CN109912515B

CN109912515B - Preparation method of rosuvastatin calcium

Info

Publication number: CN109912515B
Application number: CN201910190264.0A
Authority: CN
Inventors: 林娇华; 夏海建; 向科
Original assignee: ZHEJIANG YONGTAI TECHNOLOGY CO LTD
Current assignee: ZHEJIANG YONGTAI TECHNOLOGY CO LTD
Priority date: 2019-03-13
Filing date: 2019-03-13
Publication date: 2020-06-30
Anticipated expiration: 2039-03-13
Also published as: CN109912515A

Abstract

The invention provides a preparation method of rosuvastatin calcium, which takes allene as a raw material to prepare a rosuvastatin calcium side chain and is used for synthesizing rosuvastatin calcium.

Description

Preparation method of rosuvastatin calcium

Technical Field

The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of rosuvastatin calcium.

Background

Rosuvastatin (Rosuvastatin) is an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme a reductase (HMG-CoA reductase), and can be used for the treatment of hypercholesterolemia and mixed dyslipidemia, and can reduce elevated concentrations of low density cholesterol, total cholesterol, triglycerides and apoprotein B, while elevating the concentration of high density cholesterol; can be used for the comprehensive treatment of primary hypercholesterolemia, mixed lipodystrophy and homozygous familial hypercholesterolemia, and is called super statin.

In therapy, rosuvastatin is administered as its calcium salt and is a single enantiomer having the following chemical structure.

With regard to the synthesis of rosuvastatin calcium, various methods have been reported, for example EP0521471a1 reports the following synthesis:

the side chain compound used in the method is very expensive in market price, and the self-synthesis cannot ensure high optical purity of the side chain, so that the method is not beneficial to popularization and production.

WO0049014a1 discloses the following synthetic method:

although the side chain compound used in the method can be prepared into a high-purity side chain compound by the existing preparation method, the Wittig reaction condition involved in the method is harsh (for example, the reaction temperature is-75 ℃, deep cooling equipment is needed), and the post-treatment is extremely complicated, so that the method is not suitable for industrial production.

Bernhard Breit et al (org. Lett.2018,20,3286-3290) reported a side chain capable of synthesizing rosuvastatin calcium with high stereoselectivity using allene as a raw material. However, the method also involves the reaction under the harsh condition of-78 ℃ in the synthesis of rosuvastatin calcium, and is not favorable for industrial production.

In view of the clinical efficacy of rosuvastatin calcium, the rosuvastatin calcium has a wide market, and the synthesis method of the rosuvastatin calcium is always the key point of industrial research. The inventor researches the defects of the existing synthesis method and provides a synthesis method of rosuvastatin calcium, which is more beneficial to industrial production.

Disclosure of Invention

The invention provides a method for preparing a rosuvastatin calcium side chain by using allene as a raw material, which is further used for synthesizing rosuvastatin calcium, wherein a hydrogen peroxide-heteropoly acid oxidation system is used for oxidizing the synthesized side chain from olefin to aldehyde, so that the harsh condition of low-temperature reaction (-78 ℃) is avoided, and the industrial production is facilitated.

In order to solve the above technical problems, according to one embodiment of the present invention, the present invention provides a method for preparing rosuvastatin calcium, comprising the steps of:

1) reacting the compound of the formula I with a formaldehyde aqueous solution in the presence of a catalyst, a ligand and an auxiliary agent to obtain a compound of a formula II;

2) reacting the compound of the formula II in a hydrogen peroxide-heteropoly acid system to prepare a compound III;

3) reacting the compound III with a formula IV to generate a compound V;

4) hydrolyzing the compound of the formula V to obtain a compound of a formula VI;

5) reacting the compound shown in the formula VI under an acidic condition to obtain a compound shown in the formula VII;

6) hydrolyzing the compound in the formula VII to form salt to obtain rosuvastatin calcium;

the reaction route is as follows:

according to one embodiment of the invention, R₁Is selected from C_1-12Alkyl radical, C_6-12An aryl group; r₂Is selected from P⁺(Ph)₃X^-、PO(Ph)₂、-S(O)₂-Het, wherein X^-Represents a halide, and Het represents a 5-to 6-membered heterocyclic ring containing a nitrogen atom.

According to one embodiment of the invention, R₁Preferably C_1-6An alkyl group;

according to one embodiment of the invention, R₁Preferably methyl, ethyl, propyl, isopropyl, tert-butyl, phenyl; most preferred are methyl and ethyl.

According to one embodiment of the invention, R₂Is selected from P⁺(Ph)₃X^-、PO(Ph)₂Preferably P⁺(Ph)₃X^-Most preferably P⁺(Ph)₃Br^-。

According to one embodiment of the invention, in step 1), the catalyst is selected from palladium catalysts, preferably Pd (PPh)₃)₄、Pd(PPh₃)₂Cl₂、Pd(OAc)₂、Pd(acac)₂Bis (cinnamylpalladium chloride), bis (allylpalladium chloride), tris (dibenzylideneacetone) dipalladium, palladium chloride, bis (acetonitrile) palladium chloride, and most preferably Pd (PPh)₃)₄、Pd(PPh₃)₂Cl₂、Pd(OAc)₂、Pd(acac)₂。

According to one embodiment of the invention, the ligand is selected from phosphine ligands, preferably (S) - (-) -SEGphos, DPEphos.

According to one embodiment of the invention, the auxiliary agent is selected from the group consisting of acids, preferably p-toluenesulfonic acid, Ph₂PO₄H. Phosphoric acid, benzenesulfonic acid, methanesulfonic acid, acetic acid, most preferably p-toluenesulfonic acid.

According to one embodiment of the invention, the reaction solvent of step 1) is selected from benzene, toluene, xylene, preferably xylene.

According to one embodiment of the invention, the hydrogen peroxide used in step 2) is selected from hydrogen peroxide having a mass fraction of 30% to 60%.

In accordance with one embodiment of the present invention,the heteropoly acid used in the step 2) is selected from phosphomolybdic heteropoly acid and phosphotungstic heteropoly acid; preferably H₃PW₁₂O₄₀、H₄PMo₁₁VO₄₀、H₃PMo₁₂O₄₀、H₄PW₁₁VO₄₀。

According to one embodiment of the present invention, the reaction solvent of step 2) is an alcohol, preferably methanol, ethanol, tert-butanol, isopropanol.

According to one embodiment of the invention, the reaction temperature in step 1) is between 60 ℃ and 100 ℃ and the reaction temperature is preferably between 80 ℃ and 85 ℃.

According to one embodiment of the invention, the reaction temperature in step 2) is between 10 ℃ and 40 ℃ and the reaction temperature is preferably between 20 ℃ and 35 ℃.

According to one embodiment of the invention, the reaction of step 3) is carried out in DMSO as a solvent in the presence of a base, preferably K₂CO₃、Na₂CO₃、KHCO₃、NaHCO₃、KOH、NaOH。

According to one embodiment of the invention, the acidic conditions in step 5) are provided by hydrochloric acid.

According to one embodiment of the invention, step 5) is carried out by adding an appropriate amount of phosphoric acid in addition to providing acidic conditions using hydrochloric acid.

According to one embodiment of the invention, the appropriate amount of phosphoric acid is 1 to 3 drops, preferably 1 drop, per gram of the compound of formula VI.

According to one embodiment of the invention, step 6) is hydrolyzed in the presence of a base and then salified with a calcium salt to obtain rosuvastatin calcium.

According to one embodiment of the invention, the base of step 6) is K₂CO₃、Na₂CO₃、KHCO₃、NaHCO₃KOH or NaOH, preferably KOH or NaOH, particularly preferably 40% aqueous sodium hydroxide solution.

According to one embodiment of the invention, the calcium salt of step 6) is selected from calcium acetate, calcium nitrate, preferably calcium acetate.

In the preparation method disclosed by the invention, the raw materials used are all known compounds in the field, and can be obtained commercially or synthesized by the preparation method known in the field.

Compared with the prior art, the invention optimizes the synthesis conditions to meet the industrial production requirements, avoids the harsh conditions of low temperature (-78 ℃), and is more beneficial to realizing industrial production; meanwhile, the synthesis yield is improved.

Drawings

FIG. 1: rosuvastatin calcium synthesis roadmap of the present invention

Detailed Description

The present invention will be described in further detail with reference to examples in order to better illustrate embodiments of the present invention, but should not be construed as limiting the scope of the present invention.

Example 1

Compound II is prepared by reference to Bernhard Breit et al (org. Lett.2018,20, 3286-3290). Adding Pd (PPh) into the reaction bottle₃)₄(2.67g, 2.3mmol, 2.0 mol%), (S) - (-) -SEGphos (3.52g, 5.77mmol, 5.0 mol%) and p-toluenesulfonic acid (1.98g, 11.54mmol, 10 mol%) were added after 5min of nitrogen introduction, the compound of formula I (18.0g, 115.4mmol, 1.0 eq), 37% aqueous formaldehyde (18.6mL, 248.4mmol) and freshly distilled toluene (300mL) were added, the temperature was raised to 85 deg.C, the mixture was stirred for 10h, after cooling to room temperature, the solvent was removed under reduced pressure, and flash column chromatography (silica gel column, n-hexane: EtOA)_C2:1) to give compound II (20.2g, 94%, d.r. ═ 97:3) as a colorless, transparent liquid.¹H-NMR(400MHz,CDC1₃) δ is 5.83(ddd,1H),5.26(ddd,1H),5.13(ddd,1H),5.09(d,1H),4.74(d,1H),4.13-4.07(m,2H),3.67(s,3H),2.61(dd,1H),2.43(dd,1H),1.70(m,1H),1.49(ddd,1H), basically similar to the literature reports.

The effect of the choice of catalyst, ligand and promoter on the reaction was investigated according to the procedure of example 1 and the results are shown in table 1:

TABLE 1 Effect of different reaction conditions on yield and optical purity

Example 2

2.0g of the compound of the formula II are dissolved in 10ml of ethanol, 0.2g of heteropolyacid H are added₃PW₁₂O₄₀Dropwise adding 30% H₂O₂10ml of aqueous solution, controlling the reaction temperature at 35 ℃, reacting for 6 hours, evaporating the solvent, adding water, extracting by ethyl acetate, and obtaining an organic phase Na₂SO₄Drying, and evaporating the solvent under reduced pressure to obtain 2.0g of the compound of formula III with a yield of 99%.¹H-NMR(400MHz,CDC1₃):δ＝9.56(d,1H),5.13(m,1H),4.76(d,1H),4.12-4.06(m,2H),3.68(s,3H),2.62(dd,1H),2.44(dd,1H),1.72(m,1H),1.50(ddd,1H)。

The influence of the selection of the oxidation system and the catalyst on the reaction was investigated according to the procedure of example 2, and the results are shown in Table 2:

TABLE 2 Effect of different oxidation systems and reaction conditions on the reaction

Oxidation system	Catalyst and process for preparing same	Reaction temperature and time	Yield of
				30％H₂O₂+ tert-butanol	H₄PMo₁₁VO₄₀	30℃、4h	89％
60％H₂O₂+ ethanol	H₃PMo₁₂O₄₀	25℃、4h	96％
				30％H₂O₂+ isopropyl alcohol	H₄PW₁₁VO₄₀	35℃、4h	97％

Example 3

6.78g (0.01mol) of the compound of the formula IV and 1.88g (0.01mol) of the compound of the formula III are dissolved in 30ml of DMSO and dissolved with stirring; heating to 80 ℃; 4.14g (0.03mol) of potassium carbonate is added, stirred and reacted for 10h at 80 ℃, after the reaction is finished, 80ml of water is added, white solid is separated out, the mixture is filtered, washed by saturated salt water and 5% ethanol, and dried to obtain 4.72g of a white solid compound V, the yield is 93%, and E: Z is 97: 3.

S(ESI)m/z:508.23(M+H)⁺；¹H-NMR(400MHz,CDC1₃):δ＝7.62-7.60(m,2H),7.10-7.08(m,2H),6.59(dd,1H),5.44(dd,1H),5.11(d,1H),4.77(d,1H),4.16-4.06(m,2H),3.69(s,3H),3.57(s,3H),3.50(s,3H),3.34(m,1H),2.63(dd,1H),2.44(dd,1H),1.60-1.57(m,1H),1.35(m,1H),1.26(d,6H)。

Example 4

Dissolving 4g (7.89mmol) of the compound of formula V in 80ml ethanol, adding 0.1M aqueous sodium hydroxide solution 95ml, stirring at 80 deg.C for reaction for 15h, cooling to 0 deg.C after reaction, adjusting pH to 4 with hydrochloric acid, adding Dichloromethane (DCM)250ml, separating DCM layer, extracting aqueous layer with DCM for 3 times, 150ml each time, combining organic phases, washing with saturated common salt water, Na₂SO₄Drying and evaporation of DCM under reduced pressure gave 3.82g of compound VI.

MS(ESI)m/z:516.35(M+Na)⁺；¹H-NMR(400MHz,CDC1₃):δ＝7.63-7.61(m,2H),7.09-7.06(m,2H),6.59(dd,1H),5.45(dd,1H),5.12(d,1H),4.77(d,1H),4.15-4.06(m,2H),3.56(s,3H),3.50(s,3H),3.33(m,1H),2.64(dd,1H),2.43(dd,1H),1.60-1.56(m,1H),1.37(m,1H),1.27(d,6H)。

Example 5

Dissolving 3g of the compound of the formula VI in 15ml of toluene, adjusting the pH to 3 with 37% strength concentrated aqueous hydrochloric acid, adding 3 drops of phosphoric acid dropwise, reacting at room temperature for 6h, adding 15ml of water and 30ml of DCM, cooling to 0 ℃ and stirring with NaHCO₃Adjusting pH to 9 with water solution, immediately separating organic phase, extracting aqueous phase with DCM 3 times (10 ml each time), combining organic phases, washing with saturated saline solution 3 times, and adding Na₂SO₄Drying, and evaporating the solvent under reduced pressure to obtain 2.32g of a white solid compound of formula VII, yield 82%, HPLC 98.9%. MS (ESI) M/z 464.17(M + H)⁺；¹H-NMR(400MHz,CDC1₃):δ＝7.62-7.59(m,2H),7.12-7.07(m,2H),6.72(dd,1H),5.46(dd,1H),5.24-5.20(m,1H),4.32(tt,1H),3.56(s,3H),3.50(s,3H),3.31(1H),2.73(dd,1H),2.64(m,1H),1.90(m,1H),1.87(s,1H),1.66(m,1H),1.27(d,3H),1.25(d,3H)。

Example 6

2g of the compound of the formula VII are dissolved in 15ml of THF, 10ml of 40% aqueous sodium hydroxide solution are added dropwise within 10min, and the reaction chamber is filledStirring at room temperature for reaction for 3h, adding 50ml of water and 10ml of n-hexane, demixing, extracting the organic phase with water for 3 times, 10ml each time, combining the water phases, washing with methyl tert-butyl ether for 2 times, filtering to remove insoluble substances, cooling to 10 ℃, dropwise adding 4ml of 0.5g/ml calcium acetate solution, stirring for 30min after dropwise adding, precipitating a large amount of solid, filtering, washing the filter cake with water, and drying to obtain 1.92g of rosuvastatin calcium, E: Z>98:2。MS(ESI)m/z:1001.2(M+H)⁺，HPLC:99.4％。

All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims

1. A preparation method of rosuvastatin calcium comprises the following steps:

(1) reacting the compound of the formula I with formaldehyde in the presence of a catalyst, a ligand and an auxiliary agent to obtain a compound of a formula II;

(2) oxidizing the compound of the formula II in a hydrogen peroxide-heteropoly acid system to prepare a compound III;

(3) reacting the compound III with a formula IV to generate a compound V;

(4) hydrolyzing the compound of the formula V to obtain a compound of a formula VI;

(5) reacting the compound shown in the formula VI under an acidic condition to obtain a compound shown in the formula VII;

(6) hydrolyzing the compound of formula VII to obtain rosuvastatin calcium;

the reaction route is as follows:

wherein R is₁Is selected from C_1-12Alkyl or C_6-12An aryl group; r₂Is selected from P⁺(Ph)₃X^-Or PO (Ph)₂Wherein X is^-Represents a halide ion; the hydrogen peroxide used in the step (2) is selected from 3 in mass fraction0% -60% of hydrogen peroxide; the heteropoly acid is phosphomolybdic heteropoly acid or phosphotungstic heteropoly acid; the reaction temperature of the step (2) is 10-40 ℃; the reaction in the step (3) is carried out in the presence of DMSO as a solvent and alkali, wherein the alkali is K₂CO₃、Na₂CO₃、KHCO₃、NaHCO₃KOH or NaOH; the reaction solvent of the step 2) is methanol, ethanol, tert-butyl alcohol or isopropanol.

2. The process for the preparation of rosuvastatin calcium according to claim 1, characterized in that: r₁Is C_1-6An alkyl group; r₂Is selected from P⁺(Ph)₃Br^-。

3. The process for the preparation of rosuvastatin calcium according to claim 2, characterized in that: r₁Is methyl, ethyl, propyl, isopropyl, tert-butyl or phenyl.

4. A process for preparing rosuvastatin calcium according to claim 3, characterized by: r₁Is methyl or ethyl.

5. A process for preparing rosuvastatin calcium according to any of claims 1 to 4, characterized by: the catalyst in the step (1) is a palladium catalyst.

6. The process for the preparation of rosuvastatin calcium according to claim 5, characterized in that: the palladium catalyst is Pd (PPh)₃)₄、Pd(PPh₃)₂Cl₂、Pd(OAc)₂、Pd(acac)₂Bis (cinnamyl palladium chloride), bis (allyl palladium chloride), tris (dibenzylideneacetone) dipalladium, palladium chloride or bis (acetonitrile) palladium chloride.

7. The process for the preparation of rosuvastatin calcium according to claim 6, characterized in that: the palladium catalyst is Pd (PPh)₃)₄、Pd(PPh₃)₂Cl₂、Pd(OAc)₂Or Pd (acac)₂。

8. A process for preparing rosuvastatin calcium according to any of claims 1 to 4, characterized by: the ligand in the step (1) is a phosphine ligand, and the phosphine ligand is (S) - (-) -SEGphos or DPEphos.

9. A process for preparing rosuvastatin calcium according to any of claims 1 to 4, characterized by: the auxiliary agent in the step (1) is acid.

10. The process for the preparation of rosuvastatin calcium according to claim 9, characterized by: the acid is p-toluenesulfonic acid and Ph₂PO₄H. Phosphoric acid, benzenesulfonic acid, methanesulfonic acid or acetic acid.

11. The process for the preparation of rosuvastatin calcium according to claim 10, characterized by: the acid is p-toluenesulfonic acid.

12. A process for preparing rosuvastatin calcium according to any of claims 1 to 4, characterized by: the heteropoly acid is H₃PW₁₂O₄₀、H₄PMo₁₁VO₄₀、H₃PMo₁₂O₄₀Or H₄PW₁₁VO₄₀。

13. A process for preparing rosuvastatin calcium according to any of claims 1 to 4, characterized by: the reaction temperature of the step (1) is 60-100 ℃.

14. A process for preparing rosuvastatin calcium according to any of claims 1 to 4, characterized by: the reaction temperature of the step (1) is 80-85 ℃.

15. A process for preparing rosuvastatin calcium according to any of claims 1 to 4, characterized by: the reaction temperature of the step (2) is 20-35 ℃.

16. A process for preparing rosuvastatin calcium according to any of claims 1 to 4, characterized by: the acidic condition of step (5) is provided by hydrochloric acid.