CN114213269B - Preparation method of atorvastatin calcium intermediate - Google Patents
Preparation method of atorvastatin calcium intermediate Download PDFInfo
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- CN114213269B CN114213269B CN202111510009.3A CN202111510009A CN114213269B CN 114213269 B CN114213269 B CN 114213269B CN 202111510009 A CN202111510009 A CN 202111510009A CN 114213269 B CN114213269 B CN 114213269B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- OJRHUICOVVSGSY-RXMQYKEDSA-N (2s)-2-chloro-3-methylbutan-1-ol Chemical compound CC(C)[C@H](Cl)CO OJRHUICOVVSGSY-RXMQYKEDSA-N 0.000 title claims abstract description 19
- 229960001770 atorvastatin calcium Drugs 0.000 title claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 42
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims abstract description 36
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 26
- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000003957 anion exchange resin Substances 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 13
- 238000004519 manufacturing process Methods 0.000 claims abstract description 11
- 229920005989 resin Polymers 0.000 claims description 54
- 239000011347 resin Substances 0.000 claims description 54
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 34
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 33
- 238000002791 soaking Methods 0.000 claims description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 239000008367 deionised water Substances 0.000 claims description 18
- 229910021641 deionized water Inorganic materials 0.000 claims description 18
- 238000000967 suction filtration Methods 0.000 claims description 17
- 229920001429 chelating resin Polymers 0.000 claims description 15
- 239000003960 organic solvent Substances 0.000 claims description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 11
- 238000005406 washing Methods 0.000 claims description 11
- 239000000243 solution Substances 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 4
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 claims description 4
- 230000007935 neutral effect Effects 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 abstract description 11
- 239000002351 wastewater Substances 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 3
- 230000008929 regeneration Effects 0.000 abstract description 3
- 238000011069 regeneration method Methods 0.000 abstract description 3
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 239000002585 base Substances 0.000 description 14
- 238000004128 high performance liquid chromatography Methods 0.000 description 14
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 12
- 239000000460 chlorine Substances 0.000 description 12
- 229910052801 chlorine Inorganic materials 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 238000007605 air drying Methods 0.000 description 6
- 239000003513 alkali Substances 0.000 description 6
- 238000005303 weighing Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 4
- ADHRFDCBLJVNFO-UHFFFAOYSA-N 4-methyl-3-oxo-n-phenylpentanamide Chemical compound CC(C)C(=O)CC(=O)NC1=CC=CC=C1 ADHRFDCBLJVNFO-UHFFFAOYSA-N 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- CABVTRNMFUVUDM-VRHQGPGLSA-N (3S)-3-hydroxy-3-methylglutaryl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@@](O)(CC(O)=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 CABVTRNMFUVUDM-VRHQGPGLSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- 101710095342 Apolipoprotein B Proteins 0.000 description 2
- 102100040202 Apolipoprotein B-100 Human genes 0.000 description 2
- 108010023302 HDL Cholesterol Proteins 0.000 description 2
- 208000035150 Hypercholesterolemia Diseases 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000004064 recycling Methods 0.000 description 2
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 229940123934 Reductase inhibitor Drugs 0.000 description 1
- 239000003741 agents affecting lipid metabolism Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- BWFCZHDTTAYGNN-CNZCJKERSA-N calcium;(3r,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound [Ca].C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 BWFCZHDTTAYGNN-CNZCJKERSA-N 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000001258 dyslipidemic effect Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of an atorvastatin calcium intermediate, which takes a compound II and aniline as raw materials, adopts pretreated strong base anion exchange resin as a catalyst to carry out chemical reaction to obtain a target product compound I, and the specific synthetic route is as follows. The preparation method provided by the invention is simple, the yield and purity are higher, the yield reaches more than 98%, the purity reaches more than 99%, no nitrogen wastewater is generated in the production process, the post-treatment is simple, the production cost is low, and the method is suitable for industrial large-scale production. Compared with the catalyst in the prior art, the catalyst adopted by the invention can be recycled for more than 5 times without treatment and can be recycled after regeneration treatment.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a preparation method of an atorvastatin calcium pharmaceutical intermediate N-phenyl isobutyrylacetamide.
Background
Atorvastatin calcium (Atorvastain calium), known as (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- (phenylcarbamoyl) pyrrol-1-yl ] -3, 5-dihydroxyheptanoic acid calcium, is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. In 1997, it was proposed by the american-type scion company as a third-generation statin lipid-regulating drug, and is widely used for preventing and treating hypercholesterolemia in clinical practice. This effect is exerted by lowering the Total Cholesterol (TC), high density lipoprotein cholesterol (HDL-C), and apolipoprotein B (ApoB) levels in dyslipidemic patients. In addition, atorvastatin calcium has an anti-inflammatory effect in atherosclerotic plaques. Because of the characteristics of high efficiency, safety and the like. Is always one of the most popular drugs for treating hypercholesterolemia.
The compound N-phenylisobutyrylacetamide (compound I) is a key intermediate compound in the synthesis of atorvastatin calcium, and the preparation method mainly adopts the following route at present:
the patent CN101337906A and the patent CN106397241A report that the method for preparing the target product compound I by taking the compound II and the aniline as raw materials and taking the 4-dimethylaminopyridine as a catalyst has higher yield, but the catalyst has higher price, nitrogen wastewater is easy to generate in industrial production, the post-treatment is complicated, and the process cost is increased.
Therefore, aiming at the defects in the prior art, a novel preparation method of the atorvastatin calcium intermediate is explored, so that the method has the advantages of simple synthetic route, low cost, high yield, high purity, environmental friendliness and the like, and has great significance.
Disclosure of Invention
The invention aims to provide a preparation method of an atorvastatin calcium medical intermediate N-phenylisobutyrylacetamide based on the prior art, which uses a strong base anion exchange resin as a catalyst, has the advantages of simple preparation method, higher yield and purity, can be recycled as the resin of the catalyst, and is particularly free from nitrogen wastewater in the production process, simple in post-treatment and low in production cost, and is suitable for industrial mass production.
The technical scheme of the invention is as follows:
a process for the preparation of an atorvastatin calcium intermediate comprising the steps of:
(1) Pretreatment of resin: adding strong alkali type anion exchange resin into sodium hydroxide aqueous solution at 25-35 ℃ for soaking, separating out soaked resin, washing the resin to be neutral by adopting deionized water, adding the washed resin into an organic solvent for soaking again, filtering and drying to obtain pretreated resin;
(2) Preparation of Compound I: under the protection of nitrogen, aniline, a compound II, an organic solvent and the pretreatment resin obtained in the step (1) are uniformly mixed, chemical reaction is carried out at the temperature of 80-120 ℃, and after the reaction is finished, suction filtration, washing and drying are carried out to obtain an intermediate compound I, wherein the specific synthetic route is as follows:
for the purposes of the present invention, the strong base anion exchange resin in step (1) is a strong base anion exchange resin commercially suitable for use in the present invention, in particular Amberlite IRA402 strong base anion exchange resin (chloride type).
In the step (1), the strong base anion exchange resin is added into the sodium hydroxide aqueous solution for soaking at the temperature of 25-35 ℃, wherein the soaking time in the sodium hydroxide aqueous solution is 20-30 h, and can be, but not limited to, 20h, 22h, 24h, 26h or 30h, and the soaking time is 24h for obtaining a better effect.
Further, the solvent water in the aqueous sodium hydroxide solution is deionized water, and the concentration of the aqueous sodium hydroxide solution is 1-5 wt%, which may be but not limited to 1wt%, 2wt%, 2.5wt%, 3wt%, 3.5wt%, 4wt% or 5wt%, for obtaining better effect, the concentration of the aqueous sodium hydroxide solution is 3wt%.
In the present invention, the washed resin is soaked again in the organic solvent for 2-6 hours, which may be, but not limited to, 2 hours, 4 hours, 5 hours or 6 hours, and the soaking time is 4 hours in order to obtain a better effect.
In the step (2), the addition amount of the pretreated resin needs to be controlled, and the dosage of the resin is low, so that incomplete reaction is easy to cause; the resin is used in a relatively high amount, byproducts are easy to generate, the cost is increased, and the smooth reaction is not facilitated, so that the yield and purity of the product are relatively low. In the present invention, the mass ratio of the compound II to the pretreated resin is 1:0.4-1, which may be, but is not limited to, 1:0.4, 1:0.45, 1:0.5, 1:0.55, 1:0.6, 1:0.65, 1:0.7, 1:0.75, 1:0.8, 1:0.85, 1:0.9, 1:0.95 or 1:1, and the mass ratio of the compound II to the pretreated resin is preferably 1:0.5-0.8 for better effect and cost saving.
In the process of preparing the compound I, the material ratio of the compound II to the aniline needs to be controlled. If the material proportion is controlled improperly, by-products are easy to be generated, the yield of the compound I is reduced, and the purity is lower. In the step (2), the molar ratio of the compound II to the aniline is 1:1-1.5, which may be, but is not limited to, 1:1, 1:1.05, 1:1.1, 1:1.15, 1:1.2, 1:1.25, 1:1.3, 1:1.35, 1:1.4, 1:1.45 or 1:1.5, and the molar ratio of the compound II to the aniline is preferably 1:1-1.3 for obtaining better effects.
In the step (2), the organic solvent is selected from one or more of toluene, benzene, ethyl acetate, cyclohexane and n-hexane as in the step (1).
In the present invention, in step (2), it is necessary to control the reaction temperature during the reaction, and the reaction temperature is too high or too low, which is liable to cause side reactions, a large amount of by-products, incomplete reaction, etc., resulting in a decrease in the yield and low purity of compound I. In the present invention, the reaction temperature is controlled to 80 to 120℃and may be, but not limited to, 80℃and 85℃and 90℃and 95℃and 100℃and 105℃and 110℃and 115℃and 120℃and, in order to obtain a more preferable effect, the reaction temperature is preferably 90 to 105℃and particularly preferably 100 ℃.
Further, in the step (2), the reaction time is 14 to 20 hours, preferably 15 to 18 hours.
In a preferred embodiment, the process for the preparation of atorvastatin calcium intermediates mentioned in the present invention comprises the following more detailed steps:
(1) Pretreatment of resin: the Amberlite IRA402 strong base anion exchange resin (chlorine type) is added into 1-5wt% sodium hydroxide aqueous solution (water is deionized water) at 25-35 ℃ for soaking for 20-30 hours (preferably 24 hours), the soaked resin is separated, the resin is washed to be neutral by the deionized water, the washed resin is added into an organic solvent for soaking for 2-6 hours (preferably 4 hours), and the pretreated resin is obtained through suction filtration and forced air drying. Wherein the organic solvent is one or more of toluene, benzene, ethyl acetate, cyclohexane or n-hexane.
(2) Preparation of Compound I: under the protection of nitrogen, aniline, a compound II, an organic solvent and the pretreatment resin obtained in the step (1) are sequentially added into a reaction bottle, stirring is slowly started to uniformly mix, the temperature is increased to 80-120 ℃ (preferably 90-105 ℃, more preferably 100 ℃), and the heat preservation reaction is carried out under the condition of HPLC (high performance liquid chromatography) central control, wherein the reaction time is 14-20 h (15-18 h). After the reaction is completed, filtering, taking filtrate, washing once with dilute hydrochloric acid, washing an organic phase twice with water, and drying to obtain an intermediate compound I. Wherein the mass ratio of the compound II to the pretreated resin is 1:0.4-1 (preferably 1:0.5-0.8); the molar ratio of the compound II to the aniline is 1:1-1.5 (preferably 1:1-1.3). The organic solvent is the same as in step (1).
By adopting the technical scheme of the invention, the advantages are as follows:
the method takes the compound II and the aniline as raw materials, adopts the strong base anion exchange resin as the catalyst to react to obtain the target product compound I, has simple preparation method, higher yield and purity, the yield reaches more than 98 percent, the purity reaches more than 99 percent, no nitrogen wastewater is generated in the production process, the post-treatment is simple, the production cost is low, and the method is suitable for industrial large-scale production. Compared with the catalyst in the prior art, the catalyst adopted by the invention can be recycled for more than 5 times without treatment and can be recycled after regeneration treatment.
Detailed Description
For a better understanding of the present invention, we will further describe the present invention with reference to specific examples.
Example 1
(1) Pretreatment of resin
Weighing 100g Amberlite IRA402 alkali type anion exchange resin (chlorine type), adding 300g of 3wt% sodium hydroxide aqueous solution (water is deionized water), soaking for 24 hours at 25-35 ℃, separating out soaked resin, washing to neutrality by adopting deionized water, soaking the washed resin for 4 hours by adopting 300mL of toluene, carrying out suction filtration, and carrying out forced air drying at 30 ℃ to obtain the pretreated resin.
(2) Preparation of Compound I
Aniline (28.4 g,0.30 mol), compound II (40 g,0.28 mol), 150mL toluene, 25g of Amberlite IRA402 strong base anion exchange resin (chlorine type) pretreated in the step (1) are sequentially added into a reaction bottle under the protection of nitrogen, stirring is slowly started, the temperature is raised to 100 ℃ for reaction, HPLC (high performance liquid chromatography) central control is carried out, and the temperature is kept for 16h for reaction. After the reaction, the filtrate was collected by suction filtration, washed once with 100mL of 3N diluted hydrochloric acid, and the organic phase was washed twice with 50mL of water, and evaporated to dryness at 60℃to give 56.73g of Compound I in 98.7% yield and 99.5% purity.
(3) Recycling of resins
The solid obtained by suction filtration in the post-treatment process of the step (2) (namely Amberlite IRA402 strong base anion exchange resin) is dried and then is reused as a catalyst in the step (2) for recycling for 5 times, and the yield of the target product is as follows:
| number of cycles | Yield is good |
| 1 | 98.7％ |
| 2 | 98.1％ |
| 3 | 97.3％ |
| 4 | 96.7％ |
| 5 | 95.6％ |
Example 2
(1) Pretreatment of resin
Weighing 100g Amberlite IRA402 alkali type anion exchange resin (chlorine type), adding 300g of 3wt% sodium hydroxide aqueous solution (water is deionized water), soaking for 24 hours at 25-35 ℃, separating out the soaked resin, washing to neutrality by adopting deionized water, soaking the washed resin for 4 hours by adopting 300mL of ethyl acetate, carrying out suction filtration, and carrying out forced air drying at 30 ℃ to obtain the pretreated resin.
(2) Preparation of Compound I
Aniline (26.1 g,0.28 mol), compound II (40 g,0.28 mol), 150mL ethyl acetate, 40g of Amberlite IRA402 strong base anion exchange resin (chlorine type) pretreated in the step (1) are sequentially added into a reaction bottle under the protection of nitrogen, stirring is slowly started, the temperature is raised to 120 ℃ for reaction, HPLC (high performance liquid chromatography) central control is carried out, and the reaction is kept for 20 hours. After the reaction, the filtrate was collected by suction filtration, washed once with 100mL of 3N diluted hydrochloric acid, and the organic phase was washed twice with 50mL of water, and evaporated to dryness at 60℃to give 56.5g of Compound I in 98.3% yield and 99.3% purity.
Example 3
(1) Pretreatment of resin
Weighing 100g Amberlite IRA402 alkali type anion exchange resin (chlorine type), adding 300g of 3wt% sodium hydroxide aqueous solution (water is deionized water), soaking for 24 hours at 25-35 ℃, separating out the soaked resin, washing to neutrality by adopting deionized water, soaking the washed resin for 4 hours by adopting 300mL of normal hexane, carrying out suction filtration, and carrying out forced air drying at 30 ℃ to obtain the pretreated resin.
(2) Preparation of Compound I
Aniline (39.1 g,0.42 mol), compound II (40 g,0.28 mol), 150mL of n-hexane, 16g of Amberlite IRA402 strong base anion exchange resin (chlorine type) pretreated in the step (1) are sequentially added into a reaction bottle under the protection of nitrogen, stirring is slowly started, the temperature is raised to 80 ℃ for reaction, HPLC (high performance liquid chromatography) is controlled, and the temperature is kept for reaction for 14h. After the reaction, the filtrate was collected by suction filtration, washed once with 100mL of 3N diluted hydrochloric acid, and the organic phase was washed twice with 50mL of water, and evaporated to dryness at 60℃to give 56.32g of Compound I in 98.0% yield and 99.5% purity.
Example 4
(1) Regeneration of resins
50g of resin recycled for 5 times in the example 1 is collected, 150g of 3wt% sodium hydroxide aqueous solution (water is deionized water) is added, soaking is carried out for 24 hours at the temperature of 25-35 ℃, the soaked resin is separated, the resin is washed to be neutral by adopting deionized water, the washed resin is soaked for 4 hours by adopting 150mL of normal hexane, suction filtration is carried out, and the regenerated resin is obtained by blast drying at the temperature of 30 ℃.
(2) Preparation of Compound I
Aniline (28.4 g,0.30 mol), compound II (40 g,0.28 mol), 150mL toluene, 25g of Amberlite IRA402 strong base anion exchange resin regenerated in step (1) (chlorine type) are added into a reaction bottle in sequence under the protection of nitrogen, stirring is slowly started, the temperature is raised to 100 ℃ for reaction, HPLC (high performance liquid chromatography) is controlled, and the temperature is kept for 16h for reaction. After the reaction, the filtrate was collected by suction filtration, washed once with 100mL of 3N diluted hydrochloric acid, and the organic phase was washed twice with 50mL of water, and evaporated to dryness at 60℃to give 56.63g of Compound I in 96.8% yield and 99.2% purity.
Comparative example 1
(1) Pretreatment of resin
Weighing 100g Amberlite IRA402 alkali type anion exchange resin (chlorine type), adding 300g of 3wt% sodium hydroxide aqueous solution (water is deionized water), soaking for 24 hours at 25-35 ℃, separating out soaked resin, washing to neutrality by adopting deionized water, soaking the washed resin for 4 hours by adopting 300mL of toluene, carrying out suction filtration, and carrying out forced air drying at 30 ℃ to obtain the pretreated resin.
(2) Preparation of Compound I
Aniline (28.4 g,0.30 mol), compound II (40 g,0.28 mol), 150mL toluene, 45g of Amberlite IRA402 strong base anion exchange resin (chlorine type) pretreated in the step (1) are sequentially added into a reaction bottle under the protection of nitrogen, stirring is slowly started, the temperature is raised to 100 ℃ for reaction, HPLC (high performance liquid chromatography) central control is carried out, and the temperature is kept for 16h for reaction. After the reaction, the filtrate was collected by suction filtration, washed once with 100mL of 3N diluted hydrochloric acid, and the organic phase was washed twice with 50mL of water, and evaporated to dryness at 60℃to give 45.12g of Compound I in a yield of 78.5% and a purity of 96.8%.
Comparative example 2
(1) Pretreatment of resin
Weighing 100g Amberlite IRA402 alkali type anion exchange resin (chlorine type), adding 300g of 3wt% sodium hydroxide aqueous solution (water is deionized water), soaking for 24 hours at 25-35 ℃, separating out soaked resin, washing to neutrality by adopting deionized water, soaking the washed resin for 4 hours by adopting 300mL of toluene, carrying out suction filtration, and carrying out forced air drying at 30 ℃ to obtain the pretreated resin.
Aniline (28.4 g,0.30 mol), compound II (40 g,0.28 mol), 150mL toluene, 25g of Amberlite IRA402 strong base anion exchange resin (chlorine type) pretreated in the step (1) are sequentially added into a reaction bottle under the protection of nitrogen, stirring is slowly started, the temperature is raised to 60 ℃ for reaction, HPLC (high performance liquid chromatography) central control is carried out, and the temperature is kept for 16h for reaction. After the reaction, the filtrate was collected by suction filtration, washed once with 100mL of 3N diluted hydrochloric acid, and the organic phase was washed twice with 50mL of water, and evaporated to dryness at 60℃to give 41.61g of Compound I in a yield of 72.4% and a purity of 95.7%.
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 (8)
1. A process for the preparation of an atorvastatin calcium intermediate comprising the steps of:
(1) Pretreatment of resin: adding Amberlite IRA402 strong base anion exchange resin into 1-5wt% sodium hydroxide aqueous solution at 25-35 ℃ for soaking for 20-30 hours, separating out soaked resin, washing with deionized water to be neutral, adding the washed resin into an organic solvent for soaking for 2-6 hours again, and carrying out suction filtration and drying to obtain pretreated resin;
(2) Preparation of Compound I: under the protection of nitrogen, aniline, a compound II, an organic solvent and the pretreatment resin obtained in the step (1) are uniformly mixed, chemical reaction is carried out at the temperature of 80-120 ℃, and after the reaction is finished, suction filtration, washing and drying are carried out to obtain an intermediate compound I, wherein the specific synthetic route is as follows:
wherein the mass ratio of the compound II to the pretreated resin is 1:0.4-1; the molar ratio of the compound II to the aniline is 1:1-1.5.
2. The process for preparing an atorvastatin calcium intermediate according to claim 1, wherein in step (1), the organic solvent is one or more of toluene, benzene, ethyl acetate, cyclohexane or n-hexane; the soaking time in the organic solvent is 4h.
3. The process for preparing an atorvastatin calcium intermediate according to claim 1 wherein in step (1), the time of soaking in aqueous sodium hydroxide solution is 24 hours; the concentration of the aqueous sodium hydroxide solution was 3wt%; the solvent water in the aqueous sodium hydroxide solution is deionized water.
4. The method for preparing an atorvastatin calcium intermediate according to claim 1, wherein in the step (2), the mass ratio of the compound II to the pretreated resin is 1:0.5-0.8.
5. The method for preparing an atorvastatin calcium intermediate according to claim 1, wherein in the step (2), the molar ratio of the compound II to aniline is 1:1-1.3.
6. The method for preparing an atorvastatin calcium intermediate according to claim 1, wherein in the step (2), the reaction temperature is 90-105 ℃; the reaction time is 14-20 h.
7. The process for preparing an atorvastatin calcium intermediate of claim 6 wherein in step (2) the reaction temperature is 100 ℃; the reaction time is 15-18 h.
8. The process for preparing an atorvastatin calcium intermediate according to claim 1, wherein in step (2), the organic solvent is one or more of toluene, benzene, ethyl acetate, cyclohexane or n-hexane.
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