WO2024053350A1 - Procédé de production d'un composé aminoazide, composé diamine et edoxaban - Google Patents

Procédé de production d'un composé aminoazide, composé diamine et edoxaban Download PDF

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WO2024053350A1
WO2024053350A1 PCT/JP2023/029615 JP2023029615W WO2024053350A1 WO 2024053350 A1 WO2024053350 A1 WO 2024053350A1 JP 2023029615 W JP2023029615 W JP 2023029615W WO 2024053350 A1 WO2024053350 A1 WO 2024053350A1
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compound
aminoazide
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秀紀 落合
敦裕 山下
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株式会社カネカ
株式会社大阪合成有機化学研究所
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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
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • 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
    • 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 aminoazide compounds and diamine compounds that are useful as pharmaceutical intermediates, and a method for producing edoxaban.
  • aminoazide compound represented by the following formula (1) (hereinafter also referred to as aminoazide compound (1)) and the diamine compound represented by the following formula (3) (hereinafter also referred to as diamine compound (3)) are used for pharmaceutical synthesis. It is an important synthetic intermediate. For example, it is used as an intermediate in the synthesis of anti-blood coagulants such as edoxaban, and many synthetic methodologies have been studied for this intermediate.
  • Patent Document 1 describes that an aminoalcohol compound represented by the following formula (2) (hereinafter also referred to as aminoalcohol compound (2)) is synthesized by formula (4).
  • a method is disclosed in which the aminoazide compound (1) is obtained by deriving the aminoazide compound into a mesyloxy compound, and then reacting with sodium azide under heating conditions of 70° C. in the presence of a phase transfer catalyst.
  • Patent Document 2 after reacting diphenylphosphoryl azide (DPPA) with the amino alcohol compound (2) in the presence of diazabicycloundecene, adding an inorganic salt and heating to 90 to 130°C, the amino azide A method for obtaining compound (1) is disclosed. Furthermore, in Patent Document 3, an aminoazide compound (1) is prepared by reacting diphenylphosphoryl azide (DPPA) with an aminoalcohol compound (2) in an organic solvent at room temperature in the presence of an amidine compound such as diazabicycloundecene. A method for obtaining the information is disclosed.
  • DPPA diphenylphosphoryl azide
  • an aminoalcohol compound (2) in an organic solvent at room temperature in the presence of an amidine compound such as diazabicycloundecene.
  • Patent Documents 1 to 3 do not sufficiently suppress diastereomers (trans isomers) formed as by-products in the azidation reaction. Specifically, in the method disclosed in Patent Document 1, as described in paragraph 0014 of Patent Document 4, about 10 to 15% of diastereomers are produced. When the present inventors conducted a supplementary test on the method disclosed in Patent Document 1, the diastereoselectivity ratio of the obtained aminoazide compound (3) was low, being 1:0.18 (cis form: trans form). (See Comparative Example 1 in this specification). Furthermore, the sodium azide used in the method disclosed in Patent Document 1 has explosive properties, and there is also a safety problem.
  • the present invention was made in view of the above circumstances, and its purpose is to produce aminoazide compounds and diamine compounds with good diastereoselectivity, in which the formation of undesired diastereomers is suppressed.
  • the purpose is to provide a method.
  • trans-configuration aminoalcohol compound (2) can be azidated using diphenylphosphoryl azide, a phosphine compound, and an azo compound. It has been discovered that the aminoazide compound (1) having the following configuration can be produced with good diastereoselectivity, and the present invention has been completed.
  • the gist of the invention is as follows. [1] The following formula (1) A method for producing an aminoazide compound represented by The following formula (2) A method for producing an amino azide compound represented by formula (1), which comprises an azidation step in which an amino alcohol compound represented by formula (1) is reacted with diphenylphosphoryl azide, a phosphine compound, and an azo compound. [2] The azo compound is at least one selected from the group consisting of diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), and di-2-methoxyethyl azodicarboxylate (DMEAD), [ 1].
  • DEAD diethyl azodicarboxylate
  • DIAD diisopropyl azodicarboxylate
  • DMEAD di-2-methoxyethyl azodicarboxylate
  • Method for producing an aminoazide compound (1) of the present invention is characterized by comprising an azidation step in which diphenylphosphoryl azide, a phosphine compound, and an azo compound are reacted on the aminoalcohol compound (2). shall be.
  • the phosphine compound and the azo compound activate the hydroxyl group of the aminoalcohol compound (2), and the azide group of diphenylphosphorylazide is substituted with the activated hydroxyl group while undergoing stereoreversal, resulting in the desired aminoazide compound (1).
  • the amount of diphenylphosphoryl azide used as the azide group source is preferably 1.0 mol or more and 10 mol or less, more preferably 1.2 mol or more, and 1.5 mol per 1 mol of the amino alcohol compound (2). More preferably, the amount is more preferably 8 mol or less, and even more preferably 5 mol or less. That is, the amount of diphenylphosphoryl azide used is preferably 1.0 mol to 10 mol, more preferably 1.2 mol to 8 mol, and 1.5 mol to 5 mol, per 1 mol of amino alcohol compound (2). is even more preferable.
  • the target compound aminoazide compound (1)
  • the target compound aminoazide compound (1)
  • phosphine compound appears to act together with the azo compound to activate the amino alcohol (2).
  • This phosphine compound is not particularly limited, and, for example, tertiary phosphine is preferred.
  • the tertiary phosphine include triethylphosphine, tripropylphosphine, tributylphosphine, tri(t-butyl)phosphine, tricyclohexylphosphine, triphenylphosphine, tribenzylphosphine, tri(o-tolyl)phosphine, tri(m- Tolyl)phosphine, tri(p-tolyl)phosphine, ethylenebis(diphenylphosphine), trimethylenebis(diphenylphosphine), 1,1'-ferrocenebis(diphenylphosphine), ( ⁇ )-2,2'-bis( (diphenylphosphino)-1,1'
  • the amount of the phosphine compound used in the azidation step is not particularly limited, but is preferably 0.8 mol or more and 10 mol or less, more preferably 1.0 mol or more, and 1.0 mol or more, more preferably 1.0 mol or more, and 1.
  • the amount is more preferably .5 mol or more, more preferably 8 mol or less, and even more preferably 5 mol or less. That is, the amount of the phosphine compound to be used is preferably 0.8 mol to 10 mol, more preferably 1.0 mol to 8 mol, and 1.5 mol to 5 mol, per 1 mol of amino alcohol compound (2). More preferred.
  • the amount of the phosphine compound to be used is preferably 0.5 mol or more and 1.5 mol or less, more preferably 0.7 mol or more, even more preferably 0.9 mol or more, and 1 mol or more per 1 mol of the azo compound.
  • the amount is more preferably .3 mol or less, and even more preferably 1.1 mol or less. That is, the amount of the phosphine compound used is preferably 0.5 mol to 1.5 mol, more preferably 0.7 mol to 1.3 mol, and 0.9 mol to 1.1 mol, per 1 mol of the azo compound. More preferred is molar.
  • the azo compound used in the azidation step is not particularly limited, and examples include azodicarboxylic acid such as diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), and di-2-methoxyethyl azodicarboxylate (DMEAD).
  • DEAD diethyl azodicarboxylate
  • DIAD diisopropyl azodicarboxylate
  • DMEAD di-2-methoxyethyl azodicarboxylate
  • N,N,N',N'-tetraisopropylazodicarboxamide TIPA
  • 1,1'-(azodicarbonyl)dipiperidine ADDP
  • N,N,N',N'-tetramethylazodi carboxamide TMAD
  • azodicarbosamides such as 1,6-dimethyl-1,5,7-hexahydro-1,4,6,7-tetrazocine-2,5-dione (DHTD)
  • Carboxylates are preferred, and DEAD, DIAD, and DMEAD are more preferred.
  • the azo compound only one type may be used, or two or more types may be used in combination.
  • the amount of the azo compound used in the azidation step is not particularly limited, but is preferably 0.8 mol or more and 10 mol or less, more preferably 1.0 mol or more, and 1.0 mol or more, more preferably 1.0 mol or more, and 1.
  • the amount is more preferably .5 mol or more, more preferably 8 mol or less, and even more preferably 5 mol or less. That is, the amount of the azo compound used is preferably 0.8 mol to 10 mol, more preferably 1.0 mol to 8 mol, and 1.5 mol to 5 mol, per 1 mol of amino alcohol compound (2). More preferred.
  • a solvent may be used in the azidation step.
  • the solvent is not particularly limited as long as it does not inhibit the reaction, and examples include dipropyl ether, diisopropyl ether, dibutyl ether, dihexyl ether, butyl vinyl ether, ethylpropyl ether, cyclopentyl methyl ether, anisole, 2-methylanisole, 4-Methylanisole, 2,3-dimethylanisole, 2,6-dimethylanisole, chloroanisole, anethole, phenethole, 4-methylphenethole, n-butylphenyl ether, pentylphenyl ether, benzylethyl ether, diphenyl ether, dibenzyl Ether, veratrol, 1,2-dimethoxyethane, 1,1-diethoxyethane, 1,2-diethoxyethane, 1,2-dibutoxyethane, dimethyl acetal, t-butyl
  • ether solvents from the viewpoint of better diastereoselectivity, ether solvents, ester solvents, and hydrocarbon solvents are preferable, and tetrahydrofuran, t-butyl methyl ether, diethylene glycol dimethyl ether, ethyl acetate, and toluene are more preferable. More preferred are tetrahydrofuran, t-butyl methyl ether, ethyl acetate, and toluene, and even more preferred are tetrahydrofuran, t-butyl methyl ether, and toluene.
  • ether solvents, ester solvents, and hydrocarbon solvents are preferable, and ether solvents and ester solvents are more preferable, and tetrahydrofuran, t- Butyl methyl ether, diethylene glycol dimethyl ether, and ethyl acetate are more preferred, and tetrahydrofuran, t-butyl methyl ether, and ethyl acetate are even more preferred.
  • the amount (volume) of the solvent used in the azidation step is not particularly limited, but from the viewpoint of better diastereoselectivity, it should be twice the weight of the amino alcohol compound (2) (vol/w). ⁇ 50 times (vol/w) is preferred, and 10 times (vol/w) to 30 times (vol/w) is more preferred. Furthermore, the amount of solvent used in the azidation step is particularly preferably 10 times (vol/w) to 20 times (vol/w) from the viewpoint of improving the yield of the aminoazide compound (1).
  • the unit of vol/w is ml/g.
  • the method and order of addition of the amino alcohol compound (2), diphenylphosphoryl azide, phosphine compound, azo compound, and optionally used solvent are not particularly limited.
  • the amino alcohol compound (2), diphenylphosphoryl azide, the phosphine compound, the azo compound, and the solvent may all be added simultaneously or sequentially to the reaction vessel, and the amino alcohol compound (2), diphenylphosphoryl azide, , a phosphine compound, an azo compound, and a solvent may be mixed first, and then the remaining compound and/or solvent may be added.
  • the amino alcohol compound (2), diphenylphosphoryl azide, phosphine compound, azo compound, and solvent may be added all at once or in portions (for example, in 2 to 10 portions).
  • the azidation reaction is usually preferably carried out under an inert gas atmosphere such as nitrogen.
  • the reaction temperature in the azidation reaction may be appropriately set depending on the types of the phosphine compound, azo compound, and solvent, and the amounts of the amino alcohol compound (2), diphenylphosphoryl azide, phosphine compound, azo compound, and solvent used.
  • the temperature is preferably -20°C to 60°C, more preferably -5°C to 40°C, even more preferably 0°C to 30°C, and particularly preferably 15 to 30°C.
  • the reaction temperature is within the above range, the target compound, aminoazide compound (1), can be obtained safely with a high diastereoselectivity and preferably in a good yield.
  • the reaction time in the azidation reaction may be appropriately set depending on the types of the phosphine compound, azo compound, and solvent, and the amounts of the amino alcohol compound (2), diphenylphosphoryl azide, phosphine compound, azo compound, and solvent used. Preferably 0.5 hours to 120 hours, more preferably 1 hour to 48 hours.
  • the diastereoselectivity ratio (cis form: trans form) of the aminoazide compound (1) obtained in the azidation step is preferably in the range of 1:0.00 to 1:0.15, and preferably 1:0.00 to The ratio is more preferably 1:0.10, and even more preferably 1:0.00 to 1:0.05.
  • the yield of the aminoazide compound (1) obtained in the azidation step is preferably 15 mol% or more, more preferably 20 mol% or more, even more preferably 25 mol% or more, and there is no particular upper limit, and it is 100 mol% or more. It's okay.
  • the total of the yield of the amino azide compound (1), which is the target product in the azidation step, and the recovery rate of the amino alcohol compound (2), which is the raw material, is preferably 40 mol% or more, more preferably 45 mol% or more, and 50 mol% or more. It is more preferably mol% or more, even more preferably 55 mol% or more, and there is no particular upper limit, and it may be 100 mol%. It can be said that the higher the above-mentioned total value, the fewer side reactions occur in the azidation reaction.
  • the aminoazide compound (1) obtained in the azidation step can be used as a raw material for further reactions, and can be used, for example, as a synthetic intermediate for edoxaban, which is an anticoagulant to be described later.
  • Aminoazide compound (1) can be purified or isolated by known methods if desired, but it is safe to use it as a raw material for further reactions, preferably as a reaction mixture, without purification or isolation. It is preferable.
  • the method for producing a diamine compound (3) of the present invention is characterized by including a reduction step of reducing the aminoazide compound (1) produced by the method for producing an aminoazide compound. Since the aminoazide compound (1) obtained by the above method for producing an aminoazide compound has a high diastereoselectivity, the diamine compound obtained by the production method using this compound as a raw material also has a high diastereoselectivity.
  • Methods for reducing the azide group include, for example, catalytic reduction using a catalyst such as Pd/C, Raney nickel, or platinum; reduction using a metal hydride such as sodium borohydride or lithium aluminum hydride; Examples include a method of reduction using grade phosphine, diborane, etc.
  • a method for reducing the azide group from the viewpoint of reduction selectivity, a method of reducing using a tertiary phosphine such as triphenylphosphine, trimethylphosphine, or triethyl phosphite is preferable, and a method of reducing using triphenylphosphine is more preferable.
  • the tertiary phosphine In the reduction using a tertiary phosphine, the tertiary phosphine first acts on the azide group of the aminoazide compound (1) to form an iminophosphorane having a nitrogen-phosphorus double bond. The primary amine is then obtained by hydrolyzing the iminophosphorane formed. Since iminophosphorane is usually easily hydrolyzed, it can be hydrolyzed by adding water.
  • the amount of tertiary phosphine added is preferably 1.0 mol or more and 35 mol or less, more preferably 2.0 mol or more, per 1 mol of aminoazide compound (1). , more preferably 2.5 mol or more, more preferably 30 mol or less, even more preferably 25 mol or less. That is, the amount of tertiary phosphine added is preferably 1.0 mol to 35 mol, more preferably 2.0 mol to 30 mol, and 2.5 mol to 25 mol, per 1 mol of aminoazide compound (1). More preferred.
  • the amount of tertiary phosphine to be added is determined by the amount used in the azidation step.
  • the amount may be appropriately determined depending on the amount of diphenylphosphoryl azide or phosphine compound used, but it is preferably 0.8 mol or more and 15 mol or less, more preferably 1.0 mol or more, per 1 mol of the amino alcohol compound (2).
  • the amount is more preferably 1.3 mol or more, more preferably 10 mol or less, and even more preferably 8 mol or less.
  • the amount of tertiary phosphine added is preferably 0.8 mol to 15 mol, more preferably 1.0 mol to 10 mol, and 1.3 mol to 8 mol, per 1 mol of amino alcohol compound (2). is even more preferable.
  • the amount (volume) of water added for hydrolysis is 0.8 times (vol/w) to 20 times (vol/w) the weight of the aminoazide compound (1). vol/w) is preferable, and 1.5 times (vol/w) to 15 times (vol/w) is more preferable.
  • the amount (volume) of water added for hydrolysis is , preferably 0.5 times (vol/w) to 10 times (vol/w), and 1.0 times (vol/w) to 5 times (vol/w) the weight of the amino alcohol compound (2). is more preferable.
  • the unit of vol/w is ml/g.
  • a solvent may be used in the step of reducing the azide group.
  • the solvent is not particularly limited as long as it does not inhibit the reaction, and examples thereof include the solvents exemplified as solvents that can be used in the azidation step, and preferred embodiments are also the same.
  • Different solvents or the same solvent may be used in the azidation step and the reduction step. If the same solvent is used, production efficiency is improved by continuing to use the solvent used in the azidation step in the reduction step. It is preferable from the point of view. Even when continuing to use the solvent used in the azidation step, a new solvent may be added.
  • the amount (volume) of the solvent used in the reduction step is not particularly limited, but is preferably 5 times (vol/w) to 80 times (vol/w), and 10 times (vol/w) the weight of the aminoazide compound (1). vol/w) to 70 times (vol/w) is more preferable.
  • the amount of solvent used volume; the amount of solvent used in the azidation step
  • the amount (including the solvent) is preferably 2 times (vol/w) to 50 times (vol/w), and 10 times (vol/w) the weight of the amino alcohol compound (2).
  • the amount (volume) of the solvent to be used is preferably 5 times (vol/w) to 80 times (vol/w), and 10 times (vol/w) to 70 times the weight of the aminoazide compound (1). (vol/w) is more preferable.
  • the unit of vol/w is ml/g.
  • the reaction temperature in the reduction reaction is not particularly limited, and is preferably 0°C to 60°C, more preferably 10°C to 58°C, and even more preferably 30°C to 55°C.
  • the reaction temperature is within the above range, the diamine compound (3) can be obtained safely in good yield and with a high diastereoselectivity.
  • the reaction time in the reduction reaction is not particularly limited, and is preferably from 0.1 hour to 48 hours, more preferably from 1 hour to 36 hours.
  • the reduction step may be performed after purifying or isolating the aminoazide compound (1) obtained in the azidation step, or may be performed subsequently without purification or isolation, but is preferably performed without purification or isolation. It is preferable to carry out the reaction solution (reaction mixture) of the azidation step continuously, and it is more preferable to carry out the azidation step and the reduction step in one pot, in which the reactants are sequentially introduced into the reaction system. By performing the azidation step and the reduction step in one pot, the diamine compound (3) can be produced more safely and easily without isolating the aminoazide compound (1).
  • the diamine compound (3) can be obtained with a high diastereoselectivity without isolating and purifying the aminoazide compound. be able to.
  • a reducing agent for example, tertiary phosphine
  • a reducing agent for example, tertiary phosphine
  • the diastereoselectivity ratio (cis form: trans form) of the diamine compound (3) obtained in the reduction step is preferably in the range of 1:0.00 to 1:0.20, and preferably 1:0.00 to 1. :0.15 is more preferable, and 1:0.00 to 1:0.10 is even more preferable.
  • the yield of diamine compound (3) obtained in the reduction step is preferably 10 mol% or more, more preferably 20 mol% or more, even more preferably 25 mol% or more, and the upper limit is There is no particular requirement, and it may be 100 mol%.
  • the diamine compound (3) obtained in the reduction step can be used as a raw material for further reactions, and can be used, for example, as a synthetic intermediate for edoxaban, which is an anticoagulant to be described later.
  • the diamine compound (3) obtained in the reduction step may be isolated or purified as necessary, and for that purpose, conventional separation methods such as extraction, concentration, crystallization, column chromatography, etc. may be used as appropriate. May be combined.
  • Edoxaban (a compound represented by the following formula (X); N 1 -(5-chloropyridin-2-yl)-N 2 -((1S,2R,4S)-4-[(dimethylamino)carbonyl) used as ]-2- ⁇ [(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino ⁇ cyclohexyl)ethanediamide) be.
  • known methods may be used for the synthesis of diamine compound (3) and subsequent ones, but for example, the following synthesis route is used. Can be mentioned.
  • each compound was analyzed by high performance liquid chromatography (HPLC), and the yield, diastereoselectivity, and raw material recovery rate were calculated.
  • HPLC high performance liquid chromatography
  • the conditions for performing HPLC are as follows.
  • Mobile phase A Acetonitrile
  • Mobile phase B 0.1 wt% phosphoric acid aqueous solution
  • Gradient conditions Time (min) Mobile phase A (%) Mobile phase B (%) 0 15 85 32.5 80 20 37.49 80 20 37.5 15 85 40.1 15 85
  • Example 1 Under a nitrogen atmosphere, the amino alcohol compound represented by formula (2) (500.0 mg, 1.746 mmol) was suspended in tert-butyl methyl ether (6 mL) and cooled to 0°C. Diisopropyl azodicarboxylate (706.1 mg, 3.492 mmol) and diphenyl phosphate azide (961.0 mg, 3.492 mmol) were sequentially added to the suspension at the same temperature, and the mixture was stirred for 5 minutes. Thereafter, triphenylphosphine (915.9 mg, 3.492 mmol) was added at 0°C, and the temperature was raised to room temperature (in this specification, room temperature means 15 to 30°C).
  • Example 2 The amount of diisopropyl azodicarboxylate used was 529.6 mg (2.619 mmol), the amount of diphenylphosphate azide was 720.7 mg (2.619 mmol), and the amount of triphenylphosphine was 686.9 mg (2.619 mmol).
  • An aminoazide compound represented by formula (1) was produced in the same manner as in Example 1, except for changing to (1). When the obtained reaction solution was analyzed by HPLC, the yield of the aminoazide compound represented by formula (1) was 51.2%, the diastereoselectivity ratio was 1:0.00, and the yield of the aminoazide compound represented by formula (1) was 51.2%. The recovery rate (amino alcohol compound represented by ) was 26.6%.
  • Example 3 An aminoazide compound represented by formula (1) was produced in the same manner as in Example 1, except that the temperature was raised to 10° C. after adding triphenylphosphine.
  • the yield of the aminoazide compound represented by formula (1) was 18.1%
  • the diastereoselectivity ratio was 1:0.00
  • the yield of the aminoazide compound represented by formula (1) was 1:0.00.
  • the recovery rate (amino alcohol compound represented by ) was 27.7%.
  • Example 4 An aminoazide compound represented by formula (1) was produced in the same manner as in Example 3, except that the reaction time after adding triphenylphosphine and raising the temperature to 10° C. was changed to 21 hours.
  • the yield of the aminoazide compound represented by formula (1) was 51.0%
  • the diastereoselectivity was 1:0.00
  • the yield of the aminoazide compound represented by formula (1) was 1:0.00.
  • the recovery rate (amino alcohol compound represented by ) was 23.0%.
  • Example 5 An aminoazide compound represented by formula (1) was produced in the same manner as in Example 1, except that the temperature was raised to 40°C after the addition of triphenylphosphine and the reaction time after the temperature was raised was changed to 1 hour.
  • the yield of the aminoazide compound represented by formula (1) was 50.0%
  • the diastereoselectivity was 1:0.00
  • the raw material formula (2)
  • the recovery rate (amino alcohol compound represented by ) was 0.4%.
  • Example 6 An aminoazide compound represented by formula (1) was produced in the same manner as in Example 1, except that the amount of tert-butyl methyl ether used was changed to 12 mL.
  • the yield of the aminoazide compound represented by formula (1) was 52.1%
  • the diastereoselectivity was 1:0.00
  • the raw material formula (2)
  • the recovery rate was 21.2%.
  • Example 7 An aminoazide compound represented by formula (1) was produced in the same manner as in Example 1, except that the amount of diphenylphosphate azide used was changed to 1441.5 mg (5.238 mmol).
  • the yield of the aminoazide compound represented by formula (1) was 70.1%
  • the diastereoselectivity ratio was 1:0.00
  • the yield of the aminoazide compound represented by formula (1) was 1:0.00.
  • the recovery rate (amino alcohol compound represented by ) was 0.3%.
  • Example 9 Tert-butyl methyl ether (6 mL) was added to triphenylphosphine (915.9 mg, 3.492 mmol) under a nitrogen atmosphere, and after cooling to 0°C, diisopropyl azodicarboxylate (706.1 mg, 3.492 mmol) was added. did. After 5 minutes, diphenylphosphate azide (961.0 mg, 3.492 mmol) was added, and after another 5 minutes, the amino alcohol compound represented by formula (2) (250 mg, 0.873 mmol) was added.
  • Example 11 Dehydrated toluene (6.0 mL) was added to triphenylphosphine (686.9 mg, 2.619 mmol) under a nitrogen atmosphere, and after cooling to 0°C, diisopropyl azodicarboxylate (529.6 mg, 2.619 mmol) was added. . After 5 minutes, diphenylphosphate azide (720.7 mg, 2.619 mmol) was added, and after another 5 minutes, the amino alcohol compound represented by formula (2) (100 mg, 0.349 mmol) was added.
  • Example 12 An aminoazide compound represented by formula (1) was produced in the same manner as in Example 11, except that the reaction time after completion of addition of the amino alcohol compound represented by formula (2) was changed to 3 hours.
  • the yield of the aminoazide compound represented by formula (1) was 26.0%
  • the diastereoselectivity was 1:0.00
  • the raw material formula (2)
  • the recovery rate was 42.9%.
  • Example 13 An aminoazide compound represented by formula (1) was produced in the same manner as in Example 12, except for changing dehydrated toluene (6.0 mL) to tetrahydrofuran (6.0 mL).
  • the yield of the aminoazide compound represented by formula (1) was 40.1%
  • the diastereoselectivity ratio was 1:0.01
  • the yield of the aminoazide compound represented by formula (1) was 40.1%
  • the diastereoselectivity ratio was 1:0.01.
  • the recovery rate (amino alcohol compound represented by ) was 33.8%.
  • Example 15 Diisopropyl azodicarboxylate (529.6 mg, 2.619 mmol) was changed to di-2-methoxyethyl azodicarboxylate (613.4 mg, 2.619 mmol), and addition of an amino alcohol compound represented by formula (2)
  • An aminoazide compound represented by formula (1) was produced in the same manner as in Example 13, except that the reaction time after completion was changed to 2 hours.
  • the yield of the aminoazide compound represented by formula (1) was 27.7%
  • the diastereoselectivity ratio was 1:0.00
  • the yield of the aminoazide compound represented by formula (1) was 1:0.00.
  • the recovery rate (amino alcohol compound represented by ) was 61.1%.
  • Example 16 An aminoazide compound represented by formula (1) was produced in the same manner as in Example 12, except that diethylene glycol dimethyl ether (6.0 mL) was used instead of dehydrated toluene (6.0 mL). When the obtained reaction solution was analyzed by HPLC, the yield of the aminoazide compound represented by formula (1) was 34.1%, the diastereoselectivity was 1:0.01, and the yield of the aminoazide compound represented by formula (1) was 1:0.01. The recovery rate (amino alcohol compound represented by ) was 36.4%.
  • Example 17 An aminoazide compound represented by formula (1) was produced in the same manner as in Example 12, except that t-butyl methyl ether (6.0 mL) was used instead of dehydrated toluene (6.0 mL).
  • t-butyl methyl ether 6.0 mL
  • dehydrated toluene 6.0 mL
  • the yield of the aminoazide compound represented by formula (1) was 63.5%
  • the diastereoselectivity was 1:0.01
  • the yield of the aminoazide compound represented by formula (1) was 63.5%
  • the diastereoselectivity was 1:0.01.
  • the recovery rate (amino alcohol compound represented by ) was 36.2%.
  • Example 18 An aminoazide compound represented by formula (1) was produced in the same manner as in Example 12, except for changing dehydrated toluene (6.0 mL) to ethyl acetate (6.0 mL).
  • the yield of the aminoazide compound represented by formula (1) was 48.0%
  • the diastereoselectivity ratio was 1:0.01
  • the yield of the aminoazide compound represented by formula (1) was 48.0%
  • the diastereoselectivity ratio was 1:0.01.
  • the recovery rate (amino alcohol compound represented by ) was 16.2%.
  • Methanesulfonyl chloride (12.79 g, 111.7 mmol) was added to a 4-methyl-2-pentanone (MIBK) solution (550 mL) of the amino alcohol compound represented by formula (2) (20.00 g, 69.84 mmol). Added at room temperature. Triethylamine (13.43 g, 132.7 mmol) was added to the reaction solution at room temperature, and the mixture was stirred at that temperature for 2 hours. After adding methanol (86 mL) and water (126 mL) to the reaction solution and stirring for 15 minutes, the organic layer was separated. After washing the organic layer with a 5% aqueous sodium bicarbonate solution (100 mL), the solvent was concentrated under reduced pressure.
  • MIBK 4-methyl-2-pentanone
  • the obtained slurry solution was aged at 0° C. for 3 hours and then filtered to obtain a mesyloxy compound (compound represented by formula (4)) (21.06 g, yield 91.5%).
  • Sodium azide (1.784 g, 27.44 mmol) and dodecylpyridium chloride (1.947 g, 6.860 mmol) were added to a toluene solution (25 mL) of the obtained mesyloxy compound (5.000 g, 13.72 mmol) at room temperature. ) was added.
  • the reaction solution was analyzed by HPLC, and the yield of the aminoazide compound represented by formula (1) was 66%, and the diastereoselectivity ratio was 1:0.18. .
  • the yield was 38%, the diastereoselectivity ratio was 1:0.48, and the recovery rate of the raw material (amino alcohol compound represented by formula (2)) was 11%. Moreover, all the phosphoric acid ester intermediates represented by formula (5) disappeared.
  • the reaction solution was analyzed by HPLC, and the yield of the aminoazide compound represented by formula (1) was 67.1%, and the diastereoselectivity ratio was 1:0.00.
  • triphenylphosphine 1831.8 mg, 6.984 mmol
  • the temperature was raised to 50°C.
  • water (1 mL) was added at the same temperature and hydrolysis was carried out for 18 hours.
  • the yield of the amino azide compound represented by formula (3) from the amino alcohol compound represented by formula (2) was 47.8%.

Abstract

Le but de la présente invention est de fournir un procédé de production d'un composé aminoazide et d'un composé diamine dans lequel la formation de diastéréomères indésirables est inhibée et qui présente une bonne diastéréosélectivité. L'invention concerne un procédé de production d'un composé aminoazide représenté par la formule (1), ledit procédé étant caractérisé en ce qu'il comprend une étape d'azidation pour amener le diphénylphosphoryl azide, un composé phosphine et un composé azoïque à agir sur un composé amino-alcool représenté par la formule (2).
PCT/JP2023/029615 2022-09-09 2023-08-16 Procédé de production d'un composé aminoazide, composé diamine et edoxaban WO2024053350A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010104078A1 (fr) * 2009-03-10 2010-09-16 第一三共株式会社 Procédé de production d'un dérivé de diamine
CN113527124A (zh) * 2020-12-21 2021-10-22 浙江星月药物科技有限公司 一种依度沙班手性叠氮中间体化合物的制备方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010104078A1 (fr) * 2009-03-10 2010-09-16 第一三共株式会社 Procédé de production d'un dérivé de diamine
CN113527124A (zh) * 2020-12-21 2021-10-22 浙江星月药物科技有限公司 一种依度沙班手性叠氮中间体化合物的制备方法

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ANONYMOUS: "Reduction of tert-butyl{(1R,2S,5S)-2-amino)-5-[(dimethylamino)carbonyl]cyclohexyl}carbamate,", IP.COM NUMBER: IPCOM000242778D, 14 August 2015 (2015-08-14), XP093147058, Retrieved from the Internet <URL:https://ip.com/IPCOM/000242778> [retrieved on 20240402] *
OCHIAI HIDENORI, KUBOTA SHUNICHI, SASAGAWA MIWA, MIHARA TAIKI, YAMASHITA ATSUHIRO, NAKAMATA TOMOHIDE, NISHIYAMA AKIRA: "Stereoinvertive Deoxyamination of trans -2-Aminocyclohexanol Using Bose–Mitsunobu Azidation and Staudinger Reaction for the Stereoselective Synthesis of Edoxaban", ORGANIC PROCESS RESEARCH & DEVELOPMENT, AMERICAN CHEMICAL SOCIETY, US, vol. 27, no. 8, 18 August 2023 (2023-08-18), US , pages 1517 - 1532, XP093147057, ISSN: 1083-6160, DOI: 10.1021/acs.oprd.3c00189 *
THOMPSON A. S., ET AL.: "DIRECT CONVERSION OF ACTIVATED ALCOHOLS TO AZIDES USING DIPHENYL PHOSPHORIZIDATE. A PRACTICAL ALTERNATIVE TO MITSUNOBY CONDITIONS.", THE JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY, vol. 58., no. 22., 22 October 1993 (1993-10-22), pages 5886 - 5888., XP000650459, ISSN: 0022-3263, DOI: 10.1021/jo00074a008 *

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