CN104892601A - Preparation method of antithrombotic drug Apixaban - Google Patents
Preparation method of antithrombotic drug Apixaban Download PDFInfo
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Abstract
The invention relates to the field of medicine preparation and particularly relates to a preparation method of Apixaban. The preparation method comprises the following steps: carrying out amidation-cyclization on starting raw materials (p-chloroaniline and acyl chloride) to obtain a compound III, namely 1-(4-chlorphenyl)-2-piperidone; carrying out diazotization on raw materials (p-methoxyaniline and ethyl 2-chloroacetoacetate and then further generating Japp-Klingmann hydrazone synthesis reaction to obtain a compound VI, namely ethyl [(4-methoxyphenyl) diazanyl] chloroacetate; enabling the compound III to have a substitution reaction with raw material 5,6-dihydro-3-(4-morpholine)-2(1h)-pyridone in the presence of a catalyst to obtain a compound 2, namely 5,6-dihydro-3-(4-morpholine)-1-[4-(2-oxo-1-piperidyl) phenyl]-2(1H)-pyridone; carrying out [3+2] cyclization-elimination on the compound III and the compound VI to obtain a compound IX; reacting the compound IX with ammonia to obtain Apixaban; and washing the crude product with alcohol to obtain high-purity Apixaban, wherein the total yield is 40-50%. The preparation method has the advantages that the raw materials are simple and easily available; the cost is low; the reaction conditions are mild; the high-purity product can be obtained by simple purification since few byproducts are generated; therefore, the preparation method of Apixaban is suitable for industrial production.
Description
Technical field
The present invention relates to medicine preparation field, be specifically related to a kind of preparation method of antithrombotic reagent Eliquis.
Background technology
Eliquis (Apixaban) in European Union's approval listing in March, 2011, is a kind of oral Selective activation Xa factor inhibitor, is developed jointly by Pfizer and Bristol Myers Squibb.The clinical venous thromboembolism (VTE) for preventing the adult patients of carrying out selecting a time hip joint or knee replacements to occur.Compared with preventing the standard regimens enoxaparin of venous thromboembolism after current bone surgery, Eliquis highlights advantage in RECORD test and ADVANCE test.
The main synthesis technique of Eliquis of current International Publication has:
(1) patent WO2010/30983;
(2) patent WO03026652;
(3) patent WO03049681, US2006/0069258;
(4) patent CN101967145;
(5) patent WO2007001385;
(6) document DonaldJ.P.Pinto, MichaelJ.Orwat, Stephanie Koch, al.J.Med.Chem.2007,50 (22), 5339-5356 pages etc.
Disclosed in Auspex Pharmaceuticals companies in 2010, world patent WO2010/030983 provides the route preparing Eliquis, following chemical step.This route first with paraiodoaniline and 5-bromine valeryl chloride for raw material prepares compound 2 by amidation-cyclization, 2 in chloroform, carry out the dichloride of α-reactive hydrogen with phosphorus pentachloride again, excessive morpholine carry out condensation-eliminative reaction under existing and obtain compound 3.Then to obtain compound VI to methyl oxyaniline for recurring (the graceful Japp-Klingmann of refined-Florian Kringe) hydrazone building-up reactions after starting raw material diazotization with 2-chloroacetyl acetacetic ester, VI and compound 3 are through [3+2] cyclization-eliminative reaction strategy generating pyrazole compound 4,4 generate ammonia solution in Compound I X, the IX ethylene glycol solution at ammonia with the condensation under similar Liv Ullmann (Ullmann) reaction conditions of δ-Valerolactim obtains target product.This route Ullmann severe reaction conditions, complicated operation, single step yield is low, and by product is many, and make highway route design reasonable not, total recovery is lower, is not suitable for suitability for industrialized production and uses containing iodine raw materials cost high in reaction.
Bristol-Myers Squibb company gives a use cost the high route containing iodine organic reagent in world patent WO2003/049681 disclosed in 2003, and total recovery only has 5.2%.Bristol-Myers Squibb company again disclosed the technique patent (US2006/0069258) of this medicine in 2006, route take p-Nitroaniline as raw material, compound 5 is obtained by amidation ring-closure reaction with 5-bromine valeryl chloride, 5 after phosphorus pentachloride dichloride, and under Quilonum Retard and lithium chloride exist, heat condensation eliminates to obtain compound 8.After diazotization, Japp-Klingmann hydrazone building-up reactions is there is with 2-chloroacetyl acetacetic ester and obtains in another compound VI by starting raw material P-nethoxyaniline, compound VI and compound 8 obtain compound 9 through cyclization-eliminative reaction, 9 obtain aminocompound 10 through the reduction of palladium hydrocarbonize, 10 obtain Compound I X with 5-bromine valeryl chloride by amidation ring-closure reaction, finally in DMF and methane amide, solve target compound Eliquis through ammonia.Although this route avoid employing with cost high use expensive palladium hydrocarbonize condition containing iodine raw material, total recovery also improves, and synthetic route is longer, compound and finished product impurity wayward; Also use a large amount of 5-bromine valeryl chlorides and phosphorus pentachloride etc. unstable and the raw material of difficult aftertreatment, these deficiencies all limit suitability for industrialized production simultaneously; Final step ammonia solution employs DMF and makes solvent, and solvent is easily residual not easily to be removed, and makes product be difficult to reach API standard.
China Patent Publication No. is the synthetic route that CN101967145 discloses Apixaban, as described below.The similar 3rd kind of route of this route, be that raw material obtains compound 6 with 5-Chlorovaleryl Chloride through amidation-cyclization two step one pot reaction in the basic conditions with p-Nitroaniline, 6 carry out dichloride with phosphorus pentachloride, then carry out condensation-eliminative reaction with excessive morpholine and obtain compound 12,12 sodium reductions that cure are compound 13,13 carry out amidation-cyclization two step one pot reaction with 5-Chlorovaleryl Chloride obtains 14,14 and 3 obtain IX through [3+2] cyclization-eliminative reaction, and last ammonia solution obtains Eliquis.This route adopts one pot to cut down, and be difficult to control although can reduce route impurity, productive rate is low, and uses the instability such as a large amount of phosphorus pentachlorides and the raw material of difficult aftertreatment in reaction, limits it for suitability for industrialized production.
Summarize above-mentioned route, in the process preparing Eliquis, there is following defect: raw and auxiliary material is expensive, as expensive containing iodine reagent in used, use expensive palladium hydrocarbonize condition etc.; Or the limitation of reaction conditions causes, and overall yield is too low should not be used for suitability for industrialized production, or using the instability such as a large amount of phosphorus pentachlorides and the raw material of difficult aftertreatment in reaction, acid and containing heavy metal waste water and dregs is big for environment pollution in a large number for generation in suitability for industrialized production or reaction process to limit it.
Summary of the invention
The object of the invention is to the synthetic method that a kind of synthesis Eliquis is newly provided by the deficiency overcome in aforesaid method.Its raw material is simple and easy to get, and total recovery is high, avoid using severe toxicity and/or expensive reagent, avoiding using the raw material too much producing waste water and waste residue, and the finished product foreign matter content low production purity is high, is suitable for suitability for industrialized production.
Concrete technical scheme of the present invention is:
A preparation method for antithrombotic Eliquis, comprises the following steps:
(a) make such as formula under the compound low temperature shown in (I) with such as formula the compound generation amidate action shown in (II), after add solid alkali and phase-transfer catalyst ring closure reaction obtains such as formula the compound shown in (III);
B () is dissolved in organic solvent such as formula the compound shown in (IV), after adding concentrated acid-5-5 DEG C with sodium nitrite solution diazotization after close with the compound hydrazone under the effect of sodium-acetate shown in formula (V) compound be obtained by reacting such as formula shown in (VI);
C () adds catalyzer generation substitution reaction such as formula the compound shown in the compound shown in (III) and formula (VII) and obtains the compound shown in formula (VIII) in dimethylsulfoxide solvent;
D () is under the effect of alkali and phase-transfer catalyst, in toluene system, there is ring closure reaction such as formula the compound shown in the compound shown in (VIII) and formula (VI), after under excess acid, there is eliminative reaction obtain such as formula the compound shown in (IX);
E there is amidate action such as formula the compound shown in (IX) and obtain such as formula the compound shown in (X) in (), i.e. Eliquis in excessive alcohol-ammono-system;
Wherein, in formula (I) compound, X is selected from halogen.
In described step (a), be chlorine such as formula X in the compound shown in (I), bromine, iodine, fluorine; Such as formula the compound shown in (I) with react such as formula the compound shown in (II) in the solid alkali that adds be sodium methylate, the one in sodium ethylate or potassium tert.-butoxide or sodium tert-butoxide; Described phase-transfer catalyst is Tetrabutyl amonium bromide (TBAB), the one in benzyltriethylammoinium chloride (TEBA), tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate, and after adding phase-transfer catalyst, temperature of reaction is 10-80 DEG C.
Be bromine such as formula X in the compound shown in (I); After adding phase-transfer catalyst, temperature of reaction is room temperature reaction.
In described step (b), described concentrated acid is haloid acid, sulfuric acid, nitric acid, one or more in trifluoroacetic acid; The temperature that diazotization reaction first occurs P-nethoxyaniline is-5 DEG C-5 DEG C; Described organic solvent is methylene dichloride, chloroform, methyl alcohol, ethanol, one or more in acetone.
In described step (c), described catalyzer is cuprous iodide, the one in triphenylphosphine cuprous bromide or palladium, and the consumption of catalyzer is 0.03-0.1 equivalent; Described alkali is salt of wormwood, sodium carbonate, cesium carbonate, the one in Quilonum Retard.
In shown step (d), described alkali is one or more in triethylamine or pyridine or salt of wormwood or sodium carbonate; Described phase-transfer catalyst is Tetrabutyl amonium bromide (TBAB), the one in benzyltriethylammoinium chloride (TEBA), tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate; Described alkali and the ratio of phase-transfer catalyst are 1: 0.1-1: 1; Described acid is haloid acid (example hydrochloric acid), sulfuric acid, one or more in the protonic acids such as nitric acid.
Described alkali is salt of wormwood; Described phase-transfer catalyst is Tetrabutyl amonium bromide (TBAB).
In shown step (e), the solvent used such as formula the compound shown in (IX) and aminoacyl amination reaction is methyl alcohol, ethanol or ethylene glycol, one or more in Virahol; Alcohol-the ammonia density used such as formula the compound shown in (IX) and aminoacyl amination reaction is 10%-20%.
The preparation method of a kind of Eliquis of the present invention, acyl chlorides used is 5-bromine valeryl chloride, 5-Chlorovaleryl Chloride, the one in 5-iodine valeryl chloride.
The present invention with p-Chlorobenzoic acid amide and acyl chlorides for starting raw material, p-Chlorobenzoic acid amide drips the solution of acyl chlorides-THF in triethylamine and tetrahydrofuran (THF) (THF) under low temperature, solid alkali and phase-transfer catalyst is added after reaction for some time, room temperature reaction is complete, decompression steams THF, ethyl acetate and hydrochloric acid soln is added in system, layering, water layer is extracted with ethyl acetate again, combined ethyl acetate layer, organic layer is washed rear saturated common salt with 1N salts solution again and is washed, dry, filter, steaming desolventizes and obtains crude product normal hexane recrystallization and obtain sterling compound III 1-(4-chloro-phenyl-)-2-piperidone.Raw material P-nethoxyaniline drops into methylene dichloride, chloroform, methyl alcohol, ethanol, in system, concentrated acid is added in a kind of solvent in acetone, system is cooled to-5-5 DEG C, in system, the aqueous solution of Sodium Nitrite is dripped after temperature-stable, drip and to finish at this temperature after insulation reaction for some time, then in system, 2-chloroacetyl acetacetic ester is added, the mixed solvent of water-and above-mentioned organic solvent, sodium-acetate, finish, system is filtered after being naturally warming up to room temperature reaction 0.5-1h, consider after cake washes with water and wash with ethanol again, dry, obtain light brown compound VI [(4-p-methoxy-phenyl) diazanyl] ethyl chloroacetate.Compound III and raw material 5; 6-dihydro-3-(4-morpholine)-2 (1h)-pyridone; alkali is put in methyl-sulphoxide (DMSO) solution; catalyzer is added under stirring; finish room temperature reaction 4-10h under nitrogen protection; reaction is finished system and is cooled to 0-10 DEG C and adds 15% ammoniacal liquor and ethyl acetate, and system room temperature continues to stir 3-6h.System layering, aqueous layer with ethyl acetate merges organic layer after extracting 3-4 time, dry, filter, divide exactly solvent, obtain crude product, obtain sterling compound 25,6-dihydro-3-(4-morpholinyl)-1-[4-(2-oxo-piperidino) phenyl]-2 (1H)-pyridones with methyl alcohol and methylene dichloride recrystallization, compound VI II is dissolved in toluene, add compound VI, reflux under a kind of alkali and phase-transfer catalyst, react complete shrend to go out reaction, after extraction into ethyl acetate three times, organic phase saturated common salt is washed, organic layer is dry, after concentrated after filtering, enriched material be dissolved in methylene dichloride and add excessive acid, after stirring at room temperature for some time, add shrend go out reaction after, aqueous phase dichloromethane extraction, merge organic layer, dry, filter, purifying obtains Compound I X, it is complete to raw material reaction that Compound I X drops into excessive alcohol-ammonia 70-80 DEG C tube sealing insulation reaction, after being cooled to room temperature, system is poured in the ethanol of ice, filter, consider cake ice ethanol and wash rear drying, obtain Eliquis, crude product obtains high purity Eliquis after methanol wash column, total recovery 35%-45%.
Beneficial effect:
Technique is simple, and raw material is easy to get, pollution-free;
Reaction conditions is gentle, is easy to control, and total recovery is high;
Byproduct of reaction is few, and compound and product all obtain high purity product by recrystallization means;
Reaction time consumption is short, and economic benefit is large.
Embodiment
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.
The synthesis of embodiment 1 compound III 1-(4-chloro-phenyl-)-2-piperidone
P-Chlorobenzoic acid amide 180.0g (0.82mol) is added in 5L reaction flask, triethylamine 257.7mL (1.85mol) and tetrahydrofuran (THF) (THF) 3130mL, system is cooled to-5 DEG C, drip the solution of 196.5g (0.98mol) 5-bromine valeryl chloride and 785mLTHF, 45min drips complete, system is cooled to 0 DEG C after being naturally warming up to room temperature reaction 8-12h again, 132.8g (2.46mol) sodium methylate and Tetrabutyl amonium bromide (TBAB) 52.9g (0.16mol) is added in system, 10 DEG C of reaction 4-6hHPLC detect, react completely, decompression steams THF, 1.8L ethyl acetate and 3N hydrochloric acid soln 1.8L is added in system, layering after stirring 30min, water layer uses 3X0.8L extraction into ethyl acetate again, combined ethyl acetate layer, organic layer washes the washing of rear 1X0.8L saturated common salt with 1N salts solution 2X0.8L again, dry, filter, steaming desolventizes and obtains crude product 247.2g, purify with normal hexane and obtain sterling compound III 1-(4-iodophenyl)-2-piperidone 217.3g, productive rate: 88%, HPLC >=98.0%.
1HNMR(400MHz，CDCl
3)δ7.70(d，j＝8.4Hz，2H)，7.03(d，j＝8.8Hz，2H)，3.62(t，j＝5.9Hz，2H)，2.56(t，j＝5.7Hz，2H)，2.50-1.88(m，4H)ppm。
The synthesis of compound VI [(4-p-methoxy-phenyl) diazanyl] ethyl chloroacetate
P-nethoxyaniline 300g (2.4mol) is added in 10L reactor, trifluoroacetic acid 500mL, methyl alcohol 800mL, system is cooled to-5-5 DEG C, the aqueous solution that the water dripping Sodium Nitrite 183g (2.7mol) and 1L after temperature-stable in system is made into, 1.5h drips complete, insulation reaction 30min-1h, then in system, 2-chloroacetyl acetacetic ester 400.5g (2.4mol) is added, water 4.5L, methyl alcohol 0.5L, sodium-acetate 329.2g (4.0mol), finish, system is filtered after being naturally warming up to room temperature reaction 0.5-1h, consider after cake washes with water and use methanol wash column again, dry, obtain light brown compound VI [(4-p-methoxy-phenyl) diazanyl] ethyl chloroacetate 494.0g, productive rate: 79.0%, HPLC:98.9%, mp:87-89 DEG C.
1hNMR (400MHz, CDCl
3) δ 1.40 (t, J=7.2Hz, 3H), 3.82 (s, 3H), 4.38 (q, J=7.2Hz, 2H), 6.89 (d, J=8.8Hz, 2H) 7.17 (d, J=8.8Hz, 2H), 8.26 (br, exchangeable with D
2o, 1H), IR (KBr) υ 3256,2986,2917,2831,1706,1659,1558,1515,1222,1165,1075cm
-1, MS:255 [M-H]
-.
The synthesis of compound VI II 5,6-dihydro-3-(4-morpholinyl)-1-[4-(2-oxo-piperidino) phenyl]-2 (1H)-pyridones
1-(4-iodophenyl)-2-piperidone 215g (0.71mol) is added in 10L reaction flask; 5; 6-dihydro-3-(4-morpholine)-2 (1h)-pyridone 143g (0.78mol); sodium carbonate 301.0g (2.84mol); DMSO3.0L, adds the triphenylphosphine cuprous bromide 29.8g (0.036mol) of existing system under stirring, finish room temperature reaction about 6h under nitrogen protection; HPLC detects, and raw material reaction is complete.System is cooled to 5 DEG C and adds 15% ammoniacal liquor 3.2L and ethyl acetate 3.2L, and system room temperature continues to stir 3-6h.System layering, aqueous layer with ethyl acetate 3X1L extracts, and merges organic layer, dry, filter, divide exactly solvent, obtain crude product 249.5g, obtain sterling compound VI II 5 with methyl alcohol and methylene dichloride recrystallization, 6-dihydro-3-(4-morpholinyl)-1-[4-(2-oxo-piperidino) phenyl]-2 (1H)-pyridone 229.6g, productive rate: 91%, HPLC:98.5%;
The synthesis of Compound I X 1-(4-p-methoxy-phenyl)-7-oxo-6-[4-(2-oxo piperidine-1-base) phenyl]-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxylic acid ethyl esters
In 5L reaction flask, add compound VI II220g (0.62mol), 3.2L toluene, add compound VI 191.0g (0.74mol) under stirring, K
2cO
3257g (1.86mol) and TBAB (0.57mol) 180.0g, reflux 6.5h, HPLC detection reaction is complete, react with frozen water 1.6kg cancellation in reaction system, extract with ethyl acetate 3X1.5L, organic phase saturated aqueous common salt 2L washes, organic layer is dry, concentrate after filtering and obtain 356g yellow solid matter, in system, add 3.2L methylene dichloride and add 332mL concentrated hydrochloric acid, stirring at room temperature 3.5h, add shrend go out reaction after, aqueous phase methylene dichloride 3X1.0L extracts, merge organic layer, dry, filter, steaming desolventizes and obtains 286.0g (productive rate: 86%) yellow solid compound IX, HPLC:98.6%,
1hNMR (400Hz, CDCl
3, ppm) and δ 7.47 (m, 2H), 7.28 (m, 4H), 6.90 (m, 2H), 4.44 (m, 2H), 4.10 (t, J=6.8Hz, 2H), 3.80 (s, 3H), 3.59 (t, J=6.0Hz, 2H), 3.30 (t, J=6.8Hz, 2H), 2.53 (t, J=5.8Hz, 2H), 1.93 (m, 4H), 1.42 (t, J=7.2Hz, 3H), EI-MS (M/Z): 488.2.
The synthesis of Eliquis
The ammonia solution 242.3g of 280g (0.57mol) Compound I X and 20% methyl alcohol is added in 5L reaction flask, tube sealing is heated to 80 DEG C of reaction 5h, HPLC detection reaction is complete, stopped reaction, system stirs 2h after being cooled to room temperature, filters, and considers a small amount of methanol wash column post-drying of cake, obtain Eliquis sterling 234.4g (productive rate 89.1%), mp:145-149 DEG C.
1HNMR(400MHz，CDCl
3)δ1.92-1.94(m，4H)，2.55-2.56(m，2H)，3.37(t，2H)，3.58-3.59(m，2H)，3.82(s，3H)，4.12(t，2H)，5.47(brs，1H)，6.84(brs，1H)，6.93(d，J＝8.8Hz，2H)，7.25(d，J＝8.0Hz，2H)，7.34(d，J＝8.4，2H)，7.47(d，J＝8.8Hz，2H)；IR(KBr)υ3453，3305，3251，3178，3052，2947，2859，1673，1609，1512，1459，1400，1330，1297，1250，1151，1107，1022，986cm
-1；MS：460[M+H]
+。
Embodiment 2
The synthesis of compound III 1-(4-chloro-phenyl-)-2-piperidone
P-Chlorobenzoic acid amide 180.0g (0.82mol) is added in 5L reaction flask, triethylamine 257.7mL (1.85mol) and tetrahydrofuran (THF) (THF) 3130mL, system is cooled to-5-5 DEG C, drip the solution of 152.595-bromine valeryl chloride and 785mLTHF, 45min drips complete, system is cooled to 0 DEG C after being naturally warming up to room temperature reaction 8-12h again, 276.0g (2.46mol) potassium tert.-butoxide and benzyltriethylammoinium chloride (TEBA) 36.4g (0.16mol) is added in system, 40 DEG C of reaction 4.5h HPLC detect, react completely, decompression steams THF, 1.8L ethyl acetate and 3N hydrochloric acid soln 1.8L is added in system, layering after stirring 30min, water layer uses 3X0.8L extraction into ethyl acetate again, combined ethyl acetate layer, organic layer washes the washing of rear 1X0.8L saturated common salt with 1N salts solution 2X0.8L again, dry, filter, steaming desolventizes and obtains crude product 250.1g, purify with normal hexane and obtain sterling compound III 1-(4-iodophenyl)-2-piperidone 218.0g, productive rate: 88.3%, HPLC >=98.0%.
The synthesis of compound VI [(4-p-methoxy-phenyl) diazanyl] ethyl chloroacetate
P-nethoxyaniline 300g (2.4mol) is added in 10L reactor, hydrochloric acid 750mL, ethanol 800mL, system is cooled to 5 DEG C, the aqueous solution that the water dripping Sodium Nitrite 183g (2.7mol) and 1L after temperature-stable in system is made into, 1.5h drips complete, insulation reaction 30min-1h, then in system, 2-chloroacetyl acetacetic ester 400.5g (2.4mol) is added, water 4.5L, methylene dichloride 1L, sodium-acetate 329.2g (4.0mol), finish, system is filtered after being naturally warming up to room temperature reaction 0.5-1h, consider after cake washes with water and wash with methylene dichloride again, dry, obtain light brown compound VI [(4-p-methoxy-phenyl) diazanyl] ethyl chloroacetate 462.5g, productive rate: 74.0%, HPLC:99.2%.
The synthesis of compound VI II5,6-dihydro-3-(4-morpholinyl)-1-[4-(2-oxo-piperidino) phenyl]-2 (1H)-pyridones
1-(4-iodophenyl)-2-piperidone 215g (0.71mol) is added in 10L reaction flask; 5; 6-dihydro-3-(4-morpholine)-2 (1h)-pyridone 143g (0.78mol); Quilonum Retard 209.8g (2.84mol); DMSO 3.0L, adds cuprous iodide 13.5g (0.071mol) under stirring, finish room temperature reaction about 6h under nitrogen protection; HPLC detects, and raw material reaction is complete.System is cooled to 5 DEG C and adds 15% ammoniacal liquor 3.2L and ethyl acetate 3.2L, and system room temperature continues to stir 3-6h.Filter, filtrate layering, aqueous layer with ethyl acetate 3X1L extracts, merge organic layer, drying, filter, steaming desolventizes, obtain crude product 249.5g, sterling compound VI II5 is obtained, 6-dihydro-3-(4-morpholinyl)-1-[4-(2-oxo-piperidino) phenyl]-2 (1H)-pyridone 203.5g, productive rate: 80.6% with methyl alcohol and methylene dichloride recrystallization, HPLC:98.9%;
The synthesis of Compound I X 1-(4-p-methoxy-phenyl)-7-oxo-6-[4-(2-oxo piperidine-1-base) phenyl]-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxylic acid ethyl esters
Compound VI II 220g (0.62mol) is added in 5L reaction flask, 3.2L toluene, compound VI 191.0g (0.74mol) is added under stirring, sodium carbonate 197.2g (1.86mol) and TEBA (1.863mol) 423.6g, reflux 3.0h, HPLC detection reaction is complete, react with frozen water 3.8kg cancellation in reaction system, extract with ethyl acetate 3X1.5L, organic phase saturated aqueous common salt 2L washes, organic layer is dry, concentrate after filtering and obtain 369g yellow solid matter, in system, add 3.2L methylene dichloride and add 60% sulphuric acid soln 303.8mL, stirring at room temperature 3.5h, add shrend go out reaction after, aqueous phase methylene dichloride 3X1.0L extracts, merge organic layer, dry, filter, divide exactly solvent and obtain 298.1g (productive rate: 89.6%) yellow solid compound IX, HPLC:98.3%.
The synthesis of Eliquis
The ammonia solution 484.5g of 280g (0.57mol) Compound I X and 10% Virahol is added in 5L reaction flask, tube sealing is heated to 80 DEG C of reaction 5h, HPLC detection reaction is complete, stopped reaction, system stirs 2h after being cooled to room temperature, filter, consider a small amount of methanol wash column post-drying of cake, obtain Eliquis sterling 230.8g (productive rate 87.7%).
Embodiment 3
The synthesis of compound III 1-(4-chloro-phenyl-)-2-piperidone
P-Chlorobenzoic acid amide 180.0g (0.82mol) is added in 5L reaction flask, triethylamine 257.7mL (1.85mol) and tetrahydrofuran (THF) (THF) 3130mL, system is cooled to-5-5 DEG C, drip the solution of 196.5g (0.98mol) 5-bromine valeryl chloride and 785mLTHF, 45min drips complete, in system, 167.4g (2.46mol) sodium ethylate and tetrabutylammonium chloride 44.5g (0.16mol) is added after system is warming up to room temperature reaction 8-12h, be warming up to 80 DEG C of reaction 4-6h HPLC to detect, react completely, after system is cooled to room temperature, decompression steams THF, 1.8L ethyl acetate and 3N hydrochloric acid soln 1.8L is added in system, layering after stirring 30min, water layer uses 3X0.8L extraction into ethyl acetate again, combined ethyl acetate layer, organic layer washes the washing of rear 1X0.8L saturated common salt with 1N salts solution 2X0.8L again, dry, filter, steaming desolventizes and obtains crude product 263.2g, purify with normal hexane and obtain sterling compound III 1-(4-iodophenyl)-2-piperidone 223.5g, productive rate: 90.5%, HPLC >=98.0%.
The synthesis of compound VI [(4-p-methoxy-phenyl) diazanyl] ethyl chloroacetate
P-nethoxyaniline 300g (2.4mol) is added in 10L reactor, nitric acid 550mL, ethanol 800mL, system is cooled to-2 DEG C, the aqueous solution that the water dripping Sodium Nitrite 183g (2.7mol) and 1L after temperature-stable in system is made into, 1.5h drips complete, insulation reaction 30min-1h, then in system, 2-chloroacetyl acetacetic ester 400.5g (2.4mol) is added, water 4.5L, acetone 1.5L, sodium-acetate 329.2g (4.0mol), finish, system is filtered after being naturally warming up to room temperature reaction 0.5-1h, consider after cake washes with water and wash with methylene dichloride again, dry, obtain light brown compound VI [(4-p-methoxy-phenyl) diazanyl] ethyl chloroacetate 443g, productive rate: 70.8%, HPLC:98.6%.
The synthesis of compound VI II 5,6-dihydro-3-(4-morpholinyl)-1-[4-(2-oxo-piperidino) phenyl]-2 (1H)-pyridones
1-(4-iodophenyl)-2-piperidone 215g (0.71mol) is added in 10L reaction flask; 5; 6-dihydro-3-(4-morpholine)-2 (1h)-pyridone 143g (0.78mol); cesium carbonate 463.6g (1.42mol); DMSO3.0L, adds palladium 4.8g (0.021mol) under stirring, finish room temperature reaction about 6h under nitrogen protection; HPLC detects, and raw material reaction is complete.System is cooled to 5 DEG C and adds 15% ammoniacal liquor 3.2L and ethyl acetate 3.2L, and system room temperature continues to stir 3-6h.Filter, filtrate layering, aqueous layer with ethyl acetate 3X1L extracts, merge organic layer, drying, filters, divides exactly solvent, obtain crude product 249.5g, sterling compound VI II 5,6-dihydro-3-(4-morpholinyl)-1-[4-(2-oxo-piperidino) phenyl]-2 (1H)-pyridone 234.6g are obtained, productive rate: 93.0% with methyl alcohol and methylene dichloride recrystallization, HPLC:99.4%;
The synthesis of Compound I X 1-(4-p-methoxy-phenyl)-7-oxo-6-[4-(2-oxo piperidine-1-base) phenyl]-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxylic acid ethyl esters
Compound VI II220g (0.62mol) is added in 5L reaction flask, 3.2L toluene, compound VI 191.0g (0.74mol) is added under stirring, triethylamine 125.5g (1.24mol) and TBAB (0.124mol) 40.0g, reflux 3.0h, HPLC detection reaction is complete, react with frozen water 4.1kg cancellation in reaction system, extract with ethyl acetate 3X2.0L, organic phase saturated aqueous common salt 2L washes, organic layer is dry, concentrate after filtering and obtain 367.4g yellow solid matter, in system, add 3.2L methylene dichloride and add 60% sulphuric acid soln 300.2mL, stirring at room temperature 3.5h, add shrend go out reaction after, aqueous phase methylene dichloride 3X1.0L extracts, merge organic layer, dry, filter, steaming desolventizes and obtains 286.9g (productive rate: 86.2%) yellow solid compound IX, HPLC:97.5%.
The synthesis of Eliquis
The ammonia solution 372.7g of 280g (0.57mol) Compound I X and 15% ethanol is added in 5L reaction flask, tube sealing is heated to 80 DEG C of reaction 5h, HPLC detection reaction is complete, stopped reaction, system stirs 2h after being cooled to room temperature, filters, and considers a small amount of methanol wash column post-drying of cake, obtain Eliquis sterling 206.9g (productive rate 78.6%), mp:145-149 DEG C.
Claims (8)
1. a preparation method for antithrombotic Eliquis, comprises the following steps:
(a) make such as formula under the compound low temperature shown in (I) with such as formula the compound generation amidate action shown in (II), after add solid alkali and phase-transfer catalyst ring closure reaction obtains such as formula the compound shown in (III);
B () is dissolved in organic solvent such as formula the compound shown in (IV), after adding concentrated acid-5-5 DEG C with sodium nitrite solution diazotization after close with the compound hydrazone under the effect of sodium-acetate shown in formula (V) compound be obtained by reacting such as formula shown in (VI);
C () adds catalyzer generation substitution reaction such as formula the compound shown in the compound shown in (III) and formula (VII) and obtains the compound shown in formula (VIII) in dimethylsulfoxide solvent;
D () is under the effect of alkali and phase-transfer catalyst, in toluene system, there is ring closure reaction such as formula the compound shown in the compound shown in (VIII) and formula (VI), after under excess acid, there is eliminative reaction obtain such as formula the compound shown in (IX);
E there is amidate action such as formula the compound shown in (IX) and obtain such as formula the compound shown in (X) in (), i.e. Eliquis in excessive alcohol-ammono-system;
Wherein, in formula (I) compound, X is selected from halogen.
2. method according to claim 1, is characterized in that:
In described step (a),
Be chlorine such as formula X in the compound shown in (I), bromine, iodine, fluorine;
Add and be-5-5 DEG C such as formula temperature during compound shown in (I), the amidate action time is 8-12h, and the ring-closure reaction time is 4-6h;
The temperature of amidate action is 40-50 DEG C, and the reaction times is 4-6h;
Such as formula the compound shown in (I) with react such as formula the compound shown in (II) in the solid alkali that adds be sodium methylate, the one in sodium ethylate or potassium tert.-butoxide or sodium tert-butoxide;
Described phase-transfer catalyst is Tetrabutyl amonium bromide (TBAB), the one in benzyltriethylammoinium chloride (TEBA), tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate, and after adding phase-transfer catalyst, temperature of reaction is 10-80 DEG C.
3. method according to claim 2, is characterized in that: be bromine such as formula X in the compound shown in (I); After adding phase-transfer catalyst, temperature of reaction is room temperature reaction.
4. method according to claim 1, is characterized in that: in described step (b), and described concentrated acid is haloid acid, sulfuric acid, nitric acid, one or more in trifluoroacetic acid;
The time that diazotization reaction first occurs P-nethoxyaniline is 0.5-1h;
Described organic solvent is methylene dichloride, chloroform, methyl alcohol, ethanol, one or more in acetone.
5. method according to claim 1, is characterized in that: in described step (c), and described catalyzer is cuprous iodide, the one in triphenylphosphine cuprous bromide or palladium, and the consumption of catalyzer is 0.03-0.1 equivalent;
Described alkali is salt of wormwood, sodium carbonate, cesium carbonate, the one in Quilonum Retard.
6. method according to claim 1, is characterized in that: in shown step (d), and described alkali is one or more in triethylamine or pyridine or salt of wormwood or sodium carbonate;
Described phase-transfer catalyst is Tetrabutyl amonium bromide (TBAB), the one in benzyltriethylammoinium chloride (TEBA), tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate;
Described alkali and the ratio of phase-transfer catalyst are 1: 0.1-1: 1;
Described acid is haloid acid, sulfuric acid, one or more in the protonic acids such as nitric acid.
7. method according to claim 6, is characterized in that: described alkali is salt of wormwood;
Described phase-transfer catalyst is Tetrabutyl amonium bromide (TBAB).
8. method according to claim 1, is characterized in that: in shown step (e),
The solvent used such as formula the compound shown in (IX) and aminoacyl amination reaction is methyl alcohol, ethanol or ethylene glycol, one or more in Virahol;
Alcohol-the ammonia density used such as formula the compound shown in (IX) and aminoacyl amination reaction is 10%-20%.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105254630A (en) * | 2015-11-16 | 2016-01-20 | 江苏康缘药业股份有限公司 | Preparing method for apixaban |
| CN106117200A (en) * | 2016-06-27 | 2016-11-16 | 青岛云天生物技术有限公司 | Prevention or the preparation method for the treatment of joint replacement phlebothrombosis medicine Eliquis |
| CN116137814A (en) * | 2020-06-26 | 2023-05-19 | 大桐株式会社 | New process for the preparation of apixaban |
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