CN110642790A - Preparation method of rosuvastatin calcium and intermediate thereof - Google Patents
Preparation method of rosuvastatin calcium and intermediate thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- 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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- C07—ORGANIC CHEMISTRY
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Abstract
The invention provides a preparation method of rosuvastatin calcium and an intermediate thereof, wherein a new compound with an Evans prosthetic group structure is introduced as a key intermediate in a synthetic route, JULIA alkene is adopted, so that the E/Z selectivity is improved, conditions are mild during prosthetic group removal, isomerization can be avoided and impurities can be eliminated, the synthetic route is simple, the key intermediates (the compound of the formula 5 and the compound of the formula 6) are solid, and the product purification and the material scientific putting reaction are facilitated, so that a high-purity product is obtained.
Description
Technical Field
The invention relates to the field of medicinal chemistry, in particular to a preparation method of rosuvastatin calcium and an intermediate thereof.
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.
Rosuvastatin is administered as its calcium salt in therapy and is a single enantiomer, marketed in several countries and regions of the united states, japan, europe, china, etc., with the chemical name bis- [ E-7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] -pyrimidin-5-yl ] (3R,5S) -3, 5-dihydroxyhept-6-enoic acid ] calcium salt (2: 1) and the chemical structure is as follows:
at present, a plurality of synthetic routes of rosuvastatin calcium are reported, but most of the synthetic routes are developed for avoiding the technical protection of original manufacturers.
For example: EP0521471a1 reports the following synthetic method:
WO0049014a1 discloses the following synthetic method:
the multi-step synthesis intermediate of the synthesis route disclosed above is oily, and most of the synthesis processes adopt WITIG reaction, and the Z/E selectivity is poorly controlled.
CN201910190264 discloses the following synthesis method:
the side chain synthesized by the above-mentioned circuit is oxidized from olefin to aldehyde, so that the yield is not high, and the product purity is not high easily due to the use of an oxidation system.
In general, the technical problems of the current synthetic routes are: the synthetic route is complex, the quality control and purification of oily intermediates are difficult, the E/Z selectivity needs to be improved, and higher product purity is difficult to obtain.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a preparation method of rosuvastatin calcium and an intermediate thereof. A new compound with an Evans prosthetic group structure is introduced into the synthetic route as a key intermediate, so that the intermediate involved in the whole synthetic route is solid and convenient to purify, the provided E/Z selectivity is improved, and the product purity is high.
In order to solve the technical problems, the invention provides the following technical scheme:
in one aspect, the present invention provides a process for the preparation of rosuvastatin calcium, which comprises converting a compound of formula 6 to a compound of formula 8:
< formula 8>
< formula 6>
Wherein R is H, alkyl, phenyl, benzyl, etc.; further, R is H, C1-12Alkyl, phenyl, benzyl, etc.; further, R is H, C1-6Alkyl, phenyl, benzyl, etc.; further, R is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, n-pentyl, n-hexyl, phenyl, benzyl, etc. R may be further substituted with any group.
Further, the compound of formula 6 is oxidized under the action of alkali, and after the reaction is finished, the compound is regulated by acid, separated and reacted with a calcium reagent to prepare the compound of formula 8. Further, the reaction is carried out in a solvent selected from the group consisting of THF, dichloromethane, water, C1-C10 alcohols (e.g., methanol, ethanol, isopropanol, butanol, etc.), dichloromethane, acetonitrile, and mixtures thereof; preferred are THF/water mixtures in a volume ratio of 1:1,1:2,1:3,2:1,3:1, etc.
Still further, the base includes sodium hydroxide, lithium hydroxide, potassium carbonate, potassium phosphate, potassium hydrogen phosphate, ammonia water, and the like.
Furthermore, the oxidizing agent used in the oxidation reaction comprises hydrogen peroxide, sodium peroxide, Fenton reagent and the like.
Still further, the acid is hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, formic acid, sulfonic acid, and mixtures thereof; preferably an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid or nitric acid. Furthermore, the mass percentage concentration of the acid is 1-5%, and preferably 3%.
Further, the separation process is as follows: and adding an ether solvent into the mixture after acid adjustment for extraction and separation, and directly reacting the solvent layer with a calcium reagent after concentration. Ether type solvents include MTBE, THF, CPME and the like.
Further, the separation process is as follows: MTBE (methyl tert-butyl ether) is added into the mixture after the pH value is adjusted to 9-10 by acid for extraction and separation, and an MTBE layer is directly used for reaction with calcium acetate after being concentrated.
In another aspect, the invention provides a compound of formula 6:
< formula 6>
Wherein R is H, alkyl, phenyl, benzyl, etc.; further, R is H, C1-12Alkyl, phenyl, benzyl, etc.; further, R is H, C1-6Alkyl, phenyl, benzyl, etc.; further, R is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, n-pentyl, n-hexyl, phenyl, benzyl, etc. R may be further substituted with any group.
In yet another aspect, the present invention provides a method for preparing a compound of formula 6, comprising converting a compound of formula 5 into a compound of formula 6:
< formula 5>
Wherein R is H, alkyl, phenyl, benzyl, etc.; further, R is H, C1-12Alkyl, phenyl, benzyl, etc.; further, R is H, C1-6Alkyl, phenyl, benzyl, etc.; further, R is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, n-pentyl, n-hexyl, phenyl, benzyl, etc. R may be further substituted with any group.
Further, the compound of formula 5 is hydrolyzed by acid to prepare the compound of formula 6. Still further, the acid is hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, formic acid, sulfonic acid, and mixtures thereof; preferably an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid or nitric acid; furthermore, the mass percentage concentration of the acid is 1-10%, preferably 1-5%, preferably 5%. Further, the reaction is carried out in a solvent selected from the group consisting of THF, dichloromethane, water, C1-10Alcohols (e.g., methanol, ethanol, isopropanol, butanol, etc.), dichloromethane, acetonitrile, and mixtures thereof.
In another aspect, the invention provides a compound of formula 5:
< formula 5>
Wherein R is H, alkyl, phenyl, benzyl, etc.; further, R is H, C1-12Alkyl, phenyl, benzyl, etc.; further, R is H, C1-6Alkyl, phenyl, benzyl, etc.; further, R is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, n-pentyl, n-hexyl, phenyl, benzyl, etc. R may be further substituted with any group.
In yet another aspect, the present invention provides a method for preparing a compound of formula 5, comprising reacting a compound of formula 4 with a compound of formula Z9 to prepare a compound of formula 5:
wherein R is H, alkyl, phenyl, benzyl, etc.; further, R is H, C1-12Alkyl, phenyl, benzyl, etc.; further, R is H, C1-6Alkyl, phenyl, benzyl, etc.; further, R is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, n-pentyl, n-hexyl, phenyl, benzyl, etc. R may be further substituted with any group.
Further, the compound of the formula 4 and the compound of the formula Z9 react under the action of alkali, and the compound of the formula 5 is prepared after quenching by ammonium salt.
Further, the base is a potassium alkoxide/alcohol reagent, a sodium alkoxide/alcohol reagent, or the like; the alcohol is C1-4Alcohols of (a), for example: methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, etc. The ammonium salt is ammonium chloride and the like. The reaction is carried out in a reagent of THF, dichloromethane, water, C1-C10 alcohols (such as methanol, ethanol, isopropanol, butanol, etc.), dichloromethane, acetonitrile and mixtures thereof. The base is mixed with a solvent and then added dropwise before being added to the reaction system.
In another aspect, the present invention provides a compound of formula 4:
< formula 4>
Wherein R is H, alkyl, phenyl, benzyl, etc.; further, R is H, C1-12Alkyl, phenyl, benzyl, etc.; further, R is H, C1-6Alkyl, phenyl, benzyl, etc.; further, R is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, n-pentyl, n-hexyl, phenyl, benzyl, etc. R may be further substituted with any group.
In still another aspect, the present invention provides a method for preparing a compound of formula 4, which comprises reacting a compound of formula 3, DCC, R-oxazolidinone and DMAP to obtain a compound of formula 4:
wherein R is H, alkyl, phenyl, benzyl, etc.; further, R is H, C1-12Alkyl, phenyl, benzyl, etc.; further, R is H, C1-6Alkyl, phenyl, benzyl, etc.; further, R is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, n-pentyl, n-hexyl, phenyl, benzyl, etc. R may be further substituted with any group.
Further, the reaction is carried out in a solvent, which is water, a C1-C10 alcohol (such as methanol, ethanol, isopropanol, butanol, etc.), dichloromethane, tetrahydrofuran, acetonitrile, and mixtures thereof. The reaction is carried out at room temperature. The molar ratio of the compound of formula 3 to DCC to R-oxazolidinone was 1:1: 2. The DMAP was used in an amount of 10% wt of the total reactants.
On one hand, the invention provides a preparation method of rosuvastatin calcium, which comprises the following specific steps:
1) preparation of the Compound of formula 2
PMTA、Na2CO3And the compound of the formula 1 are heated to react to obtain a compound of a formula 2;
2) preparation of the Compound of formula 3
A compound of formula 2, amine heptamolybdate and H2O2Stirring and reacting to obtain a compound shown in a formula 3;
3) preparation of the Compound of formula 4
Reacting the compound of the formula 3, R-oxazolidinone, DCC and DMAP to obtain a compound of a formula 4; wherein R is H, alkyl, phenyl, benzyl, etc.; further, R is H, C1-12Alkyl, phenyl, benzyl, etc.; further, R is H, C1-6Alkyl, phenyl, benzyl, etc.; further, R is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, n-pentyl, n-hexyl, phenyl, benzyl, etc. R may be further substituted with any group;
4) preparation of Compounds of formula 5
Dripping t-BuOK THF/t-BuOH solution into the mixed solution of the compound of the formula 4 and the compound of the formula Z-9, continuing the reaction after the addition is finished, and dripping saturated ammonium chloride after the reaction is finished to quench to obtain a compound of the formula 5;
5) preparation of the Compound of formula 6
Dissolving the compound shown in the formula 5 in THF, dropwise adding acid, and stirring to complete hydrolysis to obtain a compound shown in the formula 6;
6) preparation of the Compound of formula 7
Compounds of formula 6 with LiOH and H2O2After the stirring reaction is completed, the mixture obtained by post-treatment is directly used for the next reaction;
7) preparation of the Compound of formula 8
Adding purified water into the mixture obtained in the last step for dissolving, dropwise adding a calcium acetate solution, stirring for reacting, centrifuging, leaching purified water, and spin-drying to obtain a rosuvastatin calcium wet refined product;
further, in step 1), the PMTA and Na2CO3And the compound of formula 1 in a molar ratio of 1:1 to 1.5: 1; preferably 1:1.2: 1; the temperature of the heating reaction is 90 ℃; the reaction is carried out in a solvent, wherein the solvent is water and C1-10Alcohols (e.g., methanol, ethanol, isopropanol, butanol, etc.), DMF, tetrahydrofuran, acetonitrile, and mixtures thereof.
Further, in the step 2), the reaction is carried out in a solvent at room temperature, wherein the solvent is water and C1-10Alcohols (e.g., methanol, ethanol, isopropanol, butanol, etc.), DMF, tetrahydrofuran, acetonitrile, and mixtures thereof. In the invention, the room temperature is 15-35 ℃, for example: 25 ℃,18 ℃ and the like.
Further, in the step 3), the molar ratio of the compound of the formula 3, R-oxazolidinone and DCC is 1:1: 2; the reaction is carried out in a solvent at room temperature, wherein the solvent is water and C1-10Alcohol (such as methanol, ethanol, isopropanol, butanol, etc.), DMF, dichloromethane, tetrahydrofuran, acetonitrileAnd mixtures thereof.
Further, in the step 4), the reaction is carried out in a solvent at room temperature, wherein the solvent is water and C1-10Alcohols (e.g., methanol, ethanol, isopropanol, butanol, etc.), DMF, dichloromethane, tetrahydrofuran, acetonitrile, and mixtures thereof.
Further, in step 5), the reaction is carried out at room temperature, and further, the acid is hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, formic acid, sulfonic acid and a mixture thereof; preferably an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid or nitric acid; furthermore, the mass percentage concentration of the acid is 1-10%, preferably 1-5%, preferably 5%.
Further, in step 6), the compound of formula 6 is dissolved in THF/H2In O, with LiOH and H2O2After the reaction is completely stirred, quenching hydrogen peroxide by saturated sodium bisulfite, distilling under reduced pressure to remove THF, adding purified water, adjusting the pH value to 9-10 by 3% HCl, adding MTBE into the reactor, stirring, separating liquid, washing the water phase once by MTBE again, distilling under reduced pressure at 40 +/-5 ℃ until the MTBE is less than or equal to 5000ppm, and directly using the obtained mixture in the next reaction.
Advantageous effects
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a preparation method of rosuvastatin calcium and an intermediate thereof. A new compound with an Evans prosthetic group structure is introduced into a synthesis route as a key intermediate, JULIA alkene is adopted, the selectivity of E/Z is improved, the conditions are mild when the prosthetic group is removed, isomerization and impurity elimination can be avoided, the synthesis route is simple, the key intermediates (the compounds shown in the formulas 5 and 6) are solid, the product purification and the material scientific putting reaction are facilitated, and therefore a high-purity product is obtained.
At present, JULIA alkene-forming reaction mostly needs ultralow temperature and expensive strong base, materials used in the synthesis route are all reagents with low price or easy obtaining in the conventional way, and the alkene-forming reaction is carried out at relatively high temperature, so that the operation is simple, the cost is low, and the pollution is small.
In the process of synthesizing rosuvastatin calcium, the harsh conditions of low-temperature reaction (the lowest temperature of the invention is only-40 ℃) are avoided, most of the intermediate synthesis process can be carried out at room temperature, the industrial production is more favorably realized, and the yield and the purity of the synthesized product are improved.
Detailed Description
The present invention will be described in further detail with reference to specific embodiments, but it should not be construed that the scope of the subject matter of the present invention is limited to the examples.
The process equipment or devices not specifically noted in the following examples are conventional in the art; all reagents are commercially available.
Example 1
Preparation of Compound 2
PMTA (3.2g,18.0mmol) was dissolved in DMF (20mL) at room temperature and Na was added sequentially2CO3(2.2g,21.6mmol) and compound 1(4g,18mmol) were heated to 90 ℃ for 24h and examined by LC-Ms.
After addition of 10mL of water, pH 5-6 was adjusted with 10% HCl, extracted with dichloromethane (40mL × 2), the organic phases were combined, dried with water (10mL × 2), and concentrated in vacuo at 40 ℃ to give an oil which was used in the next step.
LC-Ms：[M+H]＝365.20。
Preparation of Compound 3
To the oil from the previous step, iPrOH (20mL) was added at room temperature followed by heptamolybdate (1.1g) and H2O2(20mL), after the addition, the reaction was continued for 18h at 25 ℃ and the Lc-Ms detected that the reaction was complete.
Adding 60mL of dichloromethane for extraction, quenching hydrogen peroxide by using saturated sodium bisulfite, separating, washing an organic phase by using 20mL of water, drying, and carrying out vacuum concentration at 40 ℃ to obtain 4g of a product, wherein the total yield of the two steps is 56%.
LC-Ms：[M+H]＝397.05
Preparation of Compound 4
30mL of dichloromethane were added to Compound 3(4g,10.1mmol) at room temperature, followed by benzyl oxazolidinone (1.78g,10.1mmol), DCC (4.16g,20.2mmol) and DMAP (0.4g, 10% wt) and stirring continued for 18 h. Concentration in vacuo and purification by column chromatography (EA/PE ═ 1:2) gave 4.9g of product in 87% yield. LC-Ms: [ M + Na ] ═ 578.15
Preparation of Compound 5
At room temperature, the compound 4(4.0g, 7.20mmol) and Z-9(2.53g, 7.20mmol) are dissolved in 40mL of THF, the temperature is reduced to-40 ℃, a THF/t-BuOH solution of t-BuOK (1.1eq) is added dropwise, the reaction is continued for 4h after the addition, 10mL of saturated ammonium chloride is added dropwise for quenching, the temperature is raised to room temperature, the solution is stirred and separated, and the oily substance is obtained after vacuum concentration at 40 ℃. The oil was purified by column chromatography (EA/PE ═ 1:4) to give 3.8g of a white solid (R ═ benzyl) in 78% yield.
HNMR(CDCl3，400M)：δ(ppm)：1.30(8H,m),1.41(3H,s),1.55(3H,s),2.68(1H,dd),3.05(1H,dd),3.20(1H,dd),3.30(1H,dd),3.41(1H,m),3.51(3H,s),3.60(3H,s),4.20(2H,m),4.51(2H,m),4.71(1H,m),5.52(1H,dd),6.55(1H,d),7.11(2H,m),7.25(5H,m),7.68(2H,m)
Preparation of Compound 6
Compound 5(3.5g, 5.15mmol) was dissolved in THF (35mL) at rt, 5% dilute hydrochloric acid was added dropwise to pH 2-4, stirred for 2h, and hydrolysis was complete. EA (50mL) was added and extracted once, and washed with saturated brine (15mL), the layers were separated and the organic phase was concentrated in vacuo to give 3.1g of a white solid (R ═ benzyl) in 95% yield.
LC-Ms：[M+H]＝641.15
HNMR(CDCl3，400M)：δ(ppm)：1.35(2H,m),1.45(3H,s),1.60(3H,s),2.70(1H,dd),3.10(1H,dd),3.25(1H,dd),3.35(1H,dd),3.42(1H,m),3.52(3H,s),3.62(3H,s),4.21(2H,m),4.52(2H,m),4.71(1H,m),5.52(1H,dd),6.60(1H,d),7.15(2H,m),7.28(5H,m),7.70(2H,m)
Preparation of Compound 7
Compound 6(1.1g,1.7mmol) was dissolved in THF/H at 0 deg.C2To O, LiOH (0.5g,20.8mmol) and H were added in this order2O2(2mL), after the reaction was stirred completely, quenching hydrogen peroxide with saturated sodium bisulfite, removing THF by distillation under reduced pressure, adding purified water (3mL/g), adjusting the pH to 9-10 with 3% HCl, adding MTBE (8mL/g) to the reactor, stirring for 30min, separating the liquids, washing the aqueous phase once again with MTBE (8mL/g), and distilling under reduced pressure at 40 + -5 ℃ until the concentration of MTBE is less than or equal to 5000ppm, to obtain MTBEThe water liquid is directly used for the next reaction
Preparation of API
Adding purified water (20mL) into the water solution obtained in the last step, controlling the temperature to 25 ℃, dropwise adding a calcium acetate (12.3g) solution, stirring for 30min after dropwise adding, performing suction filtration, and washing with purified water to obtain a rosuvastatin calcium wet refined product. Vacuum drying at 50 + -5 deg.C to water content of less than or equal to 3.0% to obtain 0.61g white solid with yield of 71% and purity of 99.9%.
Example 2
Preparation of Compound 2
PMTA (12.0g,67.5mmol) was dissolved in DMF (50mL) at room temperature, followed by the addition of Na2CO3(7.1g,67.5mmol) and Compound 1(10g,45.0mmol) were heated to 90 ℃ and reacted for 24h to completion.
After addition of 25mL of water, pH 5-6 was adjusted with 10% HCl, extracted with dichloromethane (100mL × 2), the organic phases were combined, dried with water (25mL × 2), and concentrated in vacuo at 40 ℃ to give an oil which was used in the next step.
Preparation of Compound 3
To the oil from the previous step, iPrOH (50mL) was added at room temperature followed by heptamolybdate (2.7g) and H2O2(50mL) after the addition, the reaction was stirred at 25 ℃ for 18h to complete.
After 150mL of dichloromethane is added for extraction and liquid separation, saturated sodium bisulfite is used for quenching hydrogen peroxide for liquid separation, 50mL of water is used for washing an organic phase, drying is carried out, vacuum concentration is carried out at 40 ℃, 12.0g of a product is obtained, and the total yield of two steps is 68%.
Preparation of Compound 4
80mL of dichloromethane was added to Compound 3(12.0g,30.4mmol) at room temperature, followed by oxazolidinone (2.6g,30.4mmol), DCC (12.5g,60.8mmol) and DMAP (1.2g, 10% wt) and stirring continued for 20 h. Concentration in vacuo and purification by column chromatography (EA/PE ═ 1:2) gave 11.5g of product in 81% yield. Lc-Ms: [ M + Na ] ═ 488.12
Preparation of Compound 5
At room temperature, the compound 4(10.0g, 21.5mmol) and Z-9(7.0g, 20.0mmol) are dissolved in 50mL THF, the temperature is reduced to-40 ℃, a THF/t-BuOH solution of t-BuOK (1.1eq) is added dropwise, the reaction is continued for 4h after the addition, 5mL saturated ammonium chloride is added dropwise for quenching, the temperature is raised to room temperature, the solution is stirred and separated, and the oily substance is obtained after vacuum concentration at 40 ℃. The oil was purified by column chromatography (EA/PE ═ 1:4) to give 10.0g of a white solid (R ═ H) in 85% yield.
Lc-Ms:[M+H]＝591.22
HNMR(CDCl3，400M)：δ(ppm)：1.31(8H,m),1.42(3H,s),1.57(3H,s),2.70(1H,dd),3.10(1H,dd),3.41(1H,m),3.52(3H,s),3.60(3H,s),4.05(2H,t),4.21(2H,m),4.55(2H,t),5.52(1H,dd),6.55(1H,d),7.11(2H,m),7.68(2H,m)
Preparation of Compound 6
Compound 5(8.0g, 13.5mmol) was dissolved in THF (100mL) at room temperature, 5% dilute hydrochloric acid was added dropwise to pH 2-4, stirred for 2h, and hydrolysis was complete. EA (100mL) was added and extracted once, and washed with saturated brine (50mL), separated, and the organic phase was concentrated in vacuo to give 7.0g of a white solid (R ═ H) with a yield of 94%.
Lc-Ms:[M+H]＝551.20
HNMR(CDCl3，400M)：δ(ppm)：1.36(2H,m),1.45(3H,s),1.61(3H,s),2.70(1H,dd),3.10(1H,dd),3.41(1H,m),3.52(3H,s),3.60(3H,s),4.07(2H,t),4.22(2H,m),4.57(2H,t),5.53(1H,dd),6.60(1H,d),7.16(2H,m),7.71(2H,m)
Preparation of Compound 7
Compound 6(7.0g, 12.7mmol) was dissolved in THF/H at 0 deg.C2To O, LiOH (3.0g, 12.7mmol) and H were added in this order2O2(14mL), after the reaction is completely stirred, quenching hydrogen peroxide by saturated sodium bisulfite, removing THF by reduced pressure distillation, adding purified water (3mL/g), adjusting the pH to 9-10 by 3% HCl, adding MTBE (8mL/g) into the reactor, stirring for 30min, separating liquid, washing the aqueous phase once again by MTBE (8mL/g), and reducing the pressure distillation at 40 +/-5 ℃ until the MTBE is less than or equal to 5000ppm, wherein the obtained aqueous liquid is directly used for the next reaction
Preparation of API
Adding purified water (140mL) into the water solution obtained in the last step, controlling the temperature to 25 ℃, dropwise adding a calcium acetate (70g) solution, stirring for 30min after dropwise adding, carrying out suction filtration, and washing with purified water to obtain a rosuvastatin calcium wet refined product. Vacuum drying at 50 + -5 deg.C to water content of less than or equal to 3.0% to obtain 4.7g white solid with yield of 75% in two steps and purity of 99.9%.
It will be understood that the above embodiments are merely exemplary embodiments taken to illustrate the principles of the present invention, which is not limited thereto. It will be apparent to those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention, and these changes and modifications are also considered to be included in the scope of the invention.
Claims (10)
1. A process for the preparation of rosuvastatin calcium, comprising converting a compound of formula 6 to a compound of formula 8:
< formula 8>
< formula 6>
Wherein R is H, alkyl, phenyl, benzyl.
2. The method of claim 1, wherein the compound of formula 6 is oxidized by alkali, and after the reaction is completed, the compound is adjusted by acid, separated and reacted with a calcium reagent to obtain the compound of formula 8;
or, the separation process is as follows: and adding an ether solvent into the mixture after acid adjustment for extraction and separation, and directly reacting the solvent layer with a calcium reagent after concentration.
3. A compound of formula 6, having the formula:
< formula 6>
Wherein R is H, alkyl, phenyl, benzyl.
4. A process for preparing a compound of formula 6, comprising converting a compound of formula 5 to a compound of formula 6:
< formula 5>
Wherein R is H, alkyl, phenyl, benzyl;
or, the compound of formula 5 is hydrolyzed by acid to produce the compound of formula 6.
5. A compound of formula 5 having the formula:
< formula 5>
Wherein R is H, alkyl, phenyl, benzyl.
6. A method of preparing a compound of formula 5, comprising reacting a compound of formula 4 with a compound of formula Z9 to produce a compound of formula 5:
wherein R is H, alkyl, phenyl, benzyl;
or, the compound of formula 4 and the compound of formula Z9 react under the action of alkali, and the compound of formula 5 is prepared after quenching by ammonium salt.
7. A compound of formula 4 having the formula:
< formula 4>
Wherein R is H, alkyl, phenyl, benzyl.
8. A method for preparing a compound of formula 4, comprising reacting a compound of formula 3, DCC, R-oxazolidinone and DMAP to produce a compound of formula 4:
wherein R is H, alkyl, phenyl, benzyl.
9. A preparation method of rosuvastatin calcium is characterized by comprising the following specific steps:
1) preparation of the Compound of formula 2
PMTA、Na2CO3And the compound of the formula 1 are heated to react to obtain a compound of a formula 2;
2) preparation of the Compound of formula 3
A compound of formula 2, amine heptamolybdate and H2O2Stirring and reacting to obtain a compound shown in a formula 3;
3) preparation of the Compound of formula 4
Reacting the compound of the formula 3, R-oxazolidinone, DCC and DMAP to obtain a compound of a formula 4; wherein R is H, alkyl, phenyl, benzyl;
4) preparation of Compounds of formula 5
Dripping t-BuOK THF/t-BuOH solution into the mixed solution of the compound of the formula 4 and the compound of the formula Z-9, continuing the reaction after the addition is finished, and dripping saturated ammonium chloride after the reaction is finished to quench to obtain a compound of the formula 5;
5) preparation of the Compound of formula 6
Dissolving the compound shown in the formula 5 in THF, dropwise adding acid, and stirring to complete hydrolysis to obtain a compound shown in the formula 6;
6) preparation of the Compound of formula 7
Compounds of formula 6 with LiOH and H2O2After the stirring reaction is completed, the mixture obtained by post-treatment is directly used for the next reaction;
7) preparation of rosuvastatin calcium
Adding purified water into the mixture obtained in the last step for dissolving, dropwise adding a calcium acetate solution, stirring for reacting, centrifuging, leaching purified water, and spin-drying to obtain a rosuvastatin calcium wet refined product;
10. the method according to claim 9, wherein in step 1), the PMTA, Na2CO3And the compound of formula 1 in a molar ratio of 1:1 to 1.5: 1; the temperature of the heating reaction is 90 ℃; the reaction is carried out in a solvent, wherein the solvent is water and C1-10Alcohols, DMF, tetrahydrofuran, acetonitrile, and mixtures thereof;
in the step 2), the reaction is carried out in a solvent at room temperature, wherein the solvent is water and C1-10Alcohols, DMF, tetrahydrofuran, acetonitrile, and mixtures thereof;
in the step 3), the molar ratio of the compound of the formula 3, R-oxazolidinone and DCC is 1:1: 2; the reaction is carried out in a solvent at room temperature, wherein the solvent is water and C1-10Alcohols, DMF, dichloromethane, tetrahydrofuran, acetonitrile, and mixtures thereof;
in the step 4), the reaction is carried out in a solvent at room temperature, wherein the solvent is water and C1-10Alcohols, DMF, dichloromethane, tetrahydrofuran, acetonitrile, and mixtures thereof;
in the step 5), the reaction is carried out at room temperature, and the acid is hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, formic acid, sulfonic acid and a mixture thereof;
in step 6), the compound of formula 6 is dissolved in THF/H2In O, with LiOH and H2O2After the reaction is completely stirred, quenching hydrogen peroxide by saturated sodium bisulfite, distilling under reduced pressure to remove THF, adding purified water, adjusting the pH value to 9-10 by 3% HCl, adding MTBE into the reactor, stirring, separating liquid, washing the water phase once by MTBE again, distilling under reduced pressure at 40 +/-5 ℃ until the MTBE is less than or equal to 5000ppm, and directly using the obtained mixture in the next reaction.
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| CN111518034A (en) | 2020-08-11 |
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