道水(246 mL)に添加し水道水 (40 mL)、アセトニトリル (8 mL)を加え、5 ℃で3時間攪拌した後に桐山ロートで濾過した。結晶をアセトニトリル (17 mL)及び水道水 (44 mL)の混合液、トルエン (40 mL)で洗浄した。得られた結晶を50 ℃で減圧乾燥し、標記結晶を28.5 g (含量 97.2%, 収率64.2% from (1S,4S,5S)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one)得た。 T-Butyl alcohol (9.11 g, 123 mmol) was dissolved in acetonitrile (57 mL) and cooled to below 5 ° C. Chlorosulfonyl isocyanate (16.57 g, 117 mmol) was added dropwise over 5 hours. The resulting solution was added dropwise to a mixed solution of triethylamine (48 mL, 344 mmol) and acetonitrile (57 mL). The aqueous solution (100 mL, 99.05 g) obtained in Reference Example 1 was added dropwise, and after sodium hydroxide aqueous solution (18 mL, 25%) was poured, the mixture was stirred at 5 ° C. for 3 hours. The stirred solution was concentrated under reduced pressure to a volume of 140 mL. Citric acid (7.50 g) and ethyl acetate (220 mL) were added to the obtained solution, and a liquid separation operation was performed. The aqueous layer was extracted with ethyl acetate (80 mL) added. To the organic layer obtained by the separation operation was added brine (76 mL, 20%) to carry out a separation operation. The aqueous layer was mixed with the organic layer obtained by the extraction operation, and a liquid separation operation was performed. The two obtained organic layers were combined and concentrated under reduced pressure to a volume of 100 mL. Acetonitrile (50 mL) was added to the obtained solution, and the solution was concentrated under reduced pressure to a volume of 60 mL. This operation was repeated 5 times. Acetonitrile (60 mL), methanesulfonyl chloride (11.17 g, 98 mmol) and N-methylmorpholine (12.53 g, 124 mmol) were added to the obtained solution, and the mixture was stirred at 5 ° C. for 13 hours. Aqueous sulfuric acid solution (13 mL, 5%) was added to the resulting solution. The obtained aqueous solution was added to tap water (246 mL), tap water (40 mL) and acetonitrile (8 mL) were added, and the mixture was stirred at 5 ° C. for 3 hours and filtered through a Kiriyama funnel. The crystals were washed with a mixture of acetonitrile (17 mL) and tap water (44 mL), toluene (40 mL). The crystals obtained were dried at 50 ° C. under reduced pressure, and 28.5 g of the title crystals (content 97.2%, yield 64.2% from (1S, 4S, 5S) -4-bromo-6-oxabicyclo [3.2.1] octan-7 -one) got.
(参考例3)
tert-butyl (3aS,6S,7aR)-6-(dimethylcarbamoyl)-2,2-dioxohexahydro-2,1,3-benzothiadiazole-1(3H)-carboxylate
(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(C-2)（国際公開2014／157653号パンフレットに記載の製造方法） (Reference Example 3)
tert-butyl (3aS, 6S, 7aR) -6- (dimethylcarbamoyl) -2,2-dioxohexahydro-2,1,3-benzothiadiazole-1 (3H) -carboxylate
(3aS, 6S, 7aR) -6- (Dimethylcarbamoyl) -2,2-dioxohexahydro-2,1,3-benzothiadiazoyl-1 (3H) -carboxylate tert-butyl (C-2) ( Production method described in International Publication 2014/157653 pamphlet)
Figure JPOXMLDOC01-appb-C000051
Figure JPOXMLDOC01-appb-C000051
［式中、Bocはtert-ブトキシカルボニル基を示す。］ [Wherein, Boc represents a tert-butoxycarbonyl group. ]
　{[(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(20g)に塩化メチレン(200ml)、トリエチルアミン(18.5ml)を加え、約0 ℃に冷却した。メタンスルホニルクロリド(5.2ml)を滴下し、約1時間攪拌した。反応混合物に水(100ml)を加え、有機層を分離した。有機層の溶媒を減圧留去した。残渣にアセトニトリル(200ml)、トリエチルアミン(15.4ml)を加え、約90 ℃に加温し、約2時間攪拌した。反応混合物を室温に冷却して10％食塩水(100ml)を加え、有機層を分離した。水層を再度酢酸エチル(100ml)で抽出した。合わせた有機層を濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィ-で精製し、標題化合物(14.02g，収率74％)を粉末として得た。 Methylene chloride (200 ml) and triethylamine (18.5 ml) are added to tert-butyl {[(1R, 2R, 5S) -5- (dimethylcarbamoyl) -2-hydroxycyclohexyl] sulfamoyl} carbamate (20 g), and the temperature is about 0 ° C. Cooled to Methanesulfonyl chloride (5.2 ml) was added dropwise and stirred for about 1 hour. Water (100 ml) was added to the reaction mixture, and the organic layer was separated. The solvent of the organic layer was evaporated under reduced pressure. Acetonitrile (200 ml) and triethylamine (15.4 ml) were added to the residue, and the mixture was warmed to about 90 ° C. and stirred for about 2 hours. The reaction mixture was cooled to room temperature, 10% brine (100 ml) was added, and the organic layer was separated. The aqueous layer was again extracted with ethyl acetate (100 ml). The combined organic layer was concentrated, and the obtained residue was purified by silica gel column chromatography to give the title compound (14.02 g, yield 74%) as a powder.
1H-NMR(CDCl3)δ：1.52(9H，s)、1.66-1.79(2H，m)、1.89-1.96(1H，m)、2.10-2.21(3H，m)、2.92(3H，s)、2.92-2.98(1H，m)、3.02(3H，s)、3.86-3.90(1H，m)、4.67-4.71(1H，m)、4.81-4.83(1H，br，NH).
HRMS(ESI-)： calculated for C14H25N3O5S，［M-H］-m／z 346.1437 Found m／z 346.1446. 1 H-NMR (CDCl 3 ) δ: 1.52 (9 H, s), 1.66-1.79 (2 H, m), 1.89-1.96 (1 H, m), 2.10-2.21 (3 H, m), 2.92 (3 H, s) 2.92 to 2.98 (1 H, m), 3.02 (3 H, s), 3.86 to 3. 90 (1 H, m), 4.67 to 4. 71 (1 H, m), 4.81 to 4. 83 (1 H, br, NH).
HRMS (ESI -): calculated for C 14 H 25 N 3 O 5 S, [MH] - m / z 346.1437 Found m / z 346.1446.
(参考例4)
tert-butyl (1R,2S,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexylcarbamate oxalate
(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(C-4)（国際公開第2014／157653号パンフレットに記載の製造方法） (Reference Example 4)
tert-butyl (1R, 2S, 5S) -2-amino-5-[(dimethylamino) carbonyl] cyclohexylcarbamate oxalate
(1R, 2S, 5S) -2-amino-5-[(dimethylamino) carbonyl] cyclohexyl carbamate tert-butyl oxalate (C-4) (the production method described in WO 2014/157653)
Figure JPOXMLDOC01-appb-C000052
Figure JPOXMLDOC01-appb-C000052
［式中、Bocはtert-ブトキシカルボニル基を示す。］ [Wherein, Boc represents a tert-butoxycarbonyl group. ]
　 (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時間攪拌した。上記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、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％水酸化ナトリウム水溶液(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％水酸化ナトリウム水溶液(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（C-3）のアセトニトリル溶液(約640ml)を得た。
シュウ酸（16.24g）をアセトニトリル(640ml)、水(40m1 )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。 (1R, 2R, 4S) -2-{[(tert-butoxycarbonyl) sulfamoyl] amino} -4- (dimethylcarbamoyl) cyclohexyl methanesulfonate (80 g), acetonitrile (360 ml), triethylamine (26.6 ml) And warmed to about 70.degree. C. and stirred for about 2 hours. Water (20 ml) and pyridine (80 ml) were added to the above acetonitrile solution (467 ml), and the mixture was heated to about 75 ° C. and stirred for 6 hours. The reaction solution was cooled to about 50 ° C., water (80 ml), toluene (800 ml), 20% saline solution (80 ml) and 25% aqueous sodium hydroxide solution (120 ml) were added and allowed to stand to separate the organic layer. The obtained organic layer was washed successively with 20% brine (80 ml) and 25% aqueous sodium hydroxide solution (16 ml), and the obtained organic layer was concentrated to about 240 ml. Toluene (320 ml) is added to the concentrate, and the operation of concentration to about 240 ml is performed twice, acetonitrile (400 ml) is added to the concentrate, insolubles are removed by filtration, and (1R, 2S, 5S) -2 An acetonitrile solution (about 640 ml) of tert-butyl (amino acid 3) [amino-5-[(dimethylamino) carbonyl] cyclohexylcarbamate (C-3) was obtained.
Oxalic acid (16.24 g) was added to acetonitrile (640 ml), water (40 ml) and warmed to about 35 ° C. An acetonitrile solution (about 640 ml) of tert-butyl (1R, 2S, 5S) -2-amino-5-[(dimethylamino) carbonyl] cyclohexylcarbamate prepared by the above method is added dropwise to this solution, After stirring for about 1 hour at .degree. C., the solution was cooled to about 25.degree. C. and stirred for about 1 hour. The precipitated crystals are filtered, washed with 7% aqueous acetonitrile (300 ml), and the monohydrate of the title compound ((1R, 2S, 5S) -2-amino-5-[(dimethylamino) carbonyl] cyclohexylcarbamine Acid tert-butyl oxalate monohydrate was obtained. Acetonitrile (560 ml) was added to the monohydrate of the title compound and warmed to about 70 ° C. After stirring for about 5 hours at the same temperature, concentration was performed to about 320 ml, acetonitrile (320 ml) was added to the concentrate, 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 as an anhydride (55. 74 g, yield 82%).
 (参考例5)
ethyl 2-[(5-chloropyridine-2-yl)amino]-2-oxoacetate monohydrochloride
2-［(5-クロロピリジン-2-イル)アミノ］-2-オキソアセテート エチルエステル・1塩酸塩(国際公開第2014／157653号パンフレットに記載の製造方法) (Reference Example 5)
ethyl 2-[(5-chloropyridine-2-yl) amino] -2-oxoacetate monohydrochloride
2-[(5-chloropyridin-2-yl) amino] -2-oxoacetate ethyl ester • hydrochloride (production method described in WO 2014/157653)
Figure JPOXMLDOC01-appb-C000053
Figure JPOXMLDOC01-appb-C000053
　2-アミノ-5-クロロピリジン(10.0g)のアセトニトリル懸濁液(120ml)に、50 ℃でエチルオキサリルクロリド(11.7g)を加え、そのままの温度にて2時間攪拌した。反応液を冷却して10 ℃で結晶を濾取し、結晶をアセトニトリル(40ml)で洗浄後、減圧下乾燥して標題化合物(19.7g)を得た。 Ethyl oxalyl chloride (11.7 g) was added to an acetonitrile suspension (120 ml) of 2-amino-5-chloropyridine (10.0 g) at 50 ° C., and the mixture was stirred at the same temperature for 2 hours. The reaction solution was cooled, and the crystals were collected by filtration at 10 ° C. The crystals were washed with acetonitrile (40 ml) and dried under reduced pressure to give the title compound (19.7 g).
 (参考例6)
tert-butyl (1R,2S,5S)-2-({2-[(5-chloropyridine-2-yl)amino]-2-oxoacetyl}amino)-5-(dimethylaminocarbonyl)cyclohexylcarbamate
tert-ブチル (1R，2S，5S)-2-(｛2-［(5-クロロピリジン-2-イル)アミノ］-2-オキソアセチル｝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メート(C-5)(国際公開第2007／032498号パンフレットに記載の製造方法) (Reference Example 6)
tert-butyl (1R, 2S, 5S) -2-({2-[(5-chloropyridine-2-yl) amino] -2-oxoacetyl} amino) -5- (dimethylaminocarbonyl) cyclohexylcarbamate
tert-Butyl (1R, 2S, 5S) -2-({2-[(5-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) -5- (dimethylaminocarbonyl) cyclohexylcarbamate (C -5) (Production method described in WO 2007/032498 brochure)
Figure JPOXMLDOC01-appb-C000054
Figure JPOXMLDOC01-appb-C000054
(式中、Bocはtert-ブトキシカルボニル基を示す。) (Wherein, Boc represents a tert-butoxycarbonyl group)
　(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(C-4) (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-オキソアセテートエチルエステル・1塩酸塩(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(106.6g)を得た。 (1R, 2S, 5S) -2-amino-5-[(dimethylamino) carbonyl] cyclohexyl carbamate tert-butyl oxalate (C-4) (100.1 g) in acetonitrile suspension (550 ml) 60 Triethylamine (169 ml) was added at ° C. At the same temperature, 2-[(5-chloropyridin-2-yl) amino] -2-oxoacetate ethyl ester monohydrochloride (84.2 g) is added, and the mixture is stirred for 6 hours and then at room temperature for 16 hours did. Water was added to the reaction solution, and the mixture was stirred at 10 ° C. for 1 hour and 30 minutes, and the crystals were collected by filtration to give the title compound (106.6 g).
1H-NMR(CDCl3)δ：1.25-1.55(2H，m)，1.45(9H，s)，1.60-2.15(5H，m)，2.56-2.74(1H，brs)，2.95(3H，s)，3.06(3H，s)，3.90-4.01(1H，m)，4.18-4.27(1H，m)，4.70-4.85(0.7H，br)，5.70-6.00(0.3H，brs)，7.70(1H，dd，J＝8.8，2.4Hz)，7.75-8.00(1H，br)，8.16(1H，brd，J＝8.8Hz)，8.30(1H，d，J＝2.4Hz)，9.73(1H，s). 1 H-NMR (CDCl 3 ) δ: 1.25-1.55 (2H, m), 1.45 (9H, s), 1.60-2.15 (5H, m), 2.56-2.74 (1H, brs), 2.95 (3H, s) , 3.06 (3H, s), 3.90 to 4.01 (1H, m), 4.18 to 4.27 (1H, m), 4.75 to 4.85 (0.7 H, br), 5. 50 to 6.00 (0.3 H, brs), 7. 70 (1 H, dd, J = 8.8, 2.4 Hz), 7.75-8.00 (1 H, br), 8. 16 (1 H, brd, J = 8.8 Hz), 8.30 (1 H, d, J = 2.4 Hz), 9.73 (1 H, s).
 (参考例7)
N1-(5-chloropyridine-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-yl)carbonyl]amino}cyclohexyl)ethanediamide
N1-(5-クロロピリジン-2-イル)-N2-((1S，2R，4S)-4-［(ジメチルアミノ)カルボニル］-2-｛［(5-メチル-4，5，6，7-テトラヒドロチアゾロ［5，4-c］ピリジン-2-イル)カルボニル］アミノ｝シクロヘキシル)エタンジアミド(X)(国際公開第2007／032498号パンフレットに記載の製造方法) (Reference Example 7)
N 1- (5-chloropyridine-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-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6) , 7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide (X) (the production method described in WO 2007/032498)
Figure JPOXMLDOC01-appb-C000055
Figure JPOXMLDOC01-appb-C000055
　tert-ブチル (1R，2S，5S)-2-(｛2-［(5-クロロピリジン-2-イル)アミノ］-2-オキソアセチル｝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メート(C-5) (95.1g)のアセトニトリル(1900ml)懸濁液に、室温下、メタンスルホン酸(66ml)を加え、そのままの温度にて2時間攪拌した。反応液に氷冷下、トリエチルアミン(155ml)、5-メチル-4，5，6，7-テトラヒドロ［1，3］チアゾロ［5，4-c］ピリジン-2-カルボン酸・塩酸塩(52.5g)、1-ヒドロキシベンゾトリアゾール(33.0g)、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩(46.8g)を加え、室温にて16時間攪拌した。トリエチルアミン、水を加え、氷冷下、1時間攪拌後、結晶を濾取し、標題化合物(X)(103.2g)を得た。 tert-Butyl (1R, 2S, 5S) -2-({2-[(5-chloropyridin-2-yl) amino] -2-oxoacetyl} amino) -5- (dimethylaminocarbonyl) cyclohexylcarbamate (C -5) To a suspension of (95.1 g) in acetonitrile (1900 ml) was added methanesulfonic acid (66 ml) at room temperature, and the mixture was stirred at the same temperature for 2 hours. To the reaction solution under ice-cooling, 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, and the crystals were collected by filtration to give the title compound (X) (103.2 g).
1H-NMR(CDCl3)δ：1.60-1.98(3H，m)，2.00-2.16(3H，m)，2.52(3H，s)，2.78-2.90(3H，m)，2.92-2.98(2H，m)，2.95(3H，s)，3.06(3H，s)，3.69(1H，d，J＝15.4Hz)，3.75(1H，d，J＝15.4Hz)，4.07-4.15(1H，m)，4.66-4.72(1H，m)，7.40(1H，dd，J＝8.8，0.6Hz)，7.68(1H，dd，J＝8.8，2.4Hz)，8.03(1H，d，J＝7.8Hz)，8.16(1H，dd，J＝8.8，0.6Hz)，8.30(1H，dd，J＝2.4，0.6Hz)，9.72(1H，s).
MS(ESI)m／z：548(M＋H)＋. 1 H-NMR (CDCl 3 ) δ: 1.60-1.98 (3H, m), 2.00-2.16 (3H, m), 2.52 (3H, s), 2.78-2.90 (3H, m), 2.92-2.98 (2H, 2H) m), 2.95 (3 H, s), 3.06 (3 H, s), 3.69 (1 H, d, J = 15.4 Hz), 3.75 (1 H, d, J = 15.4 Hz), 4.07-4.15 (1 H, m), 4.66-4.72 (1 H, m), 7.40 (1 H, dd, J = 8.8, 0.6 Hz), 7.68 (1 H, dd, J = 8.8, 2.4 Hz), 8.03 (1 H, d, J = 7.8 Hz), 8.16 (1H, dd, J = 8.8, 0.6 Hz), 8.30 (1 H, dd, J = 2.4, 0.6 Hz), 9.72 (1 H, s).
MS (ESI) m / z: 548 (M + H) + .
(参考例8)
N1-(5-chloropyridine-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-yl)carbonyl]amino}cyclohexyl)ethanediamide mono-p-toluenesulfonate monohydrate
N1-(5-クロロピリジン-2-イル)-N2-((1S，2R，4S)-4-［(ジメチルアミノ)カルボニル］-2-｛［(5-メチル-4，5，6，7-テトラヒドロチアゾロ［5，4-c］ピリジン-2-イル)カルボニル］アミノ｝シクロヘキシル)エタンジアミド　p-トルエンスルホン酸塩1水和物(X-a)(国際公開第2007／032498号パンフレットに記載の製造方法) (Reference Example 8)
N 1- (5-chloropyridine-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 mono-p-toluenesulfonate monohydrate
N 1- (5-chloropyridin-2-yl) -N 2 -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4,5,6) 7,7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide p-toluenesulfonate monohydrate (Xa) (described in WO 2007/032498) Manufacturing method)
Figure JPOXMLDOC01-appb-C000056
Figure JPOXMLDOC01-appb-C000056
　N1-(5-クロロピリジン-2-イル)-N2-((1S，2R，4S)-4-［(ジメチルアミノ)カルボニル］-2-｛［(5-メチル-4，5，6，7-テトラヒドロチアゾロ［5，4-c］ピリジン-2-イル)カルボニル］アミノ｝シクロヘキシル)エタンジアミド(X)(86.8g)を60℃で30%含水エタノール（418ml）に溶解後、p-トルエンスルホン酸1水和物（29.0g）の30％含水エタノール溶液（167ml）を加えた。反応混合物を70℃で1時間攪拌し、徐々に室温まで冷却後、エタノールを加え、16時間攪拌した。反応液を氷冷下、1時間攪拌後、結晶をろ取し、標題化合物(X-a)(102.9g)を得た。 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 (X) (86.8 g) was dissolved in 30% aqueous ethanol (418 ml) at 60 ° C. A 30% aqueous ethanol solution (167 ml) of toluenesulfonic acid monohydrate (29.0 g) was added. The reaction mixture was stirred at 70 ° C. for 1 hour, gradually cooled to room temperature, ethanol was added, and stirred for 16 hours. The reaction mixture was stirred under ice-cooling for 1 hour, and the crystals were collected by filtration to give the title compound (Xa) (102.9 g).
1H-NMR(DMSO-d6)δ：1.45-1.54(1H，m)，1.66-1.78(3H，m)，2.03-2.10(2H，m)，2.28(3H，s)，2.79(3H，s)，2.91-3.02(1H，m)，2.93(3H，s)，2.99(3H，s)，3.13-3.24(2H，m)，3.46-3.82(2H，m)，3.98-4.04(1H，m)，4.43-4.80(3H，m)，7.11(2H，d，J＝7.8Hz)，7.46(2H，d，J＝8.2Hz)，8.01(2H，d，J＝1.8Hz)，8.46(1H，t，J＝1.8Hz)，8.75(1H，d，J＝6.9Hz)，9.10-9.28(1H，br)，10.18(1H，br)，10.29(1H，s).
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. 
実測値：C；50.25，H；5.36，N；13.32.
mp(分解)：245～248℃. 1 H-NMR (DMSO-d 6 ) δ: 1.45-1.54 (1 H, m), 1.66-1.78 (3 H, m), 2.03-2.10 (2 H, m), 2.28 (3 H, s), 2.79 (3 H, s), 2.91-3. 02 (1 H, m), 2. 93 (3 H, s), 2.99 (3 H, s), 3. 13-3. 24 (2 H, m), 3. 46-3. 82 (2 H, m), 3. 98-4. 04 (1 H, m), 4.43-4.80 (3 H, m), 7.11 (2 H, d, J = 7.8 Hz), 7.46 (2 H, d, J = 8.2 Hz), 8.01 (2 H, d, J = 1.8 Hz), 8.46 ( 1 H, t, J = 1.8 Hz), 8.75 (1 H, d, J = 6.9 Hz), 9.10-9.28 (1 H, br), 10.18 (1 H, br), 10. 29 (1 H, s).
MS (ESI) m / z: 548 (M + H) + .
Elemental analysis: C 24 H 30 ClN 7 O 4 S ・ C 7 H 8 O 3 S ・ H 2 O
Theoretical value: C: 50.43, H: 5.46, N; 13.28.
Found: C; 50.25, H; 5.36, N; 13.32.
mp (decomposition): 245-248 ° C.
(実施例1)
(1R,2R,4S)-2-{[(tert-butoxycarbonyl)sulfamoyl]amino}-4-(dimethylcarbamoyl)cyclohexyl methanesulfonate
(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 Example 1
(1R, 2R, 4S) -2-{[(tert-butoxycarbonyl) sulfamoyl] amino} -4- (dimethylcarbamoyl) cyclohexyl methacrylate sulfonate
(1R, 2R, 4S) -2-{[(tert-butoxycarbonyl) sulfamoyl] amino} -4- (dimethylcarbamoyl) cyclohexyl methanesulfonate
Figure JPOXMLDOC01-appb-C000057
Figure JPOXMLDOC01-appb-C000057
[規則26に基づく補充 28.08.2018]　[Repletion based on rule 26 28.08.218]
[規則91に基づく訂正 28.08.2018]　図２のようにフロー装置を設置した。Feed Aにクロロスルホニルイソシアネート、Feed Bにt-ブチルアルコール(22.77 g, 307 mmol)とアセトニトリル (200 mL)を混合した溶液を用意した。Feed Aを7.939 mL/h、Feed Bを72.06 mL/h、でそれぞれ流し、図に示した通り、0 ℃に冷却したチューブリアクター (φ0.5 mm、容積: 0.4 mL)を通し、トリエチルアミン (48 mL, 341 mmol)とアセトニトリル (33 mL)を混合した溶液に滴下した。1.27時間運転して得られた溶液に参考例1の方法で取得した水溶液 (100 mL, 99.05 g)を滴下し、水酸化ナトリウム水溶液 (18 mL, 25%)を注下した後、5 ℃で3 時間攪拌した。攪拌した溶液を容量が140 mLになるまで減圧濃縮した。得られた溶液にクエン酸 (7.50 g)、酢酸エチル (220 mL)を添加し、分液操作を行った。水層に酢酸エチル (80 mL)を添加し抽出操作を行った。分液操作で得られた有機層に食塩水 (76 mL, 20%)を添加し分液操作を行った。水層に抽出操作で得られた有機層を混合し分液操作を行った。得られた2つの有機層を混合し、容量が100 mLになるまで減圧濃縮した。得られた溶液にアセトニトリル (50 mL)を添加し容量が60 mLになるまで減圧濃縮した、この操作を5回繰り返した。得られた溶液にアセトニトリル (60 mL)、メタンスルホニルクロリド (11.17 g, 97.51 mmol)、N-メチルモルホリン (12.53 g, 124 mmol)を添加し、5 ℃で5 時間攪拌した。得られた溶液に硫酸水溶液 (13 mL, 5%)を添加した。得られた水溶液を水道水(246 mL)に添加し水道水 (40 mL)、アセトニトリル (8 mL)を加え、5 ℃で3時間攪拌した後に桐山ロートで濾過した。結晶をアセトニトリル (17 mL)及び水道水 (44 mL)の混合液、トルエン (40 mL)で洗浄した。得られた結晶を50 ℃で減圧乾燥し、標記化合物を29.79 g (含量 99.0%,収率68.2% from (1S,4S,5S)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one)得た。[Correction based on Rule 91 28.08.218] The flow device was installed as shown in FIG. A solution was prepared by mixing Chlorosulfonyl isocyanate in Feed A, t-butyl alcohol (22.77 g, 307 mmol) in Feed B, and acetonitrile (200 mL). The Feed A was flowed at 7.939 mL / h, Feed B at 72.06 mL / h, and as shown in the figure, the tube reactor (φ 0.5 mm, volume: 0.4 mL) cooled was passed through to give triethylamine (48 To the mixed solution of mL (341 mmol) and acetonitrile (33 mL) was added dropwise. The aqueous solution (100 mL, 99.05 g) obtained by the method of Reference Example 1 was added dropwise to the solution obtained by operation for 1.27 hours, and after the aqueous sodium hydroxide solution (18 mL, 25%) was poured, the solution was obtained at 5 ° C. Stir for 3 hours. The stirred solution was concentrated under reduced pressure to a volume of 140 mL. Citric acid (7.50 g) and ethyl acetate (220 mL) were added to the obtained solution, and a liquid separation operation was performed. The aqueous layer was extracted with ethyl acetate (80 mL) added. To the organic layer obtained by the separation operation was added brine (76 mL, 20%) to carry out a separation operation. The aqueous layer was mixed with the organic layer obtained by the extraction operation, and a liquid separation operation was performed. The two obtained organic layers were combined and concentrated under reduced pressure to a volume of 100 mL. Acetonitrile (50 mL) was added to the obtained solution, and the solution was concentrated under reduced pressure to a volume of 60 mL. This operation was repeated 5 times. Acetonitrile (60 mL), methanesulfonyl chloride (11.17 g, 97.51 mmol) and N-methylmorpholine (12.53 g, 124 mmol) were added to the resulting solution, and the mixture was stirred at 5 ° C. for 5 hours. Aqueous sulfuric acid solution (13 mL, 5%) was added to the resulting solution. The obtained aqueous solution was added to tap water (246 mL), tap water (40 mL) and acetonitrile (8 mL) were added, and the mixture was stirred at 5 ° C. for 3 hours and filtered through a Kiriyama funnel. The crystals were washed with a mixture of acetonitrile (17 mL) and tap water (44 mL), toluene (40 mL). The crystals obtained were dried at 50 ° C. under reduced pressure, and the title compound was obtained in 29.79 g (content 99.0%, yield 68.2% from (1S, 4S, 5S) -4-bromo-6-oxabicyclo [3.2.1] octan-7 -one) got.
　（実施例2）
　(1R,2R,4S)-2-{[(tert-butoxycarbonyl)sulfamoyl]amino}-4-(dimethylcarbamoyl)cyclohexyl methanesulfonate
　(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 (Example 2)
(1R, 2R, 4S) -2-{[(tert-butoxycarbonyl) sulfamoyl] amino} -4- (dimethylcarbamoyl) cyclohexyl methacrylate sulfonate
(1R, 2R, 4S) -2-{[(tert-butoxycarbonyl) sulfamoyl] amino} -4- (dimethylcarbamoyl) cyclohexyl methanesulfonate
[規則91に基づく訂正 28.08.2018]　
Figure JPOXMLDOC01-appb-C000059
 [Correction based on rule 91 28.08.218]
Figure JPOXMLDOC01-appb-C000059
[規則26に基づく補充 28.08.2018]　[Repletion based on rule 26 28.08.218]
[規則91に基づく訂正 28.08.2018]　図３のようにフロー装置を設置した。Feed Aにクロロスルホニルイソシアネート、Feed Bにtert-ブチルアルコール(1366 g, 18.4 mol)とアセトニトリル(12 L)を混合した溶液を用意した。Feed Aを12.66 mL/min、Feed Bを109.81 mL/min、でそれぞれ流し、図に示した通り、0 ℃に冷却したチューブリアクター (φ5 mm、容積: 112 mL)を通し、トリエチルアミン(3569 mL, 25.6 mol)とアセトニトリル (2490 mL)を混合した溶液に滴下した。51分間運転して得られた溶液に参考例1の方法で取得した水溶液(6.68 kg, 92.4% from (1S,4S,5S)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one)を滴下し、水酸化ナトリウム水溶液 (1175 mL, 25%)を注下した後、5 ℃で3 時間攪拌した。攪拌した溶液を容量が8.9 Lになるまで減圧濃縮した。得られた溶液にクエン酸 (477.84 g）、酢酸エチル (14025 mL）を添加し、分液操作を行った。水層に酢酸エチル (5100 mL）を添加し抽出操作を行った。分液操作で得られた有機層に食塩水(4845 mL, 20%)を添加し分液操作を行った。水層に抽出操作で得られた有機層を混合し分液操作を行った。得られた2つの有機層を混合し、容量が6.3 Lになるまで減圧濃縮した。得られた溶液にアセトニトリル (3188 mL)を添加し容量が3.8 Lになるまで減圧濃縮した、この操作を5回繰り返した。得られた溶液にアセトニトリル (3188 mL)、メタンスルホニルクロリド (712.3 g, 6.22 mol)、N-メチルモルホリン (798.8 g, 7.9 mol)を添加し、5 ℃で5時間攪拌した。得られた溶液に硫酸水溶液 (829 mL, 5%)を添加した。得られた水溶液を水道水(15695 mL)に添加し水道水 (2550 mL)、アセトニトリル (510 mL)を加え、5 ℃で0.5時間攪拌した後に硫酸水溶液(32.0 mL, 5%)を添加してpHを3.11に調整した。さらに5 ℃で3時間攪拌した後に硫酸水溶液(11.2 mL, 5%)を添加してpHを2.9に調整した。スラリー液をヌッチェで濾過した。結晶をアセトニトリル (1058 mL)及び水道水 (2780 mL)の混合液、トルエン(2550 mL)で洗浄後、50℃で減圧乾燥し、標記化合物を2757.9 g(含量 98.8%,収率75.5% from (1S,4S,5S)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one)得た。[Correction based on rule 91: 28.08.218] The flow device was installed as shown in FIG. A solution was prepared in which Feed A was mixed with chlorosulfonyl isocyanate, Feed B was mixed with tert-butyl alcohol (1366 g, 18.4 mol) and acetonitrile (12 L). The Feed A was flowed at 12.66 mL / min and the Feed B was flowed at 109.81 mL / min, and a tube reactor (φ 5 mm, volume: 112 mL) was passed through it as shown in the figure, and triethylamine (3569 mL, 25.6 mol) and acetonitrile (2490 mL) were added dropwise to the mixed solution. An aqueous solution (6.68 kg, 92.4% from (1S, 4S, 5S) -4-bromo-6-oxabicyclo [3.2.1] octan-7- obtained by the method of Reference Example 1 in a solution obtained by operating for 51 minutes. One) was dropped, and after adding sodium hydroxide aqueous solution (1175 mL, 25%), the mixture was stirred at 5 ° C. for 3 hours. The stirred solution was concentrated under reduced pressure to a volume of 8.9 L. Citric acid (477.84 g) and ethyl acetate (14025 mL) were added to the obtained solution, and liquid separation operation was performed. The aqueous layer was extracted with ethyl acetate (5100 mL) added. Brine solution (4845 mL, 20%) was added to the organic layer obtained by the liquid separation operation to carry out a liquid separation operation. The aqueous layer was mixed with the organic layer obtained by the extraction operation, and a liquid separation operation was performed. The two obtained organic layers were combined and concentrated under reduced pressure to a volume of 6.3 L. Acetonitrile (3188 mL) was added to the obtained solution, and the solution was concentrated under reduced pressure to a volume of 3.8 L. This operation was repeated 5 times. Acetonitrile (3188 mL), methanesulfonyl chloride (712.3 g, 6.22 mol), and N-methylmorpholine (798.8 g, 7.9 mol) were added to the obtained solution, and the mixture was stirred at 5 ° C. for 5 hours. Aqueous sulfuric acid solution (829 mL, 5%) was added to the resulting solution. The obtained aqueous solution is added to tap water (15695 mL), tap water (2550 mL) and acetonitrile (510 mL) are added, and the mixture is stirred at 5 ° C. for 0.5 hours, and then an aqueous sulfuric acid solution (32.0 mL, 5%) is added. The pH was adjusted to 3.11. After further stirring for 3 hours at 5 ° C., an aqueous sulfuric acid solution (11.2 mL, 5%) was added to adjust the pH to 2.9. The slurry solution was filtered through a Nutche. The crystals were washed with a mixture of acetonitrile (1058 mL) and tap water (2780 mL), toluene (2550 mL), dried under reduced pressure at 50 ° C., and 2757.9 g of the title compound (content 98.8%, yield 75.5% from ( 1S, 4S, 5S) -4-bromo-6-oxabicyclo [3.2.1] octan-7-one) was obtained.

Claims (14)

  1. 下記式(1)
    Figure JPOXMLDOC01-appb-C000001
     で表される化合物を、下記の溶液A
    ［溶液A：
    フロー反応装置を用い、クロロスルホニルイソシアナートと下記式(2)
    Figure JPOXMLDOC01-appb-C000002
     （式中、R1はC1-C6アルキル基、又はベンジル基（該ベンジル基のベンゼン環は、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独立して選ばれる1～2個の基を置換基として有していてもよい）を示す）
    で表される化合物の溶液をチューブリアクター内で反応させることによって得られた溶液を三級アミンの溶液に滴下することによって調製される］
    と処理することを特徴とする、下記式(3)
    Figure JPOXMLDOC01-appb-C000003
     （式中R1は上記と同義を示す）
    で表される化合物の製造方法。     Following formula (1)
    Figure JPOXMLDOC01-appb-C000001
     The compound represented by the following solution A
    [Solution A:
    Using a flow reactor, chlorosulfonyl isocyanate and the following formula (2)
    Figure JPOXMLDOC01-appb-C000002
     (Wherein, R 1 is a C1-C6 alkyl group or a benzyl group (the benzene ring of the benzyl group is independently 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 a substituent))
    Prepared by reacting a solution of a compound represented by the following formula in a tube reactor into a solution of a tertiary amine]
    And characterized by the following equation (3)
    Figure JPOXMLDOC01-appb-C000003
     (Wherein, R 1 represents the same as the above)
    Process for producing a compound represented by
  2. 三級アミンがトリエチルアミンである請求項1に記載の製造方法。 The method according to claim 1, wherein the tertiary amine is triethylamine.
  3. 請求項1又は請求項2に記載の製造方法を用いて製造した下記式(3)
    Figure JPOXMLDOC01-appb-C000004
     （式中R1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(4)
    Figure JPOXMLDOC01-appb-C000005
     （式中、R2は、C1-C6アルキル基、ハロC1-C6アルキル基、又はフェニル基（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独立して選ばれる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）
    で表される化合物で処理することを特徴とする、下記式(5)
    Figure JPOXMLDOC01-appb-C000006
     （式中、R1及びR2は上記と同義を示す）
    で表される化合物の製造方法。     The following formula (3) manufactured using the manufacturing method according to claim 1 or claim 2
    Figure JPOXMLDOC01-appb-C000004
     (Wherein, R 1 represents the same as the above)
    In the presence of a base, the compound of the following formula (4)
    Figure JPOXMLDOC01-appb-C000005
     (Wherein R 2 represents a C 1 -C 6 alkyl group, a halo C 1 -C 6 alkyl group, or a phenyl group (wherein the phenyl group represents a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a nitro group and a halogen atom More preferably selected from 1 to 2 groups as substituents); X represents a halogen atom)
    Treated with a compound represented by the following formula (5):
    Figure JPOXMLDOC01-appb-C000006
     (Wherein, R 1 and R 2 are as defined above)
    Process for producing a compound represented by
  4. 塩基がトリエチルアミン又はN-メチルモルホリンである請求項3に記載の製造方法。 The method according to claim 3, wherein the base is triethylamine or N-methylmorpholine.
  5. 下記式(6)
    Figure JPOXMLDOC01-appb-C000007
     で表される化合物を製造する方法であって、以下の工程1及び2を含む方法：
    工程1）　請求項3又は4に記載の製造方法を用いて製造した下記式(5)
    Figure JPOXMLDOC01-appb-C000008
     （式中、R1及びR2は上記と同義を示す）
    で表される化合物をトリエチルアミンで処理することによって下記式(7)
    Figure JPOXMLDOC01-appb-C000009
     （式中、R1は上記と同義を示す）
    で表される化合物を得る工程；及び、
    工程2）　工程1）で得られた式(7)で表される化合物を水及びピリジン類と処理して式(6)で表される化合物を得る工程。     Following formula (6)
    Figure JPOXMLDOC01-appb-C000007
     A process for producing a compound represented by and comprising the following steps 1 and 2:
    Process 1) Following formula (5) manufactured using the manufacturing method of Claim 3 or 4
    Figure JPOXMLDOC01-appb-C000008
     (Wherein, R 1 and R 2 are as defined above)
    Is treated with triethylamine to give the following formula (7)
    Figure JPOXMLDOC01-appb-C000009
     (Wherein, R 1 represents the same as the above)
    Obtaining a compound represented by
    Step 2) A step of treating the compound represented by Formula (7) obtained in Step 1) with water and pyridines to obtain a compound represented by Formula (6).
  6. 下記式（X-a）
    Figure JPOXMLDOC01-appb-C000010
     で表される化合物を製造する方法であって、以下の工程1から6を含む方法：
    工程1）　請求項3又は4に記載の製造方法を用いて製造した下記式(5)
    Figure JPOXMLDOC01-appb-C000011
     （式中、R1及びR2は上記と同義を示す）
    で表される化合物をトリエチルアミンで処理することによって下記式７
    Figure JPOXMLDOC01-appb-C000012
     （式中、R1は上記と同義を示す）
    で表される化合物を得る工程；
    工程2）　工程1）で得られた式(7)で表される化合物を水及びピリジン類と処理して下記式(6)
    Figure JPOXMLDOC01-appb-C000013
     （式中、R1は上記と同義を示す）
    で表される化合物を得る工程；
    工程3）　工程2）で得られた式6で表される化合物をシュウ酸塩又は硫酸塩とした後に、そのシュウ酸塩又は硫酸塩を塩基の存在下、下記式(8)
    Figure JPOXMLDOC01-appb-C000014
     で表される化合物と処理し、下記式(9)
    Figure JPOXMLDOC01-appb-C000015
     （式中、R1は上記と同義を示す）
    で表される化合物を得る工程；
    工程4）　工程3）で得られた式(9)で表される化合物の保護基R1の除去を行って下記式(10)
    Figure JPOXMLDOC01-appb-C000016
     で表される化合物を得る工程；
    工程5）　工程4）で得られた式(10)で表される化合物又はその塩を、下記式(11)
    Figure JPOXMLDOC01-appb-C000017
     で表される化合物と縮合して、下記式（X）
    Figure JPOXMLDOC01-appb-C000018
     で表される化合物を得る工程；及び、
    工程6）　工程5）で得られた式（X）で表される化合物を、含水エタノール中、p-卜ルエンスルホン酸・1水和物と処理することによって式（X-a）で表される化合物を得る工程。     Following formula (Xa)
    Figure JPOXMLDOC01-appb-C000010
     A process for producing the compound represented by and comprising the following steps 1 to 6:
    Process 1) Following formula (5) manufactured using the manufacturing method of Claim 3 or 4
    Figure JPOXMLDOC01-appb-C000011
     (Wherein, R 1 and R 2 are as defined above)
    Is treated with triethylamine to give the following formula 7
    Figure JPOXMLDOC01-appb-C000012
     (Wherein, R 1 represents the same as the above)
    Obtaining a compound represented by
    Step 2) The compound represented by the formula (7) obtained in the step 1) is treated with water and pyridines to obtain the following formula (6)
    Figure JPOXMLDOC01-appb-C000013
     (Wherein, R 1 represents the same as the above)
    Obtaining a compound represented by
    Step 3) After converting the compound represented by the formula 6 obtained in the step 2) into oxalate or sulfate, the oxalate or sulfate in the presence of a base gives the following formula (8)
    Figure JPOXMLDOC01-appb-C000014
     And the compound represented by formula (9)
    Figure JPOXMLDOC01-appb-C000015
     (Wherein, R 1 represents the same as the above)
    Obtaining a compound represented by
    Step 4) Removal of the protecting group R 1 of the compound represented by the formula (9) obtained in the step 3) is carried out to obtain a compound represented by the following formula (10)
    Figure JPOXMLDOC01-appb-C000016
     Obtaining a compound represented by
    Step 5) The compound represented by the formula (10) obtained in the step 4) or a salt thereof is converted to the following formula (11)
    Figure JPOXMLDOC01-appb-C000017
     By condensation with a compound represented by formula (X)
    Figure JPOXMLDOC01-appb-C000018
     Obtaining a compound represented by
    Step 6) A compound represented by the formula (Xa) by treating a compound represented by the formula (X) obtained in the step 5) with p-sulenesulfonic acid monohydrate in water-containing ethanol To get
  7. R1がtert-ブチル基又はベンジル基である請求項1～6のいずれか1項に記載の製造方法。 The process according to any one of claims 1 to 6, wherein R 1 is a tert-butyl group or a benzyl group.
  8. R2がメチル基である請求項3～7のいずれか1項に記載の製造方法。 The method according to any one of claims 3 to 7, wherein R 2 is a methyl group.
  9. フロー反応装置の流速が0.1 ml/min～10 L／minである請求項1～8のいずれか１項に記載の製造方法。 9. The process according to any one of claims 1 to 8, wherein the flow rate of the flow reactor is 0.1 ml / min to 10 L / min.
  10. フロー反応装置の流速が0.1 ml/min～6 L／minである請求項9に記載の製造方法。 The production method according to claim 9, wherein the flow rate of the flow reactor is 0.1 ml / min to 6 L / min.
  11. フロー反応装置の流路の内径が0.1～50mmである請求項1～10のいずれか1項に記載の製造方法。 The production method according to any one of claims 1 to 10, wherein the inner diameter of the flow path of the flow reactor is 0.1 to 50 mm.
  12. フロー反応装置の流路の内径が0.5～25mmである請求項11に記載の製造方法。 The method according to claim 11, wherein the inner diameter of the flow channel of the flow reactor is 0.5 to 25 mm.
  13. フロー反応装置の滞留時間が10～120秒である請求項1～12のいずれか１項に記載の製造方法。 The process according to any one of the preceding claims, wherein the residence time of the flow reactor is 10 to 120 seconds.
  14. フロー反応装置の滞留時間が15～90秒である請求項13に記載の製造方法。
          The process according to claim 13, wherein the residence time of the flow reactor is 15 to 90 seconds.
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WO2022103239A1 (en) * 2020-11-16 2022-05-19 보령제약 주식회사 Preparation method for edoxaban tosylate or hydrate thereof

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