CN102617542A - Method for preparing and purifying olmesartan intermediate - Google Patents
Method for preparing and purifying olmesartan intermediate Download PDFInfo
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- CN102617542A CN102617542A CN2012100696042A CN201210069604A CN102617542A CN 102617542 A CN102617542 A CN 102617542A CN 2012100696042 A CN2012100696042 A CN 2012100696042A CN 201210069604 A CN201210069604 A CN 201210069604A CN 102617542 A CN102617542 A CN 102617542A
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Abstract
The invention relates to a method for preparing and purifying an olmesartan intermediate. The preparation method comprises the following steps of: chlorinating 4,5-dimethyl-1,3-dioxa-cyclopentene-2-ketone, distilling under reduced pressure to obtain 4-chloro-4-methyl-5-methylene-1,3-dioxolane-2-ketone, and performing rearrangement reaction to generate the olmesartan intermediate; reducing the temperature to be below 50 DEG C, concentrating until a solvent is removed completely to obtain a crude product; and recrystallizing and purifying the crude product at the temperature of between -20 and 0 DEG C for 1 to 48 hours, wherein a recrystallization solvent may be one or a mixed solvent of more of an alkane solvent and an ether solvent. The preparation method is low in production cost, mild in reaction condition and easy to operate, raw materials are wide in sources, and high-content 4-chloromethyl-5-methyl-1,3-dioxa-cyclopentene-2-ketone can be obtained directly, so the method is particularly suitable for large-scale industrial production.
Description
Technical field
The invention belongs to field of medicine and chemical technology, particularly a kind of OLM-Mod midbody 4-chloromethyl-5-methyl isophthalic acid, the preparation method and the purification process of 3-dioxole-2-ketone.
Background technology
OLM-Mod (Olmesartan Medoxomil Tablets), chemistry 4-(1-hydroxyl-1-methylethyl) by name-2-propyl group-1-[2 '-(tetrazolium-5-yl) phenyl] phenyl] Methylimidazole-5-carboxylic acid, structural formula is following:
OLM-Mod is an angiotensin ii receptor antagonist.1991, olmesartan medoxomill was succeeded in developing by Japanese Sankyo Co., Ltd, and in the protection that patents of numerous countries.In April, 2002, olmesartan medoxomill obtains FDA (FDA) approval, takes the lead in going on the market in the U.S. May in the same year.By in December, 2005, olmesartan medoxomill more than 20 national and 8 countries in Asia and area listings in Europe.Its general curative effect that reduces diastolic pressure is superior to the like product that other have gone on the market; Have characteristics such as highly effective and safe, persistent and good tolerability; Especially heart, blood vessel and the kidney to the hyperpietic has directly effectively provide protection, therefore is regarded as present ideal depressor.
4-chloromethyl-5-methyl isophthalic acid, 3-dioxole-2-ketone (compound (I)) are one of important intermediate of synthetic OLM-Mod, and the research of its compound method is had important economic value and meaning, and its synthetic route is following:
U.S. Pat 4554358 discloses a kind ofly passes through 4, and 5-dimethyl-1 is behind 3-dioxole-2-ketone chloro; Decompression distillation obtains 4-chloro-4-methyl-5-methylene-1, and 3-two dislikes penta ring-2-ketone, after 90 ℃ of rearrangement reactions; Decompression distillation again; Obtain 4-chloromethyl-5-methyl isophthalic acid in 91～93 ℃ (2mmHg), 3-dioxole-2-ketone, but on commercial production the difficult vacuum that reaches 2mmHg; And 4-chloromethyl-5-methyl isophthalic acid, thereby 3-dioxole-2-ketone is prone to take place decomposition down in high heat to go bad with polymerisation, under the high temperature decomposition of decompression distillation product bigger, yield is lower, and energy consumption is bigger, production cost is higher.
Purification process for compound (I) all adopts the underpressure distillation operation on industrial production at present; Usually the total recovery of report is between 45%～55%; Product G C detection purity reaches about 90%～95% after the underpressure distillation, is difficult to reach the high purity requirement more than 98%.In addition, require condition of high vacuum degree (2mmHg) during distillation, very high to equipment requirements, further amplification is restricted, and has had a strong impact on the production capacity of this midbody.
Summary of the invention
Topic is the deficiency that overcomes prior art between technology to be solved by this invention, a kind of improved OLM-Mod midbody 4-chloromethyl-5-methyl isophthalic acid is provided, the preparation method of 3-dioxole-2-ketone.
The present invention also will provide a kind of OLM-Mod midbody 4-chloromethyl-5-methyl isophthalic acid, the purification process of 3-dioxole-2-ketone simultaneously.
To solve the above technical problem, the present invention is a technical solution adopted is: A method for the preparation of intermediates of olmesartan, olmesartan intermediates which the chemical name is 4 - chloro-5 - methyl-1, 3 - dioxolan-en-2 - one, the preparation method comprises (1), the 4,5 - dimethyl-1 ,3 - dioxolan-en-2 - one of chlorine substitution reaction, and distilled under reduced pressure to give 4 - chloro-4 - methyl-5 - methylene-1 ,3 - dioxolane -2 - one; (2), in the step (1) from 4 - chloro-4 - methyl -5 - methylene-1 ,3 - dioxolane -2 - one by rearrangement to form 4 - chloro-5 - methyl-1 ,3 - dioxolan-en-2 - one In particular, the step (2) After completing the reaction, cooling to below 50 ℃ solvent was concentrated to give the crude intermediate olmesartan; said method further comprises preparing intermediates of crude olmesartan re crystallization purification to obtain content more than 98% of the intermediate product of olmesartan.
According to the present invention, the practical implementation of step (1) and (2) can be carried out with reference to U.S. Pat 4554358 disclosed methods.
According to further embodiment of the present invention: it is one or more the mixed solvent that is selected from alkane solvent and the ether solvent that said recrystallization purifying is handled the recrystallization solvent that adopts.Said alkane solvent includes but not limited to sherwood oil, hexanaphthene, normal hexane, normal heptane etc., and said ether solvent includes but not limited to ether, MTBE, methyl-phenoxide etc.Preferably, recrystallization solvent is to be selected from a kind of in sherwood oil, hexanaphthene, normal hexane, normal heptane, ether, MTBE and the methyl-phenoxide.
Preferably, the recrystallization solvent consumption is 0.5～5 times of weight of the bullion of OLM-Mod midbody.The temperature of said recrystallization is-20 ℃～0 ℃, and the crystallization time is 1～48h.
Concrete aspect according to the present invention; Said recrystallization practical implementation is following: in the bullion of said OLM-Mod midbody, add recrystallization solvent; Stirring is cooled to-20～0 ℃, crystallization 1～48h, suction filtration; Filter cake promptly gets said OLM-Mod midbody finished product with one or more the mixed solvent washing that is selected from sherwood oil, hexanaphthene, normal hexane, normal heptane, ether, MTBE and the methyl-phenoxide.
The another technical scheme that the present invention takes is: a kind of purification process of OLM-Mod midbody; The chemical name of this said OLM-Mod midbody is 4-chloromethyl-5-methyl isophthalic acid; 3-dioxole-2-ketone, said purification process is handled for the OLM-Mod midbody being carried out recrystallization, and the temperature of said recrystallization is-20～0 ℃; The crystallization time is 1～48h, and recrystallization solvent is one or more the mixed solvent that is selected from alkane solvent and the ether solvent.
Preferably, said recrystallization solvent is to be selected from a kind of in sherwood oil, hexanaphthene, normal hexane, normal heptane, ether, MTBE and the methyl-phenoxide.The consumption of said recrystallization solvent is 4-chloromethyl-5-methyl isophthalic acid, 0.5～5 times of 3-dioxole-2-ketone weight.
Said recrystallization practical implementation is following: in said OLM-Mod midbody, add said recrystallization solvent; Stirring is cooled to-20～0 ℃; Crystallization 1～48h; Suction filtration, filter cake obtains the OLM-Mod midbody of content more than or equal to 98wt% with one or more the mixed solvent washing that is selected from sherwood oil, hexanaphthene, normal hexane, normal heptane, ether, MTBE and the methyl-phenoxide.
According to the present invention, the crystallization operation that above recrystallization is handled can be realized in common enamel reaction still, and is not high to equipment requirements.Purge process has been avoided severe condition such as high vacuum fully, is fit to suitability for industrialized production.Owing to shortened the purifying cycle, further enlarged production capacity simultaneously.The recrystallization mother liquor of filtered and recycled can be used for recrystallization next time.Generally speaking, the recrystallization mother liquor of filtered and recycled is reusable three times.
Owing to take above technical scheme, the present invention compared with prior art has following advantage:
The present invention has simplified operation steps, has improved efficient, and with respect to the method that purifying is carried out in underpressure distillation under the condition of high vacuum degree of passing through in the past, the present invention has simple to operate, and energy consumption is low, and loss is few, reduces the advantage of production stage.
Take preparation method of the present invention, following advantage arranged than in the past production technique:
1, good yield and product content: whole from 4; 5-dimethyl--1,3-dioxole-2-ketone are to 4-chloromethyl-5-methyl isophthalic acid, and the process total recovery of 3-dioxole-2-ketone surpasses 65%; 4-chloromethyl-5-the methyl isophthalic acid that obtains, 3-dioxole-2-ketone content＞98%.High purity and content guarantee that product can satisfy various pharmaceutical drugs requirements, and high yield has then reduced the cost of product.
2, simplify production stage, shorten the production cycle: the present invention can merge operate continuously with original two-step reaction, and directly obtains high-load product through the method for recrystallization, will shorten the production cycle near half the.
3, reduce energy consumption, reduced production cost.The present invention is to the purifying of the product method through the low temperature recrystallization, reduced energy consumption and cost than in the past twice distillation purifying.
Embodiment
Below in conjunction with concrete embodiment the present invention is done further detailed explanation, but the invention is not restricted to following examples.
Embodiment 1
Present embodiment provides a kind of 4-chloromethyl-5-methyl isophthalic acid, the preparation method of 3-dioxole-2-ketone (to call the OLM-Mod midbody in the following text), and it specifically comprises the steps:
(1), obtains the bullion of OLM-Mod midbody
In the 1L there-necked flask, add 4 of 40g, 5-dimethyl--1,3-dioxole-2-ketone and 320ml methylene dichloride are stirred into settled solution; Slowly be warming up to backflow, 40 ℃～42 ℃ of temperature drip 49.7g SULPHURYL CHLORIDE (1.05 equivalent), drip and finish; Back flow reaction 2h begins distillation then, rises to 90 ℃ until temperature of reaction system, insulation reaction 2h; Be cooled to below 50 ℃, be concentrated into solvent-freely, obtain OLM-Mod midbody bullion 38g.Bullion GC purity is 65%～73% (area that from the GC collection of illustrative plates, calculates, but not the real content of OLM-Mod midbody).
(2), recrystallization purifying is handled
Get OLM-Mod midbody bullion 38g, add the 20ml sherwood oil, stir and be cooled to-20 ℃～-10 ℃, crystallization 2～20h; Obtain white suspension liquid, suction filtration obtains OLM-Mod midbody finished product; The 34g (productive rate 65.5%, GC purity 98.7%) that weighs, wherein recrystallization mother liquor can be applied mechanically three times.
91～93 ℃ of finished product bp (2mmHg);
IR：v(cm
-1)：1820(C＝O)，1730(C＝C)；
1H-NMR(CDCl
3)δ(ppm)：2.18(3H，s，CH
3)，4.31(2H，s，CH
2Cl)。
Embodiment 2
Present embodiment provides a kind of 4-chloromethyl-5-methyl isophthalic acid, the preparation method of 3-dioxole-2-ketone (to call the OLM-Mod midbody in the following text):
(1), obtains the bullion of OLM-Mod midbody: with embodiment 1.
(2), recrystallization purifying is handled
Get the bullion 38g of OLM-Mod midbody, add the 20mL normal heptane, stir and be cooled to-10 ℃～-20 ℃, crystallization 2～48h obtains white suspension liquid, suction filtration, and filter cake obtains product, the 36g that weighs (productive rate 69.4%, GC purity 99.4%) with the washing of 20mL normal heptane.Wherein crystalline mother solution can be applied mechanically three times.
Embodiment 3
Get the bullion 38g (GC content is 65%73%) of OLM-Mod midbody, add the 20mL normal hexane, stir and be cooled to-10 ℃-20 ℃, crystallization 2～48h; Obtain white suspension liquid, suction filtration, filter cake washs with the 20mL normal heptane; Obtain product, the 36g that weighs (productive rate 69.4%, GC purity 99.4%).Wherein crystalline mother solution can be applied mechanically three times.
Embodiment 4
Get the bullion 38g (GC content is 65%73%) of OLM-Mod midbody, add the 20mL hexanaphthene, stir and be cooled to 0 ℃～-20 ℃, crystallization 16～48h; Obtain white suspension liquid, suction filtration, filter cake washs with the 10mL hexanaphthene; Obtain product, the 34g that weighs (productive rate 65.5%, GC purity 85.6%).
Embodiment 5
Get the bullion 38g (GC content is 65%73%) of OLM-Mod midbody, add the 20mL ether, stir and be cooled to 0～-20 ℃, crystallization 16～48h; Obtain white suspension liquid, suction filtration, filter cake washs with the 10mL ether; Obtain product, the 32g that weighs (productive rate 61.7%, GC purity 99.1%).
Embodiment 6
Get the bullion 38g (GC content is 65%73%) of OLM-Mod midbody, add the 20mL MTBE, stir and be cooled to 0～-20 ℃; Crystallization 16～48h obtains white suspension liquid, suction filtration; Filter cake washs with the 10mL MTBE; Obtain product, the 29g that weighs (productive rate 55.9%, GC purity 99.1%).
Embodiment 7
Get the bullion 38g (GC content is 65%73%) of OLM-Mod midbody, add the 20mL normal heptane, stir and be cooled to-10～-20 ℃, crystallization 2～48h; Obtain white suspension liquid, suction filtration, filter cake washs with the 20mL normal heptane; Obtain product, the 34g that weighs (productive rate 65.5%, GC purity 99.9%).
Embodiment 8
Get the bullion 38g (GC content is 65%～73%) of OLM-Mod midbody, add the 100mL normal heptane, stir and be cooled to-10～-20 ℃, crystallization 2～48h; Obtain white suspension liquid, suction filtration, filter cake washs with the 20mL normal heptane; Obtain product, the 34g that weighs (productive rate 65.5%, GC purity 99.9%).
Embodiment 9
Get the bullion 38g (GC content is 65%～73%) of OLM-Mod midbody, add the 20mL normal heptane, stir and be cooled to 0 ℃～-10 ℃, crystallization 2～48h; Obtain white suspension liquid, suction filtration, filter cake washs with the 20mL normal heptane; Obtain product, the 30g that weighs (productive rate 57.8%, GC purity 99.9%).
More than the present invention has been done detailed description; Its purpose is to let the personage that is familiar with this art can understand content of the present invention and implements; Can not limit protection scope of the present invention with this; All equivalences of doing according to spirit of the present invention change or modify, and all should be encompassed in protection scope of the present invention.
Claims (10)
- A method for preparation of intermediates of olmesartan, olmesartan that said intermediate chemical name is 4 - chloro-5 - methyl-1 ,3 - dioxolan-en-2 - one said preparation method comprises (1), the 4,5 - dimethyl-1 ,3 - dioxolan-en-2 - one of chlorine substitution reaction and distilled under reduced pressure to give 4 - chloro-4 - methyl -5 - methylene-1 ,3 - dioxolane -2 - one; (2), in the step (1) from 4 - chloro-4 - methyl-5 - methylene-1 ,3 - dioxolanes -2 - one by rearrangement to form 4 - chloro-5 - methyl-1 ,3 - dioxolan-en-2 - one, characterized in that: step (2) After the reaction , cooling to below 50 ℃ solvent was concentrated to give the crude intermediate olmesartan; said method further comprises preparing said intermediates olmesartan crude product was purified by recrystallization to obtain content more than 98wt % of olmesartan intermediate products.
- 2. OLM-Mod intermediates preparation according to claim 1 is characterized in that: it is one or more the mixed solvent that is selected from alkane solvent and the ether solvent that said recrystallization purifying is handled the recrystallization solvent that adopts.
- 3. OLM-Mod intermediates preparation according to claim 2 is characterized in that: it is to be selected from a kind of in sherwood oil, hexanaphthene, normal hexane, normal heptane, ether, MTBE and the methyl-phenoxide that said recrystallization purifying is handled the recrystallization solvent that adopts.
- 4. OLM-Mod intermediates preparation according to claim 2 is characterized in that: the recrystallization solvent consumption is 0.5～5 times of weight of the bullion of OLM-Mod midbody.
- 5. according to the described OLM-Mod intermediates preparation of each claim in the claim 1 to 4, it is characterized in that: the temperature of said recrystallization is-20 ℃～0 ℃, and the crystallization time is 1～48h.
- 6. OLM-Mod intermediates preparation according to claim 5; It is characterized in that: said recrystallization practical implementation is following: in the bullion of said OLM-Mod midbody, add said recrystallization solvent; Stirring is cooled to-20～0 ℃, crystallization 1～48h, suction filtration; Filter cake promptly gets said OLM-Mod midbody finished product with one or more the mixed solvent washing that is selected from sherwood oil, hexanaphthene, normal hexane, normal heptane, ether, MTBE and the methyl-phenoxide.
- 7. the purification process of an OLM-Mod midbody; The chemical name of this said OLM-Mod midbody is 4-chloromethyl-5-methyl isophthalic acid; 3-dioxole-2-ketone is characterized in that: said purification process is handled for said OLM-Mod midbody being carried out recrystallization, and the temperature of said recrystallization is-20～0 ℃; The crystallization time is 1～48h, and recrystallization solvent is one or more the mixed solvent that is selected from alkane solvent and the ether solvent.
- 8. the purification process of OLM-Mod midbody according to claim 7 is characterized in that: said recrystallization solvent is to be selected from a kind of in sherwood oil, hexanaphthene, normal hexane, normal heptane, ether, MTBE and the methyl-phenoxide.
- 9. the purification process of OLM-Mod midbody according to claim 7 is characterized in that: the consumption of said recrystallization solvent is said 4-chloromethyl-5-methyl isophthalic acid, 0.5～5 times of 3-dioxole-2-ketone weight.
- 10. according to the purification process of claim 7 or 8 or 9 described OLM-Mod midbodys; It is characterized in that: said recrystallization practical implementation is following: in said OLM-Mod midbody, add said recrystallization solvent; Stirring is cooled to-20～0 ℃; Crystallization 1～48h; Suction filtration, filter cake obtains the OLM-Mod midbody of content more than or equal to 98wt% with one or more the mixed solvent washing that is selected from sherwood oil, hexanaphthene, normal hexane, normal heptane, ether, MTBE and the methyl-phenoxide.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103864748A (en) * | 2014-03-05 | 2014-06-18 | 浙江华海药业股份有限公司 | Purification method of 4-chloromethyl-5-methyl-1,3-dioxole-2-ketone |
| CN105348249A (en) * | 2015-12-11 | 2016-02-24 | 六安科瑞达新型材料有限公司 | Synthetic method of 4-chloromethyl-5-methyl-1,3-dioxole-2-ketone |
| CN109942535A (en) * | 2019-04-27 | 2019-06-28 | 蚌埠学院 | A kind of -5 methyl-1 of 4- chloromethyl, the preparation method of 3 dioxole -2- ketone |
| CN111595982A (en) * | 2020-06-29 | 2020-08-28 | 珠海润都制药股份有限公司 | Method for detecting 1, 3-dioxolane impurities |
| CN112321559A (en) * | 2020-10-27 | 2021-02-05 | 浙江花蝶染料化工有限公司 | Chemical synthesis method of 4-chloromethyl-5-methyl-1, 3-dioxol-2-one |
| CN113912580A (en) * | 2021-11-03 | 2022-01-11 | 瑞孚信江苏药业股份有限公司 | Method for purifying 4- (hydroxymethyl) -5-methyl- [1,3] dioxol-2-one |
| CN115385889A (en) * | 2022-08-24 | 2022-11-25 | 珠海润都制药股份有限公司 | Preparation method of olmesartan medoxomil intermediate |
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| US4554358A (en) * | 1983-06-14 | 1985-11-19 | Kanebo, Ltd. | 4-Chloro-4-methyl-5-methylene-1,3-dioxolane-2-one |
| US5466811A (en) * | 1994-07-18 | 1995-11-14 | Merck & Co., Inc. | Dioxolenylmethyl carbamates pro moieties for amine drugs |
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| US4554358A (en) * | 1983-06-14 | 1985-11-19 | Kanebo, Ltd. | 4-Chloro-4-methyl-5-methylene-1,3-dioxolane-2-one |
| US5466811A (en) * | 1994-07-18 | 1995-11-14 | Merck & Co., Inc. | Dioxolenylmethyl carbamates pro moieties for amine drugs |
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| CN103864748A (en) * | 2014-03-05 | 2014-06-18 | 浙江华海药业股份有限公司 | Purification method of 4-chloromethyl-5-methyl-1,3-dioxole-2-ketone |
| CN103864748B (en) * | 2014-03-05 | 2019-03-01 | 浙江华海药业股份有限公司 | A kind of purification process of 4- chloromethyl -5- methyl-1,3-dioxy heterocyclic pentene -2- ketone |
| CN105348249A (en) * | 2015-12-11 | 2016-02-24 | 六安科瑞达新型材料有限公司 | Synthetic method of 4-chloromethyl-5-methyl-1,3-dioxole-2-ketone |
| CN105348249B (en) * | 2015-12-11 | 2017-06-30 | 六安科瑞达新型材料有限公司 | A kind of synthetic method of the ketone of 4 chloromethyl, 5 methyl, 1,3 dioxole 2 |
| CN109942535A (en) * | 2019-04-27 | 2019-06-28 | 蚌埠学院 | A kind of -5 methyl-1 of 4- chloromethyl, the preparation method of 3 dioxole -2- ketone |
| CN111595982A (en) * | 2020-06-29 | 2020-08-28 | 珠海润都制药股份有限公司 | Method for detecting 1, 3-dioxolane impurities |
| CN111595982B (en) * | 2020-06-29 | 2022-07-08 | 珠海润都制药股份有限公司 | Method for detecting 1, 3-dioxolane impurities |
| CN112321559A (en) * | 2020-10-27 | 2021-02-05 | 浙江花蝶染料化工有限公司 | Chemical synthesis method of 4-chloromethyl-5-methyl-1, 3-dioxol-2-one |
| CN113912580A (en) * | 2021-11-03 | 2022-01-11 | 瑞孚信江苏药业股份有限公司 | Method for purifying 4- (hydroxymethyl) -5-methyl- [1,3] dioxol-2-one |
| CN115385889A (en) * | 2022-08-24 | 2022-11-25 | 珠海润都制药股份有限公司 | Preparation method of olmesartan medoxomil intermediate |
| CN115385889B (en) * | 2022-08-24 | 2023-11-10 | 珠海润都制药股份有限公司 | Preparation method of olmesartan medoxomil intermediate |
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