CN109867695B - Novel preparation method of pitavastatin calcium intermediate - Google Patents
Novel preparation method of pitavastatin calcium intermediate Download PDFInfo
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- RHGYHLPFVJEAOC-FFNUKLMVSA-L pitavastatin calcium Chemical compound [Ca+2].[O-]C(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1.[O-]C(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 RHGYHLPFVJEAOC-FFNUKLMVSA-L 0.000 title abstract description 9
- 238000002360 preparation method Methods 0.000 title abstract description 9
- 229960003296 pitavastatin calcium Drugs 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 14
- CMSYDJVRTHCWFP-UHFFFAOYSA-N triphenylphosphane;hydrobromide Chemical compound Br.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 CMSYDJVRTHCWFP-UHFFFAOYSA-N 0.000 claims abstract description 13
- FIZDBNPUFMDGFZ-UHFFFAOYSA-N [2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]methanol Chemical compound OCC1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 FIZDBNPUFMDGFZ-UHFFFAOYSA-N 0.000 claims abstract description 7
- CPAKLXBIWIMSNE-UHFFFAOYSA-N FC(C=C1)=CC=C1C1=C(CC(C=CC=C2)=C2P(C2=CC=CC=C2)C2=CC=CC=C2)C(C2CC2)=NC2=CC=CC=C12.Br Chemical compound FC(C=C1)=CC=C1C1=C(CC(C=CC=C2)=C2P(C2=CC=CC=C2)C2=CC=CC=C2)C(C2CC2)=NC2=CC=CC=C12.Br CPAKLXBIWIMSNE-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000003960 organic solvent Substances 0.000 claims abstract description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 33
- 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 description 11
- 238000000034 method Methods 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 3
- 239000002994 raw material Substances 0.000 abstract description 6
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 239000011574 phosphorus Substances 0.000 abstract description 5
- 229910052698 phosphorus Inorganic materials 0.000 abstract description 5
- 239000002351 wastewater Substances 0.000 abstract description 3
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 239000002699 waste material Substances 0.000 abstract description 2
- 230000009286 beneficial effect Effects 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 239000012046 mixed solvent Substances 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- 108010028554 LDL Cholesterol Proteins 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 208000000563 Hyperlipoproteinemia Type II Diseases 0.000 description 1
- 102100024640 Low-density lipoprotein receptor Human genes 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010045261 Type IIa hyperlipidaemia Diseases 0.000 description 1
- NLIQETRDGNRDCT-UHFFFAOYSA-M [2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]methyl-triphenylphosphanium;bromide Chemical compound [Br-].C1=CC(F)=CC=C1C(C1=CC=CC=C1N=C1C2CC2)=C1C[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 NLIQETRDGNRDCT-UHFFFAOYSA-M 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000006353 environmental stress Effects 0.000 description 1
- 201000001386 familial hypercholesterolemia Diseases 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 150000004714 phosphonium salts Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Quinoline Compounds (AREA)
Abstract
The invention relates to a preparation method of pitavastatin calcium intermediate [ [ 2-cyclopropyl-4- (4-fluorophenyl) -3-quinolyl ] methyl ] triphenyl phosphine bromide, which comprises the following steps: reacting 2-cyclopropyl-4- (4-fluorophenyl) -3-quinoline methanol with triphenylphosphine hydrobromide in an organic solvent to obtain the target compound. The preparation method has the advantages of easily available raw materials, simple operation and high yield, effectively reduces the phosphorus-containing wastewater and the phosphorus-containing waste residue, reduces the production cost and is beneficial to large-scale production.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a novel preparation method of pitavastatin calcium intermediate [ [ 2-cyclopropyl-4- (4-fluorophenyl) -3-quinolyl ] methyl ] triphenyl phosphine bromide.
Background
Pitavastatin calcium (NK-104), developed by Kowa company, is called "super statin" (Superstatin) because of its good cholesterol-lowering effect. Pitavastatin calcium has the effect of remarkably reducing low-density lipoprotein cholesterol (LDL-C), and can be used for treating diseases such as hypercholesterolemia, familial hypercholesterolemia and the like.
Wherein [ [ 2-cyclopropyl-4- (4-fluorophenyl) -3-quinolyl ] methyl ] triphenyl phosphine bromide is one of important intermediates for preparing pitavastatin calcium. In various patent documents CN1951920A, CN101747265A, CN103508947A and the like, the compound of formula A is used for preparing 2-cyclopropyl-4- (4-fluorophenyl) quinoline-3-methanol for further synthesizing pitavastatin calcium.
In the current commercial production, the intermediate is mainly prepared by the following route, 2-cyclopropyl-4- (4-fluorophenyl) -3-quinoline methanol is used as a raw material, phosphorus tribromide is used for bromination reaction to prepare a brominated intermediate, and the brominated intermediate is separated and purified and then reacts with triphenylphosphine to obtain a phosphonium salt shown in a formula II:
although the yield and the cost are better reflected, the method generates a large amount of phosphorus-containing wastewater and has poor stability of intermediates which are not well solved all the time. At present, the environmental stress is becoming more severe, and the advantages of the route are gradually lost.
Disclosure of Invention
Aiming at the defects in the prior art, the inventor develops a new way and provides an improved method for preparing the compound of the formula II, which has the advantages of easily available raw materials, simple operation, high yield and more environmental protection. In order to achieve the above purpose, the present invention designs the following improved synthetic route: the compound of formula I and triphenylphosphine hydrobromide are used as raw materials to prepare the target product compound II through a one-step reaction. Specifically, the present invention adopts the following technical solutions.
A process for preparing ([ [ 2-cyclopropyl-4- (4-fluorophenyl) -3-quinolinyl ] methyl ] triphenylphosphonium bromide) of formula II, comprising the steps of: the 2-cyclopropyl-4- (4-fluorophenyl) -3-quinoline methanol (formula I) shown in the formula I and triphenylphosphine hydrobromide are heated and reacted in the presence of an organic solvent to directly form a compound II.
The organic solvent is selected from acetonitrile, acetonitrile/water mixed solvent, toluene, dichloromethane, tetrahydrofuran, or a mixture of two or more thereof, and preferably acetonitrile, acetonitrile/water mixed solvent, or toluene.
In one embodiment, the molar ratio of the compound of formula I to triphenylphosphine hydrobromide is 1: 1.0 to 2.0, preferably 1: 1.0 to 2.0, more preferably 1: 1.0 to 1.5, most preferably 1: 1.0 to 1.2.
The triphenylphosphine hydrobromide used as the raw material in the method is a bulk commodity, the reaction operation is simple, the reaction can be completed in one step, the product yield is high, the generation of unstable brominated intermediates is avoided, the phosphorus-containing wastewater and the phosphorus-containing waste residues are effectively reduced, the production cost is reduced, and therefore, the method is more suitable for large-scale production.
Detailed Description
The invention is further illustrated by the following examples. It is to be understood that these examples are for illustrative purposes only and are not limiting upon the present invention. Various changes or modifications thereof, which may occur to those skilled in the art based on the teachings of the present invention, are within the scope of the present invention.
The addition amount, content and concentration of various substances are referred to herein, wherein the percentage refers to the mass percentage unless otherwise specified.
In the examples herein, if no specific description is made about the reaction temperature or the operation temperature, the temperature is usually referred to as room temperature (15 to 25 ℃).
In the specific reaction, the ratio between the compound of the formula I and triphenylphosphine hydrobromide as starting materials can be adjusted appropriately according to the principle of chemical equilibrium from the economical viewpoint of the cost of the product, as will be understood by those skilled in the art.
In one embodiment, the reaction system may contain water, for example, the solvent may be acetonitrile/water mixed solvent. This is clearly different from the reaction systems of the prior art. The reaction system of the invention allows water to exist, on one hand, the treatment process of drying and/or dehydrating the compound of the formula I and the triphenylphosphine serving as raw materials is omitted, the production cost is reduced, and on the other hand, the reaction process is easier to control, and the reaction temperature, the reaction speed and the like can be adjusted.
As for the ratio of acetonitrile to water in the acetonitrile/water mixed solvent, the method of v/v is used in the examples herein.
The reaction steps are basically carried out in a solvent under the condition of heating reflux, the reaction conditions are mild, and the control is easy, so the operation is simple and safe.
Examples
Reagent: the reactants and the catalyst used in the embodiment of the invention are chemically pure, and can be directly used or simply purified according to the requirement; the organic solvent and the like are analytically pure and are directly used. The reagents were purchased from Shanghai chemical reagent company, China medicine (group).
A detection instrument:
nuclear magnetic resonance apparatus type: bruker affinity HD 600MHz, Bruker affinity III 400MHz
EXAMPLE 1 preparation of Compound II
2.9g of 2-cyclopropyl-4- (4-fluorophenyl) -3-quinolinemethanol (compound I), 3.4g of triphenylphosphine hydrobromide and 30ml of toluene are added into a 100ml three-necked bottle, heated, refluxed and stirred, cooled and crystallized after the reaction is finished, and dried to obtain a white solid. Namely [ [ 2-cyclopropyl-4- (4-fluorophenyl) -3-quinolyl ] methyl ] triphenyl phosphine bromide (compound II). Yield: 80 percent; the purity is 99.0 percent;
1H NMR(500MHz,CD3OD):δ＝0.64(br s,2H),1.05(br s,2H),2.04(m,1H),5.25(d,J＝11.5Hz,2H),6.83(br s,2H),7.15(d,J＝8.4Hz,1H),7.18–7.33(m,8H),7.38(m,1H),7.64(m,6H),7.71(m,1H),7.89(m,3H),7.94(d,J＝8.4Hz,1H).
example 2 preparation of Compound II
2.9g of 2-cyclopropyl-4- (4-fluorophenyl) -3-quinolinemethanol, 3.4g of triphenylphosphine hydrobromide and 30ml of acetonitrile were added to a 100ml three-necked flask, and the mixture was stirred under reflux under heating, and after completion of the reaction, the mixture was concentrated to dryness to obtain a white solid. Namely [ [ 2-cyclopropyl-4- (4-fluorophenyl) -3-quinolyl ] methyl ] triphenyl phosphine bromide (compound II). Yield: 96.5 percent; the purity is 98.0 percent; examples 3 to 7 preparation of Compound II
Compound II was prepared by adjusting the ratio between compound I and triphenylphosphine hydrobromide and the kind of solvent according to the procedure shown in example 1, and the results are shown in Table 1.
TABLE 1 preparation of Compound II
As can be seen from Table 1, the experimental results of acetonitrile or acetonitrile/water mixed solvent as a solvent are superior to those of dichloromethane and tetrahydrofuran in view of the combination of yield and purity of Compound II.
Claims (3)
1. A method for preparing [ [ 2-cyclopropyl-4- (4-fluorophenyl) -3-quinolyl ] methyl ] triphenyl phosphine bromide of a compound shown in formula II, comprising the following steps: heating and reacting the compound 2-cyclopropyl-4- (4-fluorophenyl) -3-quinoline methanol shown in the formula I and triphenylphosphine hydrobromide in the presence of an organic solvent to directly form a compound II;
the organic solvent is selected from acetonitrile;
the molar ratio of the compound shown in the formula I to triphenylphosphine hydrobromide is 1: 1.0 to 2.0.
2. The method according to claim 1, wherein the molar ratio of the compound of formula I to triphenylphosphine hydrobromide is 1: 1.0 to 1.5.
3. The method according to claim 1, wherein the molar ratio of the compound of formula I to triphenylphosphine hydrobromide is 1: 1.0 to 1.2.
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| CN112175007A (en) * | 2020-10-13 | 2021-01-05 | 江苏福瑞康泰药业有限公司 | Preparation method of pitavastatin calcium intermediate |
| CN115754025B (en) * | 2021-09-02 | 2024-07-02 | 上虞京新药业有限公司 | Detection method of genotoxic impurity GTI in pitavastatin calcium |
| CN115290791B (en) * | 2022-08-05 | 2023-07-25 | 华润双鹤药业股份有限公司 | Qualitative and quantitative detection method for ortho-isomer and meta-isomer of pitavastatin calcium quinoline mother nucleus |
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Address after: 312369 No.31, Weisan Road, Shangyu economic and Technological Development Zone, Hangzhou Bay, Shaoxing City, Zhejiang Province Patentee after: Shaoxing Jingxin Pharmaceutical Co.,Ltd. Country or region after: China Patentee after: SHANGHAI JINGXIN BIOLOGICAL MEDICAL Co.,Ltd. Address before: 312500, No. 31, Weisan Road, Shanghe economic and Technological Development Zone, Hangzhou Bay, Shaoxing City, Zhejiang Province Patentee before: SHANGYU JINGXIN PHARMACEUTICAL Co.,Ltd. Country or region before: China Patentee before: SHANGHAI JINGXIN BIOLOGICAL MEDICAL Co.,Ltd. |