CN103923028A - Preparation method of valsartan - Google Patents
Preparation method of valsartan Download PDFInfo
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- CN103923028A CN103923028A CN201410181379.0A CN201410181379A CN103923028A CN 103923028 A CN103923028 A CN 103923028A CN 201410181379 A CN201410181379 A CN 201410181379A CN 103923028 A CN103923028 A CN 103923028A
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- valsartan
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- methyl ester
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- amide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
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Abstract
The invention provides a preparation method of valsartan. The preparation method has the technical effects that amide methyl ester and sodium azide are used as raw materials and are catalyzed by amine salt to carry out tetrazole formation reaction; side effects are minimized by controlling the reaction course; main products are furthest generated; unreacted raw materials are recycled and reused; the yield in the preparation method is increased by more than 10% relative to the yields in existing processes; compared with the existing processes, the method has the effect that plenty of high-toxicity wastewater is no longer generated, and is easy to be widely popularized industrially.
Description
Technical field
The present invention relates to have a kind of preparation method of the depressor valsartan of significant curative effect effect.
Background technology
Valsartan is a kind of non-peptide class Angiotensin II (Ang II) receptor antagonist pharmaceuticals, in this class medicine having gone on the market, has become line medication kind the most widely.
At present, valsartan synthetic, disclosed report document has:
[J].J.Med.chem.1991.34：2525-2547；
[P].US.5399578 1995-03-21
[P].US.2006149079 2006-07-06
Comprehensive pertinent literature, detailed process is as follows:
1-be take Valine as starting raw material, and the esterification through anhydrous methanol and sulfur oxychloride, obtains Valine methyl ester hydrochloride.
2.L-valine methyl ester hydrochloride, under the effect of salt of wormwood, with the condensation of bromo sartanbiphenyl, generates N-(2 '-cyanobiphenyl-4-yl) methyl]-Valine methyl ester hydrochloride (CAS:482577-59-3), be commonly called as secondary amine methyl ester hydrochloride.
3. secondary amine methyl ester hydrochloride, under the effect of salt of wormwood, carries out acidylate with n-amyl chloride, generates N-positive pentanoyl-N-[(2 '-cyanobiphenyl-4-yl) methyl]-Valine methyl esters (CAS:137863-90-2), be commonly called as amide methyl ester.
4. amide methyl ester, in the system of sodiumazide and catalyzer, complete tetrazoleization reaction, generate N-(1-oxygen amyl group)-N-[[2 '-(1H-tetrazole-5-yl) [1,1 '-xenyl]-4-yl] methyl]-Valine methyl esters (CAS:137863-17-3), be commonly called as valsartan methyl esters, then through basic hydrolysis, obtain valsartan.
Secondary amine methyl ester hydrochloride, amide methyl ester, valsartan methyl esters concrete structure are distinguished as follows:
(secondary amine methyl ester hydrochloride)
(secondary amine methyl ester hydrochloride N-[(2 '-cyanobiphenyl-4-yl) methyl]-Valine methyl ester hydrochloride)
(amide methyl ester)
(amide methyl ester N-[2 '-(N mono-trityl)-tetrazolium-5-yl]-[(1,1 '-biphenyl-4-yl)-methyl]-N-valeryl-Valine methyl esters)
(valsartan methyl esters)
In this synthetic route, the most key sport technique segment is the tetrazoleization reaction of amide methyl ester, its directly left and right the quality and cost of valsartan.In the tetrazoleization reaction link of amide methyl ester, what success was used at present is the tetrazoleization reaction that adopts alkyl tin chloride (trimethyltin chloride or tributyltin chloride) to participate in, the technique that the triethylamine hydrochloride of take is in addition catalyzer.For the former, although can make to react completely, residual below 0.5% to amide methyl ester, but belong to high toxicity, high pollution, expensive chemical, the organotin wastewater particularly forming after reaction, is difficult to effectively process, to environmental protection, pose a big pressure, belong to the scheme of banning of eliminating.
The technique that the triethylamine hydrochloride of take is catalyzer, successfully realizes suitability for industrialized production at present, but due to the restriction of catalytic activity own, reaction can not be complete! By extending the reaction times, the transformation efficiency of reaction system valsartan methyl esters is not high yet, still has amide methyl ester residual of 25% left and right, also has plenty of the related impurities product of 10% left and right.At present, the scheme of valsartan is prepared in the tetrazole catalysis of triethylamine hydrochloride, and the most obvious short slab is after tetrazoleization has been reacted, and directly carries out basic hydrolysis! 65% valsartan methyl esters has been hydrolyzed, and 25% unreacted amide methyl ester has also been hydrolyzed, and 10% related impurities has also been hydrolyzed, and finally causes valsartan product yield to only have 72%.
Summary of the invention
Technical problem to be solved by this invention is the above-mentioned shortcoming and defect that overcomes existing synthesis technique, provides a kind of high yield, the synthetic method of the valsartan under triethylamine hydrochloride catalysis cheaply.
The problem that the present invention is the above-mentioned proposition of solution is adopted solution to be:
Take secondary amine methyl ester hydrochloride as starting raw material:
1. through chloride, make amide methyl ester;
2. again through the tetrazole reaction under triethylamine hydrochloride catalysis, obtain valsartan methyl esters, effectively isolate unreacted amide methyl ester simultaneously;
3. the basic hydrolysis of valsartan methyl esters obtains valsartan.
The invention discloses a kind of preparation method of valsartan, wherein, operation in accordance with the following steps:
1) amide methyl ester, sodiumazide are mixed mutually with reaction solvent, add catalyzer, tetrazole reaction is carried out in insulation, controls reaction process, obtains white solid valsartan methyl esters,
2) mother liquor divides and anhydrates, and steaming desolventizes, and recrystallization reclaims raw material amide methyl ester,
3), by the basic hydrolysis of valsartan methyl esters, acidifying, extracts to obtain product,
Reaction solvent is toluene, any one in DMF, ethyl acetate.
Catalyzer is any one in triethylamine hydrochloride, ammonium chloride, zinc chloride.
The mass ratio of amide methyl ester, triethylamine hydrochloride, sodiumazide is 1: 0.4～0.8: 0.2～0.4.
The process that reaction is carried out is controlled at 48～55%.
The present invention compared with prior art, has following useful technique effect:
1, with low toxicity cheaply triethylamine hydrochloride as catalyzer, carry out the tetrazole generating process participating in the expensive alkyl diazoimide tin (tributyltin chloride) of high toxicity of tetrazole substituted in reaction report, realize the environmental protection of technique;
2, amide methyl ester is realized solvent crystal and is separated out, and has improved quality product;
3, tetrazole reaction process is control effectively, avoid the generation of impurity, improved quality product and yield;
4, tetrazole is reacted to unreacted amide methyl ester and carry out efficient recovery and apply mechanically, improved product yield;
5, the yield of valsartan of the present invention improves 10% (secondary amine methyl ester hydrochloride is calculated) compared with prior art.
Embodiment
The invention discloses a kind of preparation method of valsartan, wherein, operation in accordance with the following steps:
1) amide methyl ester, sodiumazide are mixed mutually with reaction solvent, add catalyzer, tetrazole reaction is carried out in insulation, controls reaction process, obtains white solid valsartan methyl esters,
2) mother liquor divides and anhydrates, and steaming desolventizes, and recrystallization reclaims raw material amide methyl ester,
3), by the basic hydrolysis of valsartan methyl esters, acidifying, extracts to obtain product,
Reaction solvent is toluene, any one in DMF, ethyl acetate.
Catalyzer is any one in triethylamine hydrochloride, ammonium chloride, zinc chloride.
The mass ratio of amide methyl ester, triethylamine hydrochloride, sodiumazide is 1: 0.4～0.8: 0.2～0.4.
The process that reaction is carried out is controlled at 48～55%
In order to understand better the present invention, below in conjunction with test example, further set forth content of the present invention, but content of the present invention is not only confined to the following examples.
The preparation of embodiment 1:L-valine methyl ester hydrochloride:
By the methyl alcohol of 1000ml, the Valine suction reactor of 200g, is chilled under stirring below-5 ℃, drips 400g sulfur oxychloride.Dropwise, be slowly heated to back flow reaction 4.0 hours, then start evaporated under reduced pressure methyl alcohol.After methyl alcohol evaporate to dryness, drop into again the ethyl acetate of 300ml, at temperature-10～0 ℃, stir more than 3 hours.Filter, and at 60～70 ℃, under vacuum tightness >=-0.09Mpa, dry, obtain the Valine methyl ester hydrochloride of 260g, purity 99.4%.
Embodiment 2: the preparation of secondary amine methyl ester hydrochloride:
The tap water of 800ml and 240g salt of wormwood are dropped in reactor, stir the lower 2000ml of input ethyl acetate, the Valine methyl ester hydrochloride of 168g embodiment 1 preparation and the bromo sartanbiphenyl of 200g.Be heated to reflux, and maintain back flow reaction 2 hours.Standing after being chilled to 20～40 ℃, branch vibration layer, organic phase with hcl acidifying to PH=1.Filter, at 70 ± 5 ℃, vacuum tightness is dried under-0.09Mpa, obtains secondary amine methyl ester hydrochloride 260g, purity 99.6%.
Embodiment 3: the preparation of amide methyl ester:
By the tap water of 100ml, in the salt of wormwood suction reactor of 250g, stir molten rear suction 1750ml toluene, then drop into the secondary amine methyl ester hydrochloride of 225g embodiment 2 preparations.Be stirred to substantially molten clear after, at 25 ± 5 ℃, start to drip valeryl chloride 100g, control dropping temperature-10～0 ℃.Dropwise, continue-10～0 ℃ of stirring reaction 2 hours.Standing, branch vibration layer, then starts evaporated under reduced pressure toluene.After toluene evaporate to dryness, drop into again the sherwood oil of 750ml, at temperature-10～0 ℃, stir more than 3 hours.Filter, at 60～70 ℃, under vacuum tightness >=-0.09Mpa, dry, obtain amide methyl ester 250g, purity 99.3%.
Embodiment 4: the preparation of valsartan methyl esters and the recovery of amide methyl ester:
250g embodiment 3 amide methyl esters of preparation and the toluene of 2000ml are mixed mutually, then drop into the triethylamine hydrochloride of 160g, the sodium azide of 75g.Be heated with stirring to 100～105 ℃ of temperature, insulation reaction 10 hours, controls reaction process, reaction system valsartan methyl esters content 54%.After insulation reaction finishes, drop into the tap water of 1000ml, subsequently, drip hydrochloric acid and adjust PH2～3, crystallization, filters, and at 60～70 ℃, under vacuum tightness >=-0.09Mpa, dries, and obtains valsartan methyl esters 124g, purity 99.2%.
Mother liquor after valsartan methyl esters filters, first divides disacidify water, then evaporated under reduced pressure toluene.After toluene evaporate to dryness, drop into again the sherwood oil of 150ml, at temperature-10～0 ℃, stir 3 hours.Filter, at 60～70 ℃, under vacuum tightness >=-0.09Mpa, dry, obtain amide methyl ester 122g, purity 99.4%.
Embodiment 5: the preparation of valsartan:
The valsartan methyl esters of 45g embodiment 4 preparations, adds 250ml water, stirs the sodium hydrate solid of the lower 5g of input, is heated to 80 ℃, stirs 2h.Be cooled to below 35 ℃, with 3% hydrochloric acid, be adjusted to Ph=2～3, add subsequently the ethyl acetate extraction of 200ml, divide disacidify water layer, organic layer cooling, crystallization, suction filtration, at 60～70 ℃, dries under vacuum tightness >=-0.09Mpa, obtain valsartan 40g, mp108～112 ℃, [α] 20D-68 ° of (C1, methyl alcohol), purity 99.3%, related substances 0.7%, chiral isomer 0.14%[document: mp105～115 ℃, [α] 20D-67.9 ° (C1, methyl alcohol)].
Embodiment 6: the preparation of valsartan methyl esters and the recovery of amide methyl ester:
The amide methyl ester that 60g embodiment 4 is reclaimed is mixed mutually with the toluene of 500ml, then drops into the triethylamine hydrochloride of 45g, the sodium azide of 24g.Be heated with stirring to 100～105 ℃ of temperature, insulation reaction 8 hours, controls reaction process, reaction system valsartan methyl esters content 52%.After insulation reaction finishes, drop into the tap water of 1000ml, subsequently, drip hydrochloric acid and adjust PH2～3, crystallization, filters, and at 60～70 ℃, under vacuum tightness >=-0.09Mpa, dries, and obtains valsartan methyl esters 30g, purity 99.3%.
Mother liquor after valsartan methyl esters filters, first divides disacidify water, then evaporated under reduced pressure toluene.After toluene evaporate to dryness, drop into again the sherwood oil of 150ml, at temperature-10～0 ℃, stir more than 3 hours.Filter, at 60～70 ℃, under vacuum tightness >=-0.09Mpa, dry, obtain amide methyl ester 28g, purity 99.1%.
Embodiment 7: the preparation of valsartan:
The valsartan methyl esters of 30g embodiment 6 preparations, adds 170ml water, stirs the sodium hydrate solid of the lower 3.5g of input, is heated to 80 ℃, stirs 2h.Be cooled to below 35 ℃, with 3% hydrochloric acid, be adjusted to Ph=2～3, add subsequently the ethyl acetate extraction of 135ml, divide disacidify water layer, organic layer cooling, crystallization, suction filtration, at 60～70 ℃, dries under vacuum tightness >=-0.09Mpa, obtain valsartan 26.5g, mp110～114 ℃, [α] 20D-69.8 ° of (C1, methyl alcohol), purity 99.2%, related substances 0.8%, chiral isomer 0.16%[document: mp105～115 ℃, [α] 20D-67.9 ° (C1, methyl alcohol)].
The present invention compared with prior art, there is following useful technique effect: with low toxicity cheaply triethylamine hydrochloride as catalyzer, carry out the tetrazole generating process participating in the expensive alkyl diazoimide tin (tributyltin chloride) of high toxicity of tetrazole substituted in reaction report, realize the environmental protection of technique; Amide methyl ester is realized solvent crystal and is separated out, and has improved quality product; Tetrazole reaction process is control effectively, avoid the generation of impurity, improved quality product and yield; Tetrazole is reacted to unreacted amide methyl ester and carry out efficient recovery and apply mechanically, improved product yield; The yield of valsartan of the present invention improves 10% (secondary amine methyl ester hydrochloride is calculated) compared with prior art.
Claims (5)
1. a preparation method for valsartan, is characterized in that, in accordance with the following steps operation:
1) amide methyl ester, sodiumazide are mixed mutually with reaction solvent, add catalyzer, tetrazole reaction is carried out in insulation, controls reaction process, obtains white solid valsartan methyl esters,
2) mother liquor divides and anhydrates, and steaming desolventizes, and recrystallization reclaims raw material amide methyl ester,
3), by the basic hydrolysis of valsartan methyl esters, acidifying, extracts to obtain product.
2. preparation method as claimed in claim 1, is characterized in that, reaction solvent is toluene, any one in DMF, ethyl acetate.
3. preparation method as claimed in claim 1, is characterized in that, catalyzer is any one in triethylamine hydrochloride, ammonium chloride, zinc chloride.
4. preparation method as claimed in claim 1, is characterized in that, the mass ratio of amide methyl ester, triethylamine hydrochloride, sodiumazide is 1: 0.4～0.8: 0.2～0.4.
5. preparation method as claimed in claim 1, is characterized in that, the process that reaction is carried out is controlled at 48～55%.
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Cited By (5)
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| CN106038499A (en) * | 2016-06-22 | 2016-10-26 | 深圳市樊溪电子有限公司 | Valsartan dispersible tablet and preparation method thereof |
| CN107056720A (en) * | 2016-12-30 | 2017-08-18 | 湖南千金湘江药业股份有限公司 | A kind of preparation and purification method of Valsartan |
| CN111393327A (en) * | 2020-03-25 | 2020-07-10 | 河南豫辰药业股份有限公司 | Preparation method of valsartan intermediate |
| CN113264891A (en) * | 2021-05-26 | 2021-08-17 | 珠海润都制药股份有限公司 | Method for recovering L-valsartan from valsartan mother liquor containing D-valsartan |
| EP3939967A1 (en) | 2020-07-15 | 2022-01-19 | KRKA, d.d., Novo mesto | A continuous process for the preparation of (s)-methyl n-((2'-cyano-[1,1'-biphenyl]-4-yl)methyl)-n-pentanoylvalinate in a flow reactor |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106038499A (en) * | 2016-06-22 | 2016-10-26 | 深圳市樊溪电子有限公司 | Valsartan dispersible tablet and preparation method thereof |
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| CN107056720A (en) * | 2016-12-30 | 2017-08-18 | 湖南千金湘江药业股份有限公司 | A kind of preparation and purification method of Valsartan |
| CN111393327A (en) * | 2020-03-25 | 2020-07-10 | 河南豫辰药业股份有限公司 | Preparation method of valsartan intermediate |
| EP3939967A1 (en) | 2020-07-15 | 2022-01-19 | KRKA, d.d., Novo mesto | A continuous process for the preparation of (s)-methyl n-((2'-cyano-[1,1'-biphenyl]-4-yl)methyl)-n-pentanoylvalinate in a flow reactor |
| CN113264891A (en) * | 2021-05-26 | 2021-08-17 | 珠海润都制药股份有限公司 | Method for recovering L-valsartan from valsartan mother liquor containing D-valsartan |
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