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CN111606827B - Method for preparing chiral amine intermediate of edoxaban - Google Patents

Method for preparing chiral amine intermediate of edoxaban Download PDF

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CN111606827B
CN111606827B CN202010599929.6A CN202010599929A CN111606827B CN 111606827 B CN111606827 B CN 111606827B CN 202010599929 A CN202010599929 A CN 202010599929A CN 111606827 B CN111606827 B CN 111606827B
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dimethylamino
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cyclohexyl
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CN111606827A (en
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吕关锋
肖江
郭荣耀
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Inner Mongolia Jingdong Pharmaceutical 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
    • 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
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide 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
    • C07C269/04—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
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • 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
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    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
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Abstract

The invention provides a safe, simple and convenient method which is more suitable for preparing N- [ (1R, 2S, 5S) -2-amino-5- [ (dimethylamino) carbonyl ] cyclohexyl ] carbamic acid tert-butyl ester through industrial mass production. Reacting a compound N- [ (1R, 2R, 5S) -5- [ (dimethylamino) carbonyl ] -2-hydroxycyclohexyl ] carbamic acid tert-butyl ester serving as a raw material with diphenyl azide phosphate in the presence of DBU by using hydrocarbons such as toluene and N-heptane as a reaction solvent to obtain a mixture of N- [ (1R, 2R, 5S) -5- [ (dimethylamino) carbonyl ] -2- [ (diphenoxyphosphoryl) oxy ] cyclohexyl ] carbamic acid tert-butyl ester and DBU azide, adding an appropriate base, and substituting phosphate with azide groups generated in the system to obtain the corresponding azide N- [ (1R, 2S, 5S) -2-azide-5- [ (dimethylamino) carbonyl ] cyclohexyl ] carbamic acid tert-butyl ester; then reducing azido to obtain the corresponding amino compound N- [ (1R, 2S, 5S) -2-amino-5- [ (dimethylamino) carbonyl ] cyclohexyl ] carbamic acid tert-butyl ester.

Description

Method for preparing chiral amine intermediate of edoxaban
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a novel preparation method of an edoxaban hydrate p-toluenesulfonate and a key intermediate thereof. The intermediate structure of part of the edoxaban p-toluenesulfonate hydrate related by the invention is as follows:
Figure BSA0000212388440000011
background
Edoxaban p-toluenesulfonate hydrate, developed by Daiichi Sankyo corporation, was approved by the japan pharmaceutical and medical instruments integrated agency (PMDA) for sale on 2011, 4-22; 1 month 8 days 2015, approved by the U.S. Food and Drug Administration (FDA) for marketing; the drug was approved to be marketed by the European drug administration (EMA) in 2015, 6 and 19. Sold in Japan by the first Sanko corporation under the trade name of
Figure BSA0000212388440000013
It is a direct anticoagulant factor Xa inhibitor. Can be used for treating venous thromboembolism of patients after total knee joint replacement, total hip joint replacement or hip joint fracture surgery.
The current main route for preparing Edoxaban tosilate is as follows:
109TM-11 route one (US 200511948641):
Figure BSA0000212388440000012
in the route, chiral amine compound 109B9-01 and lithium salt 109A3-10 of oxamide derivative are used for generating amide under the action of a condensing agent; removing Boc-protecting group under acidic condition; and then the obtained product and 2-thiazole formic acid derivative lithium salt 109C6-10 are subjected to amide formation under the condition of a condensing agent to prepare the edoxaban.
109TM-11 route two (US 2005119486A 1):
Figure BSA0000212388440000021
in the route, chiral azide 109B8-01 is used as a starting material, boc protection is removed, the chiral azide and 2-thiazole formic acid derivative lithium salt 109C6-10 form amide under the condition of a condensing agent, azido is reduced to form amino, and the amide and lithium salt 109A3-10 of an oxamide derivative generate amide under the action of the condensing agent, so that the edoxaban is prepared.
109TM-11 route III (US 2009105491A 1):
Figure BSA0000212388440000022
the route is similar to the 109TM-11 route, except that three different derivative forms of key intermediates 109B9-11, 109A1-10, 109C6-20 are selected as reactants.
Among them, route one of 109B9-01 (US 2005119486 A1):
Figure BSA0000212388440000031
the method uses racemic 3-cyclohexene-1-formic acid as a starting material, after the starting material is split, the (1S) -3-cyclohexene-1-formic acid is separated, the iodo is carried out to obtain 109F1-01, under the alkaline condition, ester exchange is carried out to open a lactone ring and then ring closure is carried out to obtain an epoxy compound 109F3-01, the ring opening is carried out by sodium azide to obtain corresponding azide 109F4-01, pd/C catalytic hydrogenation is carried out in the presence of Boc anhydride to obtain a corresponding Boc-protected amino derivative 109F6-01, sulfonic acid esterification and sodium azide substitution are carried out to obtain an azide compound 109F8-01, hydrolysis is carried out to obtain a corresponding carboxylic acid compound 109F9-01, the corresponding amide 109B8-01 is obtained by the action of a condensing agent together with dimethylamine hydrochloride, and the azide is reduced to obtain a corresponding amino compound 109B9-01. The synthesis of the epoxy compound 109F3-01 is realized by adding expensive elemental iodine, wherein the iodine only serves as a leaving group to achieve the function of chiral selection of an intermediate, is not irreplaceable, and is not suitable from the aspect of cost control; the azide intermediate obtained by the route by using high-risk sodium azide twice needs expensive Pd/C for catalytic reduction; and the introduction of the N, N-dimethylamide group takes place in a very subsequent step; for the above reasons, the route is very disadvantageous in terms of production safety control and cost reduction, and is not suitable for industrial-scale production.
109B9-01 route two (US 2005119486A 1):
Figure BSA0000212388440000041
the route is a derivative of route one of 109B9-01; the defect of the 109B9x route I is inherited, and the number of times of Pd/C catalytic hydrogenation is increased; for the above reasons, the route is very disadvantageous in terms of production safety control and cost reduction, and is not suitable for industrial-scale production.
109B9-01 route III (US 2016016974A 1):
Figure BSA0000212388440000042
in the method, a Burgess-type reagent is used for reacting with an amino compound 109B5-01 to obtain a sulfuryl diamide derivative 109D3-01, hydroxyl at the ortho position of the sulfamide is converted into sulfonic ester, the sulfonic ester is ingeniously subjected to rearrangement and ring expansion after the intermediate state of the ternary nitrogen heterocyclic derivative is completely sulfonated to obtain a compound 109D6-01, and the intermediate 109B9-01 is obtained through hydrolysis. The route adopts tert-butyl alcohol to prepare Burgess-type reagent, and we find out when studying the process that: in the preparation of 109D3-01, when the charging amount is 5 kg-10 kg, the product 109D3-01 is easy to decompose in the post-treatment process, and the yield is greatly reduced, and the subsequent research finds that the result is caused by that the tert-butyl sulfonylcarbamate group in the structure of the compound 109D3-01 is not very stable; therefore, the route needs to be studied more carefully in the process of realizing industrial mass production in order to achieve better effect.
109B9-01 route four (W02010104106A 1):
Figure BSA0000212388440000051
in the route, ammonia water is used for carrying out ring opening on 109B4-01 to obtain a corresponding alkamine compound 109B5-01; protecting amino group with Boc-to obtain 109B6-01; conversion of the hydroxy group to the corresponding sulfonate leaving group with methanesulfonyl chloride affords 109B7-01; reacting with azide metal salt in the presence of a quaternary ammonium salt phase transfer catalyst to convert sulfonate groups into corresponding azide groups to obtain 109B8-01; catalytic hydrogenation reduction of azido group to obtain the corresponding amino compound 109B9-01. The method needs to use the highly explosive and high-risk metal azide salt, and has high risks in storage and use of the raw material metal azide salt and treatment of subsequent waste liquid; for the above reasons, this route is very disadvantageous for the control of production safety.
Disclosure of Invention
The invention provides a method for preparing an Edoxaban chiral amine intermediate by replacing nitrified metal salt with diphenylphosphoryl azide (DPPA). The method is characterized by comprising the following steps:
Figure BSA0000212388440000052
1. using a compound 109B4-01 as a raw material, and carrying out ammonolysis by ammonia water to obtain an amino alcohol compound 109B5-01; protecting the amino group with Boc-acid anhydride to obtain 109B6-01; reacting with diphenyl phosphorazidate in the presence of DBU to obtain 109B7-P1, adding proper alkali, and substituting phosphate with azide radicals generated in the system to obtain corresponding azide 109B8-01; the resulting 109B8-01 is reduced to the azido group to give the corresponding amide 109B9-01.
2. The compound 109B6-01 is used as a raw material and reacts with diphenyl phosphorazidate in the presence of DBU to obtain a compound 109B7-P1.
Figure BSA0000212388440000061
3. Reacting a compound 109B6-01 serving as a raw material with diphenyl phosphorazidate in the presence of DBU to obtain a mixture of azide acid salts of a compound 109B7-P1 and DBU; base is added and the reaction is continued with heating to give the corresponding azide.
Figure BSA0000212388440000062
4. The chiral amine intermediate of Idoxaban is obtained by reducing azide groups into amino groups by using a compound 109B8-01 as a raw material and triphenylphosphine as a reducing agent.
Figure BSA0000212388440000063
The invention adopts a new synthetic route and a new method to prepare the chiral amine intermediate of edoxaban. The advantages are that:
1. diphenyl phosphorazidate (DPPA) is used for replacing metal azide salts, so that the use of the metal azide salts is avoided, and the safety coefficient of production is improved.
2. The sulfonate compound belongs to genotoxic substances, and the novel method adopted by the invention does not need to prepare a sulfonate intermediate, thereby greatly reducing the risk that the residue of the sulfonate compound is transferred to subsequent compounds.
3. The invention reduces the azide group into amino by using triphenylphosphine, avoids using expensive Pd/C catalyst, and is more suitable for industrial production to reduce the cost.
4. Nitrosamines are among the most important chemical carcinogens. During the chemical reaction, the main sources of nitrosamine compounds are: the amide solvent and the nitrosation reagent can generate the nitrosamine compound under certain specific conditions. If DMF, DMAc, NMP and the like are used as reaction solvents, when nitrite, nitrite ester, nitrous acid and substances prepared from nitrite exist in reactants: such as sodium azide, amine compound oxides, etc., and the product may have residual nitrosamine compounds. In the process of preparing the azide compound intermediate 109B8-01, the reaction solvent is hydrocarbon, an amide solvent is not used, and azide metal salts such as sodium azide are not used; the possibility of nitrosamine compounds in the reaction process is greatly reduced, and the risk of residual nitrosamine carcinogenic compounds in the finally prepared bulk drug of the paratoluenesulfonic acid edoxaban hydrate is reduced. The general structural formula of nitrosamines is as follows:
Figure BSA0000212388440000071
abbreviations:
Figure BSA0000212388440000072
Detailed Description
Example 1 Synthesis of tert-butyl N- [ (1R, 2R, 5S) -5- [ (dimethylamino) carbonyl ] -2-hydroxycyclohexyl ] carbamate
Figure BSA0000212388440000081
109B4-01 (1200 g, 7.091mol) and concentrated ammonia (6000 g) are added into a reaction flask, and the mixture is heated to 40 ℃ for reaction for 8-10 hours. Vacuum concentrating to obtain about 2000-2500 g of residual liquid in the reaction bottle. Adding aqueous sodium hydroxide solution (prepared from 600g sodium hydroxide and 5400g water) prepared in advance and cooled to room temperature, maintaining at about 40 deg.C, and adding Boc-anhydride (1920g; after the addition, the temperature is kept between 40 ℃ and 50 ℃ for reaction for 2 to 3 hours. After cooling, dichloromethane (4800 g) was added and the aqueous phase was extracted with more dichloromethane (1200 g. Times.2). Combining the organic phases; drying with anhydrous sodium sulfate, filtering, and concentrating the dried filtrate; 6000g of toluene was added to the obtained residue, heated, stirred and dispersed for 1-2 hr, and cooled for crystallization. Filtration, collection of solids, drying to give 109B6-01 dry weight of about 1590g, yield: 78.3% (theoretical amount: 2030.75 g).
Example 2 Synthesis of tert-butyl N- [ (1R, 2S, 5S) -2-azido-5- [ (dimethylamino) carbonyl ] cyclohexyl ] carbamate
Figure BSA0000212388440000082
Toluene (3000 g) was added to the reaction flask, followed by 109B6-01 (600g, 2.095mol), DBU (420g, 2.759mol), and Diphenylphosphorylazide (DPPA) (750 g, 2.725mol). Heating to 45-50 ℃ for reaction for 2-3 hr, adding anhydrous potassium carbonate (500g, 3.618mol), continuously heating to 100-105 ℃, and stirring for reaction for 36-40 hr.
After the reaction is finished, cooling to 40-50 ℃, adding water (3000 g) into the reaction system, keeping the temperature at 40-45 ℃, stirring and extracting, keeping the temperature of a water phase at 40-45 ℃, and extracting with toluene for three times (1200g +600g multiplied by 2); combining the organic phases; drying with anhydrous sodium sulfate, filtering, collecting filtrate, and concentrating toluene under reduced pressure to obtain residue; to the residue were added ethyl acetate and n-heptane (1: 3, w/w), and the mixture was stirred at room temperature to crystallize; filtration, collection of solids, and drying gave about 495g of dry weight 109B 8-01. Yield: 75.9% (theoretical amount: 652.40 g).
Example 3 Synthesis of tert-butyl N- [ (1R, 2R, 5S) -5- [ (dimethylamino) carbonyl ] -2- [ (diphenoxyphosphoryl) oxy ] cyclohexyl ] carbamate
Figure BSA0000212388440000091
Toluene (800 g) was added to the reaction flask, followed by 109B6-01 (100g, 349.2mmol), DBU (75g, 492.6mmol), diphenyl phosphorazidate (DPPA) (150g, 545.1mmol). Heating to 45-50 ℃, keeping the temperature for reaction for 4hr, cooling to room temperature, stirring and crystallizing; filtration, collection of solids, and drying gave about 157g dry weight of 109B7-P1. Yield: 86.7% (theoretical amount: 181.08 g).
Taking part of the obtained solid, refining by hot beating with toluene to obtain purified 109B7-P1, wherein the data of nuclear magnetic spectrum are shown as follows:
1 H-NMR(500MHz，CDCl 3 )：1.40ppm(s，9H)；1.52～2.19ppm(m，2H+2H+2H)；2.78ppm(m，1H)；2.92ppm，3.00ppm(d，3H+3H)；4.10～4.12ppm(m，1H)；4.66～4.67ppm(m，1H)；5.67pm(br，1H)；7.16～7.18ppm(t，2H)；7.21～7.25ppm(m，4H)；7.32～7.35ppm(m，4H).
example 4 Synthesis of tert-butyl N- [ (1R, 2S, 5S) -2-azido-5- [ (dimethylamino) carbonyl ] cyclohexyl ] carbamate
Figure BSA0000212388440000092
Adding 1000g of toluene into a reaction bottle, adding a solution prepared from polyethylene glycol 400 (20 g), sodium azide (13g, 200.0 mmol) and 50g of water into the reaction bottle, heating to 60-65 ℃, and concentrating under reduced pressure until the water content in the reaction system is not more than 0.5 percent (about 400-500 g of collected distillate); then 109B7-P1 (50g, 96.42mmol) is added; DBU (32g, 210.2mmol) was added. Keeping the temperature at 60-65 ℃, and stirring for reaction for about 24-36 hr.
After the reaction is finished, cooling to 40-50 ℃, adding water (300 g) into the reaction system, keeping the temperature at 40-45 ℃, stirring and extracting, keeping the temperature of the water phase at 40-45 ℃, and extracting for three times (150g +100g multiplied by 2) by toluene; combining the organic phases; drying with anhydrous sodium sulfate, filtering, collecting filtrate, and concentrating toluene under reduced pressure to obtain residue; to the residue were added ethyl acetate and n-heptane (1: 3, w/w), and the mixture was stirred at room temperature to crystallize; filtration, collection of solids, and drying gave about 20.4g of dry 109B 8-01. Yield: 68.0% (theoretical amount: 30.02 g).
Example 5 Synthesis of tert-butyl N- [ (1R, 2S, 5S) -2-amino-5- [ (dimethylamino) carbonyl ] cyclohexyl ] carbamate
Figure BSA0000212388440000101
Methanol (2500 g) was added to the reaction flask, 109B8-01 (492g, 1.580mol) was added, and 10% by weight of Pd/C (54 g; water content about 56%) was added; after stirring uniformly, adding ammonium formate (250g, 3.964 mol), heating to 40-45 ℃ by using a water bath under stirring, and reacting for 3-4 hr.
After the reaction is finished, filtering; collecting the filtrate, and concentrating the dried solvent under reduced pressure to obtain a residue; dissolving the obtained residue with acetonitrile, filtering out insoluble substances, collecting filtrate, concentrating under reduced pressure to dryness, adding toluene into the residue, heating to disperse, cooling to 0-5 ℃ for crystallization, filtering, collecting solids, and drying to obtain about 316g of 109B9-01 dry weight. Yield: 70.1% (theoretical amount: 450.9 g).
Example 6 Synthesis of tert-butyl N- [ (1R, 2S, 5S) -2-amino-5- [ (dimethylamino) carbonyl ] cyclohexyl ] carbamate
Figure BSA0000212388440000102
Add methanol (4B 0 g) to the hydrogenation vessel, add 109B8-01 (60g 192.7 mmol) and add 10% Pd/C (6.3 g; water content about 56%); after stirring evenly, introducing nitrogen to replace air for 3 times; then hydrogen is introduced to replace nitrogen for 3 times; keeping the pressure in the kettle at 0.4-0.6 MPa, and heating to 50-60 ℃; the reaction was stirred until no hydrogen was absorbed.
After the reaction is finished, releasing the pressure, replacing hydrogen in the kettle with nitrogen, and transferring the reaction liquid out of the reaction kettle; filtering; collecting the filtrate, and concentrating the dried solvent under reduced pressure to obtain residue; dissolving the obtained residue with acetonitrile, filtering out insoluble substances, collecting filtrate, concentrating under reduced pressure to dryness, adding toluene into the residue, heating to disperse, cooling to 0-5 ℃ for crystallization, filtering, collecting solids, and drying to obtain about 48.2g of 109B9-01 dry weight. Yield: 87.7% (theoretical amount: 54.99 g).
Example 7 Synthesis of tert-butyl N- [ (1R, 2S, 5S) -2-amino-5- [ (dimethylamino) carbonyl ] cyclohexyl ] carbamate
Figure BSA0000212388440000111
Tetrahydrofuran (450 g) was added to the reaction flask, water (500 g) was added; stirring uniformly, adding 109B8-01 (155g, 497.8mmol), and then adding triphenylphosphine (155g, 590.9mmol); heating to 50-60 ℃; stirring and reacting for 2-3 hr; triphenylphosphine (65g, 247.8mmol) was added to the reaction; keeping the temperature and reacting for about 2-3 hr.
After the reaction is finished, cooling to 20-30 ℃; filtering; the filtrate was collected and to the filtrate was added potassium carbonate (20 g) and sodium chloride (150 g); stirring evenly, standing and separating liquid; the aqueous phase is extracted twice more with tetrahydrofuran (250g + 150g); combining tetrahydrofuran phases, and concentrating under reduced pressure to obtain a residue; dissolving the obtained residue with acetonitrile, filtering off insoluble substances, collecting filtrate, concentrating under reduced pressure to dryness, adding acetonitrile again, dissolving the residue, and filtering off insoluble substances; concentrating the obtained filtrate, adding toluene, heating for dispersion, cooling to 0-5 ℃ for crystallization, filtering, and collecting solids; the resulting solid was recrystallized from a mixed solution of acetonitrile and n-heptane to give 109B9-01 dry weight of about 123g. Yield: 86.5% (theoretical amount: 142.1 g).

Claims (3)

1. A process for the preparation of the compound tert-butyl N- [ (1r, 2s, 5s) -2-amino-5- [ (dimethylamino) carbonyl ] cyclohexyl ] carbamate 109B9-01, characterized in that: reacting a compound 109B6-01 serving as a raw material with diphenylphosphoryl azide DPPA in the presence of DBU to obtain a salt mixture of 109B7-P1 and DBU azide acid, and adding a proper alkali to obtain corresponding azide 109B8-01; then reducing to obtain corresponding amino 109B9-01;
Figure FSB0000199169580000011
2. the method of claim 1, wherein: the reaction solvent is toluene or n-heptane, the feeding mol ratio of 109B6-01 to DPPA to DBU is 1.0: 1.2-1.5; firstly heating to react to generate 109B7-P1, wherein the reaction temperature is 40-60 ℃; without separating the intermediate 109B7-P1, adding sodium carbonate or potassium carbonate or cesium carbonate, and then heating to 90-130 ℃ for reaction to generate the corresponding azide 109B8-01; the resulting 109B8-01 was then reacted with triphenylphosphine to give 109B9-01.
3. The compound tert-butyl N- [ (1R, 2R, 5S) -5- [ (dimethylamino) carbonyl ] -2- [ (diphenoxyphosphoryl) oxy ] cyclohexyl ] carbamate 109B7-P1, characterized by having the following structure:
Figure FSB0000199169580000012
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Denomination of invention: A method for preparing chiral amine intermediate of iduban

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