CN102875534B - Synthetic method of irbesartan - Google Patents
Synthetic method of irbesartan Download PDFInfo
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- CN102875534B CN102875534B CN201210347291.2A CN201210347291A CN102875534B CN 102875534 B CN102875534 B CN 102875534B CN 201210347291 A CN201210347291 A CN 201210347291A CN 102875534 B CN102875534 B CN 102875534B
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Abstract
The invention provides a method for synthesizing an intermediate 5-(4'-bromoethylbiphenyl-2-group)-1-triphenylmethyl-1H-tetrazole of irbesartan through a inorganic salt xodizing reducing system, and also provides a new relatively environment-friendly way for synthesizing irbesartan.
Description
Technical field
The invention belongs to process for preparing medicine technical field, be specifically related to a kind of novel method of green syt irbesartan.
Background technology
Irbesartan is Angiotensin II (Angiotensin II, Ang II) acceptor inhibitor, Ang I can be suppressed to be converted into AngII, can antagonizing angiotensin converting Enzyme 1 acceptor (AT1) specifically, AT28500 is greater than doubly to the antagonistic action of AT1, by optionally blocking the combination of Ang II and AT1 acceptor, suppressing the release of vasoconstriction and aldosterone, producing hypotensive effect.Can be used for treating hypertension, heart failure cardiovascular disorder and prevent the disorder of central nervous system, glaucoma, diabetic retinal and diabetic nephropathy.
Irbesartan is the medicine of Bristol Myers Squibb and French Sai Nuofei-Sheng Delabao joint development.Listing in 1997, trade(brand)name " Avapro (An Bowei) ".Its chemical name is 2-butyl-3-[[2-(1H-TETRAZOLE-5-base) xenyl-4-base] methyl]-1,3-diazaspiracyclic [4,4] nonane-1-alkene.-4-ketone, structural formula is as follows:
US Patent No. 5270317 makes public for the first time the preparation method of irbesartan and related compound thereof.In synthetic method disclosed in the patents such as US5270317, US5559233 and US5629331, all relate to and the cyano group on cyclohexyl biphenyl and trinitride are reacted, reaction times length consuming time, use the triazo-compound being easy to explode in reaction, therefore there is larger security risk in experiment with in producing.
In patent CN101648945, W02004065383, prepare irbesartan by the method for SUZUKI coupling, in reaction process, employ expensive catalyzing by metal palladium, therefore the method high cost in industrial production.In the same manner, in patent US5412102, CN1070193 patent, employ expensive catalyzer lithium aluminum hydride, nickelous chloride, be applied to high cost in production.
Te Wa company is in CN1668612 patent, disclose the method for 2-butyl-1,3-diazaspiracyclic [4.4] nonane-1-alkene-4 ketone and 5-(4 '-bromomethylbiphenyl-2-base)-1-trityl-1H tetrazolium Reactive Synthesis irbesartan under phase-transfer catalyst condition in the reaction system of the first and second phases.The method overcome the security risk that in production technique in the past, triazo-compound brings, but the purity of product is not high yet.And toluene is used in preparation process, in industrial mass production, the pungency caused, toxicity are larger.
Propose a kind of at C in Chinese patent CN102432558 patent
1-C
4chlorination, in alkane or organic acid solvent, utilizes alpha-methyl styrene to protect tetrazole, then carries out the preparation method of follow-up synthesis, overcome the processing disadvantages of security risk, high cost.But the method existence is unfavorable for industrial defect, the first, and total recovery is low especially: as described in this patent specification embodiment, its substep yield is between 70%-93.2%, even if by optimal selection, its highest total recovery also will lower than 40%.The second, in chemosynthesis, the selecting properly of blocking group is most important to the success or failure of whole building-up reactions, yield, and alpha-methyl styrene is one of important monomer of synthetic resins and plastics, and in building-up process, itself is unstable.The method utilizes alpha-methyl styrene as the protecting group in building-up process, easily polymerization occurs and affects reaction and carry out, and bringing the impurity being difficult to remove into.3rd; the method is in preparation protecting group step (formula 7 synthesis type 8 step); the organic acid adopted is trichoroacetic acid(TCA), trifluoroacetic acid, tosic acid, Phenylsulfonic acid or methylsulfonic acid; all the acid that corrodibility is stronger; large to chemical industry equipment loss, dangerous high; price also costly simultaneously, and be unfavorable for industrial production.
At present, be badly in need of that a kind of green, safety, yield are high, the novel method of the high synthesis irbesartan of purity.
Summary of the invention
The object of the invention is to overcome above-mentioned weak point of the prior art, provide a kind of green, cheap, yield is high, purity is high and simple operating steps, is beneficial to very much the synthetic method of the irbesartan of industrial mass production.
Irbesartan reaction formula of the present invention is as follows:
Particularly, technical scheme of the present invention is a kind of method of synthesizing irbesartan, comprises the steps:
(1) 5-(4 '-methyl diphenyl-2-base)-1H-tetrazole, trityl chloride, triethylamine, react in methylene dichloride, obtains 5-(4 '-methyl diphenyl-2-base)-1-trityl-1H-tetrazole.
(2) 5-(4 '-methyl diphenyl-2-base)-1-trityl-1H-tetrazole, inorganic salt oxygenant, inorganic salt reductive agent, react in methylene dichloride and water, generate 5-(4 '-bromomethylbiphenyl-2-base)-1-trityl-1H-TETRAZOLE.
(3) 5-(4 '-bromomethylbiphenyl-2-base)-1-trityl-1H-TETRAZOLE, 2-butyl-1,3-diazaspiracyclic [4.4] nonane-1-alkene-4-oxidation of ketones hydrogen, Tetrabutyl amonium bromide, mineral alkali, in methylene dichloride and water, be obtained by reacting 2-butyl-3-[2 '-(1-trityl-1H-TETRAZOLE-5-base)-biphenyl-4-ylmethyl-1,3-diazaspiracyclic [4.4] nonane-1-alkene-4-ketone.
(4) 2-butyl-3-[2 '-(1-trityl-1H-TETRAZOLE-5-base)-biphenyl-4-ylmethyl-1,3-diazaspiracyclic [4.4] nonane-1-alkene-4-ketone and acid, in alcohol, water, be obtained by reacting 2-butyl-3-[[2-(1H-TETRAZOLE-5-base) xenyl-4-base] methyl]-1,3-diazaspiracyclic [4,4] nonane-1-alkene-4-ketone salt.
(5) 2-butyl-3-[[2-(1H-TETRAZOLE-5-base) xenyl-4-base] methyl]-1,3-diazaspiracyclic [4,4] nonane-1-alkene-4-ketone salt and sodium bicarbonate, in the mixed solution of ethanol, water, is obtained by reacting irbesartan.
In above-mentioned synthesis step (2), the inorganic salt oxygenant in reaction is selected from bromate, is preferably NaBrO
3, KBrO
3, Ca (BrO
3)
2, Mg (BrO
3)
2, most preferably be NaBrO
3.
In above-mentioned synthesis step (2), the inorganic salt reductive agent sulphite in reaction, preferably from Na
2s
2o
5, NaHSO
3, Na
2s
2o
4, Na
2sO
3, K
2s
2o
5, KHSO
3, K
2s
2o
4, K
2sO
3, most preferably be Na
2s
2o
4.
In above-mentioned synthesis step (2), 5-(4 '-methyl diphenyl-2-base)-1-trityl-1H-tetrazole in reaction: inorganic salt oxygenant: the mol ratio 1: 1-5: 1-5 of inorganic salt reductive agent, is preferably 1: 2: 2.Temperature of reaction is room temperature.
In above-mentioned synthesis (3) step, after reaction terminates, adopt the fatty alcohol of C1-C4 to product crystallization purifying, be preferably and adopt Virahol to carry out crystallization purifying to product.
In above-mentioned synthesis (3) step, the mineral alkali added in reaction can be selected from KOH, NaOH, Ca (OH)
2, be preferably KOH.
In above-mentioned synthesis (4) step, the ethanol in reaction: the volume ratio of water is 1: 0.1-4, is preferably 1: 0.5.Temperature of reaction is room temperature.
In above-mentioned synthesis (5) step, it is characterized in that the pH scope of reacting is 2-8, preferred pH is 4.Temperature of reaction is room temperature, after terminating, uses dichloromethane extraction, collects organic phase, then carry out recrystallizing and refining with ethanol to product, obtain final product after washing, drying.
Technical scheme raw material of the present invention and use catalyzer, solvent all low price, be easy to obtain, grope through a large amount of experiments, in step (2), generate bromine by the redox reaction of inorganic salt and then carry out bromo-reaction, overcome in currently available technology and directly utilize expensive brominated reagent to carry out bromo, the gentle safety of whole building-up process reaction conditions, without the need to initiator.
In chemical industry synthesis, often due to the toxicity of organic solvent, harm is brought to experiment operator, and react the complete organic solvent that need discharge, also great harm is caused to the environment of surrounding.Technical solution of the present invention 5 steps in, water accounts for more than 1/3rd of solvent for use volume; Two kinds of etoh solvents, methylene dichloride choosing in addition, relative to toluene, tetracol phenixin equal solvent conventional in prior art, toxicity is also less, environmental protection.And make contriver be in surprise, after great many of experiments determination reaction conditions, adopt water, ethanol, methylene dichloride as synthetic, the technique effect reached is excellent: the yield of each step reaction all reaches more than 86%, and final product is by detecting, high purity 99.8%.
In general, synthetic schemes of the present invention is cost-saving, simple to operate, and product purity is high, extremely meets the demand of industrial production of safety, low cost.
The Chinese noun that each english abbreviation described in patent specification is corresponding is as follows: HPLC: high pressure lipuid chromatography (HPLC); NBS:N-bromo-succinimide; DCM: methylene dichloride; Tr: trityl; TrCl: trityl chloride; TLC: tlc; TLC:Thin Layer Chromatogram (tlc).
Embodiment
Referring to specific embodiment, the present invention is described.It will be appreciated by those skilled in the art that these embodiments are only for illustration of the present invention, its scope do not limited the present invention in any way.
Experimental technique in following embodiment, if no special instructions, is ordinary method.Chemical feedstocks used in following embodiment, reagent material etc., if no special instructions, be commercially available purchase product.
Embodiment 1
5-(4-methyl diphenyl-2-base)-1H-tetrazole, No. CAS: 120568-11-8, buy in Zhuhai Run Doumintong limited-liability company, purity, 98%.
Trityl chloride, No. CAS: 76-83-5 buys in Guangde Zhongxin Chemical Factory, purity, 98%.
5-(4 '-methyl diphenyl-2-base)-1H-tetrazole 234g, trityl chloride 278g is added among 5L there-necked flask, and 4.5L methylene dichloride, stirring and dissolving.Under reaction solution being placed in ice bath-5 DEG C of conditions, the dichloromethane solution 500mL of slow dropping 4mol/L triethylamine, after adding, this reaction is reacted 2h as under room temperature condition, TLC monitors reaction and completes, add pure water, separatory, collects organic phase, with anhydrous sodium sulfate drying, filter, be spin-dried for, then add ethyl acetate 100ml, recrystallization, obtain white solid product, drying, finally obtains product 5-(4 '-methyl diphenyl-2-base)-1-trityl-1H-tetrazole (Compound II per) 460g, productive rate: 96%.
Embodiment 2
5-(4 '-methyl diphenyl-2-base)-1-trityl-IH-tetrazole (Compound II per), the 1200mL methylene dichloride of 288g is added, stirring and dissolving, then the NaBrO taking 181g among 5L there-necked flask
3be dissolved among 1000mL water, be added among above-mentioned reaction system, stir, then take the Na of 209g
2s
2o
4be dissolved among 1800mL water, and be transferred among constant pressure funnel, be slowly added dropwise among above-mentioned solution, after adding, reaction reacted 3.5h as under room temperature condition, TLC monitoring is until reacted.Then saturated NaHCO is added
3solution washing, separatory, collects organic phase, then with pure water once, the dry organic phase of separatory, filters, is spin-dried for.Then add ethyl acetate 200ml, under room temperature condition, stir 1h, filter, obtain white solid product, vacuum-drying 2h at 40 DEG C, obtaining product 5-(4 '-bromomethylbiphenyl-2-base)-1-trityl-1H-TETRAZOLE (IRB-02) is 322.2g, productive rate 96%.
Embodiment 3
IRB-01 (120g, 0.52mol) is added, Bu among 2L there-necked flask
4nBr (17g, 53mmol) and IRB-02 (246g, 0.441mol), then adds 800mL methylene dichloride and stirs, be dissolved in by KOH (104g, 1.85mol) in 400mL water, slowly add among above-mentioned reaction flask.Allow this reaction mixture be placed in 50 DEG C of water-baths and react 3h, then under this reaction being cooled to room temperature condition, reaction solution is poured into separatory among separating funnel, collect organic phase, aqueous phase uses methylene dichloride (400mL) to extract once again, again collect organic phase, merge twice organic phase, wash at twice with pure water (800mL), collect organic phase, use anhydrous sodium sulfate drying 0.5h, filter, be spin-dried for, then Virahol (1200ml) washing is added, 1.5h is stirred under room temperature condition, filter, Virahol (300mL) is used to wash twice again, obtain white solid product, by it under 40 DEG C of conditions, vacuum-drying 4h, obtain product 2-butyl-3-[2 '-(1-trityl-1H-TETRAZOLE-5-base)-biphenyl-4-ylmethyl-1, 3-diazaspiracyclic [4.4] nonane-1-alkene-4-ketone 275.1g, productive rate 93%.
Embodiment 4
IRB-01 (120g is added among 2L there-necked flask, 0.52mol), Bu4NBr (17g, 53mmol) with IRB-02 (246g, 0.441mol), then add 800mL methylene dichloride to stir, by KOH (104g, 1.85mol) be dissolved in 400mL water, slowly add among above-mentioned reaction flask.Allow this reaction mixture be placed in 50 DEG C of water-baths and react 3h, then under this reaction being cooled to room temperature condition, reaction solution is poured into separatory among separating funnel, collect organic phase, aqueous phase uses methylene dichloride (400mL) to extract once again, again collect organic phase, merge twice organic phase, wash at twice with pure water (800mL), collect organic phase, use anhydrous sodium sulfate drying 0.5h, filter, be spin-dried for, then Virahol (1200ml) washing is added, 1.5h is stirred under room temperature condition, filter, propyl carbinol (300mL) is used to wash twice again, obtain white solid product, by it under 40 DEG C of conditions, vacuum-drying 4h, obtain product 2-butyl-3-[2 '-(1-trityl-1H-TETRAZOLE-5-base)-biphenyl-4-ylmethyl-1, 3-diazaspiracyclic [4.4] nonane-1-alkene-4-ketone (IRB-03) 266.3g, productive rate 90%.
Embodiment 5
IRB-01 (120g, 0.52mol) is added, Bu among 2L there-necked flask
4nBr (17g, 53mmol) and IRB-02 (246g, 0.441mol), then adds 800mL methylene dichloride and stirs, be dissolved in by KOH (104g, 1.85mol) in 400mL water, slowly add among above-mentioned reaction flask.Allow this reaction mixture be placed in 50 DEG C of water-baths and react 3h, then under this reaction being cooled to room temperature condition, reaction solution is poured into separatory among separating funnel, collect organic phase, aqueous phase uses methylene dichloride (400mL) to extract once again, again collect organic phase, merge twice organic phase, wash at twice with pure water (800mL), collect organic phase, use anhydrous sodium sulfate drying 0.5h, filter, be spin-dried for, then Virahol (1200ml) washing is added, 1.5h is stirred under room temperature condition, filter, ethanol (300mL) is used to wash twice again, obtain white solid product, by it under 40 DEG C of conditions, vacuum-drying 4h, obtain product 2-butyl-3-[2 '-(1-trityl-1H-TETRAZOLE-5-base)-biphenyl-4-ylmethyl-1, 3-diazaspiracyclic [4.4] nonane-1-alkene-4-ketone (IRB-03) 266.3g, productive rate 90%.
Embodiment 6
Among the there-necked flask of 2L, add 100gIRB-03, and then slowly additional proportion is the mixed solvent 900ml of the second alcohol and water of 2: 1.Under stirring at room temperature condition, drip 36% hydrochloric acid soln 33ml, after adding, continuation stirs 2-3h at ambient temperature.By reacting liquid filtering after having reacted, the ethanol in filtrate is spin-dried for, then remaining water and white solid product has been stirred at ambient temperature and reach 2h, again filter, with pure water washing, obtained white solid product, vacuum-drying 4h.Then this solid is placed among 2L there-necked flask, adds 1.5L acetone and stir 5-20min at ambient temperature, backflow 1h.Then slow this hot solution to be cooled, filter, use washing with acetone again, obtain white solid product, vacuum-drying 2h, finally obtain product 2-butyl-3-[[2-(1H-TETRAZOLE-5-base) xenyl-4-base] methyl]-1,3-diazaspiracyclic [4,4] nonane-1-alkene-4-ketone salt (IRB-04) is 67g, and products collection efficiency is 96%, purity 99.7%.
Embodiment 7
Among the there-necked flask of 2L, add 100gIRB-03, and then slowly additional proportion is the mixed solvent 900ml of the second alcohol and water of 1: 1.Under stirring at room temperature condition, drip 36% hydrochloric acid soln 33ml, after adding, continuation stirs 2-3h at ambient temperature.By reacting liquid filtering after having reacted, the ethanol in filtrate is spin-dried for, then remaining water and white solid product has been stirred at ambient temperature and reach 2h, again filter, with pure water washing, obtained white solid product, vacuum-drying 4h.Then this solid is placed among 2L there-necked flask, adds 1.5L acetone and stir 5-20min at ambient temperature, backflow 1h.Then slow this hot solution to be cooled, filter, use washing with acetone again, obtain white solid product, vacuum-drying 2h, finally obtains product 2-butyl-3-[[2-(1H-TETRAZOLE-5-base) xenyl-4-base] methyl]-1,3-diazaspiracyclic [4,4] nonane-1-alkene-4-ketone salt (IRB-04) is 62.4g, productive rate 90%.
Embodiment 8
Among the there-necked flask of 2L, add 100gIRB-03, and then slowly additional proportion is the mixed solvent 900ml of the second alcohol and water of 3: 1.Under stirring at room temperature condition, drip 36% hydrochloric acid soln 33ml, after adding, continuation stirs 2-3h at ambient temperature.By reacting liquid filtering after having reacted, the ethanol in filtrate is spin-dried for, then remaining water and white solid product has been stirred at ambient temperature and reach 2h, again filter, with pure water washing, obtained white solid product, vacuum-drying 4h.Then this solid is placed among 2L there-necked flask, adds 1.5L acetone and stir 5-20min at ambient temperature, backflow 1h.Then slow this hot solution to be cooled, filter, use washing with acetone again, obtain white solid product, vacuum-drying 2h, finally obtains product 2-butyl-3-[[2-(1H-TETRAZOLE-5-base) xenyl-4-base] methyl]-1,3-diazaspiracyclic [4,4] nonane-1-alkene-4-ketone salt (IRB-04) is 63.7g, and productive rate is 92%.
Embodiment 9
Among 2L there-necked flask, add IRB-04 (50g, 0.1075mol), then add the mixed solvent of 600mL second alcohol and water (2: 1), stirring and dissolving, under the condition stirred, then slowly enter the NaHCO of 6%
3solution, surveys pH value with pH meter in the process dripped, and stops adding NaHCO when pH is 4
3solution, then stirs 1h at room temperature condition.Extract 3 times with methylene dichloride (300mL), collect organic phase, be spin-dried for, obtain white solid product, transfer them among 500mL there-necked flask, adding ethanol (300mL) reflux 0.5h.This solution slow cooling to 0 DEG C is reached 2h, separate out a large amount of white solid product, filter, wash once with cold ethanol (50mL) again, obtain white solid product, by it under 40 DEG C of conditions, vacuum-drying 4h, final product irbesartan (IRB) is 44.2g, and productive rate is 96% (purity 99.8%).
The contrast experiment of the different usage quantity of embodiment 10 synthesis step (2) catalyzer
Experiment is divided into four groups, adds the catalyzer of different mass respectively: A group (90.6g NaBrO in reaction process
3, 104.4g Na
2s
2o
4), B group (181g NaBrO
3, 209g Na
2s
2o
4), C group (271.5g NaBrO
3, 313.5g Na
2s
2o
4), D group (362g NaBrO
3, 418g Na
2s
2o
4), concrete operations are as follows:
A group: 5-(4 '-methyl diphenyl-2-base)-1-trityl-1H-tetrazole (Compound II per), the 1200mL methylene dichloride that add 288g among 5L there-necked flask, stirring and dissolving, then the NaBrO taking 90.6g
3be dissolved among 1000mL water, be added among above-mentioned reaction system, stir, then take the Na of 104.4g
2s
2o
4be dissolved among 1800mL water, and be transferred among constant pressure funnel, be slowly added dropwise among above-mentioned solution, after adding, reaction reacted 3.5h as under room temperature condition, TLC monitoring is until reacted.Then saturated NaHCO is added
3solution washing, separatory, collects organic phase, then with pure water once, the dry organic phase of separatory, filters, is spin-dried for.Then add ethyl acetate 200ml, stir 1h under room temperature condition, filter, obtain white solid product, vacuum-drying 2h at 40 DEG C, obtaining product IRB-02 is 285.2g, productive rate 86%.
B group: 5-(4 '-methyl diphenyl-2-base)-1-trityl-1H-tetrazole (Compound II per), the 1200mL methylene dichloride that add 288g among 5L there-necked flask, stirring and dissolving, then the NaBrO taking 181g
3be dissolved among 1000mL water, be added among above-mentioned reaction system, stir, then take the Na of 209g
2s
2o
4be dissolved among 1800mL water, and be transferred among constant pressure funnel, be slowly added dropwise among above-mentioned solution, after adding, reaction reacted 3.5h as under room temperature condition, TLC monitoring is until reacted.Then saturated NaHCO is added
3solution washing, separatory, collects organic phase, then with pure water once, the dry organic phase of separatory, filters, is spin-dried for.Then add ethyl acetate 200ml, under room temperature condition, stir 1h, filter, obtain white solid product, vacuum-drying 2h at 40 DEG C, obtaining product 5-(4 '-bromomethylbiphenyl-2-base)-1-trityl-1H-TETRAZOLE (IRB-02) is 322.2g, productive rate 96%.
C group: 5-(4 '-methyl diphenyl-2-base)-1-trityl-1H-tetrazole (Compound II per), the 1200mL methylene dichloride that add 288g among 5L there-necked flask, stirring and dissolving, then the NaBrO taking 271.5g
3be dissolved among 1000mL water, be added among above-mentioned reaction system, stir, then take the Na of 313.5g
2s
2o
4be dissolved among 1800mL water, and be transferred among constant pressure funnel, be slowly added dropwise among above-mentioned solution, after adding, reaction reacted 3.5h as under room temperature condition, TLC monitoring is until reacted.Then saturated NaHCO is added
3solution washing, separatory, collects organic phase, then with pure water once, the dry organic phase of separatory, filters, is spin-dried for.Then add ethyl acetate 200ml, stir 1h under room temperature condition, filter, obtain white solid product, vacuum-drying 2h at 40 DEG C, obtaining product IRB-02 is 312.1g, productive rate 93%.
D group: 5-(4 '-methyl diphenyl-2-base)-1-trityl-1H-tetrazole (Compound II per), the 1200mL methylene dichloride that add 288g among 5L there-necked flask, stirring and dissolving, then the NaBrO taking 362g
3be dissolved among 1000mL water, be added among above-mentioned reaction system, stir, then take the Na of 418g
2s
2o
4be dissolved among 1800mL water, and be transferred among constant pressure funnel, be slowly added dropwise among above-mentioned solution, after adding, reaction reacted 3.5h as under room temperature condition, TLC monitoring is until reacted.Then saturated NaHCO is added
3solution washing, separatory, collects organic phase, then with pure water once, the dry organic phase of separatory, filters, is spin-dried for.Then add ethyl acetate 200ml, stir 1h under room temperature condition, filter, obtain white solid product, vacuum-drying 2h at 40 DEG C, obtaining product IRB-02 is 302.0g, productive rate 90%.
The contrast experiment of the different usage quantity of table a synthesis step (2) catalyzer
| Group | Compound II per | NaBrO 3 | Na 2S 2O 4 | (Compound II per, NaBrO 3、Na 2S 2O 4) mol ratio | Productive rate |
| A group | 288g | 90.6g | 104.4g | 1∶1∶1 | 86％ |
| B group | 288g | 181g | 209g | 1∶2∶2 | 96％ |
| C group | 288g | 271.5g | 313.5g | 1∶3∶3 | 93％ |
| D group | 288g | 362g | 418g | 1∶4∶4 | 90％ |
Conclusion: as can be seen from table a, as (Compound II per, NaBrO
3, Na
2s
2o
4) mol ratio is when being 1: 2: 2 (B group), reaction yield is the highest, reaches 96%, and reaction effect is optimum.
Embodiment 11 synthesis step (2) uses the contrast experiment of different catalysts
Experiment is divided into five groups, adds different catalyzer respectively: A group (NaBrO in reaction process
3, Na
2s
2o
4), B group (NaBrO
3, NaHSO
3), C group (NaBrO
3, Na
2s
2o
5), D group (NaBrO
3, Na
2sO
3), E group (KBrO
3, Na
2s
2o
4), reaction result is different, and concrete operations are as follows:
A group: 5-(4 '-methyl diphenyl-2-base)-1-trityl-1H-tetrazole (Compound II per), the 1200mL methylene dichloride that add 288g among 5L there-necked flask, stirring and dissolving, then the NaBrO taking 181g
3be dissolved among 1000mL water, be added among above-mentioned reaction system, stir, then take the Na of 209g
2s
2o
4be dissolved among 1800mL water, and be transferred among constant pressure funnel, be slowly added dropwise among above-mentioned solution, after adding, reaction reacted 3.5h as under room temperature condition, TLC monitoring is until reacted.Then saturated NaHCO is added
3solution washing, separatory, collects organic phase, then with pure water once, the dry organic phase of separatory, filters, is spin-dried for.Then add ethyl acetate 200ml, under room temperature condition, stir 1h, filter, obtain white solid product, vacuum-drying 2h at 40 DEG C, obtaining product 5-(4 '-bromomethylbiphenyl-2-base)-1-trityl-1H-TETRAZOLE (IRB-02) is 322.2g, productive rate 96%.
B group: 5-(4 '-methyl diphenyl-2-base)-1-trityl-1H-tetrazole (Compound II per), the 1200mL methylene dichloride that add 288g among 5L there-necked flask, stirring and dissolving, then the NaBrO taking 181g
3be dissolved among 1000mL water, be added among above-mentioned reaction system, stir, then take the NaHSO of 124.8g
3be dissolved among 1800mL water, and be transferred among constant pressure funnel, be slowly added dropwise among above-mentioned solution, after adding, reaction reacted 3.5h as under room temperature condition, TLC monitoring is until reacted.Then saturated NaHCO is added
3solution washing, separatory, collects organic phase, then with pure water once, the dry organic phase of separatory, filters, is spin-dried for.Then add ethyl acetate 200ml, under room temperature condition, stir 1h, filter, obtain white solid product, vacuum-drying 2h at 40 DEG C, obtaining product 5-(4 '-bromomethylbiphenyl-2-base)-1-trityl-1H-TETRAZOLE (IRB-02) is 312.1g, productive rate 93%.
C group: 5-(4 '-methyl diphenyl-2-base)-1-trityl-1H-tetrazole (Compound II per), the 1200mL methylene dichloride that add 288g among 5L there-necked flask, stirring and dissolving, then the NaBrO taking 181g
3be dissolved among 1000mL water, be added among above-mentioned reaction system, stir, then take the Na of 228g
2s
2o
5be dissolved among 1800mL water, and be transferred among constant pressure funnel, be slowly added dropwise among above-mentioned solution, after adding, reaction reacted 3.5h as under room temperature condition, TLC monitoring is until reacted.Then saturated NaHCO is added
3solution washing, separatory, collects organic phase, then with pure water once, the dry organic phase of separatory, filters, is spin-dried for.Then add ethyl acetate 200ml, under room temperature condition, stir 1h, filter, obtain white solid product, vacuum-drying 2h at 40 DEG C, obtaining product 5-(4 '-bromomethylbiphenyl-2-base)-1-trityl-1H-TETRAZOLE (IRB-02) is 302.0g, productive rate 90%.
D group: 5-(4 '-methyl diphenyl-2-base)-1-trityl-1H-tetrazole (Compound II per), the 1200mL methylene dichloride that add 288g among 5L there-necked flask, stirring and dissolving, then the NaBrO taking 181g
3be dissolved among 1000mL water, be added among above-mentioned reaction system, stir, then take the Na of 126g
2sO
3be dissolved among 1800mL water, and be transferred among constant pressure funnel, be slowly added dropwise among above-mentioned solution, after adding, reaction reacted 3.5h as under room temperature condition, TLC monitoring is until reacted.Then saturated NaHCO is added
3solution washing, separatory, collects organic phase, then with pure water once, the dry organic phase of separatory, filters, is spin-dried for.Then add ethyl acetate 200ml, stir 1h under room temperature condition, can not get product, productive rate 0%.
E group: 5-(4 '-methyl diphenyl-2-base)-1-trityl-1H-tetrazole (Compound II per), the 1200mL methylene dichloride that add 288g among 5L there-necked flask, stirring and dissolving, then the KBrO taking 200.4g
3be dissolved among 1000mL water, be added among above-mentioned reaction system, stir, then take the Na of 209g
2s
2o
4be dissolved among 1800mL water, and be transferred among constant pressure funnel, be slowly added dropwise among above-mentioned solution, after adding, reaction reacted 3.5h as under room temperature condition, TLC monitoring is until reacted.Then saturated NaHCO is added
3solution washing, separatory, collects organic phase, then with pure water once, the dry organic phase of separatory, filters, is spin-dried for.Then add ethyl acetate 200ml, under room temperature condition, stir 1h, filter, obtain white solid product, vacuum-drying 2h at 40 DEG C, obtaining product 5-(4 '-bromomethylbiphenyl-2-base)-1-trityl-1H-TETRAZOLE (IRB-02) is 318.8g, productive rate 95%.
The contrast experiment of table b synthesis step (2) different catalysts
| Group | Inorganic salt oxygenant | Inorganic salt reductive agent | Product quality | Productive rate |
| A group | NaBrO 3 | Na 2S 2O 4 | 322.2g | 96％ |
| B group | NaBrO 3 | NaHSO 3 | 312.1g | 93％ |
| C group | NaBrO 3 | Na 2S 2O 5 | 302.0g | 90％ |
| D group | NaBrO 3 | Na 2SO 3 | 0 | 0 |
| E group | KBrO 3 | Na 2S 2O 4 | 318.8g | 95％ |
Conclusion: from the experimental data of table b, can find out, when reaction process selects NaBrO
3as oxygenant, Na
2s
2o
4during as reductive agent (A group), product yield is the highest, reaches 96%.
Embodiment 12 synthesis step (2) uses the contrast experiment of different organic solvents
Experiment is divided into four groups, the catalyzer of different solvents is added respectively: A group (methylene dichloride), B group (ethyl acetate), C group (1,2-methylene dichloride), D group (adjacent chlorobenzene) concrete operations are as follows in reaction process:
A group: 5-(4 '-methyl diphenyl-2-base)-1-trityl-1H-tetrazole (Compound II per), the 1200mL methylene dichloride that add 288g among 5L there-necked flask, stirring and dissolving, then the NaBrO taking 181g
3be dissolved among 1000mL water, be added among above-mentioned reaction system, stir, then take the Na of 209g
2s
2o
4be dissolved among 1800mL water, and be transferred among constant pressure funnel, be slowly added dropwise among above-mentioned solution, after adding, reaction reacted 3.5h as under room temperature condition, TLC monitoring is until reacted.Then saturated NaHCO is added
3solution washing, separatory, collects organic phase, then with pure water once, the dry organic phase of separatory, filters, is spin-dried for.Then add ethyl acetate 200ml, under room temperature condition, stir 1h, filter, obtain white solid product, vacuum-drying 2h at 40 DEG C, obtaining product 5-(4 '-bromomethylbiphenyl-2-base)-1-trityl-1H-TETRAZOLE (IRB-02) is 322.2g, productive rate 96%.
B group: 5-(4 '-methyl diphenyl-2-base)-1-trityl-1H-tetrazole (Compound II per), the 1200mL ethyl acetate that add 288g among 5L there-necked flask, stirring and dissolving, then the NaBrO taking 181g
3be dissolved among 1000mL water, be added among above-mentioned reaction system, stir, then take the NaHS0 of 124.8g
3be dissolved among 1800mL water, and be transferred among constant pressure funnel, be slowly added dropwise among above-mentioned solution, after adding, reaction reacted 3.5h as under room temperature condition, TLC monitoring is until reacted.Then saturated NaHCO is added
3solution washing, separatory, collects organic phase, then with pure water once, the dry organic phase of separatory, filters, is spin-dried for.Then add ethyl acetate 200ml, under room temperature condition, stir 1h, filter, obtain white solid product, vacuum-drying 2h at 40 DEG C, obtaining product 5-(4 '-bromomethylbiphenyl-2-base)-1-trityl-1H-TETRAZOLE (IRB-02) is 134.2g, productive rate 40%.
C group: 5-(4 '-methyl diphenyl-2-base)-1-trityl-1H-tetrazole (Compound II per), 1200mL1, the 2-ethylene dichloride that add 288g among 5L there-necked flask, stirring and dissolving, then the NaBrO taking 181g
3be dissolved among 1000mL water, be added among above-mentioned reaction system, stir, then take the Na of 228g
2s
2o
5be dissolved among 1800mL water, and be transferred among constant pressure funnel, be slowly added dropwise among above-mentioned solution, after adding, reaction reacted 3.5h as under room temperature condition, TLC monitoring is until reacted.Then saturated NaHCO is added
3solution washing, separatory, collects organic phase, then with pure water once, the dry organic phase of separatory, filters, is spin-dried for.Then add ethyl acetate 200ml, under room temperature condition, stir 1h, filter, obtain white solid product, vacuum-drying 2h at 40 DEG C, obtaining product 5-(4 '-bromomethylbiphenyl-2-base)-1-trityl-1H-TETRAZOLE (IRB-02) is 302.0g, productive rate 90%.
D group: the adjacent chlorobenzene of 5-(4 '-methyl diphenyl-2-base)-1-trityl-1H-tetrazole (Compound II per), 1200mL adding 288g among 5L there-necked flask, stirring and dissolving, then the NaBrO taking 181g
3be dissolved among 1000mL water, be added among above-mentioned reaction system, stir, then take the Na of 126g
2sO
3be dissolved among 1800mL water, and be transferred among constant pressure funnel, be slowly added dropwise among above-mentioned solution, after adding, reaction reacted 3.5h as under room temperature condition, TLC monitoring is until reacted.Then saturated NaHCO is added
3solution washing, separatory, collects organic phase, then with pure water once, the dry organic phase of separatory, filters, is spin-dried for.Then add ethyl acetate 200ml, under room temperature condition, stir 1h, filter, obtain white solid product, vacuum-drying 2h at 40 DEG C, obtaining product 5-(4 '-bromomethylbiphenyl-2-base)-1-trityl-1H-TETRAZOLE (IRB-02) is 302.0g, productive rate 90%.
Table c synthesis step (2) uses the contrast experiment of differential responses organic solvent
| Group | Organic solvent | Product quality | Productive rate |
| A group | Methylene dichloride | 322.2g | 96％ |
| B group | Ethyl acetate | 134.2g | 40％ |
| C group | 1,2-ethylene dichloride | 302.0g | 90％ |
| D group | Adjacent chlorobenzene | 302.0g | 90％ |
Conclusion: from the experimental data of table c, can find out, when reaction process selects low poison solvent methylene dichloride (A group) as solvent, product yield is the highest, reaches 96%.
The contrast experiment of differential responses solvent is selected in embodiment 13 synthesis step (3)
Experiment is divided into four groups, selects different reaction solvents respectively in reaction process: A group (methylene dichloride), B group (toluene), C group (acetone), D group (tetrahydrofuran (THF)) concrete operations are as follows:
A group: add IRB-01 (120g among 2L there-necked flask, 0.52mol), Bu4NBr (17g, 53mmol) with IRB-02 (246g, 0.441mol), then add 800mL methylene dichloride to stir, by KOH (104g, 1.85mol) be dissolved in 400mL water, slowly add among above-mentioned reaction flask.Allow this reaction mixture be placed in 50 DEG C of water-baths and react 3h, then under this reaction being cooled to room temperature condition, reaction solution is poured into separatory among separating funnel, collect organic phase, aqueous phase uses methylene dichloride (400mL) to extract once again, again collect organic phase, merge twice organic phase, wash at twice with pure water (800mL), collect organic phase, use anhydrous sodium sulfate drying 0.5h, filter, be spin-dried for, then Virahol (1200ml) washing is added, 1.5h is stirred under room temperature condition, filter, Virahol (300mL) is used to wash twice again, obtain white solid product, by it under 40 DEG C of conditions, vacuum-drying 4h, obtain product 2-butyl-3-[2 '-(1-trityl-1H-TETRAZOLE-5-base)-biphenyl-4-ylmethyl-1, 3-diazaspiracyclic [4.4] nonane-1-alkene-4-ketone (IRB-03) 275.1g, productive rate 93%.
B group: add IRB-01 (120g, 0.52mol) among 2L there-necked flask, Bu
4nBr (17g, 53mmol) and IRB-02 (246g, 0.441mol), then adds 800mL toluene and stirs, be dissolved in by KOH (104g, 1.85mol) in 400mL water, slowly add among above-mentioned reaction flask.Allow this reaction mixture be placed in 50 DEG C of water-baths and react 3h, then under this reaction being cooled to room temperature condition, reaction solution is poured into separatory among separating funnel, collect organic phase, aqueous phase uses methylene dichloride (400mL) to extract once again, again collect organic phase, merge twice organic phase, wash at twice with pure water (800mL), collect organic phase, use anhydrous sodium sulfate drying 0.5h, filter, be spin-dried for, then Virahol (1200ml) washing is added, 1.5h is stirred under room temperature condition, filter, Virahol (300mL) is used to wash twice again, obtain white solid product, by it under 40 DEG C of conditions, vacuum-drying 4h, obtain product 2-butyl-3-[2 '-(1-trityl-1H-TETRAZOLE-5-base)-biphenyl-4-ylmethyl-1, 3-diazaspiracyclic [4.4] nonane-1-alkene-4-ketone (IRB-03) 275.1g, productive rate 93%.
C group: add IRB-01 (120g, 0.52mol) among 2L there-necked flask, Bu
4nBr (17g, 53mmol) and IRB-02 (246g, 0.441mol), then adds 800mL acetone and stirs, be dissolved in by KOH (104g, 1.85mol) in 400mL water, slowly add among above-mentioned reaction flask.Allow this reaction mixture be placed in 50 DEG C of water-baths and react 3h, then under this reaction being cooled to room temperature condition, reaction solution is poured into separatory among separating funnel, collect organic phase, aqueous phase uses methylene dichloride (400mL) to extract once again, again collect organic phase, merge twice organic phase, wash at twice with pure water (800mL), collect organic phase, use anhydrous sodium sulfate drying 0.5h, filter, be spin-dried for, then Virahol (1200ml) washing is added, 1.5h is stirred under room temperature condition, filter, Virahol (300mL) is used to wash twice again, obtain white solid product, by it under 40 DEG C of conditions, vacuum-drying 4h, obtain product 2-butyl-3-[2 '-(1-trityl-1H-TETRAZOLE-5-base)-biphenyl-4-ylmethyl-1, 3-diazaspiracyclic [4.4] nonane-1-alkene-4-ketone (IRB-03) 147.9g, productive rate 50%.
D group: add IRB-01 (120g, 0.52mol) among 2L there-necked flask, Bu
4nBr (17g, 53mmol) and IRB-02 (246g, 0.441mol), then adds 800mL tetrahydrofuran (THF) and stirs, be dissolved in by KOH (104g, 1.85mol) in 400mL water, slowly add among above-mentioned reaction flask.Allow this reaction mixture be placed in 50 DEG C of water-baths and react 3h, then under this reaction being cooled to room temperature condition, reaction solution is poured into separatory among separating funnel, collect organic phase, aqueous phase uses methylene dichloride (400mL) to extract once again, again collect organic phase, merge twice organic phase, wash at twice with pure water (800mL), collect organic phase, use anhydrous sodium sulfate drying 0.5h, filter, be spin-dried for, then Virahol (1200ml) washing is added, 1.5h is stirred under room temperature condition, filter, Virahol (300mL) is used to wash twice again, obtain white solid product, by it under 40 DEG C of conditions, vacuum-drying 4h, obtain product 2-butyl-3-[2 '-(1-trityl-1H-TETRAZOLE-5-base)-biphenyl-4-ylmethyl-1, 3-diazaspiracyclic [4.4] nonane-1-alkene-4-ketone (IRB-03) 236.6g, productive rate 80%.
The contrast experiment of differential responses solvent is selected in table d synthesis step (3)
| Group | Reaction organic solvent | Temperature of reaction (DEG C) | Product quality | Productive rate |
| A group | Methylene dichloride | 48 | 275.1g | 93％ |
| B group | Toluene | 85 | 275.1g | 93％ |
| C group | Acetone | 60 | 147.9g | 50％ |
| D group | Tetrahydrofuran (THF) | 80 | 236.6g | 80％ |
Conclusion: from the experimental data of above-mentioned table d, can find out, when reaction process selects methylene dichloride (A group), toluene (B group) as solvent, products collection efficiency all can reach 93%, but toluene is poisonous, and B group reaction when reaching temperature of reaction reach 85 degrees Celsius, and A group is only 48 degrees Celsius, and A group is safer.Therefore, A group is preferred embodiment.
The contrast experiment that the different pH of embodiment 14 step (5) selects
Experiment is divided into four groups, in reaction process, adds the NaHCO of 6%
3solution regulates reaction solution pH, and when the value of pH is different: A group (pH2), B group (pH4), C group (pH6), D group (pH8), the productive rate of reaction is different, and concrete operations are as follows:
A group: add IRB-04 (50g, 0.1075mol) among 2L there-necked flask, then the mixed solvent adding 600mL second alcohol and water 2: 1, stirring and dissolving, then slowly enters the NaHCO of 6% under the condition stirred
3solution, surveys pH value with pH meter in the process dripped, and stops adding NaHCO when pH is 2
3solution, then stirs 1h at room temperature condition.Extract 3 times with methylene dichloride (300mL), collect organic phase, be spin-dried for, obtain white solid product, transfer them among 500mL there-necked flask, adding ethanol (300mL) reflux 0.5h.This solution slow cooling to 0 DEG C is reached 2h, separate out a large amount of white solid product, filter, wash once with cold ethanol (50mL) again, obtain white solid product, by it under 40 DEG C of conditions, vacuum-drying 4h, obtaining final product irbesartan (IRB) is 27.6g, and productive rate is 62%.
B group: add IRB-04 (50g, 0.1075mol) among 2L there-necked flask, then the mixed solvent adding 600mL second alcohol and water (2: 1), stirring and dissolving, then slowly enters the NaHCO of 6% under the condition stirred
3solution, surveys pH value with pH meter in the process dripped, and stops adding NaHCO when pH is 4
3solution, then stirs 1h at room temperature condition.Extract 3 times with methylene dichloride (300mL), collect organic phase, be spin-dried for, obtain white solid product, transfer them among 500mL there-necked flask, adding ethanol (300mL) reflux 0.5h.This solution slow cooling to 0 DEG C is reached 2h, separate out a large amount of white solid product, filter, wash once with cold ethanol (50mL) again, obtain white solid product, by it under 40 DEG C of conditions, vacuum-drying 4h, final product irbesartan (IRB) is 44.2g, and productive rate is 96%.
C group: add IRB-04 (50g, 0.1075mol) among 2L there-necked flask, then the mixed solvent adding 600mL second alcohol and water (2: 1), stirring and dissolving, then slowly enters the NaHCO of 6% under the condition stirred
3solution, surveys pH value with pH meter in the process dripped, and stops adding NaHCO when pH is 6
3solution, then stirs 1h at room temperature condition.Extract 3 times with methylene dichloride (300mL), collect organic phase, be spin-dried for, obtain white solid product, transfer them among 500mL there-necked flask, adding ethanol (300mL) reflux 0.5h.This solution slow cooling to 0 DEG C is reached 2h, separate out a large amount of white solid product, filter, wash once with cold ethanol (50mL) again, obtain white solid product, by it under 40 DEG C of conditions, vacuum-drying 4h, final product irbesartan (IRB) is 41.5g, and productive rate is 90%.
D group: add IRB-04 (50g, 0.1075mol) among 2L there-necked flask, then the mixed solvent adding 600mL second alcohol and water (2: 1), stirring and dissolving, then slowly enters the NaHC0 of 6% under the condition stirred
3solution, surveys pH value with pH meter in the process dripped, and stops adding NaHCO when pH is 8
3solution, then stirs 1h at room temperature condition.Extract 3 times with methylene dichloride (300mL), collect organic phase, be spin-dried for, obtain white solid product, transfer them among 500mL there-necked flask, adding ethanol (300mL) reflux 0.5h.This solution slow cooling to 0 DEG C is reached 2h, separate out a large amount of white solid product, filter, wash once with cold ethanol (50mL) again, obtain white solid product, by it under 40 DEG C of conditions, vacuum-drying 4h, final product irbesartan (IRB) is 36.9g, and productive rate is 80%.
The contrast experiment of different pH in table e synthesis step (5)
| Group | pH | Product quality | Productive rate |
| A group | 2 | 27.6g | 62％ |
| B group | 4 | 44.2g | 96％ |
| C group | 6 | 41.5g | 90％ |
| D group | 8 | 36.9g | 80％ |
Conclusion: from the experimental data of above-mentioned table e, can find out, when reaction process pH is 4 (B group), products collection efficiency all can reach 96%, is preferred embodiment.
Claims (5)
1. synthesize a method for irbesartan, comprise the steps:
(1) 5-(4 '-methyl diphenyl-2-base)-1H-tetrazole, trityl chloride, triethylamine, react in methylene dichloride, obtains 5-(4 '-methyl diphenyl-2-base)-1-trityl-1H-tetrazole;
(2) 5-(4 '-methyl diphenyl-2-base)-1-trityl-1H-tetrazole, inorganic salt oxygenant, inorganic salt reductive agent, react in methylene dichloride and water, generate 5-(4 '-bromomethylbiphenyl-2-base)-1-trityl-1H-tetrazole;
Wherein, the inorganic salt oxygenant in reaction is NaBrO
3, inorganic salt reductive agent is Na
2s
2o
4;
(3) 5-(4 '-bromomethylbiphenyl-2-base)-1-trityl-1H-tetrazole, 2-butyl-1,3-diazaspiracyclic [4.4] nonane-1-alkene-4-ketone hydrogenchloride, Tetrabutyl amonium bromide, mineral alkali, in methylene dichloride and water, be obtained by reacting 2-butyl-3-[2 '-(1-trityl-1H-TETRAZOLE-5-base)-biphenyl-4-ylmethyl-1,3-diazaspiracyclic [4.4] nonane-1-alkene-4-ketone;
(4) 2-butyl-3-[2 '-(1-trityl-1H-TETRAZOLE-5-base)-biphenyl-4-ylmethyl-1,3-diazaspiracyclic [4.4] nonane-1-alkene-4-ketone, acid, in alcohol and water, be obtained by reacting 2-butyl-3-[[2-(1H-TETRAZOLE-5-base) xenyl-4-base] methyl]-1,3-diazaspiracyclic [4,4] nonane-1-alkene-4-ketone salt;
(5) 2-butyl-3-[[2-(1H-TETRAZOLE-5-base) xenyl-4-base] methyl]-1,3-diazaspiracyclic [4,4] nonane-1-alkene-4-ketone salt and sodium bicarbonate, in the mixed solution of ethanol, water, is obtained by reacting irbesartan.
2. method according to claim 1, is characterized in that, in described synthesis step (2), and 5-(4 '-methyl diphenyl-2-base)-1-trityl-1H-tetrazole: NaBrO in reaction
3: Na
2s
2o
4mol ratio be 1:1-5:1-5.
3. method according to claim 2, is characterized in that, in described synthesis step (2), and 5-(4 '-methyl diphenyl-2-base)-1-trityl-1H-tetrazole: NaBrO in reaction
3: Na
2s
2o
4mol ratio be 1:2:2.
4. method according to claim 1, is characterized in that, in described synthesis step (3), after reaction terminates, adopts C
l-C
4fatty alcohol to product crystallization purifying.
5. method according to claim 4, is characterized in that, in described synthesis (3) step, after reaction terminates, adopts Virahol to product crystallization purifying.
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