CN102070617B - Candesartan cilexetil compound and novel preparation method thereof - Google Patents
Candesartan cilexetil compound and novel preparation method thereof Download PDFInfo
- Publication number
- CN102070617B CN102070617B CN2011100322745A CN201110032274A CN102070617B CN 102070617 B CN102070617 B CN 102070617B CN 2011100322745 A CN2011100322745 A CN 2011100322745A CN 201110032274 A CN201110032274 A CN 201110032274A CN 102070617 B CN102070617 B CN 102070617B
- Authority
- CN
- China
- Prior art keywords
- tcv
- resin
- ethanol
- sepabeads
- purity
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Abstract
The invention provides a candesartan cilexetil compound and a novel preparation method thereof. Through absorption of active carbon, crystallization and adsorptive separation of macroporous absorption resin, the purpose of refined purification is achieved, and finally, the high-purity candesartan cilexeti is obtained, thereby greatly improving the purity and content of the candesartan cilexeti, improving the product quality of the preparation, reducing toxic and side effects and guaranteeing the clinical pharmacy safety of the candesartan cilexeti in preparing anti-hypertension medicaments. The novel preparation method has the advantages of simple process, low cost and high yield, and is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of process for purification of TCV 116, can obtain highly purified TCV 116 product, belong to medical technical field through method of the present invention.
Background technology
TCV 116 (Candesartan cilexetil); Another name: candesartan cilexetil is come for the former times ester, and candesartan cilexetil is applicable to hypertensive treatment; Develop jointly by Japanese Wu Tian company and Sweden Aktiebolaget Astra, go on the market in Sweden first in November, 1997.TCV 116 is white or off-white color crystalline powder, and its chemical name is: (±)-1-(hexamethylene oxo ketonic oxygen generation) ethyl-[2-oxyethyl group-1-[[2 '-(1H-tetrazole base-5) xenyl-4] methyl]-1H-benzoglyoxaline-7] carboxylicesters, molecular formula: C
33H
34N
6O
6, molecular weight: 610.67, structural formula is:
TCV 116 is hydrolyzed into the active metabolite TCV-116 in vivo rapidly.TCV-116 is an Angiotensin II AT1 receptor antagonist, through the vasoconstriction effect of the nervous plain II of antagonizing vessel with vascular smooth muscle AT1 receptors bind, thereby reduces peripheral vascular resistance.Other has and thinks: TCV-116 can be brought into play certain hypotensive effect through suppressing the acth secretion aldosterone.
Some reference disclose the technology of preparing of TCV 116; For example U.S. Pat 2010210852, US2010197933, US5196444A, WO2008012371A; Japanese Patent JP2010116409; Chinese patent CN 200510000109.6, CN200510022136.3, CN101781286A etc. have all reported the method for preparing TCV 116; But there is a common problem in the TCV 116 of these method preparations, owing to still have impurity, it is not high to obtain TCV 116 purity exactly.This is ((2 '-cyanobiphenyl base-4-yl) methyl because 1-)-2-oxyethyl group-1H-benzo [d] imidazoles-7-carboxylic acid 1-(cyclohexyl oxygen base ketonic oxygen base) ethyl ester is the arborescens form of viscosity; Come to be difficult to purifying and processing for former times during ester when it is used in the preparation candesartan cilexetil, the buttery candesartan cilexetil that is still of gained is come for the former times ester.
CN101781286A uses recrystallizing methanol to crude product, and purity is 90～91%.CN200510022136.3 relates to a kind of novel preparation process of TCV 116, and its synthesis step comprises: 1. triphenylmethyl tetrazole intermediates preparation; 2. cyclohexyl chloroethane carbonate preparation method; 3. synthesize TCV 116 with cyclohexyl chloroethane carbonate as esterifying reagent, crude product is through silica gel column chromatography separating purification, and a yield 89% gets product, then product is used the aqueous ethanolic solution crystallization, yield 92%.This method total recovery is low, and is not suitable for industrial needs.
In addition, deposit improper or shelf-time when long at TCV 116, can cause active constituents of medicine content to reduce, color and luster is strengthened, and its related substances raises.In some cases, because controlling of production process is improper, cause pharmaceutical purity also undesirable.Therefore be necessary underproof product is further carried out purifying, highly purified TCV 116 be provided with high yield.
In fact, the technician that this area has a universal experience knows clearly all difficulties that face aspect the high-purity compound obtaining, and all these just can be expected according to the theory of general separation and purification absolutely not solution need overcome many difficult problems.
Summary of the invention
The applicant is on the basis of a large amount of existing documents; Experiment through a large amount of screenings; Find above-mentioned document and general method for purifying and separating for example method such as crystallization be difficult to obtain the compound of high purity high yield, and various separation purification method and multiple conditional parameter exist the possibility and the unpredictability of varied combination.The inventor, has been surprisingly found out that a kind of process for purification of TCV-116 ester cpds, thereby has accomplished the present invention after Combination application specific method and parameters optimization through long-term conscientious research.
Macroporous adsorbent resin is one type of cross-linked polymer that better absorption property is arranged that year grows up surplus in the of nearly ten; It has plurality of advantages such as good macroporous netlike structure, specific surface area are big, physical and chemical stability is high, regeneration is easy, energy-efficient; Can be widely used in the separation and purification of effective constituent, have a great using value in that environmental protection, food and medicine etc. are multi-field.Polymeric adsorbent mainly is divided into nonpolar, low-pole and polar resin according to the polarity difference, and commonly used is styrene type and vinyl cyanide type at present.The adsorptivity of polymeric adsorbent is that its reticulated structure and bigger specific surface area make it have screenability again simultaneously owing to the result of Van der Waals force or generation hydrogen bond, is the parting material that absorption and screening principle combine.
In order to overcome the low defective of TCV 116 purity of prior art for preparing; The present invention provides a kind of process for purification of TCV 116; Carry out the purpose that separation and purification reaches refining purifying through charcoal absorption, crystallization and macroporous resin adsorption, finally obtain highly purified TCV 116.
The applicant has screened each items such as concentration, eluting solvent, polymeric adsorbent, temperature of reaction and time of gac and has investigated point through long-term conscientious big quantity research, finally obtains optimized technology.
In one aspect of the invention, the separation and the purification process of medicine comprise adsorption method, as using gac.Unfortunately, except removing color and other unwanted material, gac also irreversibly adsorbs interested medicine, and this causes productive rate obviously to reduce.In one aspect of the invention, the present invention confirms that gac can help purifying and the adsorption activity composition not basically of TCV 116, and wherein the usage quantity of gac is the 0.1%-0.5% (g/ml) of overall solution volume, is preferably 0.2-0.3% (g/ml).
Usually; In the separation and purification process; Chromatographic column filler can be silica gel, aluminum oxide or macroporous resin, and the particle diameter of used silica gel is that 45-250 μ m, aperture are the Kiselgel A of 80-100
; Be preferably particle diameter 75-150 μ m, the aperture is the Kiselgel A of 20-30
; Used aluminum oxide most preferably is neutral alumina, and used neutral alumina can be 100～200 orders or 200～300 orders; Used macroporous resin model can be Amberlite XAD-1; AmberliteXAD-2; Amberlite XAD-3; Amberlite XAD-4; Amberlite XAD-5; Amberlite XAD1-6; Amberlite XAD-7; Amberlite XAD-8; AmberliteXAD-9; Amberlite XAD-10; Amberlite XAD-11; Amberlite XAD-12; Diaion HP-10; Diaion HP-20; Diaion HP-21; Diaion HP-30; DiaionHP-40; Diaion HP-50; Diaion HP2MG; Sepabeads SP850; SepabeadsSP825; Sepabeads SP70; Sepabeads SP700; Sepabeads SP207; D-101; D-101-I; DA-201; AB-8; GDX-501; GDX-104; HPD100; HPD300; HPD700; HPD400; HPD450; HPD750; H103; H107; X-5; SIP-1100; SIP-1200; SIP-1300; SIP-1400; Hz802; Hz803; Hz816; Hz1300; Hz1400; GDX-401; GDX-601; NKA-II; NKA-9; HPD500/600.
In research process, the inventor is unexpected to find styrene tyle macroporous adsorption resin ratio aluminum oxide or silica gel column chromatography good separating effect, and has original purification effect, especially is fit to industrial production.Used macroporous resin model can be Amberlite XAD-1; AmberliteXAD-2; Amberlite XAD-3; Amberlite XAD-4; Amberlite XAD-5; Diaion HP-10; Diaion HP-20; Diaion HP-21; Diaion HP-30; DiaionHP-40; Diaion HP-50; Sepabeads SP850; Sepabeads SP825; SepabeadsSP70; Sepabeads SP700; Sepabeads SP207; GDX-104; HPD100; HPD300; HPD700; D-101; D-101-I; H103; H107; X-5; SIP-1100; SIP-1200; SIP-1300; SIP-1400; Hz802; Hz803; Hz816; Hz1300; Hz1400; Used macroporous resin model is preferably Sepabeads SP850, Sepabeads SP825, Sepabeads SP700, HPD300, H103 or H107 type macroporous adsorbent resin.
In one aspect of the invention, the required purity that obtains in the method for the invention depends on the amount of impurity and the operating environment of macroporous adsorptive resins to a certain extent.Choice of Solvent and consumption must be controlled.In one aspect of the invention, big pore adsorption resin post of the present invention comprises that diameter is about 1 to about 200cm, is preferably 5cm at least.The macroporous adsorptive resins length range is preferably about 10 centimetres to about 100 centimetres.
In one aspect of the invention, as preferably, the quality of each purifying medicine is 1 with the ratio of the quality of macroporous adsorbent resin: 10-200, the preferred mass ratio is 1: 15-100.The consumption of eluent is as long as satisfy the complete basically wash-out of medicine; Flow point Fractional Collections behind the wash-out; The content of the flow point Chinese traditional medicine of different sections is different; In order to obtain highly purified medicine (purity is greater than 99.5%), need medicament contg is merged greater than 85% flow point, preferably medicament contg is merged greater than 90% flow point.Elution speed is generally 0.1～3BV/h, is preferably 0.5～1BV/h.
In embodiments of the invention, the process for purification of TCV 116 provided by the invention comprises the steps:
(1) the TCV 116 bullion is dissolved in the organic solvent that can dissolve each other with water of 5-20 times of weight; The gac that adds overall solution volume 0.1-0.5% (g/ml); Be incubated 40～60 ℃ and stir 10-30min; Filter decarburization, collect filtrating, wherein said organic solvent is selected from one or more in acetonitrile, methyl alcohol, ethanol, Virahol, acetone, THF 、 diox, N, N,N-DIMETHYLACETAMIDE, the DMSO 99.8MIN.;
(2) above-mentioned filtrating is cooled to room temperature, adds purified water lentamente, stir and produce deposition, filter collecting precipitation;
(3) with above-mentioned deposition with 1: 1 sherwood oil (30～60 ℃)/acetic acid ethyl dissolution, add through pretreated macroporous adsorbent resin, obtain adsorbing the resin of TCV 116 after mixing thoroughly; Be added to the top of macroporous adsorptive resins then; Water, 30% ethanol elution agent wash-out successively, the ethanol position of collecting the TCV 116 wash-out, concentrating under reduced pressure; Drying obtains the purified TCV 116.
As the present invention's one preferred embodiment, wherein add the gac of overall solution volume 0.2-0.3% (g/ml) in the step (1), be incubated 50 ℃, whip attachment 10-30min.
As the present invention's one preferred embodiment; Wherein the organic solvent in the step (1) is selected from one or more in acetonitrile, methyl alcohol, ethanol, Virahol, acetone, THF 、 diox, N, N,N-DIMETHYLACETAMIDE, the DMSO 99.8MIN., is preferably selected from acetonitrile, methyl alcohol, ethanol, Virahol, the acetone one or more; Acetonitrile most preferably.
The screening method of macroporous adsorbent resin can be used known in the art than adsorptiometry, such as but not limited to reported method among " CHINA JOURNAL OF CHINESE MATERIA MEDICA " 2003,28 (3), 217 and the CN1978452A etc.
In one aspect of the invention, above-mentioned process for purification, wherein said macroporous adsorbent resin are styrene tyle macroporous adsorption resin.
In one aspect of the invention, the inventor finds styrene tyle macroporous adsorption resin ratio aluminum oxide or silica gel column chromatography good separating effect, and has original purification effect, especially is fit to industrial production.
In one aspect of the invention; Above-mentioned process for purification, wherein said styrene tyle macroporous adsorption resin are Amberlite XAD-1, Amberlite XAD-2, Amberlite XAD-3, Amberlite XAD-4, Amberlite XAD-5, Diaion HP-10, Diaion HP-20, Diaion HP-21, Diaion HP-30, Diaion HP-40, Diaion HP-50, Sepabeads SP850, Sepabeads SP825, Sepabeads SP70, SepabeadsSP700, Sepabeads SP207, GDX-104, HPD100, HPD300, HPD700, D-101, D-101-I, H103, H107, X-5, SIP-1100, SIP-1200, SIP-1300, SIP-1400, Hz802, Hz803, Hz816, Hz1300, Hz1400.
In one aspect of the invention, as preferably, described styrene tyle macroporous adsorption resin is Sepabeads SP850, Sepabeads SP825, Sepabeads SP700, HPD300, H103, H107.
In one aspect of the invention, the present invention provides the application of TCV-116 ester cpds in the preparation antihypertensive drug of the inventive method preparation, has the effect that reduces toxic side effect.
The object of the present invention is to provide a kind of process for purification of TCV 116, reach the purpose made from extra care purifying, finally obtain highly purified TCV 116 through charcoal absorption, crystallization and preparative hplc separation and purification; Improve the quality product of preparation, reduced toxic side effect, ensured safety of clinical administration; And compared with prior art, present method technology is simple, and cost is low; Yield is high, and purity is high, is suitable for suitability for industrialized production.
Embodiment
Below further explain or explanation content of the present invention, but embodiment should not be understood that the restriction to protection domain of the present invention through embodiment.
Embodiment 1
(1) is that 97.3% TCV 116 bullion is dissolved in the 1000ml acetonitrile with 100g purity, adds the 2g gac, be incubated 50 ℃ and stir 20min, filter decarburization, collect and filtrate;
(2) above-mentioned filtrating is cooled to room temperature, slowly adds purified water, stir and produce deposition, filter collecting precipitation 95.1g;
(3) with 1: 1 sherwood oil (30～60 ℃)/acetic acid ethyl dissolution of above-mentioned deposition with 200ml, add through pretreated Sepabeads SP850 type macroporous adsorbent resin 200g, obtain adsorbing the resin of TCV 116 after mixing thoroughly; Be added to the top of Sepabeads SP850 type macroporous adsorptive resins then, be washed till clarification, use 30% ethanol elution agent wash-out then with the purified water of 1～2 column volume; Collect the ethanol position of TCV 116 wash-out; Concentrating under reduced pressure, drying obtains purified TCV 116 92.5g; Yield 95.1%, purity 99.9%.
Embodiment 2
(1) is that 97.3% TCV 116 bullion is dissolved in the 500ml acetone with 100g purity, adds the 1g gac, be incubated 50 ℃ and stir 10min, filter decarburization, collect and filtrate;
(2) above-mentioned filtrating is cooled to room temperature, slowly adds purified water, stir and produce deposition, filter collecting precipitation 94.8g;
(3) with 1: 1 sherwood oil (30～60 ℃)/acetic acid ethyl dissolution of above-mentioned deposition with 200ml, add through pretreated Sepabeads SP825901 type macroporous adsorbent resin 200g, obtain adsorbing the resin of TCV 116 after mixing thoroughly; Be added to the top of Sepabeads SP825 type macroporous adsorptive resins then, be washed till clarification, use 30% ethanol elution agent wash-out then with the purified water of 1～2 column volume; Collect the ethanol position of TCV 116 wash-out; Concentrating under reduced pressure, drying obtains purified TCV 116 90.1g; Yield 92.6%, purity 99.5%.
Embodiment 3
(1) is that 97.3% TCV 116 bullion is dissolved in the 2000ml methyl alcohol with 100g purity, adds the 6g gac, be incubated 50 ℃ and stir 30min, filter decarburization, collect and filtrate;
(2) above-mentioned filtrating is cooled to room temperature, slowly adds purified water, stir and produce deposition, filter collecting precipitation 94.4g;
(3) with 1: 1 sherwood oil (30～60 ℃)/acetic acid ethyl dissolution of above-mentioned deposition with 200ml, add through pretreated HPD300 type macroporous adsorbent resin 200g, obtain adsorbing the resin of TCV 116 after mixing thoroughly; Be added to the top of HPD300 type macroporous adsorptive resins then, be washed till clarification, use 30% ethanol elution agent wash-out then with the purified water of 1～2 column volume; Collect the ethanol position of TCV 116 wash-out; Concentrating under reduced pressure, drying obtains purified TCV 116 88.4g; Yield 90.9%, purity 99.5%.
Embodiment 4
(1) is that 97.3% TCV 116 bullion is dissolved in the 1500ml ethanol with 100g purity, adds the 3g gac, be incubated 50 ℃ and stir 30min, filter decarburization, collect and filtrate;
(2) above-mentioned filtrating is cooled to room temperature, slowly adds purified water then, stir and produce deposition, filter collecting precipitation 96.3g;
(3) with 1: 1 sherwood oil (30～60 ℃)/acetic acid ethyl dissolution of above-mentioned deposition with 200ml, add through pretreated HPD300 type macroporous adsorbent resin 200g, obtain adsorbing the resin of TCV 116 after mixing thoroughly; Be added to the top of HPD300 type macroporous adsorptive resins then, be washed till clarification, use 30% ethanol elution agent wash-out then with the purified water of 1～2 column volume; Collect the ethanol position of TCV 116 wash-out; Concentrating under reduced pressure, drying obtains purified TCV 116 93.0g; Yield 95.6%, purity 99.5%.
Embodiment 5
(1) is that 97.3% TCV 116 bullion is dissolved in the 1000ml Virahol with 100g purity, adds the 2.5g gac, be incubated 50 ℃ and stir 30min, filter decarburization, collect and filtrate;
(2) above-mentioned filtrating is cooled to room temperature, slowly adds purified water then, stir and produce deposition, filter collecting precipitation 95.9g;
(3) with 1: 1 sherwood oil (30～60 ℃)/acetic acid ethyl dissolution of above-mentioned deposition with 200ml, add through pretreated HPD300 type macroporous adsorbent resin 200g, obtain adsorbing the resin of TCV 116 after mixing thoroughly; Be added to the top of HPD300 type macroporous adsorptive resins then, be washed till clarification, use 30% ethanol elution agent wash-out then with the purified water of 1～2 column volume; Collect the ethanol position of TCV 116 wash-out; Concentrating under reduced pressure, drying obtains purified TCV 116 92.7g; Yield 95.3%, purity 99.6%.
Enumerate the part comparative example of prior art similar approach or screening process of the present invention below, so that technique effect of the present invention to be described.
The comparative example 1
(1) is that 97.3% TCV 116 bullion is dissolved in the 1000ml acetonitrile with 100g purity, adds the 2g gac, be incubated 50 ℃ and stir 20min, filter decarburization, collect and filtrate;
(2) above-mentioned filtrating is cooled to room temperature, slowly adds purified water, stir and produce deposition, filter collecting precipitation 95.1g;
(3) above-mentioned deposition is dissolved with following moving phase, utilize the preparative hplc post to carry out separation and purification and obtain the TCV 116 highly finished product, wherein the moving phase used of chromatographic column is 6: 4 acetonitrile and phosphate buffered saline buffer (PH2.5) as volume ratio; Fixed phase stuffing is selected from silica gel, and flow velocity is 3.7ml/min, and the detection wavelength is 260nm; 25 ℃ of column temperatures are collected filtrating, drying under reduced pressure; Obtain purified TCV 116 85.4g, yield 87.8%, purity 98.8%.
The comparative example 2
(1) is that 97.3% TCV 116 bullion is dissolved in the 500ml acetone with 100g purity, adds the 1g gac, be incubated 50 ℃ and stir 10min, filter decarburization, collect and filtrate;
(2) above-mentioned filtrating is cooled to room temperature, slowly adds purified water, stir and produce deposition, filter collecting precipitation 94.8g;
(3) above-mentioned deposition is dissolved with moving phase, utilize the preparative hplc post to carry out separation and purification and obtain the TCV 116 highly finished product, wherein the moving phase used of chromatographic column is 7: 3 acetonitrile and phosphate buffered saline buffer (PH2.5) as volume ratio; Fixed phase stuffing is selected from aluminum oxide, and flow velocity is 3.0ml/min, and the detection wavelength is 260nm; 30 ℃ of column temperatures are collected filtrating, drying under reduced pressure; Obtain purified TCV 116 86.7g, yield 89.1%, purity 98.4%
The comparative example 3
Be 97.3% TCV 116 bullion 1: 1 sherwood oil (30～60 ℃)/acetic acid ethyl dissolution with 100g purity, add, obtain adsorbing the resin of TCV 116 after mixing thoroughly through pretreated Sepabeads SP850 type macroporous adsorbent resin 200g with 200ml; Be added to the top of Sepabeads SP850 type macroporous adsorptive resins then, be washed till clarification, use 30% ethanol elution agent wash-out then with the purified water of 1～2 column volume; Collect the ethanol position of TCV 116 wash-out; Concentrating under reduced pressure, drying obtains purified TCV 116 85.5g; Yield 87.9%, purity 98.1%.
The comparative example 4: use Amberlite XAD-4 macroporous resin column and silica gel chromatographic column according to the method described above and replace Sepabeads SP850 post that the bullion telmisartan is carried out directly making with extra care respectively; Purity after it separates and productive rate are explained and are directly used the refining effect that can not obtain satisfaction of chromatographic column all not as comparative example 3.
The comparative example 5
(1) is that 97.3% TCV 116 bullion is dissolved in the 1000ml Virahol with 100g purity, adds the 2.5g gac, be incubated 50 ℃ and stir 30min, filter decarburization, collect and filtrate;
(2) above-mentioned filtrating is cooled to room temperature, slowly adds purified water then, stir and produce deposition, filter collecting precipitation 95.9g;
(3) with 1: 1 sherwood oil (30～60 ℃)/acetic acid ethyl dissolution of above-mentioned deposition with 200ml, add through pretreated HPD300 type macroporous adsorbent resin 200g, obtain adsorbing the resin of TCV 116 after mixing thoroughly; Be added to the top of Amberlite XAD-4 type macroporous adsorptive resins then, be washed till clarification, use 30% ethanol elution agent wash-out then with the purified water of 1～2 column volume; Collect the ethanol position of TCV 116 wash-out; Concentrating under reduced pressure, drying obtains purified TCV 116 88.7g; Yield 91.2%, purity 98.5%.
Above-mentioned description of test; Compare with the aluminum oxide chromatographic column with silica gel; Adopt macroporous resin chromatography have selectivity good, be easy to desorption, adsorptive capacity is big, rate of adsorption is fast, manipulation of regeneration is simple, physical strength is high, physico-chemical property is stable and advantage such as free from environmental pollution, suitable industrial separation purifying.
The foregoing description and Comparative Examples have also proved absolutely the meliority of particular combination method of the present invention from different aspects; Especially the chromatographic condition and the optimum parameters that comprise macroporous adsorptive resins; Having brought beyond thought effect, is in theory can't rational expectation.Bound by theory not; Possibly be that the purification process that the present invention makes up has collaborative centrifugation to the impurity in the medicine; Process for purification provided by the invention has the characteristics and the obvious improvement of essence, and the beyond thought technique effect of obtaining has obtained the highly purified product of high yield.
Should be appreciated that though the present invention combines instance to carry out detailed explanation, above-mentioned explanation is intended to illustrate, and limits its summary of the invention never in any form.Concerning the art technology people, can farthest utilize the present invention based on the explanation of this paper, and can in not breaking away from claim scope of the present invention or spirit, carry out multiple modification or modification.Each reference that the application quoted is incorporated herein by reference at this in full.
Claims (5)
1. the method for making of the TCV-116 ester cpds of structure shown in the formula (I) comprises the steps:
(1) the TCV 116 bullion is dissolved in the organic solvent that can dissolve each other with water of 5-20 times of weight; The gac that adds overall solution volume 0.1%-0.5% (g/ml); Be incubated 40～60 ℃ and stir 10-30min; Filter decarburization, collect filtrating, wherein said organic solvent is selected from one or more in acetonitrile, methyl alcohol, ethanol, Virahol, acetone, THF 、 diox, N, N,N-DIMETHYLACETAMIDE, the DMSO 99.8MIN.;
(2) above-mentioned filtrating is cooled to room temperature, adds purified water lentamente, stir and produce deposition, filter collecting precipitation;
(3) above-mentioned deposition being used volume ratio is sherwood oil (30～60 ℃)/acetic acid ethyl dissolution of 1: 1; Then through absorption with macroporous adsorbent resin, after the absorption fully, water, 30% ethanol elution agent wash-out successively; Collect the ethanol position of TCV 116 wash-out; Concentrating under reduced pressure, drying obtains the purified TCV 116.
2. method for making according to claim 1 is characterized in that organic solvent in the step (1) is selected from one or more in acetonitrile, methyl alcohol, ethanol, Virahol, the acetone.
3. method for making according to claim 1 is characterized in that adding in the step (1) gac of overall solution volume 0.2-0.3% (g/ml) being incubated 50 ℃, whip attachment 10-30min.
4. according to the arbitrary described method for making of claim 1-3, it is characterized in that described macroporous adsorbent resin is a styrene tyle macroporous adsorption resin.
5. method for making according to claim 4 is characterized in that described styrene tyle macroporous adsorption resin is Sepabeads SP850, Sepabeads SP825, SepabeadsSP700, HPD300, H103 or H107 type macroporous adsorbent resin.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011100322745A CN102070617B (en) | 2011-01-28 | 2011-01-28 | Candesartan cilexetil compound and novel preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011100322745A CN102070617B (en) | 2011-01-28 | 2011-01-28 | Candesartan cilexetil compound and novel preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102070617A CN102070617A (en) | 2011-05-25 |
| CN102070617B true CN102070617B (en) | 2012-02-22 |
Family
ID=44029397
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011100322745A Expired - Fee Related CN102070617B (en) | 2011-01-28 | 2011-01-28 | Candesartan cilexetil compound and novel preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102070617B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1666989A (en) * | 2005-01-04 | 2005-09-14 | 山西爱德制药有限公司 | Candesartan Cilexetil preparing process |
| CN1953973A (en) * | 2004-05-05 | 2007-04-25 | 特瓦制药工业有限公司 | Preparation of candesartan cilexetil in high purity |
-
2011
- 2011-01-28 CN CN2011100322745A patent/CN102070617B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1953973A (en) * | 2004-05-05 | 2007-04-25 | 特瓦制药工业有限公司 | Preparation of candesartan cilexetil in high purity |
| CN1666989A (en) * | 2005-01-04 | 2005-09-14 | 山西爱德制药有限公司 | Candesartan Cilexetil preparing process |
Non-Patent Citations (1)
| Title |
|---|
| 何颖娜等.抗高血压新药-坎地沙坦酯.《重庆医学》.2004,第33卷(第12期),第1896-1898页. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102070617A (en) | 2011-05-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101643466B (en) | Epigallo-catechin gallate (EGCG) with high purity and preparation method thereof | |
| CN102050774B (en) | Oxiracetam compound and new method thereof | |
| CN102093302B (en) | Valsartan compound and new manufacturing method thereof | |
| CN113648834B (en) | Ceramic membrane and preparation method and application thereof | |
| CN103664989A (en) | Method used for preparing moxidectin using nemadectin fermentation broth | |
| CN101948450A (en) | Method for preparing orlistat | |
| CN102010454B (en) | Citicoline sodium compound and new method thereof | |
| CN113801013B (en) | Production process for extracting shikimic acid and/or ginkgo polysaccharide from ginkgo leaves | |
| CN102070617B (en) | Candesartan cilexetil compound and novel preparation method thereof | |
| CN102268025A (en) | Biapenem compound and preparation method thereof | |
| CN102260286B (en) | Method for separating and purifying crude product L-alpha-glycerophosphocholine | |
| CN102321029B (en) | Ornidazole compound and novel preparation method thereof | |
| CN102093250B (en) | Refining method of alanyl-glutamine compound | |
| CN102491940B (en) | Nisoldipine compound and novel preparation method thereof | |
| CN102391342B (en) | Dexamethasone palmitate compound and preparation method thereof | |
| CN102492020B (en) | Pidotimod compound and new preparation method thereof | |
| CN102617327B (en) | Dexibuprofen compound and preparation method thereof | |
| CN107573362A (en) | A kind of method of the separating-purifying sirolimus from zymotic fluid | |
| CN102093297B (en) | Telmisartan compound and new preparation method thereof | |
| CN102617727B (en) | Thymalfasin compound and novel preparation method thereof | |
| CN102267997B (en) | Meropenem compound and preparation method thereof | |
| CN102718669B (en) | Fluoxertine hydrochloride compound and new preparation method thereof | |
| CN102336739B (en) | Loratadine compound and preparation method thereof | |
| CN102924413B (en) | Method for purifying and decolorizing mycophenolate mofetil | |
| US8193345B2 (en) | Purification method of lactone compounds containing unsaturated alkyl group by extraction with silver ion solution |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20120222 Termination date: 20160128 |
|
| EXPY | Termination of patent right or utility model |