CN103396406A - Preparation method of candesartan cilexetil - Google Patents
Preparation method of candesartan cilexetil Download PDFInfo
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- CN103396406A CN103396406A CN2013103406703A CN201310340670A CN103396406A CN 103396406 A CN103396406 A CN 103396406A CN 2013103406703 A CN2013103406703 A CN 2013103406703A CN 201310340670 A CN201310340670 A CN 201310340670A CN 103396406 A CN103396406 A CN 103396406A
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- 229960004349 candesartan cilexetil Drugs 0.000 title claims abstract description 41
- GHOSNRCGJFBJIB-UHFFFAOYSA-N Candesartan cilexetil Chemical compound C=12N(CC=3C=CC(=CC=3)C=3C(=CC=CC=3)C3=NNN=N3)C(OCC)=NC2=CC=CC=1C(=O)OC(C)OC(=O)OC1CCCCC1 GHOSNRCGJFBJIB-UHFFFAOYSA-N 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 50
- 239000002053 C09CA06 - Candesartan Substances 0.000 claims abstract description 21
- 229960000932 candesartan Drugs 0.000 claims abstract description 21
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims abstract description 19
- 239000002253 acid Substances 0.000 claims abstract description 17
- 239000002904 solvent Substances 0.000 claims abstract description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 12
- VBMKOTRJWPIKMG-UHFFFAOYSA-N 2-ethoxy-3-[[4-[2-(1-trityltetrazol-5-yl)phenyl]phenyl]methyl]benzimidazole-4-carboxylic acid Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=NN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 VBMKOTRJWPIKMG-UHFFFAOYSA-N 0.000 claims abstract description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- -1 Candesartan acid Chemical class 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- 238000007670 refining Methods 0.000 claims description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 7
- 239000012046 mixed solvent Substances 0.000 claims description 6
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 3
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 3
- 229960004756 ethanol Drugs 0.000 claims description 3
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 2
- 239000002798 polar solvent Substances 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 14
- 238000009776 industrial production Methods 0.000 abstract 1
- 238000005580 one pot reaction Methods 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 23
- SGZAIDDFHDDFJU-UHFFFAOYSA-N candesartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SGZAIDDFHDDFJU-UHFFFAOYSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 238000005406 washing Methods 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- 239000012043 crude product Substances 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 239000012295 chemical reaction liquid Substances 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 150000001298 alcohols Chemical class 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 230000006837 decompression Effects 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 238000000746 purification Methods 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 238000001514 detection method Methods 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- VBQDSLGFSUGBBE-UHFFFAOYSA-N benzyl(triethyl)azanium Chemical compound CC[N+](CC)(CC)CC1=CC=CC=C1 VBQDSLGFSUGBBE-UHFFFAOYSA-N 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 235000007715 potassium iodide Nutrition 0.000 description 2
- 229960004839 potassium iodide Drugs 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229960001866 silicon dioxide Drugs 0.000 description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- 208000001871 Tachycardia Diseases 0.000 description 1
- 206010048007 Withdrawal hypertension Diseases 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- RBPFEPGTRLLUKI-UHFFFAOYSA-N methyl 2-ethoxy-3-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]benzimidazole-4-carboxylate Chemical compound CCOC1=NC2=CC=CC(C(=O)OC)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=NN1 RBPFEPGTRLLUKI-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 238000005554 pickling Methods 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
- XZZNDPSIHUTMOC-UHFFFAOYSA-N triphenyl phosphate Chemical compound C=1C=CC=CC=1OP(OC=1C=CC=CC=1)(=O)OC1=CC=CC=C1 XZZNDPSIHUTMOC-UHFFFAOYSA-N 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
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- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a preparation method of candesartan cilexetil. The method takes candesartan acid as a starting material to acquire trityl candesartan cilexetil by a one-pot process, and then the trityl is removed from the trityl candesartan cilexetil in lower alcohol, thus obtaining the candesartan cilexetil. The candesartan cilexetil product prepared by the method has purity up to more than 99.80%. The method reduces the operation steps of reaction and solvent consumption, shortens the reaction period, and greatly improves the yield of trityl candesartan cilexetil, thus being more suitable for industrial production.
Description
Technical field:
The present invention relates to a kind of preparation method of candesartan Cilexetil, belong to medical technical field.
Background technology:
Candesartan Cilexetil is the prodrug of Candesartan, can be in gi tract complete hydrolysis and change into the Candesartan with antihypertensive active.Candesartan Cilexetil is used for the treatment of all kinds of light moderate hypertensions clinically, this medicine usually can't be with untoward reactions such as tachycardias when reducing arteriotony, and after drug withdrawal, without the hypertension rebound phenomenon, easier in the hyperpietic, particularly the gerontal patient accepts.
Industrialized production generally prepares candesartan Cilexetil take Candesartan acid as raw material, bibliographical information with the method for synthetic candesartan Cilexetil have following several:
The Chinese patent CN1666989A the first step is reacted take methylene dichloride as solvent, through the crude product of washing, concentrated aftertreatment, need to use recrystallization from ethyl acetate/petroleum ether, yield 84.5% through the silicagel column separation and purification again.Second step, take DMF as reaction solvent, has reacted rear and has extracted with ethyl acetate, and concentrated, crude product directly drops into three-step reaction, with aqueous hydrochloric acid, reacts, and extraction finally needs silicagel column separation and purification, yield 89%.Do not report the finished product quality.Due to the needs silica gel column chromatography, therefore this technique is not suitable for industrialized production.
The W020070940152 report the first step is reacted take methylene dichloride as solvent, has reacted by twice washing, and 1 time salt is washed, and is concentrated, carries out crystallization with ethyl acetate finally, and this step yield is 83.8%.Second step reacts take DMSO as solvent, through aftertreatment, has to directly carry out three-step reaction to the wet product crude product, and take ethanol as solvent, second step is 72.5% to the finished product total recovery.Do not report the finished product quality.The method that this method adopts the reaction of 2,3 steps to merge, the impurity that produces in reaction is all brought in whole product, is unfavorable for the purifying of finished product and the lifting of quality.
The W02008012372 report the first step is reacted take methylene dichloride as solvent, through washing, concentrated, carry out crystallization with methyl tertiary butyl ether, yield 87.9%.Second step is take N,N-dimethylacetamide as solvent, and yield reaches 98%, purity 98.0%.The 3rd step react and obtains finished product with the mixed solvent of methyl alcohol and methylene dichloride, and reaction, due to the quality of not reporting dry product, can't be calculated this and go on foot yield.Finished product HPLC purity reaches 99.73%.
WO2009157001, WO2011145100 report the first step methylene dichloride is solvent, needs after reaction through washing, and pickling, salt is washed, and obtains trityl group candesartan cilexetil after dry concentrating and obtains elaboration through recrystallization again.This step yield is 70.9%.The second step solvent for use is DMF, is added to the water after having reacted, and uses ethyl acetate extraction, and concentrated product carries out recrystallization with ethyl acetate/normal hexane, and this step yield is 88.04%.The 3rd step reacted and obtains finished product with the mixed solvent of toluene and methyl alcohol, yield 78.22%, but purity only has 99.0%.
The WO2011092666 report report the first step is reacted take methylene dichloride as solvent, and through washing, concentrated, reaction yield and quality differ larger because of the different result of processing mode.Second step is take DMF as solvent, and is concentrated with dichloromethane extraction, then uses the hexanaphthene recrystallization, do not report yield.The 3rd step reacted take methylene dichloride and methyl alcohol as solvent, and yield is 84%, and purity is 99.24%.
Above method is all to adopt the reaction solution of the first step through washing, extraction, carry out again after concentrated obtaining the acid of the first step product trityl candesartan after separation and purification, drop into again second step, increased like this production process, reduce production efficiency, also increased the consumption of the first step reaction solvent simultaneously., because the first step is carried out aftertreatment and product purification purge process, to total yield, also can decrease.
Summary of the invention:
The problem to be solved in the present invention is to expect that for former the candesartan Cilexetil synthesis technique is loaded down with trivial details by Candesartan acid, and yield is not high, the problem of poor product quality.
Technical scheme of the present invention is:
A kind of preparation method of candesartan Cilexetil is characterized in that comprising following preparation process:
A kind of preparation method of candesartan Cilexetil is characterized in that comprising following preparation process:
The first step is reacted to obtain trityl candesartan acid by Candesartan acid and trityl chloride under the alkaline condition of Ph value 7 to 11, this step solvent for use is selected from methane amide, N, a kind of in dinethylformamide, N,N-dimethylacetamide, methyl-sulphoxide, N-Methyl pyrrolidone, non-protonization of HMPA polar solvent; Alkaline environment selects free triethylamine, diisopropylethylamine, saleratus, sodium bicarbonate, salt of wormwood, one or more in sodium carbonate
HPLC method monitoring reaction situation, when reaction raw materials Candesartan acid＜2%, can carry out next step reaction.Optional one of halogen catalyzer that adds: potassiumiodide, Tetrabutyl amonium bromide, chlorination triethyl benzyl ammonium.
The acid of trityl chloride Candesartan triphenyl phosphate methyl Candesartan
The trityl candesartan acid-respons liquid of second step the first step reaction gained is not treated, directly adds side chain 1-chloroethyl cyclohexyl carbonic ether, keeps alkaline environment, reacts to obtain trityl group candesartan cilexetil;
Trityl candesartan acid 1-chloroethyl cyclohexyl carbonic ether trityl group candesartan cilexetil
The 3rd step trityl group candesartan cilexetil obtains elaboration after refining, its elaboration is sloughed triphenyl in the mixed solvent of lower alcohol and toluene, obtain candesartan Cilexetil; Described lower alcohol is selected from methyl alcohol or ethanol.
The trityl group candesartan cilexetil candesartan Cilexetil
The preferred technical scheme of the present invention is that the first step temperature of reaction is controlled at 60-90 ℃.
The preferred technical scheme of the present invention is that the second step temperature of reaction is controlled at 50-60 ℃.
The preferred technical scheme of the present invention is that three-step reaction is in the mixed solvent of dehydrated alcohol and toluene, and back flow reaction is sloughed trityl, obtains candesartan Cilexetil.
The preferred technical scheme of the present invention is that three-step reaction is in the mixing solutions of anhydrous methanol and toluene, and back flow reaction, slough trityl, obtains candesartan Cilexetil.
When synthesizing trityl group candesartan cilexetil, adopt the method for two-step reaction one kettle way preparation due to present method, reduced the operation steps of reaction, shortened reaction time, and increase substantially the yield of trityl group candesartan cilexetil, be more suitable for having reduced the consumption of solvent in large production.
Example 1
The first step, add 130 kilograms of N in the 500L reactor, the N N,N-DIMETHYLACETAMIDE, stir lower 22 kilograms of Candesartan acid and 17.3 kilograms of Anhydrous potassium carbonates, 16.7 kilograms of trityl chlorides, 0.2 kilogram of the Tetrabutyl amonium bromide of dropping into, stir 10 minutes kinds, begin to warm to 63 ± 3 ℃, stirring reaction, HPLC detection reaction liquid Candesartan acid residual content＜2.0%.Reaction solution directly gives over to next step use that feeds intake.
second step, the first step reaction solution cools to 55 ℃, add 12.4 kilograms of 1-chloroethyl cyclohexyl carbonic ethers, temperature control 55-60 ℃ reaction, HPLC measured reaction liquid raw material complete reaction, reaction solution cools to 20 ℃, under stirring, reaction solution is injected at a slow speed in 400 kilograms of frozen water, separate out solid, filter, the filter cake washing, filter cake is dropped in the 500L reactor again, add 270 kilograms of methylene dichloride, stirring is molten clear with filter cake, add 150 kilograms of clear water, agitator treating 2 times, organic layer is steamed to without cut, going out 50 ℃ of decompressions, add while hot 290 kilograms of acetonitriles, under normal temperature, stirring and crystallizing is 8 hours, filter, drip washing, drain, 45-50 ℃ of oven dry obtained 37.7 kilograms of trityl group candesartan cilexetils in 12 hours, molar yield 88.4%, HPLC purity 99.5%.
The 3rd step, in the 500L reactor, add the 120 kg dehydrated alcohol, toluene 360kg, drop into 30 kilograms of trityl group candesartan cilexetils, stir and heat up, back flow reaction 5 hours, cool to 0 ℃, stirring and crystallizing 16 hours, filter to obtain 20.9 kilograms of candesartan Cilexetil crude products, molar yield 97.3%, purity 99.6%.
Refining: in the 500L reactor, add 126 kilograms of dehydrated alcohols, drop into the candesartan Cilexetil crude product, stir be warmed up to 45 ℃ complete molten clear, filter, mother liquor changes in the crystallization still, cool to 25 ℃, 25 ℃ of crystallizatioies of temperature control 24 hours, filter to obtain 17.0 kilograms of candesartan Cilexetil elaboration, refining yield 81.3%, product purity 99.9%.
Example 2
The first step, add 260 kilograms of N in the 500L reactor, dinethylformamide, stir lower 44 kilograms of Candesartan acid and 25.3 kilograms of triethylamines of dropping into, 33.5 the kilogram trityl chloride, 0.5 kilogram of chlorination triethyl benzyl ammonium, begin to warm to 80 ℃ after stirring, stirring reaction, HPLC detection reaction liquid Candesartan acid residual content＜2.0%.Reaction solution directly gives over to next step use that feeds intake.
second step, the first step reaction solution cools to 55 ℃, add 24.8 kilograms of 1-chloroethyl cyclohexyl carbonic ethers, temperature control 50-55 ℃ reaction, HPLC measured reaction liquid raw material complete reaction, reaction solution cools to 20 ℃, under stirring, reaction solution is injected at a slow speed in 800 kilograms of frozen water, separate out solid, filter, the filter cake washing, filter cake is dropped in the 1000L reactor again, add 540 kilograms of methylene dichloride, stirring is molten clear with filter cake, add 300 kilograms of clear water, agitator treating 2 times, organic layer is steamed to without cut, going out 50 ℃ of decompressions, add while hot 580 kilograms of methyl tertiary butyl ethers, 20 ℃ of stirring and crystallizing 10 hours, filter, drip washing, drain, 45-50 ℃ of decompression drying obtains 71.3 kilograms of trityl group candesartan cilexetils, molar yield 83.6%, it is 98.9% that the HPLC method detects purity.
In the 3rd step, in the 500L reactor, add 200 kilograms of dehydrated alcohols, toluene 600kg, drop into 50 kilograms of trityl group candesartan cilexetils, stir and heat up, back flow reaction, cool to 0 ℃, stirring and crystallizing 16 hours, filter to obtain 34.0 kilograms of candesartan Cilexetil crude products, molar yield 95.1%, purity 99.3%.
Refining: in the 500L reactor, add 204 kilograms of dehydrated alcohols, drop into the candesartan Cilexetil crude product, stir be warmed up to 45 ℃ complete molten clear, filter, mother liquor changes in the crystallization still, cool to 25 ℃, 25 ℃ of crystallizatioies of temperature control 24 hours, filter to obtain 27.7 kilograms of candesartan Cilexetil elaboration, refining yield 81.4%, product purity 99.9%.
Example 3
The first step, add 232 kilograms of dimethyl sulfoxide (DMSO) in the 500L reactor, stir lower 33 kilograms of Candesartan acid and 30.0 kilograms of saleratus of dropping into, 25.1 kilogram trityl chloride, 0.3 kilogram of potassiumiodide, begin to warm to 88 ± 2 ℃ after stirring, stirring reaction, HPLC detection reaction liquid Candesartan acid residual content＜2.0%.Directly next step feeds intake reaction solution.
second step, the first step reaction solution cools to 55 ℃, add 18.6 kilograms of 1-chloroethyl cyclohexyl carbonic ethers, temperature control 55-60 ℃ was reacted 6 hours, HPLC measured reaction liquid raw material complete reaction, reaction solution cools to 20 ℃, under stirring, reaction solution is injected at a slow speed in 600 kilograms of frozen water, separate out solid, filter, the filter cake washing, filter cake is dropped in the 1000L reactor again, add 405 kilograms of methylene dichloride, stirring is molten clear with filter cake, add 225 kilograms of clear water, agitator treating 2 times, organic layer is steamed to without cut, going out 50 ℃ of decompressions, add while hot 405 kilograms of ethyl acetate, 10 ℃ of stirring and crystallizing 16 hours, filter, drip washing, drain, 45-50 ℃ of decompression drying obtains 55.5 kilograms of trityl group candesartan cilexetils, molar yield 86.7%, HPLC purity 99.1%.
The 3rd step, in the 500L reactor, add 160 kilograms of dehydrated alcohols, toluene 480kg, drop into 40 kilograms of trityl group candesartan cilexetils, stir and heat up, back flow reaction 5 hours, cool to 0 ℃, stirring and crystallizing 16 hours, filter to obtain 27.7 kilograms of candesartan Cilexetil crude products, molar yield 96.7%, purity 99.3%.
Refining: in the 500L reactor, add 166 kilograms of dehydrated alcohols, drop into the candesartan Cilexetil crude product, stir be warmed up to 45 ℃ complete molten clear, filter, mother liquor changes in the crystallization still, cool to 25 ℃, 25 ℃ of crystallizatioies of temperature control 24 hours, filter to obtain 22.4 kilograms of candesartan Cilexetil elaboration, refining yield 80.9%, product purity 99.8%.
Claims (4)
1. the preparation method of a candesartan Cilexetil is characterized in that comprising following preparation process:
The first step is reacted to obtain trityl candesartan acid by Candesartan acid and trityl chloride under the alkaline condition of pH7 to 11, this step solvent for use is selected from methane amide, N, a kind of in the non-protonization polar solvents such as dinethylformamide, N,N-dimethylacetamide, methyl-sulphoxide, N-Methyl pyrrolidone, HMPA; Alkaline environment selects free triethylamine, diisopropylethylamine, saleratus, sodium bicarbonate, salt of wormwood, one or more in sodium carbonate;
The trityl candesartan acid-respons liquid of second step the first step reaction gained is not treated, directly adds side chain 1-chloroethyl cyclohexyl carbonic ether, keeps alkaline environment, reacts to obtain trityl group candesartan cilexetil;
The 3rd step trityl group candesartan cilexetil obtains elaboration after refining, its elaboration is sloughed triphenyl in the mixed solvent of ethanol and toluene, obtain candesartan Cilexetil.
2. preparation method according to claim 1, is characterized in that, the first step temperature of reaction is controlled at 60-90 ℃.
3. preparation method according to claim 1, is characterized in that, the second step temperature of reaction is controlled at 50-60 ℃.
4. preparation method according to claim 1, is characterized in that, three-step reaction is in the mixed solvent of dehydrated alcohol and toluene, and back flow reaction is sloughed trityl, obtains candesartan Cilexetil.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201310340670.3A CN103396406B (en) | 2013-08-07 | 2013-08-07 | Preparation method of candesartan cilexetil |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310340670.3A CN103396406B (en) | 2013-08-07 | 2013-08-07 | Preparation method of candesartan cilexetil |
Publications (2)
| Publication Number | Publication Date |
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| CN103396406A true CN103396406A (en) | 2013-11-20 |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104098550A (en) * | 2014-07-17 | 2014-10-15 | 浙江华海药业股份有限公司 | Method for refining trityl-candesartan |
| WO2016192099A1 (en) * | 2015-06-05 | 2016-12-08 | 浙江华海药业股份有限公司 | Method for preparing trityl candesartan |
| CN110501449A (en) * | 2019-07-26 | 2019-11-26 | 威海迪素制药有限公司 | A kind of detection method of candesartan Cilexetil genotoxicity impurity |
| CN113372338A (en) * | 2021-07-03 | 2021-09-10 | 润都制药(荆门)有限公司 | Preparation method of losartan impurity |
| CN115403567A (en) * | 2022-08-15 | 2022-11-29 | 珠海润都制药股份有限公司 | Recovery method of candesartan cilexetil mother liquor |
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| WO2009007986A1 (en) * | 2007-07-11 | 2009-01-15 | Alembic Limited | An improved process for the preparation of candesartan cilexetil |
| WO2009157001A2 (en) * | 2008-06-24 | 2009-12-30 | Hetero Research Foundation | Process for preparation of candesartan cilexetil |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2009007986A1 (en) * | 2007-07-11 | 2009-01-15 | Alembic Limited | An improved process for the preparation of candesartan cilexetil |
| WO2009157001A2 (en) * | 2008-06-24 | 2009-12-30 | Hetero Research Foundation | Process for preparation of candesartan cilexetil |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104098550A (en) * | 2014-07-17 | 2014-10-15 | 浙江华海药业股份有限公司 | Method for refining trityl-candesartan |
| WO2016192099A1 (en) * | 2015-06-05 | 2016-12-08 | 浙江华海药业股份有限公司 | Method for preparing trityl candesartan |
| CN107709313A (en) * | 2015-06-05 | 2018-02-16 | 浙江华海药业股份有限公司 | A kind of method for preparing trityl candesartan |
| EP3312174A4 (en) * | 2015-06-05 | 2019-02-13 | Zhejiang Huahai Pharmaceutical Co., Ltd | Method for preparing trityl candesartan |
| CN110501449A (en) * | 2019-07-26 | 2019-11-26 | 威海迪素制药有限公司 | A kind of detection method of candesartan Cilexetil genotoxicity impurity |
| CN113372338A (en) * | 2021-07-03 | 2021-09-10 | 润都制药(荆门)有限公司 | Preparation method of losartan impurity |
| CN115403567A (en) * | 2022-08-15 | 2022-11-29 | 珠海润都制药股份有限公司 | Recovery method of candesartan cilexetil mother liquor |
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