CN102617542B - Method for preparing and purifying olmesartan intermediate - Google Patents
Method for preparing and purifying olmesartan intermediate Download PDFInfo
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- CN102617542B CN102617542B CN201210069604.2A CN201210069604A CN102617542B CN 102617542 B CN102617542 B CN 102617542B CN 201210069604 A CN201210069604 A CN 201210069604A CN 102617542 B CN102617542 B CN 102617542B
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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 olmesartan intermediate 4-chloromethyl-5-methyl isophthalic acid, the preparation method of 3-dioxole-2-ketone and purification process.
Background technology
Olmesartan (Olmesartan Medoxomil Tablets), chemistry 4-(1-hydroxyl-1-methylethyl)-2-propyl group-1-[2 '-(tetrazolium-5-base) phenyl] phenyl by name] Methylimidazole-5-carboxylic acid, structural formula is as follows:
Olmesartan is angiotensin II receptor antagonists.1991, olmesartan medoxomill was succeeded in developing by Japanese Sankyo Co., Ltd, and in the patented protection of numerous country.In April, 2002, olmesartan medoxomill obtains FDA (FDA) approval, takes the lead in going on the market May in the same year in the U.S..By in December, 2005, olmesartan medoxomill goes on the market in more than 20, Europe country and 8, Asia country and area.Its general curative effect reducing diastolic pressure is better than other like products gone on the market; there is the features such as highly effective and safe, persistent and good tolerance; especially there is directly effective provide protection to the heart of hyperpietic, blood vessel and kidney, be therefore regarded as depressor desirable at present.
4-chloromethyl-5-methyl isophthalic acid, 3-dioxole-2-ketone (compound (I)) is one of important intermediate of synthesis Olmesartan, and have important economic worth and meaning to the research of its synthetic method, its synthetic route is as follows:
US Patent No. 4554358 discloses a kind of by 4,5-dimethyl-1, after 3-dioxole-2-ketone chloro, underpressure distillation obtains the chloro-4-methyl of 4--5-methylene radical-1,3-bis-Evil penta ring-2-ketone, after 90 DEG C of rearrangement reactions, underpressure distillation again, obtain 4-chloromethyl-5-methyl isophthalic acid in 91 ~ 93 DEG C (2mmHg), 3-dioxole-2-ketone, but in industrial production the more difficult vacuum tightness reaching 2mmHg; And 4-chloromethyl-5-methyl isophthalic acid, easily there is decomposition and aggregation reaction thus go bad in 3-dioxole-2-ketone, under high temperature, underpressure distillation decomposition product is comparatively large at high heat, and yield is lower, and energy consumption is comparatively large, and production cost is higher.
Purification process at present for compound (I) all adopts underpressure distillation to operate in industrial production, the total recovery of usual report is between 45% ~ 55%, after underpressure distillation, product G C detection purity reaches about 90% ~ 95%, is difficult to the high purity requirement reaching more than 98%.In addition, during distillation, condition of high vacuum degree (2mmHg) is required, very high to equipment requirements, amplify further and be restricted, had a strong impact on the production capacity of this intermediate.
Summary of the invention
Between technology to be solved by this invention, topic overcomes the deficiencies in the prior art, provides a kind of olmesartan intermediate 4-chloromethyl-5-methyl isophthalic acid of improvement, the preparation method of 3-dioxole-2-ketone.
The present invention also will provide a kind of olmesartan intermediate 4-chloromethyl-5-methyl isophthalic acid simultaneously, the purification process of 3-dioxole-2-ketone.
For solving above technical problem, a kind of technical scheme that the present invention takes is: a kind of preparation method of olmesartan intermediate, the chemical name of this olmesartan intermediate is 4-chloromethyl-5-methyl isophthalic acid, 3-dioxole-2-ketone, described preparation method comprises (1), makes the substitution reaction of 4,5-dimethyl-1,3-dioxole-2-ketone generation chlorine, and underpressure distillation obtains the chloro-4-methyl of 4--5-methylene radical-1,3-bis-Evil penta ring-2-ketone; (2) the chloro-4-methyl of step (1) gained 4--5-methylene radical-1, is made, 3-bis-Evil penta ring-2-ketone generates 4-chloromethyl-5-methyl isophthalic acid through rearrangement reaction, 3-dioxole-2-ketone, particularly, after step (2) reaction terminates, be cooled to less than 50 DEG C, be concentrated into solvent-free, obtain the crude product of described olmesartan intermediate; Described preparation method also comprises and carries out recrystallization purifying process to the crude product of olmesartan intermediate, obtains the olmesartan intermediate finished product that content is more than or equal to 98%.
According to the present invention, the concrete enforcement of step (1) and (2) can refer to method disclosed in US Patent No. 4554358 and carries out.
According to further embodiment of the present invention: the recrystallization solvent that described recrystallization purifying process adopts is one or more the mixed solvent be selected from alkane solvent and ether solvent.Described alkane solvent includes but not limited to sherwood oil, hexanaphthene, normal hexane, normal heptane etc., and described ether solvent includes but not limited to ether, methyl tertiary butyl ether, methyl-phenoxide etc.Preferably, recrystallization solvent is be selected from the one in sherwood oil, hexanaphthene, normal hexane, normal heptane, ether, methyl tertiary butyl ether and methyl-phenoxide.
Preferably, recrystallization solvent consumption is 0.5 ~ 5 times of the weight of the crude product of olmesartan intermediate.The temperature of described recrystallization is-20 DEG C ~ 0 DEG C, and the crystallization time is 1 ~ 48h.
According to the present invention concrete aspect, described recrystallization is specifically implemented as follows: in the crude product of described olmesartan intermediate, add recrystallization solvent, stirring is cooled to-20 ~ 0 DEG C, crystallization 1 ~ 48h, suction filtration, filter cake one or more the mixed solvent washing be selected from sherwood oil, hexanaphthene, normal hexane, normal heptane, ether, methyl tertiary butyl ether and methyl-phenoxide, obtains described olmesartan intermediate finished product.
The another technical scheme that the present invention takes is: a kind of purification process of olmesartan intermediate, the chemical name of olmesartan intermediate described in this is 4-chloromethyl-5-methyl isophthalic acid, 3-dioxole-2-ketone, described purification process is for carry out recrystallization process to olmesartan intermediate, the temperature of described recrystallization is-20 ~ 0 DEG C, the crystallization time is 1 ~ 48h, and recrystallization solvent is one or more the mixed solvent be selected from alkane solvent and ether solvent.
Preferably, described recrystallization solvent is be selected from the one in sherwood oil, hexanaphthene, normal hexane, normal heptane, ether, methyl tertiary butyl ether and methyl-phenoxide.The consumption of described recrystallization solvent is 4-chloromethyl-5-methyl isophthalic acid, 0.5 ~ 5 times of 3-dioxole-2-ketone weight.
Described recrystallization is specifically implemented as follows: in described olmesartan intermediate, add described recrystallization solvent, stirring is cooled to-20 ~ 0 DEG C, crystallization 1 ~ 48h, suction filtration, filter cake one or more the mixed solvent washing be selected from sherwood oil, hexanaphthene, normal hexane, normal heptane, ether, methyl tertiary butyl ether and methyl-phenoxide, obtains the olmesartan intermediate that content is more than or equal to 98wt%.
According to the present invention, the crystallization operation of above recrystallization process can realize in common enamel reaction still, not high to equipment requirements.Purge process completely avoid the severe condition such as high vacuum, is applicable to suitability for industrialized production.Simultaneously owing to shortening purification cycle, expand production capacity further.The recrystallization mother liquor of filtered and recycled can be used for recrystallization next time.Generally speaking, reusable three times of the recrystallization mother liquor of filtered and recycled.
Owing to taking above technical scheme, the present invention compared with prior art tool has the following advantages:
This invention simplifies operation steps, improve efficiency, relative to the method for being carried out purifying by underpressure distillation under condition of high vacuum degree 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, have following advantage compared to production technique in the past:
1, good yield and product content: whole from 4,5-dimethyl-1,3-dioxole-2-ketone is to 4-chloromethyl-5-methyl isophthalic acid, the process total recovery of 3-dioxole-2-ketone is more than 65%, 4-chloromethyl-5-the methyl isophthalic acid obtained, 3-dioxole-2-ketone content > 98%.High purity and content ensure that product can meet various pharmaceutical drugs requirement, and high yield then reduces the cost of product.
2, simplify production stage, shorten the production cycle: original two-step reaction can be merged operate continuously by the present invention, and is directly obtained the product of high-content by the method for recrystallization, will shorten nearly half the production cycle.
3, reduce energy consumption, reduce production cost.The present invention, to the method for the purifying of product by low temperature recrystallization, reduces energy consumption and cost compared to twice distillation purifying in the past.
Embodiment
Below in conjunction with specific embodiment, the present invention will be further described in detail, but the invention is not restricted to following examples.
Embodiment 1
The present embodiment provides a kind of 4-chloromethyl-5-methyl isophthalic acid, and the preparation method of 3-dioxole-2-ketone (hereinafter referred to as olmesartan intermediate), it specifically comprises the steps:
(1) crude product of olmesartan intermediate, is obtained
4,5-dimethyl-1,3-dioxole-2-ketone and the 320ml methylene dichloride of 40g are added in 1L there-necked flask, be stirred into settled solution, be slowly warming up to backflow, temperature 40 DEG C ~ 42 DEG C, drip 49.7g SULPHURYL CHLORIDE (1.05 equivalent), drip and finish, back flow reaction 2h, then distillation is started, until temperature of reaction system rises to 90 DEG C, insulation reaction 2h, is cooled to less than 50 DEG C, be concentrated into solvent-free, obtain olmesartan intermediate crude product 38g.Crude product GC purity is 65% ~ 73% (area calculated from GC collection of illustrative plates, but not the real content of olmesartan intermediate).
(2), recrystallization purifying process
Get olmesartan intermediate crude product 38g, add 20ml sherwood oil, stirring is cooled to-20 DEG C ~-10 DEG C, crystallization 2 ~ 20h, obtains white suspension liquid, suction filtration, obtain olmesartan intermediate finished product, weigh 34g (productive rate 65.5%, GC purity 98.7%), and wherein recrystallization mother liquor can apply mechanically three times.
Finished product bp 91 ~ 93 DEG C (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
The present embodiment provides a kind of 4-chloromethyl-5-methyl isophthalic acid, the preparation method of 3-dioxole-2-ketone (hereinafter referred to as olmesartan intermediate):
(1) crude product of olmesartan intermediate, is obtained: with embodiment 1.
(2), recrystallization purifying process
Get the crude product 38g of olmesartan intermediate, add 20mL normal heptane, stir and be cooled to-10 DEG C ~-20 DEG C, crystallization 2 ~ 48h, obtain white suspension liquid, suction filtration, filter cake 20mL normal heptane washs, obtain product, the 36g that weighs (productive rate 69.4%, GC purity 99.4%).Wherein crystalline mother solution can apply mechanically three times.
Embodiment 3
Get the crude product 38g (GC content is 65%73%) of olmesartan intermediate, add 20mL normal hexane, stirring is cooled to-10 DEG C-20 DEG C, crystallization 2 ~ 48h, obtains white suspension liquid, suction filtration, filter cake 20mL normal heptane washs, obtain product, the 36g that weighs (productive rate 69.4%, GC purity 99.4%).Wherein crystalline mother solution can apply mechanically three times.
Embodiment 4
Get the crude product 38g (GC content is 65%73%) of olmesartan intermediate, add 20mL hexanaphthene, stirring is cooled to 0 DEG C ~-20 DEG C, crystallization 16 ~ 48h, obtains white suspension liquid, suction filtration, filter cake 10mL hexanaphthene washs, obtain product, the 34g that weighs (productive rate 65.5%, GC purity 85.6%).
Embodiment 5
Get the crude product 38g (GC content is 65%73%) of olmesartan intermediate, add 20mL ether, stirring is cooled to 0 ~-20 DEG C, crystallization 16 ~ 48h, obtains white suspension liquid, suction filtration, filter cake 10mL washed with diethylether, obtain product, the 32g that weighs (productive rate 61.7%, GC purity 99.1%).
Embodiment 6
Get the crude product 38g (GC content is 65%73%) of olmesartan intermediate, add 20mL methyl tertiary butyl ether, stirring is cooled to 0 ~-20 DEG C, crystallization 16 ~ 48h, obtains white suspension liquid, suction filtration, filter cake 10mL methyl tertiary butyl ether washs, obtain product, the 29g that weighs (productive rate 55.9%, GC purity 99.1%).
Embodiment 7
Get the crude product 38g (GC content is 65%73%) of olmesartan intermediate, add 20mL normal heptane, stirring is cooled to-10 ~-20 DEG C, crystallization 2 ~ 48h, obtains white suspension liquid, suction filtration, filter cake 20mL normal heptane washs, obtain product, the 34g that weighs (productive rate 65.5%, GC purity 99.9%).
Embodiment 8
Get the crude product 38g (GC content is 65% ~ 73%) of olmesartan intermediate, add 100mL normal heptane, stirring is cooled to-10 ~-20 DEG C, crystallization 2 ~ 48h, obtains white suspension liquid, suction filtration, filter cake 20mL normal heptane washs, obtain product, the 34g that weighs (productive rate 65.5%, GC purity 99.9%).
Embodiment 9
Get the crude product 38g (GC content is 65% ~ 73%) of olmesartan intermediate, add 20mL normal heptane, stirring is cooled to 0 DEG C ~-10 DEG C, crystallization 2 ~ 48h, obtains white suspension liquid, suction filtration, filter cake 20mL normal heptane washs, obtain product, the 30g that weighs (productive rate 57.8%, GC purity 99.9%).
Above to invention has been detailed description; its object is to allow the personage being familiar with this art can understand content of the present invention and be implemented; can not limit the scope of the invention with this; the equivalence change that all spirit according to the present invention are done or modification, all should be encompassed in protection scope of the present invention.
Claims (6)
1. the preparation method of an olmesartan intermediate, the chemical name of olmesartan intermediate described in this is 4-chloromethyl-5-methyl isophthalic acid, 3-dioxole-2-ketone, described preparation method comprises (1), makes 4,5-dimethyl-1, the substitution reaction of 3-dioxole-2-ketone generation chlorine, and underpressure distillation obtains the chloro-4-methyl of 4--5-methylene radical-1,3-bis-Evil penta ring-2-ketone; (2) the chloro-4-methyl of step (1) gained 4--5-methylene radical-1, is made, 3-bis-Evil penta ring-2-ketone generates 4-chloromethyl-5-methyl isophthalic acid through rearrangement reaction, 3-dioxole-2-ketone, it is characterized in that: after step (2) reaction terminates, be cooled to less than 50 DEG C, be concentrated into solvent-free, obtain the crude product of described olmesartan intermediate; Described preparation method also comprises and carries out recrystallization purifying process to the crude product of described olmesartan intermediate, obtains the olmesartan intermediate finished product that content is more than or equal to 98wt%; The recrystallization solvent that described recrystallization purifying process adopts is selected from sherwood oil, normal heptane, normal hexane; The temperature of described recrystallization is-20 DEG C ~ 0 DEG C, and the crystallization time is 1 ~ 48h.
2. the preparation method of olmesartan intermediate according to claim 1, is characterized in that: recrystallization solvent consumption is 0.5 ~ 5 times of the weight of the crude product of olmesartan intermediate.
3. the preparation method of olmesartan intermediate according to claim 1, it is characterized in that: described recrystallization is specifically implemented as follows: in the crude product of described olmesartan intermediate, add described recrystallization solvent, stirring is cooled to-20 ~ 0 DEG C, crystallization 1 ~ 48h, suction filtration, filter cake one or more the mixed solvent washing be selected from sherwood oil, normal hexane, normal heptane, obtains described olmesartan intermediate finished product.
4. the purification process of an olmesartan intermediate, the chemical name of olmesartan intermediate described in this is 4-chloromethyl-5-methyl isophthalic acid, 3-dioxole-2-ketone, it is characterized in that: described purification process is for carry out recrystallization process to described olmesartan intermediate, the temperature of described recrystallization is-20 ~ 0 DEG C, the crystallization time is 1 ~ 48h, and described recrystallization solvent is selected from sherwood oil, normal heptane, normal hexane.
5. the purification process of olmesartan intermediate according to claim 4, is characterized in that: the consumption of described recrystallization solvent is described 4-chloromethyl-5-methyl isophthalic acid, 0.5 ~ 5 times of 3-dioxole-2-ketone weight.
6. the purification process of the olmesartan intermediate according to claim 4 or 5, it is characterized in that: described recrystallization is specifically implemented as follows: in described olmesartan intermediate, add described recrystallization solvent, stirring is cooled to-20 ~ 0 DEG C, crystallization 1 ~ 48h, suction filtration, filter cake one or more the mixed solvent washing be selected from sherwood oil, normal hexane, normal heptane, obtains the olmesartan intermediate that content is more than or equal to 98wt%.
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Families Citing this family (7)
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| 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 |
| 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 |
| 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 |
| CN113912580B (en) * | 2021-11-03 | 2023-06-02 | 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 |
| 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 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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2012
- 2012-03-16 CN CN201210069604.2A patent/CN102617542B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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