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WO2019004114A1 - Procédé de production de dérivé diamine par synthèse de flux - Google Patents

Procédé de production de dérivé diamine par synthèse de flux Download PDF

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Publication number
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
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following formula
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誠 道田
秀明 石河
伸也 立壁
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Daiichi Sankyo Co Ltd
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Daiichi Sankyo Co Ltd
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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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé de production permettant de synthétiser de manière efficace un composé (1-2) qui est un intermédiaire important dans la production d'edoxaban. Le procédé consiste faire goutter un composé (1-1) dans une solution A qui est obtenue en provoquant une réaction entre l'isocyanate de chlorosulfonyle et un alcool (2) à l'aide d'un dispositif de réaction à écoulement, et à faire goutter le mélange résultant dans une amine tertiaire, ce qui permet d'obtenir un composé (1-2).
PCT/JP2018/023984 2017-06-26 2018-06-25 Procédé de production de dérivé diamine par synthèse de flux Ceased WO2019004114A1 (fr)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109942600A (zh) * 2019-04-15 2019-06-28 内蒙古京东药业有限公司 一种依度沙班的制备方法
CN111393456A (zh) * 2020-03-31 2020-07-10 内蒙古京东药业有限公司 一种由三氯乙酮鎓盐衍生物制备依度沙班的方法
CN111763169A (zh) * 2020-06-30 2020-10-13 浙江苏泊尔制药有限公司 一种改良的依度沙班中间体的制备方法
WO2022103239A1 (fr) * 2020-11-16 2022-05-19 보령제약 주식회사 Procédé de préparation d'edoxaban tosylate ou de son hydrate
CN116410128A (zh) * 2023-03-24 2023-07-11 江苏宇锐医药科技有限公司 一锅法制备甲苯磺酸艾多沙班中间体的方法
CN117924118A (zh) * 2023-12-21 2024-04-26 南京威凯尔生物医药科技有限公司 一种依度沙班中间体草酸盐的晶型及其制备方法
CN118108635A (zh) * 2022-11-30 2024-05-31 中山奕安泰医药科技有限公司 一种高纯度的依度沙班中间体的制备方法
CN118108632A (zh) * 2022-11-30 2024-05-31 中山奕安泰医药科技有限公司 一种依度沙班中间体的精制方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS57120566A (en) * 1980-11-28 1982-07-27 Hoechst Ag Continuous manufacture of chloroalkylsulfonyl isocyanate
WO2003066549A2 (fr) * 2002-02-07 2003-08-14 The Scripps Research Institute Synthese de sulfamates
WO2014157653A1 (fr) * 2013-03-29 2014-10-02 第一三共株式会社 Procédés pour la préparation de dérivés diamine optiquement actifs

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS57120566A (en) * 1980-11-28 1982-07-27 Hoechst Ag Continuous manufacture of chloroalkylsulfonyl isocyanate
WO2003066549A2 (fr) * 2002-02-07 2003-08-14 The Scripps Research Institute Synthese de sulfamates
WO2014157653A1 (fr) * 2013-03-29 2014-10-02 第一三共株式会社 Procédés pour la préparation de dérivés diamine optiquement actifs

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
BURGESS ET AL.: "Conversion of Primary Alcohols to Urethanes via the Inner Salt of Methyl (Carboxysulfamoyl) Triethy lammonium Hydroxide: Methyl n-Hexy lcarbamate", ORGANIC SYNTHESIS, vol. 6, 1988, pages 788, ISSN: 2333-3553 *
BURGESS ET AL.: "Thermal Reactions of Alkyl N- Carbomethoxysulfamate Esters", JOURNAL OF ORGANIC CHEMISTRY, vol. 38, no. 1, 1973, pages 26 - 31, XP055568827, ISSN: 1520-6904 *
KOBAYASHI ET AL.: "Flow ''Fine'' Synthesis: High Yielding and Selective Organic Syhthesis by Flow Methods", CHEMISTRY AN ASIAN JOURNAL FOCUS REVIEW, vol. 11, no. 4, November 2016 (2016-11-01), pages 425 - 436, XP055568805, ISSN: 1861-471X *
METCALF ET AL.: "Design of Thermally Stable Versions of the Burgess Reagent: Stability and Reactivity Study", JOURNAL OF ORGANIC CHEMISTRY, vol. 75, 2010, pages 3447 - 3450, XP055568851, ISSN: 1520-6904 *
QIAN ET AL.: "A Continuous Flow Process Using a Sequence of Microreactors with In-line IR Analysis for the Preparation of N, N-Diethy 1-4-(3-fluoropheny lpiperidin-4- ylidenemethyl) benza mide as a Potent and Highly Selective 5-Cpioid Receptor Agonist", CHEMISTRY A EUROPEAN JOURNAL, vol. 16, no. 41, 2010, pages 12342 - 12348, XP055568820, ISSN: 1521-3765 *
YOSHIDA, JUNICHI ET AL., CHEMCIAL EQUIPMENT, vol. 44, no. 9, 1 September 2002 (2002-09-01), pages 30 - 34, ISSN: 0368-4849 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109942600A (zh) * 2019-04-15 2019-06-28 内蒙古京东药业有限公司 一种依度沙班的制备方法
CN109942600B (zh) * 2019-04-15 2021-08-20 内蒙古京东药业有限公司 一种依度沙班的制备方法
CN111393456A (zh) * 2020-03-31 2020-07-10 内蒙古京东药业有限公司 一种由三氯乙酮鎓盐衍生物制备依度沙班的方法
CN111393456B (zh) * 2020-03-31 2022-07-12 内蒙古京东药业有限公司 一种由三氯乙酮鎓盐衍生物制备依度沙班的方法
CN111763169A (zh) * 2020-06-30 2020-10-13 浙江苏泊尔制药有限公司 一种改良的依度沙班中间体的制备方法
CN111763169B (zh) * 2020-06-30 2023-06-27 浙江苏泊尔制药有限公司 一种改良的依度沙班中间体的制备方法
WO2022103239A1 (fr) * 2020-11-16 2022-05-19 보령제약 주식회사 Procédé de préparation d'edoxaban tosylate ou de son hydrate
CN118108635A (zh) * 2022-11-30 2024-05-31 中山奕安泰医药科技有限公司 一种高纯度的依度沙班中间体的制备方法
CN118108632A (zh) * 2022-11-30 2024-05-31 中山奕安泰医药科技有限公司 一种依度沙班中间体的精制方法
CN116410128A (zh) * 2023-03-24 2023-07-11 江苏宇锐医药科技有限公司 一锅法制备甲苯磺酸艾多沙班中间体的方法
CN117924118A (zh) * 2023-12-21 2024-04-26 南京威凯尔生物医药科技有限公司 一种依度沙班中间体草酸盐的晶型及其制备方法

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