CN109970673B - Preparation method of parecoxib sodium impurity - Google Patents
Preparation method of parecoxib sodium impurity Download PDFInfo
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- CN109970673B CN109970673B CN201711472181.8A CN201711472181A CN109970673B CN 109970673 B CN109970673 B CN 109970673B CN 201711472181 A CN201711472181 A CN 201711472181A CN 109970673 B CN109970673 B CN 109970673B
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- 229960003925 parecoxib sodium Drugs 0.000 title claims abstract description 19
- ICJGKYTXBRDUMV-UHFFFAOYSA-N trichloro(6-trichlorosilylhexyl)silane Chemical compound Cl[Si](Cl)(Cl)CCCCCC[Si](Cl)(Cl)Cl ICJGKYTXBRDUMV-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 239000012535 impurity Substances 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 51
- 238000000034 method Methods 0.000 claims abstract description 34
- 238000006243 chemical reaction Methods 0.000 claims abstract description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 16
- 239000003054 catalyst Substances 0.000 claims description 15
- 238000006069 Suzuki reaction reaction Methods 0.000 claims description 13
- 238000004440 column chromatography Methods 0.000 claims description 13
- 239000003446 ligand Substances 0.000 claims description 13
- 239000002585 base Substances 0.000 claims description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 11
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 claims description 10
- 239000003480 eluent Substances 0.000 claims description 9
- 239000003208 petroleum Substances 0.000 claims description 8
- 239000000243 solution Substances 0.000 claims description 8
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 claims description 8
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 7
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 6
- 239000011574 phosphorus Substances 0.000 claims description 6
- 229910052698 phosphorus Inorganic materials 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 5
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-Bis(diphenylphosphino)propane Substances C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 claims description 4
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical group [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- -1 ketene compound Chemical class 0.000 claims description 3
- 229910052763 palladium Inorganic materials 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims description 3
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 claims description 2
- SDTMFDGELKWGFT-UHFFFAOYSA-N 2-methylpropan-2-olate Chemical compound CC(C)(C)[O-] SDTMFDGELKWGFT-UHFFFAOYSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 2
- 238000005882 aldol condensation reaction Methods 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 238000006880 cross-coupling reaction Methods 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical group C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 230000037029 cross reaction Effects 0.000 claims 7
- 235000010290 biphenyl Nutrition 0.000 claims 1
- 239000004305 biphenyl Substances 0.000 claims 1
- 125000006267 biphenyl group Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 5
- 238000001308 synthesis method Methods 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 4
- 238000010923 batch production Methods 0.000 abstract description 2
- 239000007787 solid Substances 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 238000007125 Buchwald synthesis reaction Methods 0.000 description 7
- 238000001514 detection method Methods 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 102000010907 Cyclooxygenase 2 Human genes 0.000 description 2
- 108010037462 Cyclooxygenase 2 Proteins 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 238000007259 addition reaction Methods 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 238000010812 external standard method Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- ZQNVTVOTCKZKHJ-NSCUHMNNSA-N (e)-4-(4-bromophenyl)but-3-en-2-one Chemical compound CC(=O)\C=C\C1=CC=C(Br)C=C1 ZQNVTVOTCKZKHJ-NSCUHMNNSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- OBXSXZAYKLYTJI-UHFFFAOYSA-N 3-(4-bromophenyl)-5-methyl-1,2-oxazole Chemical compound O1C(C)=CC(C=2C=CC(Br)=CC=2)=N1 OBXSXZAYKLYTJI-UHFFFAOYSA-N 0.000 description 1
- BJYUOXUCQMUZRX-UHFFFAOYSA-N 4-(5-methyl-4-phenyl-1,2-oxazol-3-yl)benzenesulfonamide Chemical compound CC=1ON=C(C=2C=CC(=CC=2)S(N)(=O)=O)C=1C1=CC=CC=C1 BJYUOXUCQMUZRX-UHFFFAOYSA-N 0.000 description 1
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- UXRZLDREKITWRO-UHFFFAOYSA-N P(c1ccccc1)c1ccccc1.CC1(C)c2ccccc2Oc2ccccc12 Chemical compound P(c1ccccc1)c1ccccc1.CC1(C)c2ccccc2Oc2ccccc12 UXRZLDREKITWRO-UHFFFAOYSA-N 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000004550 Postoperative Pain Diseases 0.000 description 1
- 208000005298 acute pain Diseases 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 229940124347 antiarthritic drug Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- KHBQMWCZKVMBLN-IDEBNGHGSA-N benzenesulfonamide Chemical group NS(=O)(=O)[13C]1=[13CH][13CH]=[13CH][13CH]=[13CH]1 KHBQMWCZKVMBLN-IDEBNGHGSA-N 0.000 description 1
- UENWRTRMUIOCKN-UHFFFAOYSA-N benzyl thiol Chemical compound SCC1=CC=CC=C1 UENWRTRMUIOCKN-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000007336 electrophilic substitution reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a preparation method of parecoxib sodium impurity. In the prior art, a synthesis method of a compound PRN073-11 is not mentioned, a small amount of PRN073-11 is generated in the process of preparing a parecoxib sodium bulk drug, and when PRN073-11 used as a standard product is obtained, the PRN073-11 is obtained by adopting a multi-enrichment method. The synthesis method provided by the invention has mild reaction conditions and very simple operation, and the used reagents are conventional reagents, are easy to obtain, are not dangerous and have great application value. Compared with the enrichment method reported in the prior art, the preparation method disclosed by the invention is simpler and more accurate, saves the cost, can realize batch production, and greatly improves the product yield.
Description
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a preparation method of parecoxib sodium impurity.
Background
The parecoxib sodium has a chemical structural formula as follows:
parecoxib sodium is a cyclooxygenase-2 (COX-2) specific inhibitor. Belongs to the field of analgesic of Xibu class in antiarthritic medicine. Can be used for short-term treatment of postoperative pain. Can be clinically used for treating moderate or severe postoperative acute pain.
The synthesis method of parecoxib sodium comprises the following steps:
4- (5-methyl-3-phenylisoxazol-4-yl) benzenesulfonamide (hereinafter referred to as "compound PARE-004") is an important intermediate for preparing parecoxib sodium, and the position isomer impurity 4- (5-methyl l-4-phenylisoxazol-3-yl) benzenesulfonamide (hereinafter referred to as "PRN 073-11") is an impurity which needs to be focused in the parecoxib sodium quality standard, and has great significance for relevant research on the parecoxib sodium.
The structural formula of the parecoxib sodium impurity PRN073-11 is as follows:
the quality control of the medicine mainly comprises controlling the content of active ingredients and related substances, particularly the content of the related substances needs to meet the requirement of medical use. The substances of interest may also be referred to as impurities, which originate mainly from the preparation of the active ingredient and are produced in the degradation of the drug. The technical guidelines for the study of impurities in chemical drugs ([ H ] GPH3-1, pages 6-7) indicate that: the detection of organic impurities is generally carried out by HPLC. If the HPLC method is adopted, a peak area method is required, and an external standard method (impurity reference substance method) is adopted as a specific quantitative method, so that the external standard method is relatively accurate in quantification. However, in the existing HPLC analysis method, if no reference substance exists, the structure of the impurity with the content of less than 0.1 percent is difficult to confirm.
In the prior art, the compound PRN073-11 is generally obtained by an enrichment method, and in the prior art, a simple and efficient method for obtaining the compound PRN073-11 is not available. The main reasons are as follows:
in the process of carrying out the sulfoamination reaction on the compound PARE-013, the main products obtained by the electronic effect are the compound PARE-004 and the compound PARE-014, and only a very small amount of the compound PRN073-11 is obtained. Specifically, the first sulfonyl chloride (amine) reaction of an aromatic ring is an electrophilic substitution reaction, and the more electron-rich positions on the aromatic ring are more easily converted to sulfonyl chloride (amine). In the compound PARE-013, the A ring linked to the isoxazole is electron-rich as a whole and the B ring is electron-poor due to conjugation. Therefore, the sulfonyl chloride (amine) reaction basically only occurs in the ring A under the condition that the reaction conditions are not severe; if the reaction conditions are severe, the sulfonyl chloride (amine) reaction also occurs preferentially at the A ring and then at the B ring, so that it is difficult to prepare the compound PRN073-11 by this method.
Therefore, the preparation method of the parecoxib sodium impurity compound PRN073-11 needs to be improved so as to improve the synthesis efficiency.
Disclosure of Invention
The invention provides a synthesis method for simply, conveniently and efficiently preparing a high-purity parecoxib sodium impurity compound PRN073-11, which is not mentioned in the prior art.
The invention firstly fixes the position of the benzene sulfonamide on the oxazole ring, and then introduces the benzene ring on the alpha position of the methyl, the reaction process is simple and clear, and the used reagents are all common reagents.
The structural formula of an intermediate PARE-004 for preparing the parecoxib sodium is as follows:
the structural formula of the parecoxib sodium impurity PRN073-11 is as follows:
the invention is realized by the following technical scheme:
the preparation method of the parecoxib sodium impurity comprises the following steps:
1) performing Buchwald cross-coupling reaction on a compound PRN073-11-102 and a compound PRN073-11-003 to obtain a compound PRN 073-11-103;
2) performing sulphonylation reaction on the compound PRN073-11-103 prepared in the step 1), NCS and ammonia water to obtain a compound PRN 073-11-104;
3) performing addition reaction on the compound PRN073-11-104 prepared in the step 2) and NBS to obtain bromide PRN 073-11-105;
4) and 3) carrying out Suzuki reaction on the prepared compound PRN073-11-105 and phenylboronic acid to obtain a compound PRN 073-11.
In the step 1), the step (A) is carried out,
according to the invention, the Buchwald reaction temperature is 70-120 ℃, preferably 100-120 ℃, and further preferably 110 ℃.
According to the present invention, the Buchwald reaction is carried out in a solvent, and preferred reaction solvents include solvents such as toluene, dioxane, xylene, tetrahydrofuran, DMF, NMP, DMSO, etc., and further preferred is toluene.
According to the invention, the Buchwald reaction is carried out in the presence of a catalyst; the catalyst is a palladium-phosphorus complex, such as tetrakis (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium (Pd)2(dba)3) Etc., preferably tris (dibenzylideneacetone) dipalladium.
According to the invention, the Buchwald reaction is carried out in the presence of a base; the base is selected from sodium bis (trimethylsilyl) amide, tert-butoxide, DIEA, or the like, preferably DIEA.
According to the invention, the Buchwald reaction is carried out in the presence of a ligand; the ligand is selected from, for example, Xantphos (4, 5-bis diphenylphosphine-9, 9-dimethylxanthene) and the like.
According to the invention, the molar ratio of PRN073-11-102, compound PRN073-11-003, catalyst, ligand and base is 1 (1-3) to (0.01-0.1) to (0.05-0.5) to (1.5-2.5), for example 1:2:0.05:0.1: 1.9; according to the invention, the Buchwald reaction time can be 8-12 hours, for example 10 hours.
Optionally, the product obtained after the completion of the Buchwald reaction is purified, for example, by separating it using column chromatography, preferably using petroleum ether and ethyl acetate as eluents for the column chromatography; the volume ratio of the eluent petroleum ether to the ethyl acetate is (40-100): 1, preferably (50-70): 1, more preferably 60: 1.
in the step 2), the step (c) is carried out,
according to the present invention, the molar ratio of the compound PRN073-11-103 to NCS is 1 (1-5), preferably 1 (2-4), and more preferably 1: 3.
According to the invention, the sulphation reaction temperature is 5-35 ℃, for example 20-55 ℃; the reaction time is 4-12 hours.
According to the invention, the amount of ammonia is determined by the pH of the reaction solution, and the amount of ammonia is not more than such that the pH of the reaction solution is > 8. According to the invention, in the process of adding ammonia water, the temperature of the reaction liquid is controlled within the range of 15-20 ℃.
Optionally, the product obtained after the sulphonylation reaction is completed is purified, for example by isolating it using column chromatography, preferably using dichloromethane and methanol as eluent; the volume ratio of the dichloromethane to the methanol is (20-60): 1, preferably (20-40): 1, and more preferably 30: 1.
In the step 3), the step (c),
according to the invention, the molar ratio of the compound PRN073-11-104 to NBS is 1 (2-4), preferably 1: 3.
According to the invention, the temperature of the addition reaction is 15-35 ℃, preferably 25 ℃.
In the step 4), the step of mixing the raw materials,
according to the invention, the Suzuki reaction is carried out in a solvent, such as toluene, DMF, dioxane, or the like, which is inert to the Suzuki reaction, preferably dioxane.
According to the invention, a proper amount of water can be added into the reaction solution as a cosolvent, and the volume ratio of the solvent to the cosolvent water is (5-15): 1, preferably 10: 1.
According to the invention, the molar ratio of the compound PRN073-11-105 to the phenylboronic acid is 1 (1-5), preferably 1 (2-4), and more preferably 1: 3.
According to the invention, the Suzuki reaction is carried out in the presence of a catalyst, which may be Pd (OAc)2And the like.
According to the invention, phosphorus ligands can also be used in the Suzuki reaction, for example Ph2P(CH2)2PPh2(dppe)、Ph2P(CH2)3PPh2(dppp) or tricyclohexylphosphine.
According to the invention, the Suzuki reaction is carried out in the presence of a base selected from Ba (OH)2、Na2CO3、K2CO3Or CsCO3Etc., preferably CsCO3。
According to the invention, the molar ratio of the compound PRN073-11-105, the palladium catalyst, the phosphorus ligand and the alkali is 1 (0.05-0.5) to (2-4), preferably 1:0.1:0.2: 3.
According to the invention, the Suzuki reaction time is 0.5-24 hours, and the reaction temperature is 50-150 ℃.
Optionally, the product obtained after the Suzuki reaction is completed is purified, for example, the product is separated by column chromatography, and the eluent used for the column chromatography is preferably petroleum ether and ethyl acetate; the volume ratio of the petroleum ether to the ethyl acetate is (2-8): 1, preferably (3-5): 1, and more preferably 4: 1.
Preferably, the compound PRN073-11-102 used in step 1) is prepared by the following method:
1a) performing Claisen-Schmidt reaction on a compound PRN073-11-001 and acetone, and condensing to obtain an ketene compound PRN 073-11-101;
1b) performing a ring closing reaction on the compound PRN073-11-101 obtained in the step 1a) and the compound PRN073-10-01 to obtain a compound PRN 073-11-102.
The invention has the advantages of
1) In the prior art, a synthesis method of a compound PRN073-11 is not mentioned, wherein a small amount of PRN073-11 serving as an impurity is generated in the process of preparing a parecoxib sodium bulk drug, and when PRN073-11 serving as a standard substance is obtained, the PRN073-11 can be obtained by adopting a multi-time enrichment method. The method for synthesizing the compound PRN073-11 provided by the invention has the advantages of mild reaction conditions, simple operation, easy obtainment of all used reagents, no danger and great application value.
2) Compared with the enrichment method reported in the prior art, the preparation method disclosed by the invention is simpler and more accurate, saves the cost, can realize batch production, and greatly improves the product yield.
Detailed Description
The technical solution of the present invention will be further described in detail with reference to specific embodiments. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.
Example 1
In this example, PRN073-11-101 was prepared from PRN073-11-001, and PRN073-11-102 was prepared as a starting compound from PRN 073-11-101. The compound PRN073-11 is prepared from a compound PRN073-11-001 through multiple steps, and the specific reaction steps are as follows:
preparation of (E) -4- (4-bromophenyl) but-3-en-2-one
PRN073-11-001(200g,1.087mol,1.0eq.), acetone (252.2g,4.348mmol,4.0eq.), pure water (252.2 g), a 2L three-necked flask were added, stirred, the solid was insoluble and clear, 1% sodium hydroxide aqueous solution (250mL) was added dropwise, and after dropping, the temperature was raised to 65 ℃ for reaction for 2 hours. TLC detection (developing solvent: PE/EA: 5/1, R)f0.6), the reaction was complete, the reaction was stopped and allowed to cool to room temperature. EA (500mL) was added, the mixture was stirred and separated, and the organic phase was washed with saturated brine (300 mL. times.2), dried, and concentrated to constant weight. The residue was slurried with methyl tert-butyl ether (30mL), PE (200mL) stirred, filtered under suction, and the filter cake was rinsed with PE (20mL) to give a yellow solid, i.e., PRN073-11-101(174g, 72% yield).
Preparation of 3- (4-bromophenyl) -5-methylisoxazole
PRN073-11-101(50g,223.25mmol,1.0eq.) and methanol (625mL) are added into a 2L three-necked bottle, stirred, solid insoluble clear is added, PRN073-10-01(83.5g,446.5mmol,2.5eq.) is added, stirred, solid insoluble clear is added, potassium carbonate (123.25g,893mmol,4.0eq.) solution dissolved in water (125mL) is dropwise added, after dropwise addition, solid soluble clear (a small amount of white crystals are separated out), the temperature is raised to reflux, and reaction is carried out for 14 h. TLC detection (developing solvent: PE/EA: 15/1, R)f0.4), the reaction was stopped and the temperature was reduced to room temperature. EA (1000mL) and pure water (500mL) were added thereto, followed by stirring and liquid separation, and the organic phase was washed with saturated brine (300 mL. times.2), dried and concentrated to a constant weight. Column chromatography was performed and the residue was taken up in DCM (10mL) and taken up on a dry column, eluted with PE/EA, and the product was washed with PE/EA 90/1 and concentrated (water bath temperature < 40 ℃) to give PRN073-11-102 as a yellow solid (17g, 30.7% yield).
Preparation of 3- (4- (benzylthio) phenyl) -5-methylisoxazole
PRN073-11-102(24g,101.2mmol,1.0eq.), toluene (200mL.), benzylmercaptan (12.58g,202.4mmol,2.0eq.), and Pd were taken2(dba)3(4.632g,5.06mmol,0.05eq.), DIEA (32.2mL,1.9eq.), and Xantphos (5.86g,10.12mmol,0.1eq.) were added to a 2L three-necked flask, stirred, warmed to reflux under argon, and reacted under reflux for 10 h. TLC detection (developing solvent: PE/EA: 15/1, R)f0.2), the raw materials react completelyThe reaction was stopped and cooled to room temperature. DCM (1000mL) and pure water (500mL) were added, the mixture was stirred and separated, and the organic phase was washed with saturated brine (500 mL. times.2), dried, and concentrated to constant weight. Column chromatography was performed, the residue was dissolved in DCM (30mL), dry loaded, PE/EA eluted, the product was washed with PE/EA 60/1 (with tailing and increasing polarity as appropriate) and concentrated to give PRN073-11-103 as a yellow solid (27g, 94.9% yield).
4.4 preparation of 4- (5-methylisoxazol-3-yl) benzenesulfonamide
A1L three-necked flask was charged with PRN073-11-103(24g,85.44mmol,1.0eq.) and acetic acid (150mL), stirred to dissolve the solid, and then purified water (50mL) was added thereto, followed by stirring to precipitate a solid, and NCS (34.22g,256.32mmol,3.0eq.) was added thereto, followed by stirring at room temperature to react for 8 hours. TLC detection (derivatization with ammonia water, EA extraction) (developing solvent: PE/EA: 10/1, R)f0.5), the starting material was completely reacted.
Slowly dropping the reaction solution into ammonia water, controlling the temperature to be lower than 15-20 ℃, stirring at room temperature for 1-2 h, keeping the pH value to be more than 8, and detecting by TLC (developing agent: PE/EA is 10/1, R)f0.5), the reaction of the starting materials was completed and the reaction was stopped. EA (300mL) was added, the mixture was stirred and separated, the organic phase was washed with saturated brine (100 mL. times.2), dried, concentrated to a small amount of solvent, and a solid precipitated, which was filtered with suction to give a white solid (16g), i.e., PRN 073-11-104. The filtrate was concentrated to constant weight. Column chromatography was performed and the residue was taken up in DCM (10mL), dried, loaded with DCM/MeOH and the product was washed with DCM/MeOH 30/1 and concentrated to give a yellow solid, PRN073-11-104 (2g, 88.5% yield).
Preparation of 4- (4-bromo-5-methylisoxazol-3-yl) benzenesulfonamide
PRN073-11-105(5g,21mmol,1.0eq.) and DMF (50mL) were taken and added to a 250mL three-necked flask, stirred until clear, NBS (11.22g,63mmol,3.0eq.) was added in portions, stirred at room temperature and reacted for 4.5 h. TLC detection (developing solvent: DCM/MeOH-15/1, R)f0.4), the reaction of the starting materials was completed and the reaction was stopped. The reaction mixture was poured into ice water (300mL) to precipitate a solid, which was stirred for 1h and filtered under suction to give a pale yellow solid, i.e., PRN073-11-105(1.7g, 25.6% yield).
Preparation of 4- (5-methyl-4-phenylisoxazol-3-yl) benzenesulfonamide
PRN073-11-105(1.5g,4.75mmol,1.0eq.) and dioxane (30mL.) were added to a 250mL single-neck flask under argon, followed by pure water (3mL), cesium carbonate (4.64g,14.24mmol,3.0eq.), phenylboronic acid (1.74g,14.24mmol,3.0eq.), stirred to clear, tricyclohexylphosphine (266.38mg,0.95mmol,0.2eq.), Pd (OAc)2(106.4mg,0.475mmol,0.1eq.), stirred, heated to 100 ℃ and reacted for 5.5 h. TLC detection (developing solvent: PE/EA: 3/1, R)f0.3) (several times of development), the starting material was completely reacted, the reaction was stopped, and the temperature was lowered to room temperature. EA (100mL) and pure water (50mL) were added thereto, followed by stirring and liquid separation, and the organic phase was washed with saturated brine (50 mL. times.2), dried and concentrated to a constant weight. Purifying by column chromatography, dissolving the residue in DCM (10mL), loading by dry method, eluting with PE/EA, washing the product with PE/EA 4/1, and concentrating to obtain white solid. Isopropyl ether (4mL) was added and slurried, followed by suction filtration to give PRN073-11 as a white solid (1.0g, 67% yield).
LCMS(ES+)：m/z[M+H]+：315.14。1H-NMR(400MHz，DMSO)δ：7.84～7.86(d,J＝8.8Hz,2H),7.56～7.59(d,J＝8.4Hz,2H),2.49(s,3H),7.38～7.40(t,J＝3.6Hz,2H),7.14～7.16(m,2H),4.93(s,2H),2.47(s,3H)。
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (19)
1. The preparation method of the parecoxib sodium impurity compound PRN073-11 comprises the following steps:
1) performing Buchwald cross-coupling reaction on a compound PRN073-11-102 and a compound PRN073-11-003 to obtain a compound PRN 073-11-103;
2) performing sulphonylation reaction on the compound PRN073-11-103 prepared in the step 1), NCS and ammonia water to obtain a compound PRN 073-11-104;
3) performing substitution reaction on the compound PRN073-11-104 prepared in the step 2) and NBS to obtain bromide PRN 073-11-105;
4) and 3) carrying out Suzuki reaction on the prepared compound PRN073-11-105 and phenylboronic acid to obtain a compound PRN 073-11.
2. The process according to claim 1, wherein in step 1), the Buchwald cross-reaction is carried out in the presence of a catalyst; the catalyst is a palladium-phosphorus complex.
3. The process according to claim 1, wherein in step 1), the Buchwald cross-reaction is carried out in the presence of a base; the base is selected from sodium bis (trimethylsilyl) amide, tert-butoxide, or DIEA.
4. The process according to claim 1, wherein in step 1), the Buchwald cross-reaction is carried out in the presence of a ligand; the ligand is selected from Xantphos (4, 5-bis diphenylphosphine-9, 9-dimethyl xanthene).
5. The method of claim 1 wherein the molar ratio of PRN073-11-102, PRN073-11-003, catalyst, ligand, and base is 1 (1-3) to 0.01-0.1 (0.05-0.5) to 1.5-2.5.
6. The production method according to any one of claims 1 to 5, wherein in step 1), the Buchwald cross reaction is carried out in the presence of a catalyst; the catalyst is tris (dibenzylideneacetone) dipalladium;
the Buchwald cross reaction is carried out in the presence of a base; the alkali is DIEA;
the Buchwald cross reaction is carried out in the presence of a ligand; the ligand is Xantphos (4, 5-bis diphenyl phosphine-9, 9-dimethyl xanthene);
the molar ratio of PRN073-11-102, compound PRN073-11-003, catalyst, ligand, and base is 1:2:0.05:0.1: 1.9.
7. The preparation method of claim 1, wherein in step 1), the product is separated by column chromatography after the Buchwald cross reaction is completed, and eluents used in the column chromatography are petroleum ether and ethyl acetate;
the volume ratio of the eluent petroleum ether to the ethyl acetate is (40-100): 1.
8. the method according to claim 1, wherein in step 2), the molar ratio of the compound PRN073-11-103 to NCS is 1 (1-5).
9. The method according to claim 1, wherein the aqueous ammonia is used in an amount such that the reaction solution has a pH of >8 in step 2).
10. The method according to claim 9, wherein in the step 2), the temperature of the reaction solution is controlled within a range of 15 to 20 ℃ during the addition of the aqueous ammonia.
11. The preparation method according to any one of claims 8 to 10, wherein in step 2), the product is separated by column chromatography using dichloromethane and methanol as eluent after the completion of the sulphation reaction;
the volume ratio of the dichloromethane to the methanol is (20-60): 1.
12. The method according to claim 1, wherein in step 3), the molar ratio of PRN073-11-104 to NBS is 1 (2-4).
13. The method according to claim 1, wherein in step 4), the molar ratio of the compound PRN073-11-105 to the phenylboronic acid is 1 (1-5).
14. The method according to claim 1, wherein the Suzuki reaction is carried out in the presence of a catalyst in step 4), wherein the catalyst is Pd (OAc)2A palladium catalyst.
15. The method of claim 1, wherein in step 4), the Suzuki reaction is further performed using a phosphorus ligand Ph2P(CH2)2PPh2(dppe)、Ph2P(CH2)3PPh2(dppp) or tricyclohexylphosphine.
16. The method of claim 1, wherein in step 4), the Suzuki reaction is carried out in the presence of a base selected from Ba (OH)2、Na2CO3、K2CO3Or Cs2CO3。
17. The method of any of claims 14-16, wherein the molar ratio of PRN073-11-105, palladium catalyst, phosphorus ligand, and base is 1 (0.05-0.5) to (2-4).
18. The method of claim 17, wherein in step 4), the product is separated by column chromatography using petroleum ether and ethyl acetate as eluents after the completion of the Suzuki reaction;
the volume ratio of the eluent petroleum ether to the ethyl acetate is (2-8) to 1.
19. The method of claim 1, wherein the compound PRN073-11-102 used in step 1) is prepared by:
1a) performing Claisen-Schmidt reaction on a compound PRN073-11-001 and acetone, and condensing to obtain an ketene compound PRN 073-11-101;
1b) performing a ring closing reaction on the compound PRN073-11-101 obtained in the step 1a) and the compound PRN073-10-01 to obtain a compound PRN 073-11-102.
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| WO2012170752A1 (en) * | 2011-06-10 | 2012-12-13 | Glaxo Wellcome Manufacturing Pte Ltd | Novel compounds |
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