CN116444500A - Preparation method of pitavastatin calcium olefin epoxidation impurity - Google Patents
Preparation method of pitavastatin calcium olefin epoxidation impurity Download PDFInfo
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- CN116444500A CN116444500A CN202210011596.XA CN202210011596A CN116444500A CN 116444500 A CN116444500 A CN 116444500A CN 202210011596 A CN202210011596 A CN 202210011596A CN 116444500 A CN116444500 A CN 116444500A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- -1 pitavastatin calcium olefin Chemical class 0.000 title claims abstract description 27
- 229960003296 pitavastatin calcium Drugs 0.000 title claims abstract description 23
- 238000006735 epoxidation reaction Methods 0.000 title claims abstract description 21
- 239000012535 impurity Substances 0.000 title claims abstract description 18
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 58
- 239000002904 solvent Substances 0.000 claims abstract description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- 239000002253 acid Substances 0.000 claims abstract description 7
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical class S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 7
- 150000007529 inorganic bases Chemical class 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 5
- 239000011707 mineral Substances 0.000 claims description 5
- 150000007522 mineralic acids Chemical class 0.000 claims description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 4
- JAHBIRPTCXOGLB-UHFFFAOYSA-N 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carbaldehyde Chemical compound C1=CC(F)=CC=C1C1=C(C=O)C(C2CC2)=NC2=CC=CC=C12 JAHBIRPTCXOGLB-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical group COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- 125000004970 halomethyl group Chemical group 0.000 claims description 2
- 150000004678 hydrides Chemical class 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- HELZRPQDSQIWCN-UHFFFAOYSA-N S.CSC Chemical compound S.CSC HELZRPQDSQIWCN-UHFFFAOYSA-N 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 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 abstract description 10
- 238000000746 purification Methods 0.000 abstract description 4
- 239000013558 reference substance Substances 0.000 abstract description 4
- 238000000926 separation method Methods 0.000 abstract description 4
- 238000011282 treatment Methods 0.000 abstract description 3
- 231100000252 nontoxic Toxicity 0.000 abstract description 2
- 230000003000 nontoxic effect Effects 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- 230000001590 oxidative effect Effects 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 230000003647 oxidation Effects 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- 238000010525 oxidative degradation reaction Methods 0.000 description 3
- 238000003756 stirring Methods 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
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000003513 alkali Substances 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
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 150000002118 epoxides Chemical class 0.000 description 2
- 150000002191 fatty alcohols Chemical class 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 231100000024 genotoxic Toxicity 0.000 description 2
- 230000001738 genotoxic effect Effects 0.000 description 2
- 150000002367 halogens Chemical group 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- ULQQGOGMQRGFFR-UHFFFAOYSA-N 2-chlorobenzenecarboperoxoic acid Chemical compound OOC(=O)C1=CC=CC=C1Cl ULQQGOGMQRGFFR-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 229940123934 Reductase inhibitor Drugs 0.000 description 1
- NIEVKYPIXJDDNI-UHFFFAOYSA-N [N]=O.N1=CC=CC2=CC=CC=C12 Chemical class [N]=O.N1=CC=CC2=CC=CC=C12 NIEVKYPIXJDDNI-UHFFFAOYSA-N 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229960002797 pitavastatin Drugs 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- 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
- C07D405/02—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 two hetero rings
- C07D405/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of pitavastatin calcium olefin epoxidation impurities, in particular to a preparation method of (3R, 5S) -5- (3- (2-cyclopropyl-4- (4-fluorophenyl) -quinoline-3-yl) -ethylene oxide-2-yl) -3, 5-dihydroxyvaleric acid (I), which takes (4R-cis) -6- (halogenated methyl) -2, 2-dimethyl-1, 3-dioxane-4-acetic ester (II) as a raw material, and prepares a compound of the formula (I) through sulfonium salt (III), epoxidation, acid deprotection and alkaline hydrolysis. The preparation method provided by the invention adopts the Kawauki reaction to obtain the olefin epoxide, has the advantages of simple preparation process, good reproducibility, low cost, safe and nontoxic solvent, convenient and easily obtained routine, simple post-treatment, simple separation and purification mode and short preparation period, and is suitable for preparing the reference substances for researching the quality of pitavastatin calcium and preparation products thereof in a large scale.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of pitavastatin calcium olefin epoxidation impurity (3R, 5S) -5- (3- (2-cyclopropyl-4- (4-fluorophenyl) -quinoline-3-yl) -ethylene oxide-2-yl-) -3, 5-dihydroxyvaleric acid.
Background
Pitavastatin calcium (Pitavastatin Calcium), a 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitor developed by the chemical industry co-product and japan and co-product, was first marketed in japan in 2003, and was mainly adapted to hypercholesterolemia, and is called "super statin" because of its excellent cholesterol lowering effect. Pitavastatin calcium has the following structural formula:
the special oxidative degradation test shows that the pitavastatin calcium can generate a plurality of oxidative degradation impurities in the presence of an oxidant, wherein the olefin epoxidation impurity (I) contains a warning structure of genotoxic cancerogenic impurities, so that the pitavastatin calcium olefin epoxidation impurity is necessary to be separated and prepared, and a reference substance is provided for checking, quantifying and qualitatively analyzing the technological impurities, the degradation impurities and the genotoxic impurities of pitavastatin calcium raw medicines and preparation products thereof, so that the quality of the pitavastatin calcium products is ensured, and the medication safety of patients is ensured.
The pitavastatin calcium olefin epoxide preparation methods reported in the current literature are all prepared by taking pitavastatin calcium or ester thereof as raw materials and adopting an oxidant oxidative degradation method.
Chinese patent CN109020962a and indian patent IN2014MU02014 report that pitavastatin calcium is used as a substrate, and an olefin epoxide is obtained by oxidizing urea oxide or m-chloroperoxybenzoic acid. The oxidation reaction selectivity is poor and the yield is very low in addition to the olefin epoxide and quinoline nitroxide. Actual test results show that the products are mostly lactones and cannot obtain epoxides.
Chinese patent CN113527269a reports that quinoline nitrogen oxides are also present with pitavastatin ester as a substrate through chloroperoxybenzoic acid, urea oxide oxidation and hydrogen peroxide oxidation, and the report adopts a preparation liquid chromatograph to separate a plurality of oxidation products, and then prepares epoxide through inorganic base hydrolysis. The method has a plurality of side reactions, generates a plurality of oxidation products, has the yield of only 2-10%, and can be prepared only by a preparation liquid chromatograph, which is difficult to realize in a common laboratory.
Therefore, the field needs a preparation method of pitavastatin calcium olefin epoxidation impurity with simple operation, high product yield, easy separation and purification and high product purity, which is used for preparing the work reference substance of pitavastatin calcium olefin epoxidation impurity.
Disclosure of Invention
The invention provides a preparation method of pitavastatin calcium olefin epoxidation impurity (3R, 5S) -5- (3- (2-cyclopropyl-4- (4-fluorophenyl) -quinoline-3-yl) -ethylene oxide-2-yl-) -3, 5-dihydroxyvaleric acid (I), which aims to overcome the defects of the prior preparation technology.
Specifically, the compound of the formula (I) is prepared by taking (4R-cis) -6- (halomethyl) -2, 2-dimethyl-1, 3-dioxane-4-acetic ester (II) as a raw material through sulfonium salt formation, epoxidation, acid deprotection and alkaline hydrolysis.
The preparation method of the invention comprises the following steps:
wherein X is halogen, R is C1-C4 alkyl or benzyl; the compound of formula (IV) is 2-cyclopropyl-4- (4-fluorophenyl) -quinoline-3-carbaldehyde, and the structural formula is as follows:
further, the halogen is fluorine, chlorine or bromine.
In the present invention, the compound of formula (II) is reacted with dimethyl sulfide to produce a sulfonium salt compound of formula (III).
Further, the compound of the formula (III) is prepared by adding the formula (II) into a solvent and adding dimethyl sulfide into sulfonium salt.
Further, in the step of forming sulfonium salt, the solvent is one or more of dichloromethane, acetonitrile, acetone, butanone and ethyl acetate; in some examples, the solvent is used in an amount to volume mass ratio of (1 to 30) mL/g, preferably in an amount of (5 to 15) mL/g; in some examples, the molar ratio of dimethyl sulfide to the compound of formula (II) is from (1 to 5): 1, with a preferred molar ratio being from (2 to 4): 1.
In the invention, the compound of formula (III) is subjected to a Kawasky reaction epoxidation reaction with the compound of formula (IV) under the action of alkali to obtain the compound of formula (V).
Further, adding a compound of formula (III) into a solvent, adding a base at a certain temperature, and adding a compound of formula (IV) to carry out a Kawasky reaction epoxidation to obtain a compound of formula (V).
Further, in the epoxidation step, the solvent is one of dichloromethane, acetonitrile, tetrahydrofuran and C1-C4 fatty alcohol, or a mixed solvent of the solvent and water, wherein the solvent refers to the dichloromethane, the acetonitrile, the tetrahydrofuran or the C1-C4 fatty alcohol, and the mixing ratio of the solvent and the water can be conventionally configured according to experimental requirements; in some examples, the reaction temperature is from-30 ℃ to 30 ℃, with a preferred temperature of from-30 ℃ to 0 ℃; in some examples, the base is triethylamine, DIPEA (diisopropylethylamine), DBU (1, 8-diazabicyclo [5.4.0] undec-7-ene), alkali metal, alkaline earth metal carbonate, hydride, C1-C6 alkyl alkoxide; in some examples, the solvent is used in an amount to volume mass ratio of (1 to 50) mL/g, preferably in an amount of (20 to 40) mL/g; in some examples, the base is used in a molar ratio to the compound of formula (III) of from (1 to 10): 1, preferably in a molar ratio of from (1 to 5): 1; in some examples, the amount of the compound of formula (IV) used to the compound of formula (II) is in the molar ratio of (0.5 to 3): 1.
In the present invention, the compound of formula (V) is deprotected by an inorganic acid and hydrolyzed by an inorganic base to give the compound of formula (I).
Further, adding the compound of formula (V) into a solvent, adding an inorganic acid solution to remove isopropylidene, adding an inorganic alkali solution to hydrolyze ester groups, adjusting pH, extracting, and concentrating to obtain the compound of formula (I).
Further, in the steps of inorganic acid deprotection and inorganic alkaline hydrolysis, the solvent is acetonitrile, tetrahydrofuran, methanol or ethanol; in some examples, the mineral acid is hydrochloric acid; in some examples, the inorganic base is sodium hydroxide or lithium hydroxide; in some examples, the pH is 3 to 6, preferably 3 to 4; in some examples, the extraction solvent is methyl tert-butyl ether, ethyl acetate, dichloromethane, diethyl ether, toluene; in some examples, the solvent is used in an amount to volume mass ratio of (1 to 20) mL/g, preferably in an amount of (10 to 15) mL/g; in some examples, the molar ratio of the amount of the mineral acid to the compound of formula (V) is (1-1.5): 1; in some examples, the molar ratio of the inorganic base to the compound of formula (V) is from (1 to 3.0): 1.
The beneficial effects of the invention are as follows:
the pitavastatin calcium olefin epoxidation impurity provided by the invention has the advantages of simple preparation process, good reproducibility, low cost, safe and nontoxic solvent, convenient and easily obtained routine solvent, simple post-treatment, simple separation and purification mode and short preparation period, and is suitable for preparing the reference substances for researching the quality of pitavastatin calcium and preparation products thereof in a large scale.
Compared with the methods disclosed by the patents CN109020962A and CN113527269A for oxidizing and degrading by adopting a strong oxidant, the preparation method of pitavastatin calcium olefin epoxidation impurities provided by the invention has the advantages of simplicity, few byproducts, high reaction conversion rate and product yield, simple post-treatment, separation and purification without preparation of liquid chromatography, and easiness in realization. The obtained pitavastatin calcium olefin epoxidation impurity has extremely high purity, and can obtain a sample with the purity of more than 99.0 percent.
Detailed Description
The invention is described below with reference to specific examples. It will be appreciated by those skilled in the art that these examples are for illustration of the invention only and are not intended to limit the scope of the invention in any way.
The raw materials and reagents in the examples of the invention are all commercially available products.
Example 1
(1) Preparation of the Compound of formula (III) (X=Cl, R=t-Bu)
4R-cis) -6- (chloromethyl) -2, 2-dimethyl-1, 3-dioxane-4-acetic acid tert-butyl ester (II, 10g,35.9 mmol) and methylene chloride (100 mL) were added to a reaction flask, stirred well, and dimethyl sulfide (6.7 g,107.7 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours. After the completion of the reaction, the solvent and excess dimethyl sulfide were distilled off under reduced pressure to give an off-white solid, i.e., the compound of formula (III) (12.4 g, molar yield 100%).
ESI-MS m/z：305.1[M-Cl] +
(2) Preparation of the Compound of formula (V) (X=Cl, R=t-Bu)
The compound of formula (III) (10 g,29.3 mmol) and dichloromethane (300 mL) were added to a reaction flask, stirred well, cooled to below 0deg.C, and DBU (8.9 g,58.6 mmol) and 2-cyclopropyl-4- (4-fluorophenyl) -quinoline-3-carbaldehyde (IV, 17.1g,58.6 mmol) were added sequentially. The reaction mixture was warmed to room temperature naturally and stirred for an additional 24 hours. After the reaction, saturated brine was added, and the mixture was left to stand and separated. The aqueous layer was extracted with dichloromethane. The organic phases are combined, the solvent is distilled off under reduced pressure, and the residue is purified by flash column chromatography on silica gel [ eluent: n-hexane: ethyl acetate (20-5:1) ] to afford the compound of formula (v) (13.7 g, molar yield 87.8%) as a pale yellow solid.
ESI-MS m/z：534.3[M+H] +
(3) Preparation of Compounds of formula (I)
A compound of formula (V) (10 g,18.7 mmol) and acetonitrile (150 mL) were added to the reaction flask, stirred well, and 1mol/L HCl solution (23 mL) was added. The reaction mixture was stirred at room temperature for 6 hours. A1 mol/L NaOH solution (47 mL) was added and stirring was continued for 2 hours. After the reaction, the pH is adjusted to 3-4 by 0.5mol/L hydrochloric acid, and ethyl acetate is added for extraction. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give a pale yellow solid, i.e., the compound of formula (I) (7.8 g, molar yield 95.1%). Purity (HPLC) 99.5%.
1 H NMR(400MHz,MeOD)δ:7.89(d,J＝8.0Hz,1H,Ar-H),7.60(t,J＝8.0Hz,1H,Ar-H),7.43～7.46(m,1H,Ar-H),7.22～7.31(m,5H,Ar-H),4.53～4.56(m,1H,-CH),4.09(bs,2H,-CH),3.07～3.19(m,1H,-CH),2.42～2.48(m,2H,-CH 2 ),1.90～1.96(m,1H,-CH),1.66～1.86(m,2H,-CH 2 ),0.96～1.18(m,4H,-CH 2 )；ESI-MS m/z：438.3[M+H] + 。
Example 2
(1) Preparation of a compound of formula (iii) (x=br, r=bn)
4R-cis) -6- (bromomethyl) -2, 2-dimethyl-1, 3-dioxane-4-acetic acid benzyl ester (II, 10g,28.0 mmol) and acetone (100 mL) were added to a reaction flask, stirred well, and dimethyl sulfide (7.7 g,140.0 mmol) was added. The reaction mixture was stirred at room temperature for 30 hours. After the reaction, the mixture was cooled to a temperature below 10 ℃, filtered, and vacuum-dried to obtain a white solid (10.8 g, 92.3% molar yield) of the compound of formula (III).
ESI-MS m/z：339.1[M-Br] +
(2) Preparation of a compound of formula (v) (x=br, r=bn)
A compound of formula (III) (10 g,23.8 mmol) and tetrahydrofuran (300 mL) were added to a reaction flask, stirred well, cooled to below-15℃and potassium tert-butoxide (8.0 g,71.4 mmol) and 2-cyclopropyl-4- (4-fluorophenyl) -quinoline-3-carbaldehyde (IV, 10.4g,35.7 mmol) were added sequentially. The reaction mixture was warmed to room temperature naturally and stirred for an additional 24 hours. After the reaction, saturated brine was added, and the mixture was left to stand and separated. The aqueous layer was extracted with dichloromethane. The organic phases are combined, the solvent is distilled off under reduced pressure, and the residue is purified by flash column chromatography on silica gel [ eluent: n-hexane: ethyl acetate (10-5:1) ] to afford the compound of formula (v) (11.6 g, molar yield 85.9%) as a pale yellow solid.
ESI-MS m/z：568.3[M+H] +
(3) Preparation of Compounds of formula (I)
A reaction flask was charged with the compound of formula (V) (10 g,17.6 mmol) and tetrahydrofuran (100 mL), and 1mol/L HCl solution (26 mL) was added with stirring. The reaction mixture was stirred at room temperature for 4 hours. 1mol/L NaOH solution (52 mL) was added, the temperature was raised to 40℃and stirring was continued for 2 hours. After the reaction, the pH is regulated to 3-4 by 0.5mol/L hydrochloric acid, and methyl tertiary butyl ether is added for extraction. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give a pale yellow solid, i.e., the compound of formula (I) (7.1 g, molar yield 92.2%). Purity (HPLC) 99.2%.
Claims (10)
1. The preparation method of pitavastatin calcium olefin epoxidation impurity (3R, 5S) -5- (3- (2-cyclopropyl-4- (4-fluorophenyl) -quinolin-3-yl) -ethylene oxide-2-yl-) -3, 5-dihydroxyvaleric acid (I) is characterized in that (4R-cis) -6- (halomethyl) -2, 2-dimethyl-1, 3-dioxane-4-acetate (II) is taken as a raw material, and the compound of the formula (I) is prepared through sulfonium salt formation, epoxidation, acid deprotection and alkaline hydrolysis; the preparation process is as follows:
wherein X is halogen, and R is C1-C4 alkyl or benzyl. The compound of formula (IV) is 2-cyclopropyl-4- (4-fluorophenyl) -quinoline-3-carbaldehyde, and the structural formula is as follows:
2. the process according to claim 1, wherein the sulfonium salt compound of formula (III) is obtained by reacting a compound of formula (II) with dimethyl sulfide.
3. The preparation method according to claim 2, wherein the compound of formula (iii) is prepared by adding dimethyl sulfide sulfonium salt to a solvent.
4. The preparation method according to claim 3, wherein the solvent is one or more of dichloromethane, acetonitrile, acetone, butanone and ethyl acetate; preferably, the volume to mass ratio of the solvent to the compound of formula (II) is (1-30) mL/g, more preferably (5-15) mL/g; preferably, the molar ratio of the dimethyl sulfide to the compound of formula (II) is from (1 to 5): 1, more preferably from (2 to 4): 1.
5. The process according to claim 1, wherein the compound of formula (V) is prepared by the epoxidation of a compound of formula (III) by means of a Karaoke reaction with a compound of formula (IV).
6. The process of claim 5, wherein the compound of formula (V) is prepared by adding a compound of formula (III) to a solvent, adding a base at a certain temperature, and then adding a compound of formula (IV) to carry out a Kawasky reaction epoxidation.
7. The method according to claim 6, wherein the solvent is one of dichloromethane, acetonitrile, tetrahydrofuran, C1-C4 aliphatic alcohols, or a mixed solvent thereof with water; preferably, the reaction temperature is-30 ℃ to 30 ℃, more preferably-30 ℃ to 0 ℃; preferably, the base is triethylamine, DIPEA, DBU, alkali metal, alkaline earth metal carbonate, hydride or C1-C6 alkyl alkoxide; preferably, the ratio of the solvent to the compound of formula (III) is (1-50) mL/g, preferably (20-40) mL/g; preferably, the molar ratio of the base used to the compound of formula (III) is from (1 to 10): 1, more preferably from (1 to 5): 1; preferably, the molar ratio of the compound of formula (IV) to the compound of formula (II) is from (0.5 to 3): 1.
8. The process according to claim 1, wherein the compound of formula (V) is prepared by deprotection with an inorganic acid and hydrolysis with an inorganic base.
9. The process according to claim 8, wherein the compound of formula (V) is prepared by adding a mineral acid solution to a solvent to remove isopropylidene groups, adding a mineral base solution to hydrolyze ester groups, adjusting pH, extracting, and concentrating.
10. The preparation method according to claim 9, wherein the solvent is acetonitrile, tetrahydrofuran, methanol, ethanol; preferably, the inorganic acid is hydrochloric acid; preferably, the inorganic base is sodium hydroxide or lithium hydroxide; preferably, the pH is 3 to 6, more preferably 3 to 4; preferably, the extraction solvent is methyl tertiary butyl ether, ethyl acetate, methylene chloride, diethyl ether or toluene; preferably, the ratio of the amount of solvent to the volume mass of the compound of formula (V) is (1-20) mL/g, more preferably (10-15) mL/g; preferably, the molar ratio of the amount of said mineral acid to the compound of formula (V) is from (1 to 1.5): 1; preferably, the molar ratio of the amount of the inorganic base to the compound of formula (V) is from (1 to 3.0): 1.
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