CN108689878B - Process for preparing optically active diamino derivatives - Google Patents

Process for preparing optically active diamino derivatives Download PDF

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CN108689878B
CN108689878B CN201710228369.1A CN201710228369A CN108689878B CN 108689878 B CN108689878 B CN 108689878B CN 201710228369 A CN201710228369 A CN 201710228369A CN 108689878 B CN108689878 B CN 108689878B
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benzyl
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CN108689878A (en
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徐立
陈冲
罗立军
杜小华
朱国良
梅义将
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Zhejiang Jiuzhou Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
    • 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
    • C07C269/04—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 from amines with formation of carbamate groups
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract

The invention provides an optically active diamino derivative, an intermediate thereof and a preparation method thereof. Intermediates F1 and F in the (1R, 2R, 5S) configuration, respectively, and compounds of formula H in the (1R, 2S, 5S) configuration,
Figure DDA0001265955910000011
wherein R is 1 An alkyl-or aryl-amino protecting group, such as benzyl, alkyl-substituted benzyl or alkoxy-substituted benzyl, alkoxycarbonyl or benzyloxycarbonyl; r is R 2 An alkoxycarbonyl, alkyl, aryl amino protecting group such as t-butoxycarbonyl, benzyloxycarbonyl or methoxycarbonyl, X is hydroxy, halogen, OMs, OTf or OTs; r is
Figure DDA0001265955910000012
Or an alkoxy group; r is R 3 For amino groups protected by amino protecting groups of the amide type, imines such as phthalimido, succinimido or naphthalimido or diphenyl azido phosphate, -N 3 Amino or substituted amino.

Description

Process for preparing optically active diamino derivatives
Technical Field
The invention relates to the field of medicine synthesis, in particular to an optically active diamino derivative, an intermediate and a preparation method thereof.
Background
The compound having the following structure of formula L-1 or formula L-2 is an optically active diamino derivative, and is an intermediate for synthesizing edoxaban:
Figure BDA0001265955900000011
in Chinese patent application CN103080078A (applicant: first Co., ltd.) a salt of this optically active diamino derivative of the same structure is disclosed. And in paragraph [0010] of the specification, equation of reaction involved in this compound is disclosed in chemical 3:
Figure BDA0001265955900000012
as disclosed in this patent application, this process exists in that compound 2, when azidated, forms the trans isomer of compound 3, which in turn, upon reduction, is reduced to form the 1 a-trans form. In order to solve this problem, a problem b is called in this patent application, in which a monohydrate crystal of a cis-diamino derivative represented by formula 1b having high purity and high selectivity is obtained by adding water to a crystallization solvent and utilizing the difference in water solubility between the monohydrate crystal represented by formula 1b and the monohydrate crystal of formula 1 b-trans. However, there is another problem in this route that, due to the presence of active hydrogen on NH linked to t-butoxycarbonyl in the azide reaction, impurities of the following structure are formed:
Figure BDA0001265955900000021
patent application CN201180042413.0 (applicant: first co-product, application date: 2011, 7, 1) discloses the same azide reaction, expressed by the following reaction equation:
Figure BDA0001265955900000022
CN106008556 (applicant: kebei source biomedical technology) discloses a process for preparing optically active diamino derivatives,
Figure BDA0001265955900000031
in the same manner as described above, the presence of active hydrogen in NH bonded to t-butoxycarbonyl group in the azide reaction also causes the formation of impurities having the above-described structure.
Considering that the above is only one method for obtaining high-purity optically active diamino derivatives, in view of the selection of various process routes in industrial production, it is necessary to develop other more preparation methods of optically active diamino derivatives for selection in industrial production.
Disclosure of Invention
The present invention provides optically active diamino derivatives, intermediates thereof and methods for preparing the same. Finally, the diamino derivatives prepared have higher optical purity and several different new intermediates are obtained. This not only demonstrates the novelty of the preparation process of the present invention, but also the high purity optically active product demonstrates the significant technical effect of the present invention.
In order to achieve the technical purpose of the invention, the invention provides the following technical scheme:
the first aspect of the present invention provides an intermediate F1 or F in the (1R, 2R, 5S) configuration,
Figure BDA0001265955900000032
wherein R is 1 R is an alkyl amino protecting group or an aryl amino protecting group 2 Is an alkoxycarbonyl amino protecting group or an alkyl amino protecting group or an aryl amino protecting group, X is hydroxy, halogen, OMs, OTf or OTs; r is
Figure BDA0001265955900000033
Or an alkoxy group.
More preferably, R 1 Benzyl, alkyl-substituted benzyl or alkoxy-substituted benzyl, alkoxycarbonyl or benzyloxycarbonyl, and the like; r is R 2 Is tert-butoxycarbonyl, benzyloxycarbonyl or methoxycarbonyl.
More preferably, R 1 Is benzyl, R 2 T-butoxycarbonyl and X is hydroxy.
Most preferably, R 1 Is benzylRadical R 2 Is tert-butyloxycarbonyl, X is hydroxy, R is
Figure BDA0001265955900000041
The intermediate compound of the formula F is prepared from a compound of the formula D through ring opening and protecting group loading, and the reaction formula is as follows:
Figure BDA0001265955900000042
wherein R, R 1 ，R 2 X is as defined above.
The reaction of the upper protecting groups may be performed with 1 protecting group or two protecting groups. As in the previous R 1 Protecting group, and preparing F1 compound. Then the compound of the formula F is prepared by carrying out a second protective group reaction and replacing hydrogen with other protective groups. Of course, it is also possible to make the exchange between the various protecting groups possible via the addition of protecting groups and the removal of protecting groups or via the addition of protecting groups.
More preferably, the protecting group is reacted twice. The reaction formula is as follows:
Figure BDA0001265955900000043
wherein R is 1 Is benzyl, R 2 Is tert-butyloxycarbonyl, X is hydroxy, halogen, OMs, OTf or OTs; r is
Figure BDA0001265955900000044
Or an alkoxy group.
More preferably, after undergoing ring opening, the reaction of first feeding benzyl and then feeding t-butoxycarbonyl is as follows:
Figure BDA0001265955900000045
wherein,,
Figure BDA0001265955900000051
or alkoxy, X is as defined above.
In a second aspect the invention provides a compound of formula H in the (1R, 2S, 5S) configuration,
Figure BDA0001265955900000052
wherein R is
Figure BDA0001265955900000053
Or alkoxy, R 1 ，R 2 Is as defined above. R is R 3 Is amino protected by amide amino protecting group, imine or azido diphenyl phosphate, -N 3 Amino or substituted amino.
More preferably, R 1 Benzyl, alkyl-substituted benzyl or alkoxy-substituted benzyl, R 2 Is tert-butoxycarbonyl, benzyloxycarbonyl or methoxycarbonyl, R 3 Is phthalimido, succinimido or naphthalimido or diphenyl azide phosphate, -N 3 Amino or substituted amino.
Most preferably, R 1 Is benzyl, R 2 Is tert-butyloxycarbonyl, R 3 Is phthalimide or amino.
The compound of formula H of the present invention may be prepared by a casting reaction or further hydrolysis reaction of the compound of formula F1, or may be prepared by a diazotization reaction or further reduction reaction. The reaction formula is:
Figure BDA0001265955900000054
wherein R is
Figure BDA0001265955900000055
Or alkoxy, R 1 Benzyl, alkyl-substituted benzyl or alkoxy-substituted benzyl, R 2 Is tert-butoxycarbonyl, benzyloxycarbonyl or alkoxycarbonyl,R 3 is phthalimido, succinimido or naphthalimido, -N 3 Amino or substituted amino, X is hydroxy, halogen, OMs, OTf or OTs.
The above-mentioned casting reaction and diazotization reaction can all implement inversion on C configuration. The carbon at the 2-position is reversed from the R configuration to the S configuration.
The above-mentioned casting reaction may be carried out under anhydrous conditions in which the solvent is not an alcohol,
Figure BDA0001265955900000061
wherein R is
Figure BDA0001265955900000062
Or alkoxy, R 1 Benzyl, alkyl-substituted benzyl or alkoxy-substituted benzyl, R 2 Is tert-butoxycarbonyl, benzyloxycarbonyl or methoxycarbonyl, R 3 Is phthalimide, X is hydroxy.
The light delay reaction is carried out under the action of phosphine compounds or azo compounds.
According to the above-mentioned casting reaction, the reaction temperature may be 0 to 30 ℃.
According to the above-mentioned casting reaction, the reaction solvent may be a lower ester or alkylbenzene or acetonitrile or an organic amine; more preferably ethyl acetate, toluene dichloromethane, acetonitrile, dimethylformamide.
The above-mentioned casting reaction may further include a hydrolysis reaction which may be carried out under the action of hydrazine hydrate or an inorganic acid or base such as hydrochloric acid or sodium hydroxide, most preferably hydrazine hydrate.
According to the hydrolysis reaction, the reaction temperature is 40-110 ℃.
According to the hydrolysis reaction, the reaction solvent may be water or methyl benzene or organic amine or alkylbenzene or alcohol; most preferably, the reaction solvent is water or toluene.
The above-described azide reaction may be carried out under the action of a phase transfer catalyst,
Figure BDA0001265955900000063
wherein R is
Figure BDA0001265955900000064
Or alkoxy, R 1 Benzyl, alkyl-substituted benzyl or alkoxy-substituted benzyl, R 2 Is tert-butoxycarbonyl, benzyloxycarbonyl or alkoxycarbonyl, R 3 is-N 3 X is hydroxy, halogen, OMs, OTf or OTs.
According to the above-mentioned azide reaction, the phase transfer catalyst may be a quaternary ammonium salt or a quaternary phosphonium salt or a pyridinium compound or a crown ether; more preferably tetramethylammonium chloride, tetrahexylammonium chloride, tetraethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, tetrabutylammonium sulfate, trioctylmethylammonium chloride, tetrabutylphosphonium chloride, dodecylpyridinium chloride; more preferably trioctyl methyl ammonium chloride, tetrabutyl ammonium chloride, tetramethyl ammonium chloride, tetraethyl ammonium chloride, tetrahexyl ammonium chloride, dodecyl pyridinium chloride; most preferred is tetrabutylammonium chloride and dodecylpyridinium chloride.
According to the above described azide reaction, the molar ratio of the compound of formula F1 to the phase transfer catalyst may be 1: (0.05 to 3), most preferably 1: (0.1-0.5).
According to the above described azide reaction, the reaction temperature may be-78 ℃ to the boiling point of the solvent, most preferably 50 ℃ to 90 ℃.
According to the above-mentioned azide reaction, the reaction time may be 24 to 96 hours, and most preferably 60 to 70 hours, of the boiling point of the solvent.
According to the above-mentioned azide reaction, the reaction solvent may be one or more of water, thionyl chloride, acetonitrile, ethyl acetate, hydrocarbon solvents, alcohol solvents, ether solvents, amide solvents, cyclic urea solvents, and halogenated hydrocarbon solvents; more preferably, the reaction solvent may be one or more of water, thionyl chloride, acetonitrile, ethyl acetate, N-hexane, N-pentane, benzene, toluene, xylene, methanol, ethanol, propanol, isopropanol, N-butanol, t-butanol, diethyl ether, isopropyl ether, methyl t-butyl ether, tetrahydrofuran, cyclopentyl methyl ether, dimethoxyethane, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, 1, 3-dimethyl-2-imidazolidinone, 1, 3-dimethyl-3, 4,5, 6-tetrahydro-2 (1H) -pyrimidinone, chloroform, dichloromethane, and 1, 2-dichloroethane; most preferably, the reaction solvent may be one or more of dimethylacetamide and N-methyl-2-pyrrolidone.
The above-described azide reaction may further include a reduction reaction, which may be performed under the action of a hydrogen source/metal catalyst.
According to the above reduction reaction, the metal catalyst/hydrogen source may be hydrazine/palladium-carbon, hydrazine/Raney nickel, hydrazine/Raney cobalt, hydrazine/palladium-carbon, hydrazine/Raney nickel hydrate, hydrazine/Raney cobalt hydrate, cyclohexene/palladium-carbon, cyclohexene/Raney nickel, cyclohexene/Raney cobalt, tetrahydronaphthalene/palladium-carbon, tetrahydronaphthalene/Raney nickel, formate/palladium-carbon, formate/Raney nickel, formate/Raney cobalt, more preferably hydrazine/palladium-carbon, hydrazine/Raney nickel, hydrazine/Raney cobalt, hydrazine/palladium-carbon, hydrazine/Raney nickel hydrate, cyclohexene/palladium-carbon, cyclohexene/Raney nickel, cyclohexene/Raney cobalt, tetrahydronaphthalene/palladium-carbon, tetrahydronaphthalene/nickel, formate/palladium-nickel, tetralin/nickel formate/sodium formate/cobalt formate/ammonium formate/cobalt, ammonium formate/cobalt formate/ammonium formate/nickel formate/ammonium formate/cobalt formate/ammonium formate/nickel.
According to the above reduction reaction, the reaction temperature may be-78 ℃ to the boiling point of the solvent, most preferably 25 ℃ to 70 ℃.
According to the reduction reaction, the reaction solvent can be one or more of water, thionyl chloride, acetonitrile, ethyl acetate, hydrocarbon solvents, alcohol solvents, ether solvents, amide solvents, cyclic urea solvents and halogenated hydrocarbon solvents; more preferably, the reaction solvent may be one or more of water, thionyl chloride, acetonitrile, ethyl acetate, N-hexane, N-pentane, benzene, toluene, xylene, methanol, ethanol, propanol, isopropanol, N-butanol, t-butanol, diethyl ether, isopropyl ether, methyl t-butyl ether, tetrahydrofuran, cyclopentyl methyl ether, dimethoxyethane, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, 1, 3-dimethyl-2-imidazolidinone, 1, 3-dimethyl-3, 4,5, 6-tetrahydro-2 (1H) -pyrimidinone, chloroform, dichloromethane, and 1, 2-dichloroethane; more preferably, the reaction solvent can be one or more of methanol, ethanol, propanol, isopropanol, n-butanol and tert-butanol; more preferably, the reaction solvent may be ethanol.
The optically active diamino derivative of the present invention may be a compound of formula H, or may be another diamino derivative prepared by deprotecting a compound of formula H via other protecting groups known in the art, directly or indirectly.
The optically active diamino derivatives of the present invention can be further prepared by salt formation reactions, such as acid reactions commonly used in the art. The acid may be oxalic acid, citric acid, p-toluenesulfonic acid and the like. More preferably oxalic acid.
The present invention provides optically active diamino derivatives, intermediates thereof and methods for preparing the same. Because the nitrogen of the intermediate compound of the formula F1 is connected with an amino protecting group and no active hydrogen exists, impurities which are difficult to remove in the prior art and have large amounts are not formed, and finally, the prepared diamino derivative has high optical purity, and several different novel intermediates are obtained. These illustrate the preparation method of the optically active diamino derivative of the invention, which is a route with industrial advantages.
Detailed Description
In order to further understand the present invention, a method for producing the optically active diamino derivative provided by the present invention will be described in detail with reference to examples. It should be understood that these examples are presented merely to further illustrate the features of the present invention and are not intended to limit the scope of the invention or the scope of the claims.
Example 1:
Figure BDA0001265955900000081
2.2g of compound D, 22ml of toluene and 1.3g of benzylamine are put into a four-mouth bottle, the temperature is raised to 80-90 ℃, and the temperature is kept for 4-6 hours. Concentrating to dryness to obtain 3.2 target product F1 with the yield of 90%.
Example 2:
Figure BDA0001265955900000091
into a four-necked flask, 5g of Compound F1, 50ml of ethanol, 5ml of water and 30% of 23ml of sodium hydroxide were placed. Raising the temperature to 40-45 ℃ and dripping 5g of BOC 2 O anhydride, after dripping, reacting for 4-6 h. After the reaction, concentrating to dry ethanol, adding EA (50 ml), water (30 ml), layering, washing the organic layer with 10ml saturated brine, drying, suction filtering, concentrating to dry to obtain 6.1g of target product F with the yield of 91% and the purity of 98%.
Example 3:
Figure BDA0001265955900000092
2.5g of compound F,2g of phthalimide, 4g of triphenylphosphine and 50ml of tetrahydrofuran are put into a four-mouth bottle, the temperature is reduced by 0 to 5 ℃ under the protection of nitrogen, 2.4g of diethyl azodicarboxylate is added dropwise, the temperature is kept for 4 to 6 hours after the dripping, and the reaction is complete. 20ml of water, 30ml of EA was added to extract an organic layer, and the organic layer was washed with 10ml of saturated saline, dried with 3g of anhydrous sodium sulfate, suction-filtered, and the filtrate was concentrated to dryness to give 4g of Compound H in a yield of 82% and a purity of 98%.
Example 5:
Figure BDA0001265955900000093
4G of compound G, 40ml of toluene and 8ml of hydrazine hydrate are put into a four-mouth bottle, and the temperature is raised to 90-100 ℃ and the temperature is kept for 12-16 hours. After completion of the reaction, 10ml of water was added to separate the layers, and the organic layer was washed with 10ml of saturated brine and concentrated to dryness to give 3.5g of Compound H in a yield of 81% and a purity of 98%.
Example 6:
Figure BDA0001265955900000101
3.5g of compound H, 1.5g of palladium-carbon, 35ml of methanol and 1.0 megaPa of hydrogen pressure are put into an autoclave, and the temperature is controlled to be 20-30 ℃ and the temperature is kept for 4-6 hours. The reaction was completed, suction filtration was carried out, and the filtrate was concentrated to dryness to give 3.0g of compound K with a purity of 98%.
Example 7:
Figure BDA0001265955900000102
3.0g of compound K, 30ml of acetonitrile, heating to 40-50 ℃,2g of oxalic acid and preserving heat for 1h at 40-50 ℃ are put into a four-mouth bottle. Cooling to 20-30 ℃ and preserving heat for 1h. Filtering, vacuum drying oven at 40-50 deg.c for 14-16 hr to obtain diamino derivative oxalate 1.7g, yield 82% and purity 99%.

Claims (8)

1. An intermediate F1 or F in the (1R, 2R, 5S) configuration has the following structural formula:
Figure FDA0004024887140000011
wherein R is 1 Is benzyl; r is R 2 Is an alkoxycarbonyl amino protecting group or an alkyl amino protecting group or an aryl amino protecting group, X is a hydroxyl group; r is
Figure FDA0004024887140000012
Or an alkoxy group.
2. An intermediate F1 or F in the (1R, 2R, 5S) configuration has the following structural formula:
Figure FDA0004024887140000013
wherein R is 1 Is benzyl; r is R 2 T-butoxycarbonyl, benzyloxycarbonyl or methoxycarbonyl; x is hydroxy; r is
Figure FDA0004024887140000014
Or an alkoxy group.
3. A compound of formula H in the (1 r,2s,5 s) configuration having the structural formula:
Figure FDA0004024887140000015
R，R 1 ，R 2 as defined in claim 1; r is R 3 Is an amino group protected by an amide-based amino protecting group.
4. A preparation method of a compound of formula H is characterized in that the compound of formula F is prepared by a photo-delay reaction or a further hydrolysis reaction after the photo-delay reaction,
Figure FDA0004024887140000016
wherein R is
Figure FDA0004024887140000017
Or alkoxy, R 1 Is benzyl, R 2 Is tert-butoxycarbonyl, benzyloxycarbonyl or alkoxycarbonyl, R 3 Is phthalimide or amino, X is hydroxy.
5. A process for the preparation of intermediate F1 or F in the (1R, 2R, 5S) configuration according to claim 1, characterized in that it is prepared from the compound of formula D by ring opening and addition of a protecting group,
Figure FDA0004024887140000021
wherein R, R 1 ，R 2 X is as defined in claim 1.
6. The process of claim 5, wherein R is
Figure FDA0004024887140000022
R 1 Is benzyl, R 2 Is tert-butyloxycarbonyl.
7. The preparation method according to claim 4, wherein the reaction solvent of the casting reaction is ethyl acetate or alkylbenzene or acetonitrile or organic amine, and the casting reaction is performed under the action of phosphine reagents and azo compounds.
8. The process according to claim 4, wherein the hydrolysis reagent is an inorganic acid or a base.
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CN111606827B (en) * 2020-06-23 2022-10-25 内蒙古京东药业有限公司 Method for preparing chiral amine intermediate of edoxaban
CN111606826B (en) * 2020-07-02 2022-02-22 沧州那瑞化学科技有限公司 Preparation method of edoxaban intermediate

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1438993A (en) * 2000-04-05 2003-08-27 第一制药株式会社 Ethylenediamine derivatives
CN105658642A (en) * 2013-10-25 2016-06-08 蓝图药品公司 Inhibitors of fibroblast growth factor receptor
CN106316889A (en) * 2015-06-15 2017-01-11 上海阳帆医药科技有限公司 Preparation method of Edoxaban intermediate

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1438993A (en) * 2000-04-05 2003-08-27 第一制药株式会社 Ethylenediamine derivatives
CN105658642A (en) * 2013-10-25 2016-06-08 蓝图药品公司 Inhibitors of fibroblast growth factor receptor
CN106316889A (en) * 2015-06-15 2017-01-11 上海阳帆医药科技有限公司 Preparation method of Edoxaban intermediate

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