CN1190436C - Process for preparing granisetron and its salt - Google Patents
Process for preparing granisetron and its salt Download PDFInfo
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- CN1190436C CN1190436C CN 02117486 CN02117486A CN1190436C CN 1190436 C CN1190436 C CN 1190436C CN 02117486 CN02117486 CN 02117486 CN 02117486 A CN02117486 A CN 02117486A CN 1190436 C CN1190436 C CN 1190436C
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- compound
- indazole
- granisetron
- tropine
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Abstract
The present invention relates to a method for preparing the granisetron compound of the formula (I) and salts thereof, which mainly comprises the following steps: the compound of the formula (III) and the compound of the formula (VIII) are condensed when condensing agents exist to prepare and obtain the compound of the formula (IX); then, the compound of the formula (IX) is methylated to prepare and obtain the compound of the formula (I) or salts thereof, wherein the compound of the formula (VIII) is obtained by that the compound of the formula (VII) is catalyzed and hydrogenated by raney nickel. The method of the present invention can prepare and obtain the compound of the formula (I) at a high yield.
Description
The present invention relates to organic chemistry filed, particularly, the present invention relates to a kind of novel method for preparing granisetron.
Granisetron (Granisetron) is the 5-HT3 receptor antagonist, discloses this compound and preparation method thereof and its purposes as the 5-HT3 receptor antagonist among the European patent EP 200444A.Its preparation method is that the product after indazole-3-carboxylic acid methylization and 3 α-Gao tropine alkanamine prepared in reaction are obtained the granisetron compound.
The inventor finds by the synthetic method of research granisetron: indazole-3-carboxylic acid and the solvability of methylate in solvent thereof are not good, the reaction conditions of indazole-3-carboxylic acid methyl reaction is more violent, reaction yield is lower, usually yield has only about 50%, have influence on the total recovery of synthetic granisetron, and N-(interior-the 9-methyl-9-azabicyclic [3.3.1] ninth of the ten Heavenly Stems-the 3-yl)-indazole-3-carboxamide compounds has well fat-soluble, it is relatively gentleer that this compound carries out the reaction conditions of methylation reaction, the reaction yield height, yield is more than 85%; In addition, most products of as catalyzer the high tropine ketoxime of 3-(VII) hydrogenating reduction being obtained with Raney Ni of the inventor are required 3 α-Gao tropine alkanamines (VIII); In addition, the inventor adopts strong condensing agent carbonyl dimidazoles (CDI) that indazole-3-carboxylic acid (III) and 3 α-Gao tropine alkanamine (VIII) condensation are obtained N-(interior-the 9-methyl-9-azabicyclic [3.3.1] ninth of the ten Heavenly Stems-the 3-yl)-indazole-3-carboxamide compounds (IX) expeditiously.The present invention has improved the total recovery of preparation granisetron or its salt significantly by taking above-mentioned technique means.
Therefore, the purpose of this invention is to provide the novel method that a kind of high yield prepares granisetron and salt thereof.
Method of the present invention is to be raw material with istain (II), uses the sodium hydroxide open loop, obtains hydrazine with the tin protochloride reduction after the diazotization, closes ring then and obtains indazole-3-carboxylic acid (III), and wherein reductive agent can replace with S-WAT; Side chain 3 α-Gao tropine alkanamine (VIII) is to be raw material with cheap citric acid (IV), oxidation obtains Bing Tongersuosuan (V) through sulphur trioxide, Bing Tongersuosuan (V) obtains pseudopunicine (VI) through classical Mannich (Mannich) reaction, pseudopunicine (VI) and azanol reaction obtain the high tropine ketoxime of 3-(VII), and the high tropine ketoxime of 3-(VII) obtains 3 α-Gao tropine alkanamine (VIII) with the Raney Ni hydrogenating reduction; Indazole-3-carboxylic acid (III) carbonyl dimidazoles (CDI) effect down and 3 α-Gao tropine alkanamine (VIII) condensation obtain N-(interior-the 9-methyl-9-azabicyclic [3.3.1] ninth of the ten Heavenly Stems-the 3-yl)-indazole-3-carboxamide compounds (IX), wherein CDI can use DCC (N, N '-dicyclohexylcarbodiimide), DEPC (diethyl cyanophosphonate), DPPA (iterating diphenyl phosphate) replaces; Compound (IX) methylates through methyl-sulfate and obtains granisetron compound or its salt (I), and wherein methylating reagent can replace with methyl iodide, and product adds the ethanol solution of hydrogen chloride acidifying and obtains granisetron hydrochloride crude product.Granisetron hydrochloride crude product obtains pure granisetron hydrochloride through the alcohol-water recrystallization; With granisetron hydrochloride dissolving crude product in water, transfer to alkalescence with sodium bicarbonate, dichloromethane extraction obtains the granisetron free alkali, through dehydration, obtain granisetron free alkali crude product behind the concentrating under reduced pressure, obtain pure granisetron free alkali through ethanol-normal hexane crystallization.
Concrete synthetic route is as follows:
Step 1: by istain (II) preparation indazole-3-carboxylic acid cpd (III)
Step 2: prepare Bing Tongersuosuan compound (V) by citric acid (IV) oxidation
Step 3: by Bing Tongersuosuan (V) process Mannich prepared in reaction pseudopunicine compound (VI)
Step 4: prepare the high tropine ketoxime of 3-(VII) by pseudopunicine (VI) and azanol reaction
Step 5: prepare 3 α-Gao tropane amine compound (VIII) by the high tropine ketoxime of 3-(VII) catalytic hydrogenating reduction
Step 6: by indazole-3-carboxylic acid (III) and 3 α-Gao tropine alkanamine (VIII) condensation prepared N-(interior-the 9-methyl-9-azabicyclic [3.3.1] ninth of the ten Heavenly Stems-the 3-yl)-indazole-3-carboxamide compounds (IX)
Step 7: with the methylate granisetron compound or its salt of the formula of preparing (I) of compound (IX)
Further specify the present invention below by embodiment.The preparation method who it should be understood that the embodiment of the invention is only used for illustrating the present invention, rather than limitation of the present invention, and the simple modifications to preparation method of the present invention under design prerequisite of the present invention all belongs to the scope of protection of present invention.Except as otherwise noted, the percentage ratio among the present invention is weight percentage.
The analytical instrument of using among the present invention is:
Mass spectrum: HP5989B MSD EI 70ev
Proton nmr spectra: DWX500
Embodiment 1: indazole-3-carboxylic acid (III) synthetic
In the aqueous solution of 400ml, add sodium hydroxide 28 grams, stir 30 ℃ of addings of maintenance, 100 gram istains (II) after 10 minutes, add the back and under this temperature, continue stirring one hour, be cooled to 0 ℃, and keep 0 ℃, the sodium nitrite in aqueous solution 100ml of adding 47%.Be added dropwise among the aqueous sulfuric acid 1360ml of 1mol/L under this mixing solutions kept 10 ℃, add the back and continue down to stir one hour in 10 ℃.Add tin protochloride 367.3 grams then, concentrated hydrochloric acid 578.2 grams stirred two hours down in normal temperature.Reaction finishes after-filtration and gets indazole-3-carboxylic acid (III) crude product, adds activated carbon decolorizing, and the water recrystallization obtains indazole-3-carboxylic acid (III) 28 grams.Fusing point: 262.5-263.5 ℃.Yield: 25.4%.
Indazole-3-carboxylic acid (III) analytical data:
1H-NMR (DMSO) 13.78 (1H s-COOH), 13.01 (1H s-HN-), 8.11-7.26 (hydrogen of 4H m phenyl ring)
Mass spectrum: M+162
Embodiment 2: Bing Tongersuosuan (V) synthetic
25% of adding 630ml oleum in reaction flask, be cooled to 0 ℃, keep 10 ℃ of citric acids (IV) that add 306 grams down, be warmed up to 32 ℃ of reactions four hours after adding, be cooled to 0 ℃ then again, keep 25 ℃ of water that add 1200ml down, add postcooling to 0 ℃, filter, with the ethyl acetate washing secondary of ice, vacuum-drying obtains 150 gram Bing Tongersuosuans (V).Yield: 70.5%.
Embodiment 3: pseudopunicine (VI) synthetic
In reaction flask, add 150 gram Bing Tongersuosuans (V), 69 gram methylamine hydrochlorides, the glutaraldehyde of 135ml50%, the Sodium phosphate dibasic of 108 grams and the water of 1600ml stirred 24 hours down in normal temperature.Adding the 120ml concentrated hydrochloric acid reacted one hour down at 70 ℃, be cooled to room temperature, add the aqueous sodium hydroxide solution of the 10mol/L of 350ml, divide three extractions with the methylene dichloride of 3000ml, organic layer is used the water washing of 700ml saturated common salt once, and uses anhydrous sodium sulfate drying.After most methylene dichloride was steamed in decompression, residuum obtained 44 gram pseudopunicines (VI) by the product of 100-105 ℃/20mmHg of rectifying collection.Yield: 37.2%.
Synthesizing of the high tropine ketoxime of embodiment 4:3-(VII)
Add 44g sodium-acetate, 40g oxammonium hydrochloride, 200ml methyl alcohol in reaction flask, stirring at normal temperature one hour is filtered, and with 100ml methanol wash filter cake, adds 44 gram pseudopunicines (VI) in the filtrate, 100ml methyl alcohol stirring at normal temperature four hours.Be concentrated into driedly after reaction finishes, add the 160ml water dissolution, add the aqueous sodium hydroxide solution of the 10mol/L of 100ml, divide three extractions with the methylene dichloride of 1500ml, organic layer is used the water washing of 400ml saturated common salt once, and uses anhydrous sodium sulfate drying.After most methylene dichloride was steamed in decompression, residuum added the normal hexane crystallization, filtered and obtained the high tropine ketoxime of 35g3-(VII).Fusing point: 130-131 ℃.Yield: 72.4%.
Synthesizing of embodiment 5:3 α-Gao tropine alkanamine (VIII)
In the hydrogenation still, add the high tropine ketoxime of 35g3-(VII), Raney Ni 10g, ammonium acetate 18 grams, 300m ethanol, 50 ℃ of controlled temperature, hydrogen pressure 20-25kg/cm
2Reacted 24 hours.Remove by filter Raney Ni, be concentrated into driedly, add entry 300ml dissolving, add the aqueous sodium hydroxide solution of the 10mol/L of 350ml, divide three extractions with the methylene dichloride of 900ml, the water washing of organic layer usefulness 300ml saturated common salt once, the organic layer anhydrous sodium sulfate drying.After most methylene dichloride was steamed in decompression, residuum obtained 21 gram 3 α-Gao tropine alkanamines (VIII) by the product of 118-119 ℃/15mmHg of rectifying collection.Yield: 65.4%.
3 α-Gao tropine alkanamine (VIII) analytical data:
1H-NMR (CDCl
3) 3.22 (1H, H
2N-CH-), 3.02-2.99 (2H, NH
2-), 2.46 (3H ,-N-CH
3), 2.29 (2H ,-CH-N-CH-), 1.95 (3H), 1.47 (1H), 1.2-.095 (5H)
Mass spectrum: M+154
Embodiment 6:N-(interior-the 9-methyl-9-azabicyclic [3.3.1] ninth of the ten Heavenly Stems-the 3-yl)-indazole-3-carboxamide compounds (IX) synthetic
Under the nitrogen protection, in reaction flask, add 22 gram indazole-3-carboxylic acids (III), 25 gram carbonyl dimidazoles (CDI), the DMF of 440ml at room temperature reacted four hours.Add 21 gram α-Gao tropine alkanamines (VIII) then, reaction is 12 hours under same temperature.After reaction finishes reaction solution is poured in the frozen water, with the ethyl acetate extraction of 1200ml three times, ethyl acetate is used the water washing of 300ml saturated common salt once mutually, and the 300ml water washing once and is used anhydrous sodium sulfate drying.Ethyl acetate is to the greatest extent steamed in decompression, and residuum is refining with the ethyl acetate of 50ml.Obtain the compound (IX) of 24.5 grams.Yield: 60.5%.
Compound (IX) analytical data:
1H-NMR (DMSO) 8.20 (1H m＞NH), 8.08-7.22 (hydrogen of 4H m phenyl ring), 4.41 (1H m J=8.2-CH-), 2.97 (2H d2-CH-), 2.41 (3H s-CH
3), 2.21-0.89 (5-CH of 10H m
2-)
Mass spectrum: M+298
Embodiment 7:N-(interior-the 9-methyl-9-azabicyclic [3.3.1] ninth of the ten Heavenly Stems-the 3-yl)-1-methyl-indazole-3-carboxamide compounds (I) synthetic
Under the nitrogen protection, in reaction flask, add 2.24 gram sodium Metal 99.5s, the 120ml Virahol, reacting by heating is complete.Controlled temperature adds 24 for 60 ℃ and digests compound (IX), stirs 10 minutes, is added dropwise to 9.2ml methyl-sulfate and 40ml Virahol, adds the back and continues to stir two hours in same temperature.Be evaporated to driedly, add entry 300ml dissolving, divide three extraction with the methylene dichloride of 900ml, organic layer with the water washing of 300ml saturated common salt once, usefulness deionized water 300ml washing once, the organic layer anhydrous sodium sulfate drying adds activated carbon decolorizing.After most methylene dichloride was steamed in decompression, residuum added the 160ml dissolve with ethanol, transferred PH=1, crystallisation by cooling with 7% ethanol solution of hydrogen chloride.Filtration obtains 25 gram N-(interior-the 9-methyl-9-azabicyclic [3.3.1] ninth of the ten Heavenly Stems-the 3-yl)-1-methyl-indazole-3-carboxamide hydrochloride compound (I) crude products, yield: 89.1%.Water-ethyl alcohol recrystallization obtains hydrochloride (I) 20 grams of N-(interior-the 9-methyl-9-azabicyclic [3.3.1] ninth of the ten Heavenly Stems-the 3-yl)-1-methyl-indazole-3-carboxamide compounds.Yield: 71.3%.
Compound (I):
1H-NMR (CDCl
3) 8.40-6.77 (hydrogen of four groups of multiplet phenyl ring of 4H), 4.56 (1H m J=7.8-CH-), 4.08 (3H s-CH
3), 3.09 (2 of 2H d-CH-), 2.51 (3H s-CH
3), 2.56-1.04 (5-CH of 10H m
2-)
Mass spectrum: M+312
The advantage of maximum of the present invention has solved the amino problem that methylates. Because compound (III) And product the dissolubility in solvent of compound (III) after methylating is not good, usually should be anti-Answer reaction condition more violent, reaction yield is lower, and yield approximately only has 50%, and chemical combination Thing (IX) has well fat-soluble, the reaction condition of this compound (IX) methylation reaction Relatively gentle, reaction yield height, yield be more than 85%, like this Granisetron total receipts of synthesizing Rate will be greatly improved. In addition, the high tropine ketoxime of 3-(VII) is take Raney Ni as catalysis What the overwhelming majority obtained behind the agent hydrogenating reduction is that 3 α-(this point can for Gao tropine alkanamine (VIII) Compose data with the hydrogen from formula (IX) compound: 4.41 (1H m J=8.2-CH) or formulas (I) The hydrogen spectrum data of compound: 4.56 (1H m J=7.8-CH-) are proven), and by-product Thing 3 β-Gao tropane amine content is very little, because synthetic middle need of Granisetron compound (I) What use is 3 α-Gao tropine alkanamine (VIII) rather than 3 β-Gao tropine alkanamine, therefore, The present invention has improved the efficient of synthetic Granisetron compound or its salt (I) widely. The present invention Method in the condensation reaction of indazole-3-carboxylic acid (III) and 3 α-Gao tropine alkanamine (VIII) In adopted strong condensing agent carbonyl dimidazoles (CDI), also improved the yield of compound (IX). Therefore, by utilizing method of the present invention can improve significantly preparation Granisetron or its salt Total recovery.
Claims (4)
1. the granisetron compound of a preparation formula (I) and the method for salt thereof comprise the steps:
A. by istain (II) preparation indazole-3-carboxylic acid cpd (III)
B. prepare Bing Tongersuosuan compound (V) by citric acid (IV) oxidation
C. prepare pseudopunicine compound (VI) by Bing Tongersuosuan (V) through Mannich reaction
D. prepare the high tropine ketoxime of 3-(VII) by pseudopunicine (VI) and azanol reaction
E. prepare 3 α-Gao tropane amine compound (VIII) by the high tropine ketoxime of 3-(VII) catalytic hydrogenating reduction
F. by indazole-3-carboxylic acid (III) and 3 α-Gao tropine alkanamine (VIII) condensation prepared N-(interior-the 9-methyl-9-azabicyclic [3.3.1] ninth of the ten Heavenly Stems-the 3-yl)-indazole-3-carboxamide compounds (IX)
The granisetron compound or its salt of the formula of preparing (I) that g. compound (IX) methylated
2. according to the process of claim 1 wherein that the catalyzer among the step e is a raney nickel catalyst.
3. according to the method for claim 2, wherein use carbonyl dimidazoles among the step f as condensing agent.
4. according to the method for claim 3, wherein use methyl-sulfate or methyl iodide in the step g as methylating reagent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02117486 CN1190436C (en) | 2002-04-19 | 2002-04-19 | Process for preparing granisetron and its salt |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02117486 CN1190436C (en) | 2002-04-19 | 2002-04-19 | Process for preparing granisetron and its salt |
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| CN1451660A CN1451660A (en) | 2003-10-29 |
| CN1190436C true CN1190436C (en) | 2005-02-23 |
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| CN 02117486 Expired - Lifetime CN1190436C (en) | 2002-04-19 | 2002-04-19 | Process for preparing granisetron and its salt |
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Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2012500276A (en) * | 2008-08-19 | 2012-01-05 | サイノファーム タイワン リミテッド | Granisetron hydrochloride polymorph and process for producing the same |
| US20110172428A1 (en) | 2010-01-12 | 2011-07-14 | Shan-Ming Kuang | Methods for the preparation of indazole-3-carboxylic acid and n-(s)-1-azabicyclo[2.2.2]oct-3-yl-1h-indazole-3-carboxamide hydrochloride salt |
| CN103319396A (en) * | 2012-03-21 | 2013-09-25 | 黑龙江福和华星制药集团股份有限公司 | Method for preparing 1-methylindole-3-carboxylic acid |
| CN104311550B (en) * | 2014-09-12 | 2017-02-01 | 河南普瑞制药有限公司 | Preparation method of 6-hydroxytropinone |
| CN109053413A (en) * | 2018-08-04 | 2018-12-21 | 许昌恒生制药有限公司 | A kind of preparation method of cholinolytic class pharmaceutical intermediate |
| CN110804051B (en) * | 2019-10-17 | 2020-10-20 | 杭州励德生物科技有限公司 | Preparation method of granisetron intermediate |
| CN111285848A (en) * | 2020-04-10 | 2020-06-16 | 苏州敬业医药化工有限公司 | Purification method of 5-bromo-2- (2-methyl-2H-tetrazole-5-yl) pyridine |
| WO2022241188A1 (en) * | 2021-05-14 | 2022-11-17 | Theravance Biopharma R&D Ip, Llc | Enantioselective synthesis of aminotropane compound |
| CN115372487B (en) * | 2021-05-18 | 2023-10-10 | 成都倍特得诺药业有限公司 | HPLC determination method for impurity E in granisetron hydrochloride |
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2002
- 2002-04-19 CN CN 02117486 patent/CN1190436C/en not_active Expired - Lifetime
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