CN116813555A - Preparation method of rosuvastatin calcium intermediate - Google Patents
Preparation method of rosuvastatin calcium intermediate Download PDFInfo
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- CN116813555A CN116813555A CN202310534743.6A CN202310534743A CN116813555A CN 116813555 A CN116813555 A CN 116813555A CN 202310534743 A CN202310534743 A CN 202310534743A CN 116813555 A CN116813555 A CN 116813555A
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- 229960004796 rosuvastatin calcium Drugs 0.000 title claims abstract description 51
- LALFOYNTGMUKGG-BGRFNVSISA-L rosuvastatin calcium Chemical compound [Ca+2].CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O.CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O LALFOYNTGMUKGG-BGRFNVSISA-L 0.000 title claims abstract description 51
- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- 238000006243 chemical reaction Methods 0.000 claims abstract description 77
- 238000000034 method Methods 0.000 claims abstract description 44
- -1 lithium aluminum tetrahydride Chemical compound 0.000 claims abstract description 15
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 96
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical group [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 77
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 50
- 229940125782 compound 2 Drugs 0.000 claims description 47
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 39
- 239000002904 solvent Substances 0.000 claims description 31
- 229940126214 compound 3 Drugs 0.000 claims description 26
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 25
- 238000010438 heat treatment Methods 0.000 claims description 18
- 238000010992 reflux Methods 0.000 claims description 18
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 17
- 238000002156 mixing Methods 0.000 claims description 17
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 11
- 239000003054 catalyst Substances 0.000 claims description 8
- 229940125904 compound 1 Drugs 0.000 claims description 7
- 239000002585 base Substances 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 19
- 239000003638 chemical reducing agent Substances 0.000 abstract description 9
- 238000009776 industrial production Methods 0.000 abstract description 4
- 239000012279 sodium borohydride Substances 0.000 abstract description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 abstract description 4
- 239000000463 material Substances 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- 238000003756 stirring Methods 0.000 description 47
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 32
- 239000011259 mixed solution Substances 0.000 description 32
- 239000000047 product Substances 0.000 description 23
- 238000001035 drying Methods 0.000 description 18
- 239000012043 crude product Substances 0.000 description 16
- 238000004821 distillation Methods 0.000 description 16
- 238000010898 silica gel chromatography Methods 0.000 description 16
- 239000007787 solid Substances 0.000 description 16
- 238000001816 cooling Methods 0.000 description 15
- 238000010791 quenching Methods 0.000 description 15
- 230000000171 quenching effect Effects 0.000 description 15
- 230000001105 regulatory effect Effects 0.000 description 15
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- FZTLLUYFWAOGGB-UHFFFAOYSA-N 1,4-dioxane dioxane Chemical compound C1COCCO1.C1COCCO1 FZTLLUYFWAOGGB-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 230000001603 reducing effect Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- CHMLXRMRDRNBMV-UHFFFAOYSA-N 4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-propan-2-ylpyrimidine-5-carboxylic acid Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1C(O)=O CHMLXRMRDRNBMV-UHFFFAOYSA-N 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 208000032928 Dyslipidaemia Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 108010028554 LDL Cholesterol Proteins 0.000 description 1
- 208000017170 Lipid metabolism disease Diseases 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000003570 air Substances 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
- 229910010277 boron hydride Inorganic materials 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000002485 combustion reaction Methods 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 238000005839 oxidative dehydrogenation reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- TYRDEZUMAVRTEO-UHFFFAOYSA-N pyrimidin-5-ylmethanol Chemical compound OCC1=CN=CN=C1 TYRDEZUMAVRTEO-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供一种瑞舒伐他汀钙中间体的制备方法，在反应过程中，以四甲基硅氧烷作为还原剂，避免了现有硼氢化钠、四氢铝锂等危险物料带来的安全隐患，反应原料廉价易得，反应条件温和，操作过程简单，操作安全性高，生产成本较低，收率和纯度较高，收率达到90％以上，纯度达到99％以上，适合工业化生产。The invention provides a preparation method of rosuvastatin calcium intermediate. During the reaction process, tetramethylsiloxane is used as a reducing agent, which avoids the risks caused by existing dangerous materials such as sodium borohydride and lithium aluminum tetrahydride. Potential safety hazards, the reaction raw materials are cheap and easy to obtain, the reaction conditions are mild, the operation process is simple, the operation safety is high, the production cost is low, the yield and purity are high, the yield reaches more than 90%, the purity reaches more than 99%, and it is suitable for industrial production .
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of a rosuvastatin calcium intermediate.
Background
Rosuvastatin calcium is a selective HMG-CoA reductase inhibitor, a statin, used in combination with exercise, diet control and weight loss to treat hypercholesterolemia and other related symptoms, and also to prevent cardiovascular disease. The LDL-C reducing effect on various dyslipidemia patients is obviously better than that of other medicines of the same type, the lipid-lowering standard rate of the patients can be obviously improved, the tolerance is good, and the lipid-lowering oral liquid is known as super statin in the lipid-lowering market.
4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] pyrimidine-5-methanol (compound 1) is an important intermediate for synthesizing rosuvastatin calcium, and the synthesis method has important significance for the preparation method of rosuvastatin calcium.
The synthesis of intermediate 1 was reported in US patent 8222412, the specific synthetic route is as follows: the compound 4 is subjected to oxidative dehydrogenation and nucleophilic substitution reaction to obtain a compound 3, and diisobutyl aluminum hydride is reduced at the temperature of minus 78 ℃ to obtain a pyrimidine methyl alcohol intermediate 1, and the synthetic route has simple operation and high yield, but has the following problems: the intermediate 3 adopts isopropanol for recrystallization, so that the cost is high; the synthesis of the intermediate 1 uses diisobutyl aluminum hydride as a reducing agent to react at the low temperature of minus 78 ℃, and the reaction requires no water and oxygen, is difficult to operate and is not suitable for industrial production; few manufacturers for producing diisobutyl aluminum hydride in China, most of which are imported from abroad, and the cost is high; diisobutyl aluminum hydride is easy to catch fire when meeting water, a large amount of hydrogen is released during post-treatment, and the diisobutyl aluminum hydride is easy to explode when meeting sparks.
Both US20130143908A1 and chinese CN103570762B disclose a method for reducing compound 2 to compound 1, the specific synthetic route being as follows: the reducing agent used is a borohydride such as sodium borohydride, potassium borohydride, lithium borohydride, and the like. Compared with diisobutylaluminum hydride, the cost of borohydride is reduced, but water, moist air, acids, oxidants, high heat and open flame can cause combustion, and certain potential safety hazard exists.
At present, in the synthesis method of the rosuvastatin calcium intermediate, aluminum hydride or boron hydride is mostly used as a reducing agent, and the two reducing agents have obvious potential safety hazards, so that a safe and effective reducing agent is found, and the method has important significance for the synthesis of the rosuvastatin calcium intermediate.
Disclosure of Invention
The invention aims to provide a preparation method of rosuvastatin calcium intermediate, which takes [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonyl-amino) -pyrimidine-5-yl ] -methyl formate (compound 3) as a raw material to carry out hydrolysis reaction to prepare [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methylsulfonyl-amino) -pyrimidine-5-yl ] -formic acid (compound 2), the obtained compound 2 is subjected to reduction reaction to generate a target product intermediate (compound 1), and in the reaction process, tetramethyl siloxane with high safety is used as a reducing agent to replace the traditional materials with high dangerousness such as sodium borohydride, lithium aluminum hydride and the like, so that the production cost can be reduced, the operation safety can be improved, the reaction conditions of each step are mild, the operation is simple, and the industrial production is facilitated.
The technical scheme of the invention is as follows:
a preparation method of rosuvastatin calcium intermediate, which comprises the following steps:
(1) After uniformly mixing the compound 3, alkali, the solvent 1 and water, heating to a reflux temperature for chemical reaction to prepare a compound 2;
(2) After the compound 2 and the solvent 2 are uniformly mixed, tetramethyl siloxane and a catalyst are added, and chemical reaction is carried out at 60-100 ℃ to obtain an intermediate compound 1, wherein the specific synthetic route is as follows:
for the purposes of the present invention, in step (1), the base is lithium hydroxide, sodium hydroxide or potassium hydroxide, preferably lithium hydroxide.
In a preferred embodiment, in step (1), the molar ratio of compound 3 to base is 1:0.3-2, which may be, but is not limited to, 1:0.3, 1:0.5, 1:0.8, 1:1.0, 1:1.2, 1:1.5, 1:1.8, 1:2.0, preferably 1:0.5-1.5; more preferably 1:1.0.
Further, the solvent 1 is Dimethylformamide (DMF), tetrahydrofuran (THF) or 1,4-Dioxane (1, 4-Dioxane), preferably Dimethylformamide (DMF).
In a preferred embodiment, in step (1), the mass to volume ratio of compound 3 to solvent 1 is 1:2.5-6.5 g/ml, which may be, but is not limited to, 1:2.5g/ml, 1:2.8g/ml, 1:3.0g/ml, 1:3.5g/ml, 1:3.8g/ml, 1:3.9g/ml, 1:4.0g/ml, 1:4.1g/ml, 1:4.3g/ml, 1:4.5g/ml, 1:5.0g/ml, 1:5.5g/ml, 1:6.0g/ml or 1:6.5g/ml, preferably 1:3.5-4.5 g/ml, more preferably 1:4g/ml.
In a preferred embodiment, in step (1), the mass to volume ratio of compound 3 to solvent water is 1:2.5-6.5 g/ml, which may be, but is not limited to, 1:2.5g/ml, 1:2.8g/ml, 1:3.0g/ml, 1:3.5g/ml, 1:3.8g/ml, 1:3.9g/ml, 1:4.0g/ml, 1:4.1g/ml, 1:4.3g/ml, 1:4.5g/ml, 1:5.0g/ml, 1:5.5g/ml, 1:6.0g/ml or 1:6.5g/ml, preferably 1:3.5-4.5 g/ml, more preferably 1:4g/ml.
In a preferred embodiment, in step (1), in the preparation of compound 2, the following more detailed steps are included: after the compound 3, alkali, the solvent 1 and water are uniformly mixed, heating to reflux temperature for chemical reaction, monitoring by TCL until the raw materials are completely reacted, removing the solvent by reduced pressure distillation, adding hydrochloric acid in the stirring process, adjusting the pH of the mixed solution to 3, extracting with ethyl acetate for three times after uniform stirring, and drying and concentrating to obtain white solid, namely the compound 2.
For the present invention, in step (2), tetramethyl siloxane (TMDS) is used as the reducing agent, and the molar ratio of the compound 2 to tetramethyl siloxane (TMDS) is 1:2-6, which may be, but is not limited to, 1:2, 1:3, 1:4, 1:5, 1:6, preferably 1:3-5, more preferably 1:4.
In the context of the present invention,in step (2), cu (OTf) 2 Or Cu (OAc) 2 As the catalyst, preferably, the catalyst is Cu (OTf) 2 。
In a preferred embodiment, the molar ratio of compound 2 to catalyst is 1:0.01 to 0.1, which may be, but is not limited to, 1:0.01, 1:0.02, 1:0.03, 1:0.04, 1:0.05, 1:0.07, 1:0.08, 1:0.09 or 1:0.1, preferably 1:0.03 to 0.08, more preferably 1:0.05.
In the present invention, in the step (2), the reaction temperature is 60 to 100 ℃, and may be, but not limited to, 60 ℃, 65 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃, 90 ℃, 95 ℃ or 100 ℃, preferably 70 to 90 ℃, more preferably 80 ℃.
Further, the reaction time is 10 to 20 hours, preferably 16 hours.
For the purposes of the present invention, in step (2), solvent 2 is 2-methyltetrahydrofuran (2-Me THF), tetrahydrofuran (THF) or toluene (MePh), preferably 2-methyltetrahydrofuran (2-Me THF).
In a preferred embodiment, in step (1), the mass to volume ratio of compound 2 to solvent 2 is 1:2.5 to 6.5g/ml, which may be, but is not limited to, 1:2.5g/ml, 1:2.8g/ml, 1:3.0g/ml, 1:3.5g/ml, 1:3.8g/ml, 1:3.9g/ml, 1:4.0g/ml, 1:4.1g/ml, 1:4.3g/ml, 1:4.5g/ml, 1:5.0g/ml, 1:5.5g/ml, 1:6.0g/ml or 1:6.5g/ml, preferably 1:4.0 to 5.0g/ml, more preferably 1:4.1g/ml.
In a preferred embodiment, in step (2), in the preparation of compound 1, the following more detailed steps are included: after the compound 2 and the solvent 2 are uniformly mixed, tetramethyl siloxane and a catalyst are added for chemical reaction at 60-120 ℃, the obtained reaction liquid is cooled to 15-25 ℃, water is added for quenching reaction, DCM is used for extraction three times, magnesium sulfate is dried and evaporated under reduced pressure, and the obtained crude product is purified by silica gel column chromatography to obtain the target product rosuvastatin calcium intermediate (compound 1).
By adopting the technical scheme of the invention, the advantages are as follows:
the invention provides a preparation method of rosuvastatin calcium intermediate, which uses tetramethyl siloxane as a reducing agent in the reaction process, avoids potential safety hazards caused by dangerous materials such as sodium borohydride, lithium aluminum hydride and the like, has the advantages of low price and easy acquisition of reaction raw materials, mild reaction conditions, simple operation process, high operation safety, lower production cost, higher yield and purity, higher yield up to 90%, higher purity up to 99% and suitability for industrial production.
Detailed Description
The following description of the technical solutions of the preparation method of rosuvastatin calcium intermediate according to the present invention will be made clearly and completely with reference to specific examples of the present invention, and it is apparent that the described examples are only some of examples of the present invention, but not all examples. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
A preparation method of rosuvastatin calcium intermediate, which comprises the following steps:
(1) 38.1g of compound 3, 2.4g of lithium hydroxide (LiOH), 150mL of Dimethylformamide (DMF) and 150mL of water are added into a reaction bottle, in the stirring process, the temperature is raised to the reflux temperature for chemical reaction, TCL is monitored until the raw materials are completely reacted, the solvent is removed by reduced pressure distillation, hydrochloric acid is added in the stirring process, the pH value of the mixed solution is regulated to 3, the mixed solution is extracted three times by ethyl acetate after being stirred uniformly, and then the white solid, namely the compound 2, is obtained after drying and concentration, and the yield is 97.3%.
(2) In a sealed tube, 36.7g of Compound 2 and 150mL of 2-methyltetrahydrofuran (2-Me THF) were added, and after mixing, 53.7g of TMDS and 1.8g of Cu (OTf) were added 2 Heating to 80 ℃ and stirring for reaction for 16 hours, cooling to 15-25 ℃, and adding water for quenching reaction. The crude product is purified by silica gel column chromatography, the yield of the target product rosuvastatin calcium intermediate is 98.8%, the purity of the product is 99.5%, the total yield of the two steps is 96.1%, and the specific synthetic route is as follows:
example 2
A preparation method of rosuvastatin calcium intermediate, which comprises the following steps:
(1) 38.1g of compound 3, 4.0g of sodium hydroxide (NaOH), 150mL of Dimethylformamide (DMF) and 150mL of water are added into a reaction bottle, in the stirring process, the temperature is raised to the reflux temperature for chemical reaction, TCL is monitored until the raw materials are completely reacted, the solvent is removed by reduced pressure distillation, hydrochloric acid is added in the stirring process, the pH of the mixed solution is regulated to 3, the mixed solution is extracted three times by ethyl acetate after being stirred uniformly, and then the white solid is obtained after drying and concentration, namely the compound 2, and the yield is 95.2%.
(2) In a sealed tube, 36.7g of Compound 2 and 150mL of 2-methyltetrahydrofuran (2-Me THF) were added, and after mixing, 53.7g of TMDS and 1.8g of Cu (OTf) were added 2 Heating to 80 ℃ and stirring for reaction for 16 hours, cooling to 15-25 ℃, and adding water for quenching reaction. The crude product obtained is purified by silica gel column chromatography to obtain the target product rosuvastatin calcium intermediate with 97.4% yield, 99.2% purity and 92.7% total yield in two steps.
Example 3
A preparation method of rosuvastatin calcium intermediate, which comprises the following steps:
(1) 38.1g of compound 3, 5.6g (potassium hydroxide) KOH, 150mL of Dimethylformamide (DMF) and 150mL of water are added into a reaction bottle, in the stirring process, the temperature is raised to the reflux temperature for chemical reaction, TCL is monitored until the raw materials are completely reacted, the solvent is removed by reduced pressure distillation, hydrochloric acid is added in the stirring process, the pH of the mixed solution is regulated to 3, the mixed solution is extracted three times by ethyl acetate after being stirred uniformly, and then the white solid is obtained after drying and concentration, namely the compound 2, and the yield is 96.5%.
(2) In a sealed tube, 36.7g of Compound 2 and 150mL of 2-methyltetrahydrofuran (2-Me THF) were added, and after mixing, 53.7g of TMDS and 1.8g of Cu (OTf) were added 2 Heating to 80 ℃ and stirring for reaction for 16 hours, cooling to 15-25 ℃, adding water for quenchingAnd (3) reacting. The crude product obtained is purified by silica gel column chromatography, thus obtaining the target product rosuvastatin calcium intermediate with the yield of 98.2%, the product purity of 99.4% and the total yield of 94.8% in two steps.
Example 4
A preparation method of rosuvastatin calcium intermediate, which comprises the following steps:
(1) 38.1g of compound 3, 2.4g of lithium hydroxide (LiOH), 150mL of Tetrahydrofuran (THF) and 150mL of water are added into a reaction bottle, in the stirring process, the temperature is raised to the reflux temperature for chemical reaction, TCL is monitored until the raw materials are completely reacted, the solvent is removed by reduced pressure distillation, hydrochloric acid is added in the stirring process, the pH value of the mixed solution is regulated to 3, the mixed solution is extracted three times by ethyl acetate after being stirred uniformly, and then the white solid is obtained after drying and concentration, namely the compound 2, and the yield is 96.1%.
(2) In a sealed tube, 36.7g of Compound 2 and 150mL of 2-methyltetrahydrofuran (2-Me THF) were added, and after mixing, 53.7g of TMDS and 1.8g of Cu (OTf) were added 2 Heating to 80 ℃ and stirring for reaction for 16 hours, cooling to 15-25 ℃, and adding water for quenching reaction. The crude product obtained is purified by silica gel column chromatography to obtain the target product rosuvastatin calcium intermediate with 97.5% yield, 98.3% purity and 93.7% total yield in two steps.
Example 5
A preparation method of rosuvastatin calcium intermediate, which comprises the following steps:
(1) 38.1g of compound 3, 2.4g of lithium hydroxide (LiOH), 150mL of 1,4-Dioxane (1, 4-Dioxane) and 150mL of water are added into a reaction bottle, in the stirring process, the temperature is raised to a reflux temperature for chemical reaction, TCL is monitored until the raw materials are completely reacted, the solvent is removed by distillation under reduced pressure, hydrochloric acid is added in the stirring process, the pH value of the mixed solution is regulated to 3, after the mixed solution is uniformly stirred, ethyl acetate is used for three times for extraction, and then the mixed solution is dried and concentrated to obtain white solid, namely compound 2, and the yield is 95.5%.
(2) In a sealed tube, 36.7g of Compounds 2 and 15 were added0mL of 2-methyltetrahydrofuran (2-Me THF), after mixing well, 53.7g of TMDS and 1.8g of Cu (OTf) were added 2 Heating to 80 ℃ and stirring for reaction for 16 hours, cooling to 15-25 ℃, and adding water for quenching reaction. The crude product obtained by three times of extraction with DCM, drying with magnesium sulfate and reduced pressure evaporation is purified by silica gel column chromatography to obtain the target product rosuvastatin calcium intermediate with 97.2% yield, 98.6% purity and 92.8% total yield in two steps.
Example 6
A preparation method of rosuvastatin calcium intermediate, which comprises the following steps:
(1) 38.1g of compound 3, 2.4g of lithium hydroxide (LiOH), 150mL of Dimethylformamide (DMF) and 150mL of water are added into a reaction bottle, in the stirring process, the temperature is raised to the reflux temperature for chemical reaction, TCL is monitored until the raw materials are completely reacted, the solvent is removed by reduced pressure distillation, hydrochloric acid is added in the stirring process, the pH value of the mixed solution is regulated to 3, the mixed solution is extracted three times by ethyl acetate after being stirred uniformly, and then the white solid, namely the compound 2, is obtained after drying and concentration, and the yield is 97.3%.
(2) In a sealed tube, 36.7g of Compound 2 and 150mL of 2-methyltetrahydrofuran (2-Me THF) were added, and after mixing well, 26.6g of TMDS and 1.8g of Cu (OTf) were added 2 Heating to 80 ℃ and stirring for reaction for 16 hours, cooling to 15-25 ℃, and adding water for quenching reaction. The crude product obtained is purified by silica gel column chromatography to obtain the target product rosuvastatin calcium intermediate with a yield of 94.3%, a purity of 99.1% and a total yield of 91.8% in two steps.
Example 7
A preparation method of rosuvastatin calcium intermediate, which comprises the following steps:
(1) 38.1g of compound 3, 2.4g of lithium hydroxide (LiOH), 150mL of Dimethylformamide (DMF) and 150mL of water are added into a reaction bottle, in the stirring process, the temperature is raised to the reflux temperature for chemical reaction, TCL is monitored until the raw materials are completely reacted, the solvent is removed by reduced pressure distillation, hydrochloric acid is added in the stirring process, the pH value of the mixed solution is regulated to 3, the mixed solution is extracted three times by ethyl acetate after being stirred uniformly, and then the white solid, namely the compound 2, is obtained after drying and concentration, and the yield is 97.3%.
(2) In a sealed tube, 36.7g of Compound 2 and 150mL of 2-methyltetrahydrofuran (2-Me THF) were added, and after mixing well, 79.8g of TMDS and 1.8g of Cu (OTf) were added 2 Heating to 80 ℃ and stirring for reaction for 16 hours, cooling to 15-25 ℃, and adding water for quenching reaction. The crude product obtained by three times of extraction with DCM, drying with magnesium sulfate and reduced pressure evaporation is purified by silica gel column chromatography to obtain the target product rosuvastatin calcium intermediate with a yield of 96.6%, a product purity of 98.5% and a total yield of 94.0% in two steps.
Example 8
A preparation method of rosuvastatin calcium intermediate, which comprises the following steps:
(1) 38.1g of compound 3, 2.4g of lithium hydroxide (LiOH), 150mL of Dimethylformamide (DMF) and 150mL of water are added into a reaction bottle, in the stirring process, the temperature is raised to the reflux temperature for chemical reaction, TCL is monitored until the raw materials are completely reacted, the solvent is removed by reduced pressure distillation, hydrochloric acid is added in the stirring process, the pH value of the mixed solution is regulated to 3, the mixed solution is extracted three times by ethyl acetate after being stirred uniformly, and then the white solid, namely the compound 2, is obtained after drying and concentration, and the yield is 97.3%.
(2) In a sealed tube, 36.7g of Compound 2 and 150mL of 2-methyltetrahydrofuran (2-Me THF) were added, and after mixing, 53.3g of TMDS and 0.9g of Cu (OAc) were added 2 Heating to 80 ℃ and stirring for reaction for 16 hours, cooling to 15-25 ℃, and adding water for quenching reaction. The crude product obtained is purified by silica gel column chromatography to obtain the target product rosuvastatin calcium intermediate with the yield of 95.8%, the product purity of 99.4% and the total yield of 93.2% in two steps.
Example 9
A preparation method of rosuvastatin calcium intermediate, which comprises the following steps:
(1) 38.1g of compound 3, 2.4g of lithium hydroxide (LiOH), 150mL of Dimethylformamide (DMF) and 150mL of water are added into a reaction bottle, in the stirring process, the temperature is raised to the reflux temperature for chemical reaction, TCL is monitored until the raw materials are completely reacted, the solvent is removed by reduced pressure distillation, hydrochloric acid is added in the stirring process, the pH value of the mixed solution is regulated to 3, the mixed solution is extracted three times by ethyl acetate after being stirred uniformly, and then the white solid, namely the compound 2, is obtained after drying and concentration, and the yield is 97.3%.
(2) In a sealed tube, 36.7g of Compound 2 and 150mL of toluene (MePh) were added, and after mixing, 53.3g of TMDS and 1.8g of Cu (OTf) were added 2 Heating to 80 ℃ and stirring for reaction for 16 hours, cooling to 15-25 ℃, and adding water for quenching reaction. The crude product obtained by three times of extraction with DCM, drying with magnesium sulfate and reduced pressure evaporation is purified by silica gel column chromatography to obtain the target product rosuvastatin calcium intermediate with a yield of 94.1% and a product purity of 98.8% and a total yield of 91.6% in two steps.
Example 10
A preparation method of rosuvastatin calcium intermediate, which comprises the following steps:
(1) 38.1g of compound 3, 2.4g of lithium hydroxide (LiOH), 150mL of Dimethylformamide (DMF) and 150mL of water are added into a reaction bottle, in the stirring process, the temperature is raised to the reflux temperature for chemical reaction, TCL is monitored until the raw materials are completely reacted, the solvent is removed by reduced pressure distillation, hydrochloric acid is added in the stirring process, the pH value of the mixed solution is regulated to 3, the mixed solution is extracted three times by ethyl acetate after being stirred uniformly, and then the white solid, namely the compound 2, is obtained after drying and concentration, and the yield is 97.3%.
(2) In a sealed tube, 36.7g of Compound 2 and 150mL of Tetrahydrofuran (THF) were added, and after mixing well, 53.3g of TMDS and 1.8g of Cu (OTf) were added 2 Heating to 80 ℃ and stirring for reaction for 16 hours, cooling to 15-25 ℃, and adding water for quenching reaction. The crude product obtained is purified by silica gel column chromatography to obtain the target product rosuvastatin calcium intermediate with 92.9% yield, 99.2% purity and 90.4% total yield in two steps.
Comparative example 1
A preparation method of rosuvastatin calcium intermediate, which comprises the following steps:
(1) 38.1g of compound 3, 2.4g of lithium hydroxide (LiOH), 150mL of Dimethylformamide (DMF) and 150mL of water are added into a reaction bottle, in the stirring process, the temperature is raised to the reflux temperature for chemical reaction, TCL is monitored until the raw materials are completely reacted, the solvent is removed by reduced pressure distillation, hydrochloric acid is added in the stirring process, the pH value of the mixed solution is regulated to 3, the mixed solution is extracted three times by ethyl acetate after being stirred uniformly, and then the white solid, namely the compound 2, is obtained after drying and concentration, and the yield is 97.3%.
(2) In a sealed tube, 36.7g of Compound 2 and 150mL of 2-methyltetrahydrofuran (2-Me THF) were added, and after mixing well, 15.1g of NaBH was added 4 And 1.8g Cu (OTf) 2 Heating to 80 ℃ and stirring for reaction for 16 hours, cooling to 15-25 ℃, and adding water for quenching reaction. The crude product obtained is purified by silica gel column chromatography to obtain the target product rosuvastatin calcium intermediate with 89.2% yield, 99.5% purity and 86.8% total yield in two steps.
Comparative example 2
A preparation method of rosuvastatin calcium intermediate, which comprises the following steps:
(1) 38.1g of compound 3, 2.4g of lithium hydroxide (LiOH), 150mL of Dimethylformamide (DMF) and 150mL of water are added into a reaction bottle, in the stirring process, the temperature is raised to the reflux temperature for chemical reaction, TCL is monitored until the raw materials are completely reacted, the solvent is removed by reduced pressure distillation, hydrochloric acid is added in the stirring process, the pH value of the mixed solution is regulated to 3, the mixed solution is extracted three times by ethyl acetate after being stirred uniformly, and then the white solid, namely the compound 2, is obtained after drying and concentration, and the yield is 97.3%.
(2) In a sealed tube, 36.7g of Compound 2 and 150mL of 2-methyltetrahydrofuran (2-Me THF) were added, and after mixing well, 56.9g of DIBAL-H and 1.8g of Cu (OTf) were added 2 Heating to 80 ℃ and stirring for reaction for 16 hours, cooling to 15-25 ℃, and adding water for quenching reaction. The crude product obtained is purified by silica gel column chromatography to obtain the target product rosuvastatin calcium intermediate with 88.3% yield, 99.5% purity and 85.9% total yield in two steps.
Comparative example 3
(1) 38.1g of compound 3, 2.4g of lithium hydroxide (LiOH), 150mL of Dimethylformamide (DMF) and 150mL of water are added into a reaction bottle, in the stirring process, the temperature is raised to the reflux temperature for chemical reaction, TCL is monitored until the raw materials are completely reacted, the solvent is removed by reduced pressure distillation, hydrochloric acid is added in the stirring process, the pH value of the mixed solution is regulated to 3, the mixed solution is extracted three times by ethyl acetate after being stirred uniformly, and then the white solid, namely the compound 2, is obtained after drying and concentration, and the yield is 97.3%.
(2) In a sealed tube, 36.7g of Compound 2 and 150mL of 2-methyltetrahydrofuran (2-Me THF) were added, and after mixing well, 13.4g of TMDS and 1.8g of Cu (OTf) were added 2 Heating to 80 ℃ and stirring for reaction for 16 hours, cooling to 15-25 ℃, and adding water for quenching reaction. The crude product obtained is purified by silica gel column chromatography, the yield of the target product rosuvastatin calcium intermediate is 87.2%, the purity of the product is 98.3%, and the total yield of the two steps is 84.8%.
Comparative example 4
(1) 38.1g of compound 3, 2.4g of lithium hydroxide (LiOH), 150mL of Dimethylformamide (DMF) and 150mL of water are added into a reaction bottle, in the stirring process, the temperature is raised to the reflux temperature for chemical reaction, TCL is monitored until the raw materials are completely reacted, the solvent is removed by reduced pressure distillation, hydrochloric acid is added in the stirring process, the pH value of the mixed solution is regulated to 3, the mixed solution is extracted three times by ethyl acetate after being stirred uniformly, and then the white solid, namely the compound 2, is obtained after drying and concentration, and the yield is 97.3%.
(2) In a sealed tube, 36.7g of Compound 2 and 150mL of 2-methyltetrahydrofuran (2-Me THF) were added, and after mixing, 53.7g of TMDS and 18.1g of Cu (OTf) were added 2 Heating to 80 ℃ and stirring for reaction for 16 hours, cooling to 15-25 ℃, and adding water for quenching reaction. The crude product obtained is purified by silica gel column chromatography to obtain the target product rosuvastatin calcium intermediate with 86.8% yield, 97.2% purity and 84.5% total yield in two steps.
Comparative example 5
(1) 38.1g of compound 3, 2.4g of lithium hydroxide (LiOH), 150mL of Dimethylformamide (DMF) and 150mL of water are added into a reaction bottle, in the stirring process, the temperature is raised to the reflux temperature for chemical reaction, TCL is monitored until the raw materials are completely reacted, the solvent is removed by reduced pressure distillation, hydrochloric acid is added in the stirring process, the pH value of the mixed solution is regulated to 3, the mixed solution is extracted three times by ethyl acetate after being stirred uniformly, and then the white solid, namely the compound 2, is obtained after drying and concentration, and the yield is 97.3%.
(2) In a sealed tube, 36.7g of Compound 2 and 150mL of 2-methyltetrahydrofuran (2-Me THF) were added, and after mixing, 53.7g of TMDS and 1.8g of Cu (OTf) were added 2 Heating to 120 ℃ and stirring for reaction for 16 hours, cooling to 15-25 ℃, and adding water for quenching reaction. The crude product obtained is purified by silica gel column chromatography to obtain the target product rosuvastatin calcium intermediate with 88.4% yield, 99.5% purity and 86.0% total yield in two steps.
The above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments may be modified or some technical features may be replaced equivalently; such modifications and substitutions do not depart from the spirit of the invention.
Claims (10)
1. The preparation method of the rosuvastatin calcium intermediate is characterized by comprising the following steps of:
(1) After uniformly mixing the compound 3, alkali, the solvent 1 and water, heating to a reflux temperature for chemical reaction to prepare a compound 2;
(2) After the compound 2 and the solvent 2 are uniformly mixed, tetramethyl siloxane and a catalyst are added, and chemical reaction is carried out at 60-100 ℃ to obtain an intermediate compound 1, wherein the specific synthetic route is as follows:
2. the process for the preparation of rosuvastatin calcium intermediate according to claim 1, characterized in that in step (1), the base is lithium hydroxide, sodium hydroxide or potassium hydroxide, preferably lithium hydroxide; the molar ratio of the compound 3 to the base is 1:0.3-2, preferably 1:0.5-1.5, more preferably 1:1.0.
3. A process for the preparation of rosuvastatin calcium intermediate according to claim 1, characterized in that in step (1), said solvent 1 is dimethylformamide, tetrahydrofuran or 1,4-dioxane, preferably dimethylformamide; the mass volume ratio of the compound 3 to the solvent 1 is 1:2.5-6.5 g/ml, preferably 1:3.5-4.5 g/ml, more preferably 1:4g/ml.
4. The process for the preparation of rosuvastatin calcium intermediate according to claim 1, characterized in that in step (1), the mass/volume ratio of compound 3 to water is 1:2.5-6.5 g/ml, preferably 1:3.5-4.5 g/ml, more preferably 1:4g/ml.
5. The process for the preparation of rosuvastatin calcium intermediate according to claim 1, characterized in that in step (2), the molar ratio of compound 2 to tetramethyl siloxane is 1:2-6.
6. The process for preparing rosuvastatin calcium intermediate according to claim 5, characterized in that in step (2), the molar ratio of said compound 2 to tetramethyl siloxane is 1:3-5.
7. The process for the preparation of rosuvastatin calcium intermediate according to claim 6, characterized in that in step (2), the molar ratio of compound 2 to tetramethyl siloxane is 1:4.
8. The process for the preparation of rosuvastatin calcium intermediate according to claim 1, characterized in that in step (2), the catalyst is Cu (OTf) 2 Or Cu (OAc) 2 Preferably Cu (OTf) 2 The method comprises the steps of carrying out a first treatment on the surface of the The molar ratio of the compound 2 to the catalyst is 1:0.01-0.1, preferably 1:0.03-0.08, more preferably 1:0.05.
9. The process for the preparation of rosuvastatin calcium intermediate according to claim 1, characterized in that in step (2), the reaction temperature is 70 to 90 ℃, preferably 80 ℃; the reaction time is 10 to 20 hours, preferably 16 hours.
10. A process for the preparation of rosuvastatin calcium intermediate according to claim 1, characterized in that in step (2), said solvent 2 is 2-methyltetrahydrofuran, tetrahydrofuran or toluene, preferably 2-methyltetrahydrofuran; the mass volume ratio of the compound 2 to the solvent 2 is 1:2.5-6.5 g/ml, preferably 1:4.0-5.0 g/ml, more preferably 1:4.1g/ml.
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