CN103864698A - Method for preparing rosuvastatin calcium - Google Patents
Method for preparing rosuvastatin calcium Download PDFInfo
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- CN103864698A CN103864698A CN201410069742.XA CN201410069742A CN103864698A CN 103864698 A CN103864698 A CN 103864698A CN 201410069742 A CN201410069742 A CN 201410069742A CN 103864698 A CN103864698 A CN 103864698A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
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Abstract
The invention discloses a method for preparing rosuvastatin calcium. The method is characterized by comprising three steps of preparation of a substrate, preparation of a chirality side chain, and preparation of calcium salt, wherein the substrate is 3, 5-dicarbonyl-6-benzyloxy-ethyl caproate, amide is the key intermediate of 3, 5-dicarbonyl-6-benzyloxy-ethyl caproate and is benzyloxy-N, O-dimethylacetamide; the preparation method comprises steps of (A) preparing the benzyloxyacetic acid through reaction of benzyl alcohol and bromoacetic acid; and (B) preparing the benzyloxy-N, O-dimethylacetamide through reaction of benzyloxyacetic acid and N,O-dimethyl hydroxylamine hydrochloride. The method has the beneficial effects of shortening the technological processes, improving the technological efficiency, being convenient to quality control and industrialization, reducing the input of raw material energy source wool, lowering the cost, abandoning toxic substances, and improving environmental protection level.
Description
Technical field
The present invention relates to a kind of method of preparing calcium salt compound, particularly a kind of processing method of preparing rosuvastain calcium.
Background technology
Rosuvastain calcium is a kind of Vasculocardiology Deparment medication of hyperlipidaemia for the treatment of hypercholesterolemia, for being even more important of modern 3 high crowds.
Current, the processing method of preparing rosuvastain calcium mainly comprises the preparation of substrate; The preparation of chiral side chain; 3 steps of preparation of calcium salt; The key intermediate that wherein acid amides is prepared as substrate, its preparation method comprises the following steps:
1. the preparation of benzyloxy acetic acid, is reacted with bromoacetic acid and is generated benzyloxy acetic acid by benzylalcohol (phenylcarbinol); Reaction expression formula is:
2. the preparation of benzyloxy Acetyl Chloride 98Min., by benzyloxy acetic acid and SOCl
2reaction generates benzyloxy Acetyl Chloride 98Min., and reaction expression formula is:
3. benzyloxy-N, the preparation of O-N,N-DIMETHYLACETAMIDE, by benzyloxy Acetyl Chloride 98Min. and N, the reaction of O-dimethyl hydroxylamine hydrochloride generates benzyloxy-N, O-N,N-DIMETHYLACETAMIDE, reaction expression formula is:
In the method, the preparation of acid amides has adopted acyl chlorides in a large number, and this element is with very strong toxicity, easily decomposes, and etching apparatus, pollutes large; And because acyl chlorides is too active, cause the yield fluctuation of product large.
At chiral side chain synthesis phase, the synthetic of two hydroxyls generally needs multiple chemical steps progressively to obtain chiral hydroxyl group at side chain, and the method operational cycle is long, and the energy and raw material consumption are large, cause production cost high.
Therefore, need to improve the existing processing method of preparing rosuvastain calcium.
Summary of the invention
Goal of the invention of the present invention is: for the problem of above-mentioned existence, provide a kind of processing method of preparing rosuvastain calcium.
The technical solution used in the present invention is such:
A processing method of preparing rosuvastain calcium, is characterized in that: comprise the preparation of substrate; The preparation of chiral side chain; 3 steps of preparation of calcium salt; Described substrate is 3,5-dicarbapentaborane-6-benzyloxy ethyl hexanoate, described chiral side chain adopts 3,5-dicarbapentaborane-6-benzyloxy ethyl hexanoate is the de-benzene preparation of raw material dehydrogenation, wherein acid amides is substrate 3, the key intermediate of 5-dicarbapentaborane-6-benzyloxy ethyl hexanoate, and described acid amides is benzyloxy-N, O-N,N-DIMETHYLACETAMIDE, its preparation method comprises the following steps:
1. the preparation of benzyloxy acetic acid, is reacted with bromoacetic acid and is generated benzyloxy acetic acid by benzylalcohol (phenylcarbinol); Its chemical equation is:
2. benzyloxy-N, the preparation of O-N,N-DIMETHYLACETAMIDE, by benzyloxy acetic acid and N, the reaction of O-dimethyl hydroxylamine hydrochloride generates benzyloxy-N, O-N,N-DIMETHYLACETAMIDE, its chemical equation is:
Further, the concrete reaction process of the preparation of above-mentioned steps 1 benzyloxy acetic acid is:
A) in reactor, add tetrahydrofuran (THF), at N
2protection, stirs lower room temperature and drops into NaH;
B) phenylcarbinol is slowly added to reactor, in 0.5～1h, add, under room temperature, stir 2h;
C) under room temperature, bromoacetic acid is dissolved in to THF and is slowly added drop-wise to reactor, drip and finish 20～60 DEG C of reaction 16-20h;
D) add water and extract benzylalcohol sodium;
E) add toluene and wash water twice;
F) water layer adds the HCl acidifying of 5mol/L, until pH value is 3;
G) after acidifying, separate organic acid, water layer adds toluene extraction;
H) merge organic acid and toluene layer and be dried, detection level;
Further, step 2 benzyloxy-N, the concrete reaction process of preparation of O-N,N-DIMETHYLACETAMIDE is:
A) in reactor, add benzyloxy acetic acid and toluene;
B) under room temperature, once add carbonylic imidazole, stir 0.5-1h;
C) once add N, O-dimethyl hydroxylamine hydrochloride, stirs 1-2h;
D) slowly drip triethylamine, drip and finish, reaction 8-10h;
E) add HCl (1N) pickling, stir 10-15min, static 0.5-1h layering;
F) except upper aqueous layer, toluene layer adds washing, obtains toluene layer dry concentrated;
G) HPLC detection level, calculated yield.
Further, described 3,5-dihydroxyl-6-benzyloxy ethyl hexanoate adopts di-carbonyl reduction enzyme that the reduction of 3,5-dicarbapentaborane-6-benzyloxy ethyl hexanoate is obtained.
In sum, owing to having adopted technique scheme, the invention has the beneficial effects as follows:
1, improved reaction efficiency.Owing to having adopted di-carbonyl reduction enzyme that 3,5-dicarbapentaborane-6-benzyloxy ethyl hexanoate is reduced into 3,5-dihydroxyl-6-benzyloxy ethyl hexanoate, make the two hydroxyls of one-step synthesis, improve reaction efficiency and raw material availability.
2, shortened reaction process.In the preparation of acid amides, two steps are synthetic, simplified schedule of operation, reduced the demand of raw material and the energy, reduced cost, improved quality, increased the controllability of quality product.
3, the N that novel process is used, O-dimethyl hydroxylamine hydrochloride and triethylamine are few more a lot of than old technology, and triethylamine easily causes the eutrophication of water; Abandoned acyl chlorides this poisonous, corrodibility is high, heavy-polluted raw material, makes production process environmental protection more.
Embodiment
Below in conjunction with embodiment, the present invention is described in detail.
In order to make object of the present invention, technical scheme and advantage clearer, below in conjunction with embodiment, the present invention is further elaborated.Should be appreciated that specific embodiment described herein, only in order to explain the present invention, is not intended to limit the present invention.
Embodiment 1:
Prepare a processing method for rosuvastain calcium, comprise the preparation of substrate; The preparation of chiral side chain; 3 steps of preparation of calcium salt, described substrate is 3,5-dicarbapentaborane-6-benzyloxy ethyl hexanoate, wherein acid amides is substrate 3, the key intermediate of 5-dicarbapentaborane-6-benzyloxy ethyl hexanoate, it is the de-benzene preparation of raw material dehydrogenation that described chiral side chain adopts 3,5-dihydroxyl-6-benzyloxy ethyl hexanoate, and wherein the preparation method of acid amides comprises the following steps:
Reactions steps 1:
Reaction process is:
1) in reactor, add tetrahydrofuran (THF), in N2 protection, stir lower room temperature and drop into NaH (60%);
2) phenylcarbinol is slowly added to reactor, in 0.5h～1h, add, under room temperature, stir 2h;
3) under room temperature, bromoacetic acid is dissolved in to THF and is slowly added drop-wise to reactor, drip and finish 20～60 DEG C of reaction 16h;
4) add water and extract benzylalcohol sodium;
5) add toluene and wash water twice;
6) water layer adds the HCl acidifying of 5mol/L, until pH value is 3;
7) after acidifying, separate organic acid, water layer adds toluene extraction;
8) merge organic acid and toluene layer and be dried, detection level.
Reactions steps 2:
Reaction process is:
1) in 5000mL reactor, add benzyloxy acetic acid 200g, with toluene 2400mL;
2) under room temperature, once add carbonylic imidazole, stir 0.5h;
3) once add the N of 100g, O-dimethyl hydroxylamine hydrochloride, stirs 1h;
4) slowly drip 250mL triethylamine, drip and finish, reaction 8h;
5) add HCl (1N) pickling of 2000mL, stir 10min, static 30min layering;
6) except upper aqueous layer, toluene layer adds 2000mL washing, obtains toluene layer dry concentrated;
7) HPLC detection level, calculated yield.
The beneficial effect of the present embodiment is: the preparation of acid amides is become to 2 steps by 3 step reactions, shorten process time cost, improved production efficiency, simultaneously because flow process shortens, be convenient to the quality of final product to control, and reduced input and the loss of raw material.Meanwhile, abandon this poisonous, the heavy-polluted material of burn into of acyl chlorides, made technological process environmental protection more.
Embodiment 2:
On the basis of embodiment 1, in the preparation of the two hydroxyls of the synthetic link of chiral side chain, adopt di-carbonyl reduction enzyme that 3,5-dicarbapentaborane-6-benzyloxy ethyl hexanoate is reduced into 3,5-dihydroxyl-6-benzyloxy ethyl hexanoate, its reaction expression formula is as follows:
The beneficial effect of the present embodiment is: by di-carbonyl reduction enzyme one-step synthesis 3,5-dihydroxyl-6-benzyloxy ethyl hexanoate, has reduced processing step, has improved process controllability; Reduce energy consumption and the raw material consumption in preparation simultaneously, improved process efficiency, facilitated quality control, adopted the method production chiral side chain of biocatalysis to improve the Environmental Protection Level of production process simultaneously, reduced pollution.
The foregoing is only preferred embodiment of the present invention, not in order to limit the present invention, all any amendments of doing within the spirit and principles in the present invention, be equal to and replace and improvement etc., within all should being included in protection scope of the present invention.
Claims (4)
1. a processing method of preparing rosuvastain calcium, is characterized in that: comprise the preparation of substrate; The preparation of chiral side chain; 3 steps of preparation of calcium salt; Described substrate is 3,5-dicarbapentaborane-6-benzyloxy ethyl hexanoate, described chiral side chain adopts 3,5-dicarbapentaborane-6-benzyloxy ethyl hexanoate is the de-benzene preparation of raw material dehydrogenation, wherein acid amides is substrate 3, the key intermediate of 5-dicarbapentaborane-6-benzyloxy ethyl hexanoate, and described acid amides is benzyloxy-N, O-N,N-DIMETHYLACETAMIDE, its preparation method comprises the following steps:
A. the preparation of benzyloxy acetic acid, is reacted with bromoacetic acid and is generated benzyloxy acetic acid by benzylalcohol (phenylcarbinol); Its chemical equation is:
B. benzyloxy-N, the preparation of O-N,N-DIMETHYLACETAMIDE, by benzyloxy acetic acid and N, the reaction of O-dimethyl hydroxylamine hydrochloride generates benzyloxy-N, O-N,N-DIMETHYLACETAMIDE, its chemical equation is:
2. processing method according to claim 1, is characterized in that: described 3,5-dihydroxyl-6-benzyloxy ethyl hexanoate adopts di-carbonyl reduction enzyme reduction 3,5-dicarbapentaborane-6-benzyloxy ethyl hexanoate to obtain.
3. processing method according to claim 1, is characterized in that: steps A comprises following sub-step:
A) in reactor, add tetrahydrofuran (THF), at N
2protection, stirs lower room temperature and drops into NaH;
B) phenylcarbinol is slowly added to reactor, in 0.5～1h, add, under room temperature, stir 2h;
C) under room temperature, bromoacetic acid is dissolved in to THF and is slowly added drop-wise to reactor, drip and finish 20～60 DEG C of reaction 16-20h;
D) add water and extract benzylalcohol sodium;
E) add toluene and wash water twice;
F) water layer adds the HCl acidifying of 5mol/L;
G) after acidifying, separate organic acid, water layer adds toluene extraction;
H) merge organic acid and toluene layer and be dried, detection level.
4. processing method according to claim 1, is characterized in that: step B comprises following sub-step:
A) in reactor, add benzyloxy acetic acid and toluene;
B) under room temperature, once add carbonylic imidazole, stir 0.5-1h;
C) once add N, O-dimethyl hydroxylamine hydrochloride, stirs 1-2h;
D) slowly drip triethylamine, drip and finish, reaction 8-10h;
E) add HCl (1N) pickling, stir 10-15min, static 0.5-1h layering;
F) except upper aqueous layer, toluene layer adds washing, obtains toluene layer dry concentrated;
G) HPLC detection level, calculated yield.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410069742.XA CN103864698A (en) | 2014-02-27 | 2014-02-27 | Method for preparing rosuvastatin calcium |
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| CN201410069742.XA CN103864698A (en) | 2014-02-27 | 2014-02-27 | Method for preparing rosuvastatin calcium |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110343134A (en) * | 2019-08-04 | 2019-10-18 | 张震 | A kind of preparation method of bis- (2,4,6- trimethylbenzoyl) phenyl phosphine oxides of photoinitiator |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1687087A (en) * | 2005-05-16 | 2005-10-26 | 浙江海正药业股份有限公司 | Method for preparing Rosuvastain and its intermediate |
| WO2006106526A1 (en) * | 2005-04-04 | 2006-10-12 | Unichem Laboratories Limited | Process for preparation of calcium salt of rosuvastatin |
| CN101376647A (en) * | 2007-08-31 | 2009-03-04 | 中山奕安泰医药科技有限公司 | Method for synthesizing rosuvastatin intermediate and rosuvastatin |
| WO2013185309A1 (en) * | 2012-06-13 | 2013-12-19 | 上海迪赛诺药业有限公司 | Rosuvastatin calcium and method for preparing intermediate thereof |
-
2014
- 2014-02-27 CN CN201410069742.XA patent/CN103864698A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006106526A1 (en) * | 2005-04-04 | 2006-10-12 | Unichem Laboratories Limited | Process for preparation of calcium salt of rosuvastatin |
| CN1687087A (en) * | 2005-05-16 | 2005-10-26 | 浙江海正药业股份有限公司 | Method for preparing Rosuvastain and its intermediate |
| CN101376647A (en) * | 2007-08-31 | 2009-03-04 | 中山奕安泰医药科技有限公司 | Method for synthesizing rosuvastatin intermediate and rosuvastatin |
| WO2013185309A1 (en) * | 2012-06-13 | 2013-12-19 | 上海迪赛诺药业有限公司 | Rosuvastatin calcium and method for preparing intermediate thereof |
Non-Patent Citations (4)
| Title |
|---|
| ARMEN A. TUDJARIAN等: "[3,3]-Sigmatropic Rearrangement/5-exo-dig Cyclization Reactions of Benzyl Alkynyl Ethers: Synthesis of Substituted 2-Indanones and Indenes", 《THE JOURNAL OF ORGANIC CHEMISTRY》 * |
| WU XU-RI等: "Two step process for diketo reduction catalyzed by diketoreductase", 《JOURNAL OF CHINA PHARMACEUTICAL UNIVERSITY》, vol. 41, no. 5, 31 December 2010 (2010-12-31), pages 408 - 413 * |
| WU XU-RI等: "Two step process for diketoreduction catalyzed by diketoreductase", 《JOURNAL OF CHINA PHARMACEUTICAL UNIVERSITY》 * |
| ZHIWEI GUO等: "Synthesis of ethyl and t-butyl (3R,5S)-dihydroxy-6-benzyloxy hexanoates via diastereo- and enantioselective microbial reduction", 《TETRAHEDRON: ASYMMETRY》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110343134A (en) * | 2019-08-04 | 2019-10-18 | 张震 | A kind of preparation method of bis- (2,4,6- trimethylbenzoyl) phenyl phosphine oxides of photoinitiator |
| CN110343134B (en) * | 2019-08-04 | 2022-03-15 | 张震 | Preparation method of photoinitiator bis (2,4, 6-trimethylbenzoyl) phenylphosphine oxide |
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