CN100462360C - N-cyclohexyl-5-(4-chlorobutyl)-1H-tetrazole synthesis method - Google Patents
N-cyclohexyl-5-(4-chlorobutyl)-1H-tetrazole synthesis method Download PDFInfo
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- CN100462360C CN100462360C CNB2005100288043A CN200510028804A CN100462360C CN 100462360 C CN100462360 C CN 100462360C CN B2005100288043 A CNB2005100288043 A CN B2005100288043A CN 200510028804 A CN200510028804 A CN 200510028804A CN 100462360 C CN100462360 C CN 100462360C
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Abstract
The invention discloses a process for synthesizing N-cyclohexyl-5-(4-chlorobutyl)-1H-tetrazolium comprising the following steps: (1) using 5-chlorovaleronitrile and cyclohexanol as raw material, obtaining 5-chloro-N-cyclohexylpentanamide through concentrated sulfuric acid catalysis, (2) subjecting the 5-chloro-N-cyclohexylpentanamide to phosphorus pentachloride, then charging azide cyclization reagent for reaction at the temperature of 0-80 deg. C.
Description
Technical field
The present invention relates to the synthetic method of a kind of product N-cyclohexyl-5-(4-chlorobutyl)-1H-tetrazole (abbreviation tetrazole).
Background technology
Tetrazole shown in the compound 1 is the important intermediate of synthetic medicament for resisting platelet aggregation Cilostazole (Cilostazol), and it prepares gained by Compound I I 5-chloro-N-cyclohexyl valeramide.
Have method to mention with the 5-chloro pentane acid and generate acyl chlorides under the effect of thionyl chloride, with the synthetic II of cyclo-hexylamine reaction, the route of this method has two-step reaction again, and required quantity of solvent is bigger, and the industrial production cost is higher.Also have method to mention with hexamethylene lactone and hexahydroaniline reaction, generate 5-hydroxy-n-cyclohexyl valeramide, this method need consume too much phosphorus pentachloride, need handle more spent acid when producing greatly.
Bibliographical information the has been arranged relevant synthetic method of tetrazole, they have used the benzole soln of hydrazoic acid or solid sodiumazide as cyclization reagent.Hydrazoic acid is a kind of high explosivity, high toxicity, and lower boiling acids (Bp:37 ℃) is not so be the synthetic optimal reagent of tetrazole; And higher temperature and the long reaction times of the reaction needed of sodiumazide causes the content of impurity in the reaction process to increase, and has brought very big trouble for the purifying of product.
Summary of the invention
Deficiency at the prior art existence, the object of the present invention is to provide a kind of new methodology of organic synthesis of preparation N-cyclohexyl-5-(4-chlorobutyl)-1H-tetrazole, utilize synthetic method of the present invention, can simplify the synthesis step of 5-chloro-N-cyclohexyl valeramide, reduce the cost of synthetic tetrazole.
Realize that technical scheme of the present invention is as follows:
The synthetic method of a kind of N-cyclohexyl-5-(4-chlorobutyl)-1H-tetrazole, its synthesis step is as follows:
A, be raw material with 5-chlorine valeronitrile and hexalin, the mole proportioning of 5-chlorine valeronitrile and hexalin is 1:1-1:2, and temperature of reaction is 5-50 ℃, through sulphuric acid catalysis reaction 1-5 hours, obtains 5-chloro-N-cyclohexyl valeramide; Wherein the mol ratio of the vitriol oil used of 5-chlorine valeronitrile and catalysis is 1:4-1:12.
B, 5-chloro-N-cyclohexyl valeramide are handled through phosphorus pentachloride, the mole proportioning of 5-chloro-N-cyclohexyl valeramide and phosphorus pentachloride is 1:1-1:2, add nitrine cyclization reagent again, the mole proportioning of 5-chloro-N-cyclohexyl valeramide and nitrine cyclization reagent is 1:1-1:5, under 0 ℃-80 ℃ temperature, reacted 2-12 hours, obtain
N-cyclohexyl-5-(4-chlorobutyl)-1H-tetrazole.
Wherein temperature of reaction is very big to the reaction yield influence in the A step, if temperature of reaction is higher than 50 ℃, itrile group in the raw material can be by sulphuric acid hydrolysis, if temperature is lower than 5 ℃, level of response is slow, so temperature of reaction is elected 5 ℃-50 ℃ as, preferably adopts to raise 5 ℃ in per 30 minutes, up to 25 ℃-30 ℃ of interior temperature, be incubated 2 hours temperature control method.The proportioning of reaction raw materials 5-chlorine valeronitrile and hexalin also directly influences reaction yield, when both are 1:1, follows the tracks of through GC, 25% not reaction of 5-chlorine valeronitrile is arranged, and when both were 1:2, reaction was just very abundant, yield is about 90%, and purity is higher than 98% behind the recrystallization.
Wherein the nitrine cyclization reagent described in the B step is a kind of in trimethyl azide silicon or the two phenoxy group phosphoryl azides.
System after the described B step reaction is poured in the frozen water, the water organic solvent extraction, organic phase is washed with saturated aqueous common salt and sodium bicarbonate aqueous solution, after underpressure distillation steams solvent, concentrated solution is separated out cotton-shaped solid N-cyclohexyl-5-(4-the chlorobutyl)-1H-tetrazole of white with the mixed liquid recrystallization of ethyl acetate and sherwood oil, and product purity is usually more than 99%.
The present invention replaces hydrazoic acid or sodiumazide as cyclization reagent with trimethyl azide silicon, and trimethyl azide silicon is a kind of relatively stable trinitride safe in utilization, even be heated to decomposition temperature, also can not blast.
Preparation trimethyl azide silicon is with after sodiumazide and the toluene mixing under nitrogen protection; splash into trimethylchlorosilane; 70 degree insulations prepared gained after 18 hours, can prevent entering of steam with nitrogen protection, and trimethyl azide silicon is met water can generate hydrazoic acid.The toxicity of trimethyl azide silicon and danger all are lower than hydrazoic acid, and is comparatively safe during use.
The diphenylphosphine acylazide also is stable trinitride, has commercially availablely, is generally used in polypeptide synthetic.
The present invention utilizes hexalin and 5-chlorine valeronitrile to be raw material, replaces hydrazoic acid or sodiumazide or diphenylphosphine acylazide as cyclization reagent with trimethyl azide silicon, reacts to make product N-cyclohexyl-5-of the present invention (4-chlorobutyl)-1H-tetrazole.Synthetic method of the present invention have reduce cost, reaction scheme safety, environmental protection, products therefrom purity advantages of higher.
Specific implementation method
How further specify the present invention below in conjunction with specific embodiment realizes:
Embodiment 1
The preparation of 5-chloro-N-cyclohexyl valeramide:
In the bottle of 1L, add the vitriol oil 400 grams, cryosel is bathed 0-5 ℃ of coolings, in system, be added dropwise to 5-chlorine valeronitrile (58.75 gram), the mixed solution of hexalin (100 gram), dropwise insulation 30 minutes, 5 degree raise in per subsequently 30 minutes, temperature is 25-30 degree in reaction, be incubated 2 hours, gas phase is followed the tracks of peak area up to 5-chlorine valeronitrile less than 1%, and above-mentioned reaction solution is poured in the 1000 gram trash ices, add the extraction of 200ml methyl iso-butyl ketone (MIBK), water merges organic phase with methyl iso-butyl ketone (MIBK) extraction (200ml * 3) extraction, washs with sodium bicarbonate aqueous solution, be neutral up to water, use the saturated common salt water washing more once, dry back concentrates and obtains 148 gram light yellow solids, and the thick product of gained recrystallization in 400ml sherwood oil (60-90 ℃) obtains white solid 5-chloro-N-cyclohexyl valeramide 97 grams.
Embodiment 2
The preparation of 5-chloro-N-cyclohexyl valeramide:
In the bottle of 1L, add the vitriol oil 300 grams, cryosel is bathed 0-5 ℃ of coolings, in system, be added dropwise to 5-chlorine valeronitrile (58.75 gram), the mixed solution of hexalin (75 gram), dropwise insulation 30 minutes, 5 degree raise in per subsequently 30 minutes, temperature is 25-30 degree in reaction, be incubated 4 hours, gas phase is followed the tracks of peak area up to 5-chlorine valeronitrile less than 1%, and above-mentioned reaction solution is poured in the 1000 gram trash ices, add the extraction of 200ml methyl iso-butyl ketone (MIBK), water merges organic phase with methyl iso-butyl ketone (MIBK) extraction (200ml * 3) extraction, washs with sodium bicarbonate aqueous solution, be neutral up to water, use the saturated common salt water washing more once, dry back concentrates and obtains 110 gram light yellow solids, and the thick product of gained recrystallization in 400ml sherwood oil (60-90 ℃) obtains white solid 5-chloro-N-cyclohexyl valeramide 75 grams.
Embodiment 3
The preparation of N-cyclohexyl-5-(4-chlorobutyl)-1H-tetrazole:
With 76.5 gram sodiumazide, 500mL toluene is thrown respectively in the four-hole bottle of 1L under nitrogen protection, under 30 ℃, splashes into 128 gram trimethylchlorosilanes fast, and system is slightly muddy, and faint intensification phenomenon is arranged.Dropwise, be warmed up to 70 ℃ in 2-3 hour, insulation reaction after 18 hours removes heating, system naturally cools to room temperature, stop to stir, the above-mentioned toluene solution for preparing is transferred to stand-byly in the dropping funnel (noted dryly, meet water or damp atmosphere and have HN
3Emit)
With embodiment 1 or embodiment 2 prepared 5-chloro-N-cyclohexyl valeramide 72.5 grams, toluene 600mL throws respectively in the four-hole bottle of 2L, after the stirring at room 40 minutes, after treating that solid dissolves fully, be cooled to 0 ℃, add 72.8 gram phosphorus pentachlorides then, and temperature control is in 0-5 ℃, 30 minutes reinforced finishing in batches, remove ice-water bath, naturally being raised to room temperature, at room temperature stirring 2 hours, is clear soln up to system, temperature control 20-25 ℃ drips the trimethyl azide silicon toluene solution for preparing down fast, drip off in one hour, be warming up to 50 ℃ of reactions then, be incubated after 6 hours, HPLC follows the tracks of below the 5-chloro-N-cyclohexyl valeramide to 3%, system is poured in the frozen water of 1L, water extracts (200ml * 2) with toluene, organic phase saturated aqueous common salt and sodium bicarbonate aqueous solution washed twice respectively, each 500mL, after underpressure distillation steamed toluene, concentrated solution obtained solid 44 grams, purity (HPLC 99.5%) with the mixed liquid recrystallization of ethyl acetate and sherwood oil.
Embodiment 4
The preparation of N-cyclohexyl-5-(4-chlorobutyl)-1H-tetrazole:
With embodiment 1 or embodiment 2 prepared 5-chloro-N-cyclohexyl valeramide 72.5 grams, toluene 700mL throws respectively in the four-hole bottle of 1L, after the stirring at room 40 minutes, after treating that solid dissolves fully, be cooled to 0 ℃, add 74.2 gram phosphorus pentachlorides then in batches, and temperature control is in 0-5 ℃, and 30 minutes reinforced finishing remove ice-water bath, naturally be raised to room temperature, at room temperature stirring 2 hours, is clear soln up to system, and temperature control 20-25 ℃ adds 333.2g diphenylphosphine acylazide down, be warming up to 50 ℃ of reactions then, be incubated after 8 hours, HPLC follows the tracks of below the 5-chloro-N-cyclohexyl valeramide to 3%, system is poured in the frozen water of 500mL, water extracts (200ml * 2) with toluene, organic phase saturated aqueous common salt and sodium bicarbonate aqueous solution washed twice respectively, each 500mL is after underpressure distillation steams toluene, concentrated solution obtains solid 36 grams, purity (HPLC 99.3%) with the mixed liquid recrystallization of ethyl acetate and sherwood oil.
Claims (6)
1. the synthetic method of a N-cyclohexyl-5-(4-chlorobutyl)-1H-tetrazole, its synthesis step is as follows:
A, be raw material with 5-chlorine valeronitrile and hexalin, the mole proportioning of 5-chlorine valeronitrile and hexalin is 1:1-1:2, and temperature of reaction is 5-50 ℃, through sulphuric acid catalysis reaction 1-5 hours, obtains 5-chloro-N-cyclohexyl valeramide;
B, 5-chloro-N-cyclohexyl valeramide are handled through phosphorus pentachloride, add nitrine cyclization reagent again, react 2-12 hours under 0 ℃-80 ℃ temperature, obtain N-cyclohexyl-5-(4-chlorobutyl)-1H-tetrazole;
Wherein, described nitrine cyclization reagent is a kind of in trimethyl azide silicon or the diphenylphosphine acylazide.
2. the synthetic method of a kind of N-cyclohexyl-5-according to claim 1 (4-chlorobutyl)-1H-tetrazole is characterized in that: the mol ratio of the vitriol oil that 5-chlorine valeronitrile in the described A step and catalysis are used is 1:4-1:12.
3. the synthetic method of a kind of N-cyclohexyl-5-according to claim 1 (4-chlorobutyl)-1H-tetrazole is characterized in that: the 5-chloro-N-cyclohexyl valeramide in the described B step and the mole proportioning of phosphorus pentachloride are 1:1-1:2.
4. the synthetic method of a kind of N-cyclohexyl-5-according to claim 1 (4-chlorobutyl)-1H-tetrazole, it is characterized in that: the phosphorus pentachloride in the described B step adds under 0 ℃ in batches, add controlled temperature at-5-10 ℃, added the back stirring at room 2 hours.
5. the synthetic method of a kind of N-cyclohexyl-5-according to claim 1 (4-chlorobutyl)-IH-tetrazole is characterized in that: the mole proportioning of 5-chloro-N-cyclohexyl valeramide and nitrine cyclization reagent is 1:1-1:5.
6. the synthetic method of a kind of N-cyclohexyl-5-according to claim 1 (4-chlorobutyl)-1H-tetrazole, it is characterized in that: the system after the described B step reaction is poured in the frozen water, the water organic solvent extraction, organic phase is washed with saturated aqueous common salt and sodium bicarbonate aqueous solution, after underpressure distillation steamed solvent, concentrated solution obtained solid N-cyclohexyl-5-(4-chlorobutyl)-IH-tetrazole with the mixed liquid recrystallization of ethyl acetate and sherwood oil.
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| EP2545040B1 (en) * | 2010-03-12 | 2013-12-11 | Bayer Intellectual Property GmbH | Process for the preparation of 5-substituted 1-alkyltetrazoles |
| CN107266330A (en) * | 2017-07-20 | 2017-10-20 | 上海立科化学科技有限公司 | A kind of 5 chlorine N cyclohexyl pentanamide synthetic methods |
| CN111233777A (en) * | 2020-03-31 | 2020-06-05 | 上海立科药物化学有限公司 | Synthesis method of N-cyclohexyl-5- (4-chlorobutyl) -1H-tetrazole |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4277479A (en) * | 1978-09-01 | 1981-07-07 | Otsuka Pharmaceutical Co., Ltd. | Tetrazolylalkoxycarbostyril derivatives and pharmaceutical compositions containing them |
| WO2005019204A1 (en) * | 2003-08-26 | 2005-03-03 | Dipharma S.P.A. | A process for the preparation of cilostazol and of the intermediates thereof |
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2005
- 2005-08-15 CN CNB2005100288043A patent/CN100462360C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4277479A (en) * | 1978-09-01 | 1981-07-07 | Otsuka Pharmaceutical Co., Ltd. | Tetrazolylalkoxycarbostyril derivatives and pharmaceutical compositions containing them |
| WO2005019204A1 (en) * | 2003-08-26 | 2005-03-03 | Dipharma S.P.A. | A process for the preparation of cilostazol and of the intermediates thereof |
Non-Patent Citations (4)
| Title |
|---|
| 医药新品种西洛他唑的合成研究. 唐传久等.安徽化工，第3期. 2004 |
| 医药新品种西洛他唑的合成研究. 唐传久等.安徽化工，第3期. 2004 * |
| 血小板阻聚药物中间体N-环己基-5-氯丁基-1H-四氮唑的合成. 贾义霞等.合成化学，第11卷第(2)期. 2003 |
| 血小板阻聚药物中间体N-环己基-5-氯丁基-1H-四氮唑的合成. 贾义霞等.合成化学，第11卷第(2)期. 2003 * |
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Denomination of invention: N- -5- (Ding Ji 4- cyclohexyl chloride) synthesis method of -1H- tetrazole Effective date of registration: 20100301 Granted publication date: 20090218 Pledgee: Pudong Productivity Promotion Center, Shanghai Pledgor: Like Medicine Chemistry Co., Ltd., Shanghai Registration number: 2010990000713 |
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