CN106916139A - A kind of preparation method of improved Eprosartan intermediate - Google Patents
A kind of preparation method of improved Eprosartan intermediate Download PDFInfo
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- CN106916139A CN106916139A CN201710321624.7A CN201710321624A CN106916139A CN 106916139 A CN106916139 A CN 106916139A CN 201710321624 A CN201710321624 A CN 201710321624A CN 106916139 A CN106916139 A CN 106916139A
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- CN
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- Prior art keywords
- thenylidene
- reaction
- hexamethylene
- polar aprotic
- diethyl malonate
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Links
- 239000002080 C09CA02 - Eprosartan Substances 0.000 title claims abstract description 11
- OROAFUQRIXKEMV-LDADJPATSA-N eprosartan Chemical compound C=1C=C(C(O)=O)C=CC=1CN1C(CCCC)=NC=C1\C=C(C(O)=O)/CC1=CC=CS1 OROAFUQRIXKEMV-LDADJPATSA-N 0.000 title claims abstract description 11
- 229960004563 eprosartan Drugs 0.000 title claims abstract description 11
- 238000002360 preparation method Methods 0.000 title description 5
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 16
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 14
- 239000002904 solvent Substances 0.000 claims abstract description 9
- 239000000654 additive Substances 0.000 claims abstract description 5
- 230000000996 additive effect Effects 0.000 claims abstract description 5
- 238000006555 catalytic reaction Methods 0.000 claims abstract 2
- 230000000977 initiatory effect Effects 0.000 claims abstract 2
- 239000000463 material Substances 0.000 claims abstract 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 16
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 14
- 239000003880 polar aprotic solvent Substances 0.000 claims description 14
- -1 2- thenylidene diethyl malonates Chemical class 0.000 claims description 12
- 239000005711 Benzoic acid Substances 0.000 claims description 7
- 235000010233 benzoic acid Nutrition 0.000 claims description 7
- 150000003053 piperidines Chemical class 0.000 claims description 7
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 5
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Natural products O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims 1
- CNUDBTRUORMMPA-UHFFFAOYSA-N formylthiophene Chemical class O=CC1=CC=CS1 CNUDBTRUORMMPA-UHFFFAOYSA-N 0.000 abstract description 8
- 230000035484 reaction time Effects 0.000 abstract description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 abstract 1
- 239000002253 acid Substances 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- 238000010992 reflux Methods 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 239000004519 grease Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000012266 salt solution Substances 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- OXHNLMTVIGZXSG-UHFFFAOYSA-N 1-Methylpyrrole Chemical class CN1C=CC=C1 OXHNLMTVIGZXSG-UHFFFAOYSA-N 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 238000006000 Knoevenagel condensation reaction Methods 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 206010019842 Hepatomegaly Diseases 0.000 description 1
- 208000007443 Neurasthenia Diseases 0.000 description 1
- 206010003549 asthenia Diseases 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000035488 systolic blood pressure Effects 0.000 description 1
- 238000004065 wastewater treatment Methods 0.000 description 1
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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of method for preparing the thenylidene diethyl malonate of Eprosartan intermediate 2, it with 2 thiophenecarboxaldehydes and diethyl malonate is initiation material that the method is, under the co-catalysis of soda acid, hexamethylene is used as reaction dissolvent, strengthen polar non-solute as solvent additive, prepare the thenylidene diethyl malonate of Eprosartan intermediate 2.The present invention can greatly shorten the reaction time, and can obtain the thenylidene diethyl malonate of Eprosartan intermediate 2 of high-purity.
Description
Technical field
The invention belongs to medicinal chemistry art, and in particular to highly polar aprotic solvent as solvent additive, promotion
The preparation method of Eprosartan intermediate 2- thenylidene diethyl malonates.
Background of invention
Eprosartan (English name Eprosartan), chemical entitled (E)-[[2- butyl -1- [(4- hydroxy phenyls) first
Base] -1H- imidazoles -5- bases] methylene] -2- thiophene propionic acid, its structural formula is as follows：
Eprosartan is the drug for hypertension of SmithKline Beecham's exploitation.Clinical research show to slight, moderate and
Severe hypertension patient presses two aspects effective in cure in reduction systolic pressure and diastole.
Due to the particularity of its structure, the method for preparing Eprosartan of report is seldom, public in such as patent EP 970073
The synthetic method opened, although condensation reaction needs to carry out under low pressure, when amplifying production, keeps pressure to be not easy to remain more long
Time, meanwhile, the time of reaction is very long.But, because its is low for equipment requirements, the raw material for using is relatively inexpensive, meanwhile, it is not used
Relatively hazardous reagent, therefore, a succinct effective synthetic method of still can yet be regarded as is also main flow that current pharmacy corporation is used
Synthetic route.Wherein 2- thenylidenes diethyl malonate is the key intermediate of the route, and its structural formula is as follows：
Richard M.Keenan et al. (J.Med.Chem., 1993,36,1880-1892) report 2 thiophene carboxaldehyde with
Diethyl malonate is synthesized 2- thenylidene diethyl malonates by Knoevenagel.The method uses hexamethylene
As solvent, but this preparation method due to hexamethylene boiling point it is relatively low, water separation ability is not good, so the reaction time is relatively long (20h).
Paula Abeijon et al. (Eur.J.Org.Chem., 2006,3,759-764) are reported using toluene as solvent, backflow
At a temperature of 6.5h can both smoothly complete reaction, but, the reflux temperature of toluene is higher, to process equipment requirement it is higher, meanwhile,
If shop worker's Long Term Contact toluene, can occur the occupational hazards such as neurasthenia syndrome, hepatomegaly.Therefore, in the urgent need to
One method, you can to substitute toluene as reaction dissolvent using hexamethylene, when can overcome hexamethylene as solvent reaction again
Between it is long, the shortcomings of purity is relatively low.
Pleasurable, Boucard Valerie (Macromolecules, 2001,34,4308-4313) are reported
To the research in terms of Knoevenagel reaction mechanisms.In the text, highly polar aprotic solvent proved by experimental data, to such
Type reaction has good facilitation.But, typical highly polar aprotic solvent, such as DMF is uncomfortable
Conjunction is used on a large scale in pharmaceuticals industry, because the wastewater treatment difficulty containing DMF is larger, is easily made
Into environmental pollution.Meanwhile, Knoevenagel reactions are reversible reactions, if during the course of the reaction, it is impossible to effectively removal reaction
The water of generation, will cause reaction to carry out not thoroughly, and raw material will have a large amount of residuals, but highly polar aprotic solvent boiling point is higher,
In simple equipment, it is difficult to realize azeotropic water removing.
The present invention combines both advantages, both using hexamethylene hypotoxicity, the advantages of easy to recovery of applied, also using highly polar
Aprotic solvent to react facilitation, meanwhile, highly polar aprotic solvent has outstanding water solubility, can be after the reaction
Smoothly removed during treatment, the product quality without influenceing pharmaceutical intermediate.
The content of the invention
The invention provides a kind of highly polar aprotic solvent as solvent additive, the synthesis 2- thenylidenes of promotion
The method of diethyl malonate.Its preparation method is that diethyl malonate is used as reactant, hexamethylene conduct with 2 thiophene carboxaldehyde
Solvent, piperidines, used as catalyst, highly polar aprotic solvent in a heated condition, synthesizes 2- to benzoic acid as solvent additive
Thenylidene diethyl malonate.Synthetic route is as follows：
One or more highly polar aprotic solvent of the present invention is selected from：DMF (DMF),
DMA (DMAc), dimethyl sulfoxide (DMSO) (DMSO), 1-METHYLPYRROLIDONE (NMP), hexamethylphosphoric acid triamide
(HMPA)。
The highly polar aprotic solvent and hexamethylene volume range are 0.05:1~0.5:1.
Range of reaction temperature of the invention is 70 DEG C~85 DEG C.
The present invention reports the synthesis 2- thenylidene diethyl malonates that a kind of highly polar aprotic solvent promotes
Method.The synthetic method has reaction condition gentle, and process is simple, the reaction time is short, and accessory substance is few, and yield is good, can obtain
The advantages of high-purity product.
Specific embodiment
Following embodiment is to describe the present invention in detail, but should not be construed as limiting the invention.
Embodiment 1：
The synthesis of 2- thenylidene diethyl malonates：
In to the there-necked flask of 500mL, 34.6g (216mmol) diethyl malonate, 24.6g (219mmol) 2- are sequentially added
Thiophenecarboxaldehyde, 2.5g (29mmol) piperidines, 155mL hexamethylenes, then 0.1g (0.8mmol) benzoic acid is put into, 10mL N, N- diformazans
Base formamide.Hexamethylene reflux temperature is heated to, by fraction water device water-dividing, 5h is reacted.100mL water washings are added to remove N, N- bis-
NMF, 70mL saturated sodium bicarbonate solutions be washed once, and salt solution washed once, and sodium sulphate is dried, and filters out filter cake, be filtered
Liquid is concentrated to give grease 51.2g, HPLC purity：95%, yield：94%.
Embodiment 2：
The synthesis of 2- thenylidene diethyl malonates：
In to the there-necked flask of 500mL, 34.6g (216mmol) diethyl malonate, 24.6g (219mmol) 2- are sequentially added
Thiophenecarboxaldehyde, 2.5g (29mmol) piperidines, 155mL hexamethylenes, then 0.1g (0.8mmol) benzoic acid is put into, 10mL dimethyl is sub-
Sulfone.Hexamethylene reflux temperature is heated to, by fraction water device water-dividing, 4h is reacted.100mL water washings are added to remove dimethyl sulfoxide (DMSO),
70mL saturated sodium bicarbonate solutions be washed once, and salt solution washed once, and sodium sulphate is dried, and filters out filter cake, and filtrate is concentrated to give
Grease 51.7g, HPLC purity：96%, yield：95%.
Embodiment 3：
The synthesis of 2- thenylidene diethyl malonates：
In to the there-necked flask of 500mL, 34.6g (216mmol) diethyl malonate, 24.6g (219mmol) 2- are sequentially added
Thiophenecarboxaldehyde, 2.5g (29mmol) piperidines, 155mL hexamethylenes, then 0.1g (0.8mmol) benzoic acid is put into, 30mL N, N- diformazans
Base formamide.Hexamethylene reflux temperature is heated to, by fraction water device water-dividing, 2h is reacted.100mL water washings are added to remove N, N- bis-
NMF, 70mL saturated sodium bicarbonate solutions be washed once, and salt solution washed once, and sodium sulphate is dried, and filters out filter cake, be filtered
Liquid is concentrated to give grease 51.7g, HPLC purity：97%, yield：95%.
Embodiment 4：
The synthesis of 2- thenylidene diethyl malonates：
In to the there-necked flask of 500mL, 34.6g (216mmol) diethyl malonate, 24.6g (219mmol) 2- are sequentially added
Thiophenecarboxaldehyde, 2.5g (29mmol) piperidines, 155mL hexamethylenes, then put into 0.1g (0.8mmol) benzoic acid, 10mLN- methyl pyrroles
Pyrrolidone.Hexamethylene reflux temperature is heated to, by fraction water device water-dividing, 3h is reacted.100mL water washings are added to remove N- methyl pyrroles
Pyrrolidone, 70mL saturated sodium bicarbonate solutions be washed once, and salt solution washed once, and sodium sulphate is dried, and filters out filter cake, and filtrate is dense
Contracting obtains grease 49.0g, HPLC purity：95%, yield：90%.
Embodiment 5：
The synthesis of 2- thenylidene diethyl malonates：
In to the there-necked flask of 500mL, 34.6g (216mmol) diethyl malonate, 24.6g (219mmol) 2- are sequentially added
Thiophenecarboxaldehyde, 2.5g (29mmol) piperidines, 155mL hexamethylenes, then 0.1g (0.8mmol) benzoic acid is put into, 5mL N- methyl pyrroles
Pyrrolidone and 5mL N,N-dimethylformamides.Hexamethylene reflux temperature is heated to, by fraction water device water-dividing, 5h is reacted.Add
100mL water washings remove 1-METHYLPYRROLIDONE and DMF, and 70mL saturated sodium bicarbonate solutions washed once,
Salt solution be washed once, and sodium sulphate is dried, and filters out filter cake, and filtrate is concentrated to give grease 49.5g, HPLC purity：93%, receive
Rate：91%.
Claims (4)
1. a kind of method for preparing Eprosartan intermediate 2- thenylidene diethyl malonates, the method is：2- thiophene
Formaldehyde and diethyl malonate are initiation material, under the co-catalysis of piperidines and benzoic acid, hexamethylene as reaction dissolvent, plus
Highly polar aprotic solvent obtains 2- thenylidene diethyl malonates as solvent additive reaction.
2. the method for claim 1, it is characterised in that one or more the highly polar aprotic solvent is selected from：
DMF (DMF), DMA (DMAc), dimethyl sulfoxide (DMSO) (DMSO), 1-METHYLPYRROLIDONE
(NMP), hexamethylphosphoric acid triamide (HMPA).
3. the method for claim 1, it is characterised in that highly polar aprotic solvent is with hexamethylene volume range
0.05:1~0.5:1.
4. the method for claim 1, it is characterised in that range of reaction temperature is 70 DEG C~85 DEG C.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710321624.7A CN106916139A (en) | 2017-05-09 | 2017-05-09 | A kind of preparation method of improved Eprosartan intermediate |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201710321624.7A CN106916139A (en) | 2017-05-09 | 2017-05-09 | A kind of preparation method of improved Eprosartan intermediate |
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| CN201710321624.7A Pending CN106916139A (en) | 2017-05-09 | 2017-05-09 | A kind of preparation method of improved Eprosartan intermediate |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101033222A (en) * | 2007-03-31 | 2007-09-12 | 浙江华海药业股份有限公司 | Method of preparing eprosartan intermediate |
| WO2009084028A2 (en) * | 2007-12-03 | 2009-07-09 | Neuland Laboratories Ltd | Improved process for manufacturing anhydrous (e)-3-[2-butyl-1- {(4-carboxyphenyl) methyl}-1h-imidazole-5-yl]-(thiophen-2- ylmethyl)prop-2-enoic acid methane sulfonate |
-
2017
- 2017-05-09 CN CN201710321624.7A patent/CN106916139A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101033222A (en) * | 2007-03-31 | 2007-09-12 | 浙江华海药业股份有限公司 | Method of preparing eprosartan intermediate |
| WO2009084028A2 (en) * | 2007-12-03 | 2009-07-09 | Neuland Laboratories Ltd | Improved process for manufacturing anhydrous (e)-3-[2-butyl-1- {(4-carboxyphenyl) methyl}-1h-imidazole-5-yl]-(thiophen-2- ylmethyl)prop-2-enoic acid methane sulfonate |
Non-Patent Citations (1)
| Title |
|---|
| ЛОПОВ Ю.B. ET AL.: "ИССЛЕДОВПРОАНИЕ ПРОЦЕССА КОНДЕНСАЦИИ М-ФЕНОКСИБЕНЭАЛЬДЕГИДА С СН-КИСЛОТАМИ", 《KHIMICHESKAYA PROMYSHLENNOST》 * |
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Application publication date: 20170704 |