CN104098550A - Method for refining trityl-candesartan - Google Patents
Method for refining trityl-candesartan Download PDFInfo
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- CN104098550A CN104098550A CN201410352477.6A CN201410352477A CN104098550A CN 104098550 A CN104098550 A CN 104098550A CN 201410352477 A CN201410352477 A CN 201410352477A CN 104098550 A CN104098550 A CN 104098550A
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- Prior art keywords
- candesartan
- trityl
- temperature
- trityl candesartan
- kind solvent
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- 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 title claims abstract description 58
- 238000000034 method Methods 0.000 title claims abstract description 16
- 238000007670 refining Methods 0.000 title claims abstract description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 33
- 239000002904 solvent Substances 0.000 claims abstract description 27
- 239000007787 solid Substances 0.000 claims abstract description 5
- 238000001816 cooling Methods 0.000 claims abstract description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- 238000010009 beating Methods 0.000 claims description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 238000000967 suction filtration Methods 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- 239000000047 product Substances 0.000 claims description 11
- 239000012065 filter cake Substances 0.000 claims description 10
- -1 methyl-formiate Chemical compound 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000012043 crude product Substances 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 3
- 239000012535 impurity Substances 0.000 claims description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 2
- 238000001035 drying Methods 0.000 abstract 1
- 238000004537 pulping Methods 0.000 abstract 1
- 239000002053 C09CA06 - Candesartan Substances 0.000 description 18
- 229960000932 candesartan Drugs 0.000 description 18
- 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 description 17
- 229960004349 candesartan cilexetil Drugs 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000010583 slow cooling Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 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 description 2
- 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 description 2
- RQXXCWHCUOJQGR-UHFFFAOYSA-N 1,1-dichlorohexane Chemical compound CCCCCC(Cl)Cl RQXXCWHCUOJQGR-UHFFFAOYSA-N 0.000 description 1
- 101800004538 Bradykinin Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 102100035792 Kininogen-1 Human genes 0.000 description 1
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 1
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 238000003809 water extraction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention provides a method for refining trityl-candesartan. The method comprises the following steps: (1) pulping and filtrating a crude trityl-candesartan product utilizing a first kind solvent; (2) after dissolving the solid obtained by filtrating in step (1) into a second kind solvent again, dropwise adding acetonitrile into the solution, cooling the solution to crystallize, and drying to obtain a refined trityl-candesartan product. The method for refining the trityl-candesartan, provided by the invention is simple in operation and achieves high refining yield rate, and the purity of the refined trityl-candesartan can reach to 99.9%.
Description
Technical field
The invention belongs to organic chemistry filed, be specifically related to a kind of method of refining trityl candesartan.
Background of invention
Candesartan Cilexetil, shown in its structural formula as I.
Candesartan Cilexetil does not suppress kininase II, does not affect bradykinin enzyme liberating, is a kind of antihypertensive drug with bright market prospects.
CN91102569.3 and CN 98101894.7 have all reported the synthetic route of candesartan Cilexetil, and its synthetic route comprises the following steps:
A) ethyl ester of candesartan (II) hydrolysis obtains Candesartan (III);
B) Candesartan (III) is reacted with triphenylmethyl chloride and is generated trityl candesartan (IV), to protect tetrazole base hydrogen;
C) trityl candesartan (IV) obtains trityl group candesartan cilexetil (V) with 1-halogenated ethyl cyclohexyl carbonic ether;
D) trityl group candesartan cilexetil (V) Deprotection obtains candesartan Cilexetil (I), and synthetic route is as follows:
In the process of preparation trityl candesartan (IV), there is following problem in said synthesis route: the bi triphenyl Candesartan shown in the formula VI of generation 5%～8%, and this impurity is more difficult to be removed; In addition, because intermediate (II) hydrolysis reaction is incomplete, cause containing in trityl candesartan (IV) a certain amount of by product trityl candesartan ethyl ester (VII); In addition because upper protective reaction is incomplete, thereby cause containing unreacted Candesartan (III) in trityl candesartan ((IV)).
Above-mentioned impurity all affects the purity of trityl candesartan, and then also can affect quality and the yield of the finished product.
Summary of the invention
A kind of method that the object of this invention is to provide refining trityl candesartan, particularly in refining trityl candesartan crude product, contain the two trityl candesartan (VI) of by product, trityl candesartan ethyl ester (VII) and Candesartan (III)
Technical scheme provided by the invention comprises the following step:
(1) trityl candesartan crude product is first pulled an oar with first kind solvent, filter;
(2) step (1) is filtered to the solid obtaining and be dissolved in after the second solvent again, drip acetonitrile, cooling crystallization, oven dry, obtain trityl candesartan highly finished product;
Described first kind solvent is selected from: one or more of methyl alcohol, ethanol, Virahol, propyl carbinol, the trimethyl carbinol;
Described Equations of The Second Kind solvent is selected from: one or several of ethyl acetate, methyl-formiate, ethyl formate, tetrahydrofuran (THF) equal solvent, preferably tetrahydrofuran (THF).
Described temperature of pulling an oar in first kind solvent is 25～80 ℃, and the quality of first kind solvent used is 4～8 times of trityl candesartan quality.
The quality of Equations of The Second Kind solvent used is 2～6 times of trityl candesartan quality.
Acetonitrile quality used is 3～8 times of trityl candesartan quality, and dropping temperature is 40～80 ℃.
Concrete steps of the present invention are:
(1), by first kind solvent making beating for trityl candesartan crude product, control 25～80 ℃ of making beating temperature, beating time is 0.5～3 hour, making beating finishes rear holding temperature-10～20 ℃ stirs 1～5 hour, suction filtration;
(2), by filtering the solid obtaining in step (1), be dissolved in Equations of The Second Kind solvent, control 40～80 ℃ of temperature, be stirred to molten clearly, then control 40～80 ℃ of temperature and drip acetonitriles.After dropping finishes, be cooled to-10～20 ℃, stir 1～4 hour.Suction filtration, appropriate acetonitrile washing for filter cake, obtains trityl candesartan wet product, controls baking oven vacuum tightness 0.08～0.10MPa, and 30～80 ℃ of oven dry of temperature, obtain trityl candesartan highly finished product.
Trityl candesartan process for purification provided by the invention is simple to operate, and refining yield is high, and after trityl candesartan is refining, purity can reach 99.9%, and single mixing is less than 0.10%.
Embodiment
Below in conjunction with specific embodiment, the present invention is further explained, but protection scope of the present invention is not limited in this:
Preparation example
In 500ml four-hole bottle, add Candesartan 30g, 310g methylene dichloride, adds 8.2g triethylamine, 30～35 ℃ of mixed solutions that stir and drip triphenylmethyl chloride 25g and 250g methylene dichloride, insulation reaction to reaction is finished.25～30 ℃ of temperature controls, add water extraction, layering.Remove dichloro hexane under reduced pressure, add again 300g methyl alcohol, 0～5 ℃ of temperature control, stirring and crystallizing 11 hours, filters, obtain triphenyl Candesartan 40.5g, yield 87.1%, it is 91.5% that HPLC detects purity, bi triphenyl Candesartan 4.5%, Candesartan 2.6%, trityl candesartan ethyl ester is 1.1%.
Embodiment 1
In 2L four-hole bottle, add the trityl candesartan 100g of preparation example 1 gained, add methyl alcohol 600g to control 40 ℃～60 ℃ making beating of temperature 2 hours, after making beating finishes, extremely-5～5 ℃ of slow coolings, 0～5 ℃ of stirring of holding temperature 2 hours, suction filtration.Filter cake is dissolved in 600g tetrahydrofuran (THF), controls 50～80 ℃ of temperature, be stirred to molten clearly, then control 50～80 ℃ of temperature and drip 650g acetonitriles.After dropping finishes, slow cooling to 0～5 ℃, stir 2～3 hours.Suction filtration, filter cake obtains trityl candesartan wet product with appropriate acetonitrile solvent washing, controls baking oven vacuum tightness 0.08～0.10MPa, and 50～60 ℃ of oven dry of temperature, obtain trityl candesartan 93.8g, and yield is 93.8%.It is 99.96% that HPLC detects purity, bi triphenyl Candesartan 0.01%, and Candesartan 0.02%, trityl candesartan ethyl ester is 0.005%.
Embodiment 2
In 2L four-hole bottle, add the trityl candesartan 100g of preparation example 1 gained, add methyl alcohol 600g, control 40 ℃～60 ℃ making beating of temperature 2 hours, making beating finishes rear slow cooling to 0～5 ℃, 0～5 ℃ of stirring of holding temperature 1.5 hours, suction filtration.Filter cake is dissolved in 500g ethyl acetate, controls 70～80 ℃ of temperature, be stirred to molten clearly, then control 45～75 ℃ of temperature and drip 600g acetonitriles.After dropping finishes, be cooled to-5～5 ℃, stir 2 hours.Suction filtration, filter cake obtains trityl candesartan wet product with appropriate acetonitrile solvent washing, controls baking oven vacuum tightness 0.08～0.10MPa, and 50～70 ℃ of oven dry of temperature, obtain trityl candesartan 92.9g, and yield is 92.9%.It is 99.93% that HPLC detects purity, bi triphenyl Candesartan 0.01%, and Candesartan 0.03%, trityl candesartan ethyl ester is 0.01%.
Embodiment 3
In 2L four-hole bottle, add the trityl candesartan 100g of preparation example 1 gained, add ethanol 500g, control 40 ℃ of making beating of temperature 2 hours, after finishing, making beating is cooled to 0～5 ℃, 0～5 ℃ of stirring of holding temperature 1.5～2 hours, suction filtration.The filter cake obtaining is dissolved in 500g ethyl acetate, controls 50～70 ℃ of temperature, be stirred to molten clearly, then control 50～70 ℃ of temperature and drip 550g acetonitriles.After dropping finishes, be cooled to 0～5 ℃, stir 2 hours.Suction filtration, filter cake washs to obtain trityl candesartan wet product with appropriate acetonitrile solvent, controls baking oven vacuum tightness 0.08～0.10MPa, and 50～70 ℃ of oven dry of temperature, obtain trityl candesartan 93.5g, and yield is 93.5%.It is 99.90% that HPLC detects purity, bi triphenyl Candesartan 0.03%, and Candesartan 0.05%, trityl candesartan ethyl ester is 0.01%.
Embodiment 4
In 2L four-hole bottle, add the trityl candesartan 100g of preparation example 1 gained, add propyl carbinol 600g, control 40 ℃～80 ℃ making beating of temperature 2 hours, after finishing, making beating is cooled to 0～5 ℃, 0～5 ℃ of stirring of holding temperature 1.5 hours, suction filtration.The filter cake obtaining is dissolved in 500g tetrahydrofuran (THF), controls 50～70 ℃ of temperature, be stirred to molten clearly, then control 50～80 ℃ of temperature and drip 550g acetonitriles.After dropping finishes, be cooled to 0～5 ℃, stir 2 hours.Suction filtration, filter cake washs to obtain trityl candesartan wet product with appropriate acetonitrile solvent, controls baking oven vacuum tightness 0.08～0.10MPa, and 50～70 ℃ of oven dry of temperature, obtain trityl candesartan 94.2g, and yield is 94.2%.It is 99.87% that HPLC detects purity, bi triphenyl Candesartan 0.03%, and Candesartan 0.06%, trityl candesartan ethyl ester is 0.02%.
Claims (7)
1. a method for refining trityl candesartan, is characterized in that:
(1) by first kind solvent making beating for trityl candesartan crude product, filter;
(2) step (1) is filtered to the solid obtaining and be dissolved in after the second solvent again, drip acetonitrile, cooling crystallization, oven dry, obtain trityl candesartan highly finished product;
Described first kind solvent is selected from: one or more of methyl alcohol, ethanol, Virahol, propyl carbinol, the trimethyl carbinol;
Described Equations of The Second Kind solvent is selected from: one or several of ethyl acetate, methyl-formiate, ethyl formate, tetrahydrofuran (THF) equal solvent.
2. method according to claim 1, is characterized in that described Equations of The Second Kind solvent is tetrahydrofuran (THF).
3. method according to claim 1, is characterized in that described temperature of pulling an oar in first kind solvent is 25～80 ℃, and the quality of first kind solvent used is 4～8 times of trityl candesartan quality.
4. method according to claim 1, the quality that it is characterized in that Equations of The Second Kind solvent used is 2～6 times of trityl candesartan quality.
5. method according to claim 1, the quality that it is characterized in that acetonitrile used is 3～8 times of trityl candesartan quality, dropping temperature is 40～80 ℃.
6. method according to claim 1, concrete steps are:
(1), by first kind solvent making beating for trityl candesartan crude product, control 25～80 ℃ of making beating temperature, beating time is 0.5～3 hour, making beating finishes rear holding temperature-10～20 ℃ stirs 1～5 hour, suction filtration;
(2), by filtering the solid obtaining in step (1), be dissolved in Equations of The Second Kind solvent, control 40～80 ℃ of temperature, be stirred to molten clearly, then control 40～80 ℃ of temperature and drip acetonitriles.After dropping finishes, be cooled to-10～20 ℃, stir 1～4 hour.Suction filtration, filter cake washs with acetonitrile, obtains trityl candesartan wet product, controls baking oven vacuum tightness 0.08～0.10MPa, and 30～80 ℃ of oven dry of temperature, obtain trityl candesartan highly finished product.
7. according to the method described in claim 1～6, it is characterized in that containing in trityl candesartan crude product following impurity:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410352477.6A CN104098550A (en) | 2014-07-17 | 2014-07-17 | Method for refining trityl-candesartan |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410352477.6A CN104098550A (en) | 2014-07-17 | 2014-07-17 | Method for refining trityl-candesartan |
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| CN104098550A true CN104098550A (en) | 2014-10-15 |
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| CN201410352477.6A Pending CN104098550A (en) | 2014-07-17 | 2014-07-17 | Method for refining trityl-candesartan |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106699737A (en) * | 2016-12-07 | 2017-05-24 | 浙江华海药业股份有限公司 | Refining method of candesartan |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1055927A (en) * | 1990-04-27 | 1991-11-06 | 武田药品工业株式会社 | Benzimidazole derivatives and their preparation and use |
| WO2007094015A1 (en) * | 2006-02-15 | 2007-08-23 | Matrix Laboratories Ltd | An improved process for the preparation of candesartan cilexetil |
| CN103396406A (en) * | 2013-08-07 | 2013-11-20 | 威海迪素制药有限公司 | Preparation method of candesartan cilexetil |
-
2014
- 2014-07-17 CN CN201410352477.6A patent/CN104098550A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1055927A (en) * | 1990-04-27 | 1991-11-06 | 武田药品工业株式会社 | Benzimidazole derivatives and their preparation and use |
| WO2007094015A1 (en) * | 2006-02-15 | 2007-08-23 | Matrix Laboratories Ltd | An improved process for the preparation of candesartan cilexetil |
| CN103396406A (en) * | 2013-08-07 | 2013-11-20 | 威海迪素制药有限公司 | Preparation method of candesartan cilexetil |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106699737A (en) * | 2016-12-07 | 2017-05-24 | 浙江华海药业股份有限公司 | Refining method of candesartan |
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Application publication date: 20141015 |
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