CN102408353A - Preparation method of candesartan intermediate - Google Patents
Preparation method of candesartan intermediate Download PDFInfo
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- CN102408353A CN102408353A CN2011104292109A CN201110429210A CN102408353A CN 102408353 A CN102408353 A CN 102408353A CN 2011104292109 A CN2011104292109 A CN 2011104292109A CN 201110429210 A CN201110429210 A CN 201110429210A CN 102408353 A CN102408353 A CN 102408353A
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Abstract
The invention discloses a preparation method of a candesartan intermediate. In the method, a heterogeneous reaction system is adopted and a nucleophilic substitution reaction is performed in the presences of a phase transfer catalyst and a basic catalyst, thus the solubility of the basic catalyst in the reaction system can be increased, the dosage of the basic catalyst can be reduced, the dosage of the added phase transfer catalyst is lower and the phase transfer catalyst is cheap. The reaction also has the advantages of no heating step, simplicity in operation, high reaction rate, high conversion rate and the like; and the energy consumption can be saved, environmental pollutions can be reduced and the production cost can be lowered.
Description
Technical field
The present invention relates to a kind of TCV-116 intermediates preparation.
Background technology
TCV-116 (Candesartan) is a kind of long lasting Angiotensin II hypotype I receptor antagonist; Be mainly used in illnesss such as treatment hypertension; Its chemical name is ± 2-oxyethyl group-1-[[2 '-(1H-tetrazole-5-yl) xenyl-4-yl] methyl]-1H-benzoglyoxaline-7-carboxylic acid that its chemical structural formula is as shown in the formula shown in (1).
At present; The synthetic route of TCV-116 is more; Wherein a main route is: with the 3-nitrophthalic acid is raw material, makes midbody 3-nitro-2-t-butoxycarbonyl amino oil of Niobe through mono-esterification, azide, amidation, again through nucleophilic substitution, take off tertbutyloxycarbonyl, reduction, cyclization, tetrazoleization and make 2-oxyethyl group-1-[[2 '-(1H-tetrazole-5-yl) xenyl-4-yl] methyl]-1H-benzoglyoxaline-7-carboxylate methyl ester; After hydrolysis makes end product TCV-116 (Naka T; Nishikawa K etc., EP459136,1991).
In said synthesis route; Midbody 3-nitro-2-t-butoxycarbonyl amino oil of Niobe needs to carry out nucleophilic substitution reaction with 4-brooethyl-2 '-cyanobiphenyl, to generate another midbody 2-[N-(tertbutyloxycarbonyl)-N-[(2 '-cyanobiphenyl-4-yl) methyl] amino]-3-ethyl nitrobenzoate.Because this nucleophilic substitution reaction need use inorganic base catalyst, therefore, the solvent that adopts DMF, methyl alcohol or ethanol etc. and water to dissolve each other usually in the traditional technology can be dissolved in the solvent inorganic base catalyst.Yet the solubleness of mineral alkali in organic solvent is limited, in order to reach good catalytic effect, often need add a large amount of mineral alkalis, causes to waste raw material, and aftertreatment also bothers.In addition, need washing remove mineral alkali after reaction finishes, used water-soluble solvent also gets in the waste water thus, can't reclaim to recycle, and also easy simultaneously contaminate environment has strengthened the cost of WWT.
Midbody 3-nitro-2-t-butoxycarbonyl amino oil of Niobe nucleo philic substitution reaction, take off tertbutyloxycarbonyl after; Obtain another midbody 2-[N-[(2 '-cyanobiphenyl-4-yl) methyl] amino]-3-nitrobenzoic acid methyl esters, need use reductive agent that the nitroreduction on its phenyl ring is amino subsequently.Method of reducing commonly used in traditional technology has: catalytic hydrogenation method, sodium sulphite-thiosulfuric acid sodium reduction, stannous chloride reducing process and iron reduction method etc.Yet all there are some shortcomings in the traditional reduction method: 1, catalytic hydrogenation method, and high to equipment requirements, employed reductive agent palladium carbon expensive, and use hydrogen dangerous high; 2, sodium sulphite-thiosulfuric acid sodium reduction reacts not thorough, and waste material is more, has strengthened the cost of waste material treatment, and high, dangerous high, the complex operation of temperature of reaction; 3, tin protochloride method be the most general method of using at present, but because tin is heavy metal, cost is high, and contaminate environment, influences quality product; 4, iron reduction method can produce a large amount of iron mud, contaminate environment after reaction finishes.
In order to overcome the defective of existing TCV-116 synthesis technique, the present invention improves above-mentioned operational path, so that a kind of better TCV-116 preparation technology to be provided.
Summary of the invention
The purpose of this invention is to provide a kind of TCV-116 intermediates preparation, this method adopts heterogeneous reaction system to carry out nucleophilic substitution reaction, and can simplify the operation, enhance productivity, and the waste that reduces inorganic base catalyst and solvent.
As further improvement, this method has also adopted Hydrazine Hydrate 80-gac as reductive agent, can be amino with the nitroreduction on the phenyl ring more easily, reduces production costs significantly.
Technical solution of the present invention is following:
A kind of TCV-116 intermediates preparation may further comprise the steps:
1) carries out acyl chloride reaction by 2-carboxyl-3-ethyl nitrobenzoate (compound 1) and thionyl chloride, generate 2-chloroformyl-3-ethyl nitrobenzoate (compound 2);
2) by 2-chloroformyl-3-ethyl nitrobenzoate (compound 2) and triazo-compound reaction, generate 3-nitro-2-formyl triazobenzene ethyl formate (compound 3);
3) by 3-nitro-2-formyl triazobenzene ethyl formate (compound 3) and trimethyl carbinol reaction, generate 2-t-butoxycarbonyl amino-3-ethyl nitrobenzoate (compound 4);
4) carry out nucleophilic substitution reaction by 2-t-butoxycarbonyl amino-3-ethyl nitrobenzoate (compound 4) and 4 '-brooethyl-2-cyanobiphenyl, generate 2-[N-(tertbutyloxycarbonyl)-N-[(2 '-cyanobiphenyl-4-yl) methyl] amino]-3-ethyl nitrobenzoate (compound 5).
Further, preparation method of the present invention, further comprising the steps of:
5) slough tertbutyloxycarbonyl protection base, obtain 2-[N-[(2 '-cyanobiphenyl-4-yl) methyl] amino]-3-ethyl nitrobenzoate (compound 6);
6) 2-[N-[(2 '-cyanobiphenyl-4-yl) methyl] amino]-3-ethyl nitrobenzoate (compound 6) is reduced to 2-[N-[(2 '-cyanobiphenyl-4-yl) methyl] amino]-3-subcutin (compound 7).
In step 1), compound 1 is 1 with the mol ratio of thionyl chloride: 2-1: 5, be preferably 1: 3; Compound 1 is at room temperature to react with thionyl chloride, and reaction solvent is methylene dichloride, chloroform or acetone.
In step 2) in, described triazo-compound is sodium azide or nitrine potassium; Compound 2 is 1 with the mol ratio of triazo-compound: 2-1: 6, be preferably 1: 4; Compound 2 is under the temperature below 20 ℃, to react with triazo-compound; Compound 2 adopts methylene dichloride, chloroform or acetone as solvent; And triazo-compound adopts N, and dinethylformamide, DMAC N,N or dioxane are as solvent.
In step 3), compound 3 is 1 with the weight ratio of the trimethyl carbinol: 2-1: 3, be preferably 1: 2; Compound 3 is under 50 ℃-80 ℃, to react with the trimethyl carbinol.
In step 4), the mol ratio of compound 4 and 4 '-brooethyl-2-cyanobiphenyl is 1: 1-1: 1.8, be preferably 1: 1; Compound 4 and 4 '-brooethyl-2-cyanobiphenyl is in heterogeneous reaction system, in the presence of phase-transfer catalyst and basic catalyst, at room temperature reacts; Described heterogeneous reaction system is methylene dichloride-water reaction system or chloroform-water reaction system; Described phase-transfer catalyst is a quaternary ammonium salt-type phase transfer catalyst; Comprise benzyltriethylammoinium chloride, Tetrabutyl amonium bromide, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate, tri-n-octyl methyl ammonium chloride, DTAC and tetradecyl trimethyl ammonium chloride etc.; The mol ratio of 2-t-butoxycarbonyl amino-3-ethyl nitrobenzoate and phase-transfer catalyst is 100: 1-100: 3, be preferably 100: 1; Described basic catalyst is selected from sodium hydroxide, Pottasium Hydroxide, sodium methylate or sodium ethylate etc., and the mol ratio of 2-t-butoxycarbonyl amino-3-ethyl nitrobenzoate and basic catalyst is 1: 2-1: 4, be preferably 1: 3.
In step 5), adopt the vitriol oil as catalyzer,, react under 60 ℃-80 ℃ as reaction solvent with methyl alcohol, ethanol, acetone or acetonitrile, the protection of the tertbutyloxycarbonyl in the compound 5 base is sloughed.Compound 5 is 1 with the mol ratio of the vitriol oil: 1-1: 3, be preferably 1: 2.
In step 6), adopt Hydrazine Hydrate 80-gac as reductive agent, compound 6 and Hydrazine Hydrate 80 weight ratio be 1: 1-1: 3, be preferably 1: 1; Compound 6 and gac weight ratio be 1: 0.1-1: 0.5, be preferably 1: 0.1; Compound 6 is under 60 ℃-80 ℃, to react with reductive agent, and reaction solvent employing weight ratio is 1: 1 mixed solvents such as THF-methylene dichloride, methyl alcohol-methylene dichloride, ethanol-methylene dichloride or methyl alcohol-chloroform.
Above-mentioned preparing method's process route chart is following:
The present invention improves traditional TCV-116 preparation technology; In step 4), adopted heterogeneous reaction system to realize nucleophilic substitution reaction; This method can improve the solubleness of basic catalyst in reaction system; Thereby reduce the consumption of basic catalyst, and the phase-transfer catalyst consumption that is added is also less, and low price; This reaction also has the heating of need not, fast, the transformation efficiency advantages of higher of simple to operate, speed of reaction, can energy efficient, reduce environmental pollution, and reduce production costs.In addition, in step 6), adopt Hydrazine Hydrate 80-gac, can be amino with the nitroreduction on the phenyl ring more easily, and can reduce production costs significantly as reductive agent.
Description of drawings
Fig. 1 is the mass spectrum of embodiment six prepared compounds 6;
Fig. 2 is embodiment six prepared compounds 6
1The HNMR collection of illustrative plates;
Fig. 3 and Fig. 4 are the partial enlarged drawing of Fig. 2;
Fig. 5 is embodiment six prepared compounds 6
13The CNMR collection of illustrative plates;
Fig. 6 is the partial enlarged drawing of Fig. 5;
Fig. 7 is the infared spectrum of embodiment six prepared compounds 6.
Fig. 8 is the mass spectrum of embodiment seven prepared compounds 7;
Fig. 9 is embodiment seven prepared compounds 7
1The HNMR collection of illustrative plates;
Figure 10 is the partial enlarged drawing of Fig. 9;
Figure 11 is embodiment seven prepared compounds 7
13The CNMR collection of illustrative plates;
Figure 12 is the partial enlarged drawing of Figure 11;
Figure 13 is the infared spectrum of embodiment seven prepared compounds 7.
Embodiment
Through specific embodiment the present invention is done further detailed explanation below.
Embodiment one: the preparation of 2-carboxyl-3-ethyl nitrobenzoate (compound 1)
200g ethanol, 100g 3-nitro phthalyl alcohol are added retort, and stirring and dissolving drips the 30g vitriol oil, is warming up to 80 ℃; Stirring reaction 8 hours adopts liquid chromatograph that reaction process is monitored, when title product peak>=93%, raw material peak≤2%, and stopped reaction; After reaction finished, concentrating under reduced pressure became oily; Add the methylene dichloride dissolving, add saturated brine washing dichloromethane layer then, wash 3 times; Concentrate dichloromethane layer to oily, add ether and carry out crystallization, obtain compound 1.Through detecting, productive rate is 85%, and degree of purity of production is 98%.
Embodiment two: the preparation of 2-chloroformyl-3-ethyl nitrobenzoate (compound 2)
100g methylene dichloride, 100g compound 1,150g thionyl chloride are added retort, at room temperature carry out stirring reaction; When the reaction solution clarification, reaction finishes, and is concentrated into oily and obtains compound 2.Through detecting, degree of purity of production is 97%.
Embodiment three: the preparation of 3-nitro-2-formyl triazobenzene ethyl formate (compound 3)
To embodiment two prepared compounds 2 retort in add the 300g methylene dichloride, be cooled to below 20 ℃ subsequent use; In another retort, add the 100g DMAC N,N, stir and add the 97.8g sodium azide down, be cooled to below 20 ℃, the dichloromethane solution of compound 2 is added drop-wise in this retort, dropwised afterreaction 2 hours; Adopt liquid chromatograph that reaction process is monitored, when title product peak>=93%, raw material peak≤1%, stopped reaction; After reaction finishes, add 300g salt solution and wash, and use anhydrous magnesium sulfate drying, filtrate decompression is concentrated into oily, obtains compound 3.Through detecting, degree of purity of production is 97.5%.
Embodiment four: the preparation of 2-t-butoxycarbonyl amino-3-ethyl nitrobenzoate (compound 4)
In embodiment three prepared compounds 3, add the 200g trimethyl carbinol while hot, stir down and slowly be warming up to 60 ℃, reacted 2 hours; Adopt liquid chromatograph that reaction process is monitored, when title product peak>=94%, raw material peak≤1%, stopped reaction; Reaction is concentrated into oily after finishing, and adds ETHYLE ACETATE and carries out crystallization, and low temperature (below 0 ℃) stirred 2 hours, got rid of filter, obtained compound 4.Through detecting, productive rate is 75.5% (overall yields of three step gained of embodiment two to embodiment four), and degree of purity of production is 98%.
Embodiment five: the preparation of 2-[N-(tertbutyloxycarbonyl)-N-[(2 '-cyanobiphenyl-4-yl) methyl] amino]-3-ethyl nitrobenzoate (compound 5)
After reaction finished, standing demix added the 100g methylene dichloride and extracts in water layer; The combined dichloromethane layer washs with clear water; Concentrate dichloromethane layer to oily, add 50g ETHYLE ACETATE and carry out crystallization, stir, slowly be cooled to below 0 ℃, stirred 2 hours, get rid of filter; With the washing of the ETHYLE ACETATE of small amount of cold,, obtain compound 5 with 50 ℃ warm air dryings 6 hours.Through detecting, productive rate is 87%, and degree of purity of production is 99.0%.
Get the compound 5 that present embodiment makes and make liquid-phase chromatographic analysis with the standard substance of compound 5, under the same conditions, both RTs are consistent.
Embodiment six: the preparation of 2-[N-[(2 '-cyanobiphenyl-4-yl) methyl] amino]-3-ethyl nitrobenzoate (compound 6)
70g compound 5 is dissolved in the 350g methyl alcohol, drips the 27g vitriol oil, temperature is controlled at 60 ℃, reacted 3 hours; Adopt liquid chromatograph that reaction process is monitored, when title product peak>=97%, raw material peak≤1%, stopped reaction; After reaction finishes, be concentrated into oily; Add ethanol and carry out crystallization, stirred 2 hours, get rid of filter, obtain compound 6.Through detecting, productive rate is 96%, and degree of purity of production is 99.0%.
Get the compound 6 that present embodiment makes and make liquid-phase chromatographic analysis with the standard substance of compound 6, under the same conditions, both RTs are consistent.
Get the compound 6 that present embodiment makes and adopt mass spectrum, NMR spectrum and ir spectra to identify respectively, qualification result shows (shown in Fig. 1-7), and the prepared compound of present embodiment is a target compound.
Embodiment seven: the preparation of 2-[N-[(2 '-cyanobiphenyl-4-yl) methyl] amino]-3-subcutin (compound 7)
60g compound 6,200g THF, 200g methylene dichloride are added retort, stirred 10 minutes; Add the 12.5g gac, be warming up to 60 ℃, drip the 60g Hydrazine Hydrate 80, dropwised in about 30 minutes, kept this thermotonus 12 hours; Adopt liquid chromatograph that reaction process is monitored, when title product peak>=94%, raw material peak≤0.3%, stopped reaction.
Reaction is cooled to 25 ℃ after finishing; Add 200g methylene dichloride, 300g water, stirred standing demix 10 minutes; Water layer is used the 200g dichloromethane extraction, and the combined dichloromethane layer washs with clear water; Filter dichloromethane layer, filtrating is concentrated into dried pasty state (as far as possible doing); Add 200g ethanol and carry out crystallization, rising temperature for dissolving is cooled to then below 0 ℃ and lets reaction product separate out, and stirs 2 hours, gets rid of filter, obtains compound 7.Through detecting, productive rate is 93%, and degree of purity of production is 98%.
Get the compound 7 that present embodiment makes and make liquid-phase chromatographic analysis with the standard substance of compound 7, under the same conditions, both RTs are consistent.
Get the compound 7 that present embodiment makes and adopt mass spectrum, NMR spectrum and ir spectra to identify respectively, qualification result shows (shown in Fig. 8-13), and the prepared compound of present embodiment is a target compound.
Above-listed detailed description is to the specifying of one of the present invention possible embodiments, and this embodiment is not in order to limiting claim of the present invention, and the equivalence that all the present invention of disengaging do is implemented or change, all should be contained in the claim of this case.
Claims (10)
1. TCV-116 intermediates preparation may further comprise the steps:
1) carries out acyl chloride reaction by 2-carboxyl-3-ethyl nitrobenzoate and thionyl chloride, generate 2-chloroformyl-3-ethyl nitrobenzoate;
2) by 2-chloroformyl-3-ethyl nitrobenzoate and triazo-compound reaction, generate 3-nitro-2-formyl triazobenzene ethyl formate;
3) by 3-nitro-2-formyl triazobenzene ethyl formate and trimethyl carbinol reaction, generate 2-t-butoxycarbonyl amino-3-ethyl nitrobenzoate;
4) carry out nucleophilic substitution reaction by 2-t-butoxycarbonyl amino-3-ethyl nitrobenzoate and 4 '-brooethyl-2-cyanobiphenyl, generate 2-[N-(tertbutyloxycarbonyl)-N-[(2 '-cyanobiphenyl-4-yl) methyl] amino]-3-ethyl nitrobenzoate;
It is characterized in that in step 4), described nucleophilic substitution reaction is in the presence of phase-transfer catalyst and basic catalyst, in heterogeneous reaction system, carries out.
2. preparation method according to claim 1 is characterized in that: in step 4), the mol ratio of 2-t-butoxycarbonyl amino-3-ethyl nitrobenzoate and 4 '-brooethyl-2-cyanobiphenyl is 1: 1-1: 1.8.
3. preparation method according to claim 1 is characterized in that: in step 4), described heterogeneous reaction system is methylene dichloride-water reaction system or chloroform-water reaction system.
4. preparation method according to claim 1; It is characterized in that: in step 4); Described phase-transfer catalyst is a quaternary ammonium salt-type phase transfer catalyst, and the mol ratio of 2-t-butoxycarbonyl amino-3-ethyl nitrobenzoate and phase-transfer catalyst is 100: 1-100: 3.
5. preparation method according to claim 4 is characterized in that: described quaternary ammonium salt-type phase transfer catalyst comprises benzyltriethylammoinium chloride, Tetrabutyl amonium bromide, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate, tri-n-octyl methyl ammonium chloride, DTAC and tetradecyl trimethyl ammonium chloride.
6. preparation method according to claim 1; It is characterized in that: in step 4); Described basic catalyst is selected from sodium hydroxide, Pottasium Hydroxide, sodium methylate or sodium ethylate, and the mol ratio of 2-t-butoxycarbonyl amino-3-ethyl nitrobenzoate and basic catalyst is 1: 2-1: 4.
7. preparation method according to claim 1 is characterized in that: in step 4), described nucleophilic substitution reaction is at room temperature to carry out.
8. according to one of them described preparation method of claim 1-7, it is characterized in that further comprising the steps of:
5) slough tertbutyloxycarbonyl protection base, obtain 2-[N-[(2 '-cyanobiphenyl-4-yl) methyl] amino]-3-ethyl nitrobenzoate;
6) 2-[N-[(2 '-cyanobiphenyl-4-yl) methyl] amino]-3-ethyl nitrobenzoate is reduced to 2-[N-[(2 '-cyanobiphenyl-4-yl) methyl] amino]-3-subcutin.
9. preparation method according to claim 8; It is characterized in that: in step 6); With Hydrazine Hydrate 80-gac is reductive agent, is that reaction media carries out reduction reaction with THF-methylene dichloride, methyl alcohol-methylene dichloride, ethanol-methylene dichloride or methyl alcohol-chloroform mixed solvent.
10. preparation method according to claim 9 is characterized in that: in step 6), 2-[N-[(2 '-cyanobiphenyl-4-yl) methyl] amino]-3-ethyl nitrobenzoate and Hydrazine Hydrate 80 weight ratio be 1: 1-1: 3; The weight ratio of 2-[N-[(2 '-cyanobiphenyl-4-yl) methyl] amino]-3-ethyl nitrobenzoate and gac is 1: 0.1-1: 0.5.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020140193A1 (en) * | 2019-01-02 | 2020-07-09 | 临海市华南化工有限公司 | Synthesis method for candesartan cilexetil intermediate |
| CN113929597A (en) * | 2020-06-29 | 2022-01-14 | 临海市华南化工有限公司 | Method for synthesizing candesartan cilexetil intermediate |
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| WO2006038223A1 (en) * | 2004-10-06 | 2006-04-13 | Matrix Laboratories Ltd | A process for preparation of 2-n-butyl -4-chloro - 1 - {[2`- (2-triphenylmethyl - 2h - tetrazole - 5- yl) - 1, 1’ - biphenyl-4-yl] methyl}-lh- imidazoie-5-methanol (intermediate of losartan) |
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- 2011-12-16 CN CN2011104292109A patent/CN102408353A/en active Pending
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| WO2006038223A1 (en) * | 2004-10-06 | 2006-04-13 | Matrix Laboratories Ltd | A process for preparation of 2-n-butyl -4-chloro - 1 - {[2`- (2-triphenylmethyl - 2h - tetrazole - 5- yl) - 1, 1’ - biphenyl-4-yl] methyl}-lh- imidazoie-5-methanol (intermediate of losartan) |
Non-Patent Citations (2)
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| 杨池等: "坎地沙坦酯合成路线图解", 《中国医药工业杂志》 * |
| 马成: "几种生物活性分子的合成研究", 《浙江大学博士后学位论文》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020140193A1 (en) * | 2019-01-02 | 2020-07-09 | 临海市华南化工有限公司 | Synthesis method for candesartan cilexetil intermediate |
| CN113544113A (en) * | 2019-01-02 | 2021-10-22 | 临海市华南化工有限公司 | Synthesis method of candesartan cilexetil intermediate |
| CN113544113B (en) * | 2019-01-02 | 2023-12-26 | 临海市华南化工有限公司 | Synthesis method of candesartan cilexetil intermediate |
| CN113929597A (en) * | 2020-06-29 | 2022-01-14 | 临海市华南化工有限公司 | Method for synthesizing candesartan cilexetil intermediate |
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Application publication date: 20120411 |