CN104961722B - Method for preparing eprosartan intermediate by using reaction auxiliary agent - Google Patents
Method for preparing eprosartan intermediate by using reaction auxiliary agent Download PDFInfo
- Publication number
- CN104961722B CN104961722B CN201510276613.2A CN201510276613A CN104961722B CN 104961722 B CN104961722 B CN 104961722B CN 201510276613 A CN201510276613 A CN 201510276613A CN 104961722 B CN104961722 B CN 104961722B
- Authority
- CN
- China
- Prior art keywords
- diethyl malonate
- reaction
- mass
- orthoformate
- cyclohexane
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Abstract
The invention discloses a method for preparing an eprosartan intermediate 2-thienylmethylene diethyl malonate by using a reaction auxiliary agent, which comprises the steps of taking cyclohexane as a reaction solvent and piperidine and benzoic acid as catalysts for 2-thiophenecarboxaldehyde and diethyl malonate, and adding one or more orthoformates as reaction auxiliary agents into a reaction solution to react to obtain the 2-thienylmethylene diethyl malonate. The synthesis method has the advantages of mild reaction conditions, simple process, short reaction time, few byproducts, good yield, capability of obtaining high-purity products and the like.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of an eprosartan intermediate 2-thienylmethylenemalonic acid diethyl ester promoted by using a reaction auxiliary agent.
Background
Eprosartan (the british name Eprosartan), chemically (E) - [ [ 2-butyl-1- [ (4-hydroxyphenyl) methyl ] -1H-imidazol-5-yl ] methylene ] -2-thiophenepropanoic acid, having the following structural formula:
eprosartan is an antihypertensive drug developed by steckel. Clinical studies have shown that it is effective in lowering both systolic and diastolic blood pressure in patients with mild, moderate and severe hypertension.
Due to the structural particularity, few processes for preparing eprosartan are reported, such as the synthesis process disclosed in patent EP 970073, and although the condensation reaction needs to be carried out at low pressure, the holding pressure is not easy to maintain for a long time and the reaction time is long when the production is scaled up. But because the requirement on equipment is low, the used raw materials are cheaper, and dangerous reagents are not used, the method is still a simple and effective synthesis method. Wherein, the 2-thienylmethylene diethyl malonate is a key intermediate of the route, and the structural formula is as follows:
richard M. Keenan et al (J. Med. chem., 1993, 36, 1880-1892) reported the synthesis of diethyl 2-thienylmethylmalonate from 2-thiophenecarboxaldehyde and diethyl malonate. The method adopts cyclohexane as a solvent, but the preparation method has longer reaction time (20h) and lower purity because the boiling point of the cyclohexane is lower and the water-separating capacity is poor. Paula Abeijon et al (Eur. J. org. chem., 2006, 3, 759-764) report that toluene is used as a solvent, the reaction can be smoothly completed within 6.5 hours at a reflux temperature, but the reflux temperature of toluene is high, the requirements on process equipment are high, and occupational hazards such as asthenia syndrome, hepatomegaly and the like can occur if workers in a workshop contact with toluene for a long time. Therefore, a method is urgently needed, namely cyclohexane can be used for replacing toluene as a reaction solvent, and the defects of long reaction time, low purity and the like of cyclohexane as a solvent can be overcome. The invention not only avoids using toluene as a reaction solvent, but also overcomes the defects of long reaction time and low purity of cyclohexane as a solvent.
Disclosure of Invention
The invention provides a method for synthesizing 2-thienylmethylene diethyl malonate promoted by reaction auxiliary agents. The preparation method takes 2-thiophenecarboxaldehyde and diethyl malonate as reactants, cyclohexane as reaction solvent, piperidine and benzoic acid as catalysts, orthoformate as reaction auxiliary agent, and 2-thiophenemethylene diethyl malonate is synthesized under the heating condition. The synthetic route is as follows:
the reaction auxiliary agent has the action principle that: the 2-thiophenecarboxaldehyde and diethyl malonate are subjected to brain-WeChat reaction to obtain 2-thiophenemethylene diethyl malonate, and simultaneously, one molecule of water is generated. And trimethyl orthoformate can react with the byproduct water to consume water (see the following reaction formula), thereby driving the reaction to the right. The unreacted orthoformate remains as formate and alcohol during the post-treatment washing. The formic ether and alcohol generated in the reaction process and the post-treatment process can be smoothly removed in the vacuum distillation process due to low boiling point, and the product quality is not influenced.
Specifically, the method comprises the following steps: the 2-thiophenecarboxaldehyde and diethyl malonate take cyclohexane as a reaction solvent, piperidine and benzoic acid as catalysts, and one or more orthoformates are added into the reaction liquid as reaction auxiliary agents to react to obtain the 2-thiophenemethylene diethyl malonate.
In this process the one or more orthoformates are selected from: trimethyl orthoformate, triethyl orthoformate, triisopropyl orthoformate.
The ratio of the orthoformate to the diethyl malonate in the method is 1: 1-3: 1.
The volume dosage (mL) of the reaction solvent cyclohexane used in the method is 3-7 times, preferably 4-6 times of the mass dosage (g) of the reactant diethyl malonate; the mass amount (g) of the catalyst piperidine is 0.03-0.25 time, preferably 0.05-0.10 time of the mass amount (g) of the reactant diethyl malonate; the mass amount (g) of the catalyst benzoic acid is 0.001-0.03 times, preferably 0.005-0.015 times of the mass amount (g) of the reactant diethyl malonate. The reaction temperature of the method is 50-81 ℃.
The method for synthesizing 2-thienylmethylenemalonic acid diethyl ester promoted by using the reaction auxiliary agent has the advantages that the method does not need to be carried out at a reflux temperature, a water separation device is not needed in the reaction, and the reaction time of the eprosartan intermediate 2-thienylmethylenemalonic acid diethyl ester can be shortened. Therefore, the method has the advantages of mild reaction conditions, simple process, short reaction time, few byproducts, good yield, capability of obtaining high-purity products and the like.
Detailed Description
The invention is further illustrated with reference to the following examples, which, however, do not constitute any limitation of the invention.
Example 1:
synthesis of diethyl 2-thienylmethylmalonate:
into a 500 mL three-necked flask were charged 34.6 g (216 mmol) of diethyl malonate, 24.6 g (219mmol) of 2-thiophenecarboxaldehyde, 2.5 g (29 mmol) of piperidine, and 155 mL of cyclohexane in this order, and further charged 0.3 g (2.5 mmol) of benzoic acid and 25.4 g (240 mmol) of trimethyl orthoformate. Heating to 80 ℃ and reacting for 5 h. Cyclohexane was distilled under reduced pressure until no significant liquid flowed out, then 160 mL ethyl acetate was added, washed twice with 70 mL 10% mass fraction hydrochloric acid, once with 70 mL saturated sodium bicarbonate solution, once with brine, dried over sodium sulfate, the filter cake was filtered off, and the filtrate was concentrated to give 51.7g of an oil, HPLC purity: 96%, yield: 94 percent.
Example 2:
synthesis of diethyl 2-thienylmethylmalonate:
into a 500 mL three-necked flask were charged 34.6 g (216 mmol) of diethyl malonate, 24.6 g (219mmol) of 2-thiophenecarboxaldehyde, 2.5 g (29 mmol) of piperidine, and 155 mL of cyclohexane in this order, and further charged 0.3 g (2.5 mmol) of benzoic acid and 35.6 g (240 mmol) of triethyl orthoformate. Heating to 80 ℃ and reacting for 5 h. Cyclohexane was distilled under reduced pressure until no significant liquid flowed out, then 160 mL ethyl acetate was added, washed twice with 70 mL 10% mass fraction hydrochloric acid, once with 70 mL saturated sodium bicarbonate solution, once with brine, dried over sodium sulfate, the filter cake was filtered off, and the filtrate was concentrated to give 51.2g of an oil, HPLC purity: 95%, yield: 93 percent.
Example 3:
synthesis of diethyl 2-thienylmethylmalonate:
into a 500 mL three-necked flask were charged 34.6 g (216 mmol) of diethyl malonate, 24.6 g (219mmol) of 2-thiophenecarboxaldehyde, 2.5 g (29 mmol) of piperidine, and 155 mL of cyclohexane in this order, and further charged 0.3 g (2.5 mmol) of benzoic acid, 12.7 g (120 mmol) of trimethyl orthoformate, and 17.8 g (120 mmol) of triethyl orthoformate. Heating to 80 ℃ and reacting for 5 h. Cyclohexane was distilled under reduced pressure until no significant liquid flowed out, then 160 mL ethyl acetate was added, washed twice with 70 mL 10% mass fraction hydrochloric acid, once with 70 mL saturated sodium bicarbonate solution, once with brine, dried over sodium sulfate, the filter cake was filtered off, and the filtrate was concentrated to give 51.6g of an oil, HPLC purity: 97%, yield: 94 percent.
Example 4:
synthesis of diethyl 2-thienylmethylmalonate:
into a 500 mL three-necked flask were charged 34.6 g (216 mmol) of diethyl malonate, 24.6 g (219mmol) of 2-thiophenecarboxaldehyde, 2.5 g (29 mmol) of piperidine, and 155 mL of cyclohexane in this order, and further charged 0.3 g (2.5 mmol) of benzoic acid and 50.8 g (480 mmol) of trimethyl orthoformate. Heating to 80 ℃ and reacting for 4 h. Cyclohexane was distilled under reduced pressure until no significant liquid flowed out, then 160 mL ethyl acetate was added, washed twice with 70 mL 10% mass fraction hydrochloric acid, once with 70 mL saturated sodium bicarbonate solution, once with brine, dried over sodium sulfate, the filter cake was filtered off, and the filtrate was concentrated to give 52.7g of an oil, HPLC purity: 97%, yield: 96 percent.
Example 5:
synthesis of diethyl 2-thienylmethylmalonate:
into a 500 mL three-necked flask were charged 34.6 g (216 mmol) of diethyl malonate, 24.6 g (219mmol) of 2-thiophenecarboxaldehyde, 2.5 g (29 mmol) of piperidine, and 155 mL of cyclohexane in this order, and further charged 0.3 g (2.5 mmol) of benzoic acid and 25.4 g (240 mmol) of trimethyl orthoformate. Heating to 60 ℃, and reacting for 8 h. Cyclohexane was distilled under reduced pressure until no significant liquid flowed out, then 160 mL ethyl acetate was added, washed twice with 70 mL 10% mass fraction hydrochloric acid, once with 70 mL saturated sodium bicarbonate solution, once with brine, dried over sodium sulfate, the filter cake was filtered off, and the filtrate was concentrated to give 51.2g of an oil, HPLC purity: 96%, yield: 93 percent.
Claims (5)
1. A method for preparing an eprosartan intermediate diethyl 2-thienylmethylenemalonate by using a reaction auxiliary agent is characterized in that: the 2-thiophenecarboxaldehyde and diethyl malonate take cyclohexane as a reaction solvent, piperidine and benzoic acid as catalysts, one or more orthoformate is/are added into the reaction liquid as a reaction auxiliary agent to react to obtain 2-thiophenemethylene diethyl malonate, and the volume usage (mL) of the reaction solvent cyclohexane used in the method is 3-7 times of the mass usage (g) of the reactant diethyl malonate; the mass usage (g) of the catalyst piperidine is 0.03-0.25 times of the mass usage (g) of the reactant diethyl malonate; the mass amount (g) of the catalyst benzoic acid is 0.001-0.03 time of that (g) of the reactant diethyl malonate.
2. The process according to claim 1, characterized in that said one or more orthoformates are selected from: trimethyl orthoformate, triethyl orthoformate, triisopropyl orthoformate.
3. The method of claim 1, wherein the ratio of the amount of orthoformate to the amount of diethyl malonate species is in the range of 1:1 to 3: 1.
4. The process according to claim 1, characterized in that the volume dosage (mL) of the reaction solvent cyclohexane used in the process is 4-6 times the mass dosage (g) of the reactant diethyl malonate; the mass usage (g) of the catalyst piperidine is 0.05-0.10 times of the mass usage (g) of the reactant diethyl malonate; the mass amount (g) of the catalyst benzoic acid is 0.005-0.015 time of the mass amount (g) of the reactant diethyl malonate
5. The process according to claim 1, wherein the reaction temperature is 50 ℃ to 81 ℃.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201510276613.2A CN104961722B (en) | 2015-05-27 | 2015-05-27 | Method for preparing eprosartan intermediate by using reaction auxiliary agent |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201510276613.2A CN104961722B (en) | 2015-05-27 | 2015-05-27 | Method for preparing eprosartan intermediate by using reaction auxiliary agent |
Publications (2)
Publication Number | Publication Date |
---|---|
CN104961722A CN104961722A (en) | 2015-10-07 |
CN104961722B true CN104961722B (en) | 2020-06-19 |
Family
ID=54215846
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201510276613.2A Active CN104961722B (en) | 2015-05-27 | 2015-05-27 | Method for preparing eprosartan intermediate by using reaction auxiliary agent |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN104961722B (en) |
-
2015
- 2015-05-27 CN CN201510276613.2A patent/CN104961722B/en active Active
Non-Patent Citations (1)
Title |
---|
Synthesis and biological evaluation of [carboxyl-11C]eprosartan;Ola Aberg等;《Journal of Labelled Compounds and Radiopharmaceuticals》;20090601;第52卷;第295-303页 * |
Also Published As
Publication number | Publication date |
---|---|
CN104961722A (en) | 2015-10-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP2262756B1 (en) | Process for preparing alkyl 2-alkoxymethylene-4,4-difluoro-3-oxobutyrates | |
JP2010265193A (en) | Method for producing alkyl chlorohydrin ether and method for producing alkyl glycidyl ether | |
CN110937985B (en) | Synthesis method of paradol | |
CN103044468B (en) | Preparation method of N-(2-pyrazine carbonyl)-L-phenylalanine-L- leucine boracic acid | |
CN104961722B (en) | Method for preparing eprosartan intermediate by using reaction auxiliary agent | |
JP5338798B2 (en) | Process for producing tetrahydropyran-4-one and pyran-4-one | |
CN114315609B (en) | Technological method for preparing cis-2-aminocyclohexanol | |
CA2916886A1 (en) | Process for the preparation of 3-heptanol from a mixture comprising 2-ethylhexanal and 3-heptyl formate | |
CN112047815B (en) | Preparation method of cannabidiol compound | |
CN114716331A (en) | Preparation method of dopamine hydrochloride | |
JP6427787B2 (en) | Method for producing dehydrolinalyl acetate (II) | |
CN109956899B (en) | Preparation method of vitamin B6 | |
KR102224268B1 (en) | Trimethylolpropane manufacturing device and method using thereof | |
CN114436873B (en) | Preparation method of tranexamic acid | |
CN102702192A (en) | Synthesis method of vinpocetine | |
KR20070069216A (en) | Cyclopentane carboxylate compounds, process and intermediates for preparing the same and use thereof | |
JP5476549B2 (en) | Process for producing 2,3-dihydro-thieno [3,4-b] furan derivative and novel compound used therefor | |
JP6433809B2 (en) | Process for producing 1- (3-hydroxymethylpyridyl-2-)-2-phenyl-4-methylpiperazine | |
JP6543824B2 (en) | Process for producing dehydro linalyl acetate (I) | |
KR100638171B1 (en) | Preparation method of 2,N-dimethyl-N-3,3-diphenylpropyl-1-amino-2-propanol | |
CN102464594A (en) | Preparation method of intermediate compound of pregabalin | |
CN102516043A (en) | Preparation method of Sarpogrelate intermediate 2-((3-methoxy) phenethyl) phenol | |
CN111057031A (en) | Preparation method of benzofuranone | |
JPH02235835A (en) | Preparation of 5-chloropentanone-2 | |
JP2007314457A (en) | Manufacturing method of 4-hydroxymethyltetrahydropyran |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |