CN109134395A - The synthetic method of Parecoxib Sodium Isomeric impurities - Google Patents
The synthetic method of Parecoxib Sodium Isomeric impurities Download PDFInfo
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- CN109134395A CN109134395A CN201811115517.XA CN201811115517A CN109134395A CN 109134395 A CN109134395 A CN 109134395A CN 201811115517 A CN201811115517 A CN 201811115517A CN 109134395 A CN109134395 A CN 109134395A
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- 239000012535 impurity Substances 0.000 title claims abstract description 23
- 238000010189 synthetic method Methods 0.000 title claims abstract description 22
- 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
- 238000006243 chemical reaction Methods 0.000 claims abstract description 99
- 150000001875 compounds Chemical class 0.000 claims abstract description 85
- 239000003513 alkali Substances 0.000 claims abstract description 23
- 238000004519 manufacturing process Methods 0.000 claims abstract description 16
- 238000005917 acylation reaction Methods 0.000 claims abstract description 5
- 238000006722 reduction reaction Methods 0.000 claims abstract description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 3
- 238000006467 substitution reaction Methods 0.000 claims abstract description 3
- 230000006103 sulfonylation Effects 0.000 claims abstract description 3
- 238000005694 sulfonylation reaction Methods 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 34
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 33
- -1 J-1 compound Chemical class 0.000 claims description 32
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 16
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 12
- 150000001989 diazonium salts Chemical class 0.000 claims description 12
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 238000005660 chlorination reaction Methods 0.000 claims description 8
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 229910052763 palladium Inorganic materials 0.000 claims description 6
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 5
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- 235000010288 sodium nitrite Nutrition 0.000 claims description 3
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 229910005948 SO2Cl Inorganic materials 0.000 claims description 2
- 229910006074 SO2NH2 Inorganic materials 0.000 claims description 2
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 claims description 2
- 239000003638 chemical reducing agent Substances 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 125000000565 sulfonamide group Chemical group 0.000 claims description 2
- QUTGXAIWZAMYEM-UHFFFAOYSA-N 2-cyclopentyloxyethanamine Chemical compound NCCOC1CCCC1 QUTGXAIWZAMYEM-UHFFFAOYSA-N 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 87
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- 230000015572 biosynthetic process Effects 0.000 description 36
- 238000003786 synthesis reaction Methods 0.000 description 36
- 239000000243 solution Substances 0.000 description 31
- 239000007787 solid Substances 0.000 description 29
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- 238000003756 stirring Methods 0.000 description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 24
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 18
- 239000012074 organic phase Substances 0.000 description 18
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 238000001914 filtration Methods 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 239000003208 petroleum Substances 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 229910021529 ammonia Inorganic materials 0.000 description 8
- 239000012954 diazonium Substances 0.000 description 8
- 238000006073 displacement reaction Methods 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 8
- 239000005457 ice water Substances 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000012141 concentrate Substances 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 4
- 102000010907 Cyclooxygenase 2 Human genes 0.000 description 4
- 108010037462 Cyclooxygenase 2 Proteins 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 230000003111 delayed effect Effects 0.000 description 4
- 238000003810 ethyl acetate extraction Methods 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 150000002431 hydrogen Chemical class 0.000 description 4
- TZRHLKRLEZJVIJ-UHFFFAOYSA-N parecoxib Chemical compound C1=CC(S(=O)(=O)NC(=O)CC)=CC=C1C1=C(C)ON=C1C1=CC=CC=C1 TZRHLKRLEZJVIJ-UHFFFAOYSA-N 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 238000004064 recycling Methods 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- PNDVLJQMORRYJM-UHFFFAOYSA-M sodium;acetic acid;nitrite Chemical compound [Na+].ON=O.CC([O-])=O PNDVLJQMORRYJM-UHFFFAOYSA-M 0.000 description 4
- 239000001119 stannous chloride Substances 0.000 description 4
- 235000011150 stannous chloride Nutrition 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 101710128782 Liver carboxylesterase Proteins 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 230000000146 antalgic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 208000008784 apnea Diseases 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 229940111134 coxibs Drugs 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 229960004662 parecoxib Drugs 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- 239000004317 sodium nitrate Substances 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 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
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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a kind of synthetic method of Parecoxib Sodium Isomeric impurities; the structure of the Parecoxib Sodium Isomeric impurities is as shown in formula one and formula two; the synthetic method includes that I compound represented of formula with formula II or III compound represented of formula reacts IV compound represented of production in the presence of alkali; corresponding Parecoxib Sodium Isomeric impurities are generated by reduction reaction, diazotising, sulfonylation, amino substitution reaction and acylation reaction; overall yield of reaction is higher than 22%; target product purity is greater than 99%
Description
Technical field
The invention belongs to SC 69124 sodium impurities to synthesize field, in particular to a kind of synthesis of Parecoxib Sodium Isomeric impurities
Method.
Background technique
SC 69124 (Parecoxib) is the novel non_steroidal anti_inflammatory drug of one kind of Pfizer Inc.'s listing
(NSAID), a kind of highly selective COX-2 inhibitors can be hydrolyzed into rapidly by liver carboxy-lesterase after intravenous injection and cut down ground
Former times cloth inhibits cyclooxygenase-2 (COX-2) that arachidonic acid synthesis prostaglandin is blocked to play anti-inflammatory and antalgic by specificity
Effect.It is to 28000 times that the inhibiting effect of COX-2 is Cycloxygenase -1 (COX-1).Due to its selective depression COX-2, greatly
Reduce gastrointestinal side effect, and the adverse reaction that apnea inhibits greatly, is widely used in Postoperative Analgesia After in recent years.
Parecoxib Sodium structural formula is as follows:
When being synthetically prepared Parecoxib Sodium bulk pharmaceutical chemicals, find its there are position Isomeric impurities, to these impurity without
Control will seriously affect Drug safety and validity.Wherein there is the synthesis of 7 position Isomeric impurities to there is no in the whole world any
Reported in literature is impurity J, O, L, Q, K, N, R respectively, and structural formula is as follows:
Summary of the invention
For overcome the deficiencies in the prior art, the present invention provides a kind of method for synthesizing Parecoxib Sodium Isomeric impurities.
Specific technical solution of the present invention is as follows:
The present invention provides a kind of synthetic method of Parecoxib Sodium Isomeric impurities, wherein Parecoxib Sodium Isomeric impurities
As shown in formula one and formula two, the synthetic method includes the following steps: structure
1): I compound represented of formula reacts IV institute of production with formula II or III compound represented of formula in the presence of alkali
The compound shown；
2): IV compound represented of formula is through V compound represented of reduction reaction production；
3): V compound represented of formula passes through VI compound represented of diazotising and sulfonylation production；
4): VI compound represented of formula is by Parecoxib Sodium Isomeric impurities shown in amino substitution reaction production one；
5): compound described in formula one by occurring SC 69124 shown in acylation reaction production two under alkaline condition
Sodium Isomeric impurities；
Reaction equation is as follows:
Wherein, R1And R2It is not simultaneously H and NO2, R3 and R4 are not H and NH simultaneously2, R5And R6It is not simultaneously H and SO2Cl, R7
And R8It is not simultaneously H and SO2NH2, R9It is not simultaneously C with R2H5CONHSO2。
Further to improve, the synthetic method of I compound represented of formula includes the following steps:
11) compound described in X-1 and hydroxylamine hydrochloride generate X-2 compound represented in the presence of alkali；
12) X-2 compound represented I compound represented of production after chlorination；
Reaction equation is as follows:
Further to improve, the synthetic method of II compound represented of formula is as follows:
J-1 compound represented and acetic anhydride II compound represented of production in the presence of alkali；
Reaction equation is as follows:
It is as follows by reacting Parecoxib Sodium Isomeric impurities shown in the formula one and formula two of preparation above:
Further to improve, the alkali is sodium ethoxide or triethylamine, shown in I compound represented of formula, formula II or formula III
The molar ratio of compound and alkali is 1.05-1.1:1:0.2-0.5.
Further to improve, reducing agent used in step 2) reduction reaction is the palladium carbon that palladium mass fraction is 5%, shown in formula IV
Compound and palladium carbon mass ratio be 1:0.1-0.08.
Further to improve, diazotising specific method described in step 3) is V compound represented of formula and concentrated hydrochloric acid and Asia
Sodium nitrate generates diazonium compound, and diazonium compound reacts VI compound represented of production with sulfide, copper chloride.
Further to improve, V compound represented, sodium nitrite and the cuprous molar ratio of chlorine are 1:1.01-1.03:
0.022-0.024。
Further to improve, the acylating reagent of the step 5) acylation reaction is propionyl chloride, and alkali used is triethylamine, formula one
The molar ratio of the compound, propionyl chloride and alkali is 1:1.3-1.5:1.3-1.5.
Further to improve, the molar ratio of X-1 compound represented, hydroxylamine hydrochloride and alkali is 1:1.03-1.05:2.1-
2.2, the alkali is sodium bicarbonate；Preferably, the chlorination reagent of chlorination is N- chlorosuccinimide, is changed shown in X-2
The molar ratio for closing object and chlorination reagent is 1:1.08-1.1.
Further to improve, the molar ratio of J-1 compound represented, acetic anhydride and alkali is 1:5:0.6, and the alkali is N- first
Base imidazoles
Parecoxib Sodium Isomeric impurities yield made from the synthetic method of Parecoxib Sodium Isomeric impurities provided by the invention
Height, overall yield of reaction is greater than 22%, and purity is greater than 99%.
Specific embodiment
The synthesis of 1 2- of embodiment (5- methyl -3- phenyl -4- isoxazolyl) benzsulfamide (compound shown in formula J)
S1: the synthesis of II compound represented of formula
Reaction equation is as follows:
Feed ratio:
Technical process:
18.1g J-1 compound represented, 51g acetic anhydride and 4.92g N- methylimidazole, room temperature are added into reaction flask
6h is reacted, after monitoring fully reacting, reaction solution is cooled to 0 DEG C, 100mL water is added and stirs 1.5h, is extracted with dichloromethane three
It is secondary, merge organic phase, organic phase is successively respectively washed twice with saturated sodium bicarbonate aqueous solution, water and sodium-chloride water solution, anhydrous
Sodium sulphate dries, filters, and filtrate concentration is spin-dried for after petroleum ether is added in concentrate, obtains 14.46g solid, yield 80.8%.
The synthesis of S2:J-2 compound represented
Reaction equation is as follows:
Feed ratio:
Technical process:
10.6g benzaldehyde is dissolved in 100mL methanol, 7.245g hydroxylamine hydrochloride and 23.32g are dissolved in 15mL water and formed
Aqueous solution is added in reaction solution, after 30 DEG C of reaction 2h, removes methanol under reduced pressure, 100mL water is added, and three times with ether extraction, merges
Organic phase, saturated common salt are washed twice, and anhydrous sodium sulfate dries, filters, filtrate concentration, dry, obtain 10.24g solid, yield
84.6%.
The synthesis of S3:J-3 compound represented
Reaction equation is as follows:
Feed ratio:
Technical process:
12.1g J-2 compound represented is dissolved in 120mL DMF, 14.63g NCS is added portionwise at 5 DEG C, adds
To finish, 35 DEG C of reaction 6h, after completion of the reaction, remove DMF under reduced pressure, water stirring is added, methylene chloride extracts three times, merge organic phase,
Organic phase washed with water and saturated common salt washing, anhydrous sodium sulfate dry, filter, and are concentrated, obtain 13.26g solid, yield
85.5%.The synthesis of S4:J-4 compound represented
Reaction equation is as follows:
Feed ratio:
Technical process:
17.05g J-3, II compound represented of 17.9g formula and 1.36g sodium ethoxide are added in 200mL tetrahydrofuran,
It is passed through nitrogen, is poured into ice water after completion of the reaction in 70 DEG C of reaction 3h, aqueous layer with ethyl acetate extraction, anhydrous sodium sulfate is done
Dry, concentration is chromatographed with petroleum ether and ethyl acetate (10:3) column, obtains 21.5g white solid, yield 76.8%.
The synthesis of S5:J-5 compound represented
Reaction equation is as follows:
Feed ratio:
Technical process:
28g J-4 compound represented and 300mL methanol are added in hydrogen reaction kettle, 2.8g is added after nitrogen displacement
The palladium carbon that palladium mass percent is 5%, is passed through hydrogen, reacts in 80 DEG C, after reaction, palladium carbon recycling is recovered by filtration,
Filtrate concentration, it is dry, obtain 23.31g solid, yield 93.2%.
The synthesis of S6:J-6 compound represented
Reaction equation is as follows:
Feed ratio:
Technical process:
25g J-5 compound represented and 50mL concentrated hydrochloric acid are sequentially added into reaction flask, 0 DEG C is cooled under stirring, are delayed
The slow 300mL that is added contains 6.969g NaNO2Acetic acid, 0 DEG C of temperature control, finish, react 1h after, obtain diazonium salt solution；By 50mL
Toluene is cooled to 0 DEG C, and 10mL acetic acid is added in storage temperature, and 10 DEG C of temperature control are passed through sulfur dioxide gas to being saturated, and 0.2948g is added
Stannous chloride, stirring, obtains sulfur dioxide solution；Diazonium salt solution is slowly added dropwise into sulfur dioxide solution, control reaction
Temperature is 0 DEG C, after completion of the reaction, removes acetic acid, and water layer is extracted with dichloromethane three times, merges organic phase, is concentrated, dry, is obtained
25.04g white solid, yield 75.2%.
The synthesis of S7:2- (5- methyl -3- phenyl -4- isoxazolyl) benzsulfamide (J compound represented)
Reaction equation is as follows:
Feed ratio:
Technical process:
Under ice-water bath, 50mL methylene chloride, stirring are added into reaction flask, system vacuumizes displacement ammonia, is at
33.3g J-6 compound represented is dissolved in 250mL methylene chloride by the ammonia environment of 1.5 atmospheric pressure, then instills reaction
It in bottle, is stirred to react, after fully reacting, methylene chloride is evaporated off, 37% aqueous hydrochloric acid solution 100mL is added dropwise into reaction flask, stir,
Crystallization, filtering, filter cake is dissolved in 200mL methylene chloride, wash the pH to 7 of organic layer with 10% sodium carbonate liquor, then with water with
Saturated sodium chloride solution respectively washes twice, and anhydrous sodium sulfate dries, filters, and is concentrated to give 28.17g white solid, yield 89.7%,
Purity 99.5%.
1H NMR(400MHz,d6- DMSO): δ 2.33 (s, 3H), 7.26 (m, 2H), 7.28 (m, 1H), 7.32 (m, 1H),
7.37 (m, 2H), 7.51 (s, 2H), 7.60 (td, J=7.2Hz, J=1.2Hz, 1H), 7.65 (td, J=7.2Hz, J=
1.2Hz, 1H), 8.04 (d, J=7.6Hz, 1H)
Embodiment 2N- [[2- (5- methyl -3- phenyl -4- isoxazolyl) phenyl] sulfonyl] propionamide (chemical combination shown in O
Object) synthesis
Reaction equation is as follows:
Feed ratio:
Technical process:
300mL methylene chloride is added into reaction flask, ice bath is cooled to 0 DEG C, be added 31.4g J compound represented,
13.8g propionyl chloride and 15.15g triethylamine react at room temperature 1h, monitor fully reacting, and the stirring of 300mL water is added, separates organic layer,
It is successively respectively washed twice with water and saturated common salt water washing, anhydrous sodium sulfate is dry, concentration, concentrate ethyl acetate and petroleum
Ether (2:5) recrystallization, crosses liquation crystalline substance, filtering, and filtration cakes torrefaction obtains 33.8g white solid, yield 91.2%, purity 99.2%.
1H NMR(400MHz,d6- DMSO): δ 0.68 (t, J=7.6Hz, 3H), 1.97 (m, 1H), 1.61 (m, 1H), 2.19
(s, 3H), 7.27 (m, 2H), 7.31 (m, 1H), 7.34 (m, 2H), 7.45 (dd, J=7.6Hz, J=1.2Hz, 1H), 7.74
(td, J=7.6Hz, J=1.2Hz, 1H), 7.78 (td, J=7.6Hz, J=1.2Hz, 1H), 8.18 (dd, J=7.6Hz, J=
1.2Hz,1H),11.86(s,1H).
The synthesis of 3 2- of embodiment (5- methyl 4-phenyl -3- isoxazolyl) benzsulfamide (compound shown in formula L)
The synthesis of S1:Q-2 compound represented
Reaction equation is as follows:
Feed ratio:
Technical process:
15.1g Q-1 compound represented is dissolved in 200mL methanol, 71.07g hydroxylamine hydrochloride and 22.26g are dissolved in
Aqueous solution is formed in 20mL water to be added in reaction solution, after 35 DEG C of reaction 2h, removes methanol under reduced pressure, 200mL water is added, is extracted with ether
It taking three times, merges organic phase, saturated common salt is washed twice, and anhydrous sodium sulfate dries, filters, filtrate concentration, and it is dry, obtain 14.08g
Solid, yield 84.8%.
The synthesis of S2:Q-3 compound represented
Reaction equation is as follows:
Feed ratio:
Technical process:
16.6g Q-2 compound represented is dissolved in 200mL DMF, 14.63g NCS is added portionwise at 0 DEG C, adds
To finish, 35 DEG C of reaction 6h, after completion of the reaction, remove DMF under reduced pressure, water stirring is added, methylene chloride extracts three times, merge organic phase,
Organic phase washed with water and saturated common salt washing, anhydrous sodium sulfate dry, filter, and are concentrated, obtain 16.84g solid, yield
84.2%.The synthesis of S3:Q-4 compound represented
Reaction equation is as follows:
Feed ratio:
Technical process:
21g Q-3, III compound represented of 11.6g formula and 5.05g triethylamine are added in 300mL toluene, nitrogen is passed through
Gas pours into ice water after completion of the reaction in 75 DEG C of reaction 3h, and aqueous layer with ethyl acetate extraction, anhydrous sodium sulfate is dry, concentration,
It is chromatographed with petroleum ether and ethyl acetate (10:3) column, obtains 21.63g white solid, yield 77.3%.
The synthesis of S4:Q-5 compound represented
Reaction equation is as follows:
Feed ratio:
Technical process:
28g Q-4 compound represented and 300mL methanol are added in hydrogen reaction kettle, 2.24g is added after nitrogen displacement
The palladium carbon that palladium mass percent is 5%, is passed through hydrogen, reacts in 85 DEG C, after reaction, palladium carbon recycling is recovered by filtration,
Filtrate concentration, it is dry, obtain 23.2g solid, yield 92.8%.
The synthesis of S5:Q-6 compound represented
Reaction equation is as follows:
Feed ratio:
Technical process:
25g Q-5 compound represented and 50mL concentrated hydrochloric acid are sequentially added into reaction flask, 0 DEG C is cooled under stirring, are delayed
The slow 300mL that is added contains 7.107g NaNO2Acetic acid, 0 DEG C of temperature control, finish, react 1h after, obtain diazonium salt solution；By 50mL
Toluene is cooled to 0 DEG C, and 10mL acetic acid is added in storage temperature, and 10 DEG C of temperature control are passed through sulfur dioxide gas to being saturated, and 0.3216g is added
Stannous chloride, stirring, obtains sulfur dioxide solution；Diazonium salt solution is slowly added dropwise into sulfur dioxide solution, control reaction
Temperature is 0 DEG C, after completion of the reaction, removes acetic acid, and water layer is extracted with dichloromethane three times, merges organic phase, is concentrated, dry, is obtained
25.12g white solid, yield 75.4%.
The synthesis of S6:2- (5- methyl 4-phenyl -3- isoxazolyl) benzsulfamide (L compound represented)
Reaction equation is as follows:
Feed ratio:
Technical process:
Under ice-water bath, 50mL methylene chloride, stirring are added into reaction flask, system vacuumizes displacement ammonia, is at
33.3g Q-6 compound represented is dissolved in 250mL methylene chloride by the ammonia environment of 1.5 atmospheric pressure, then instills reaction
It in bottle, is stirred to react, after fully reacting, methylene chloride is evaporated off, 37% aqueous hydrochloric acid solution 100mL is added dropwise into reaction flask, stir,
Crystallization, filtering, filter cake is dissolved in 200mL methylene chloride, wash the pH to 7 of organic layer with 10% sodium carbonate liquor, then with water with
Saturated sodium chloride solution respectively washes twice, and anhydrous sodium sulfate dries, filters, and is concentrated to give 28.25g white solid, yield 90.0%,
Purity 99.6%.
1H NMR(400MHz,d6- DMSO): δ 2.51 (s, 3H), 7.17 (m, 5H), 7.29 (m, 3H), 7.56 (td, J=
7.6Hz, J=1.2Hz, 1H), 7.65 (td, J=7.6Hz, J=1.2Hz, 1H), 8.04 (dd, J=8.0Hz, J=1.2Hz,
1H).
Embodiment 4N- [[2- (5- methyl 4-phenyl -3- isoxazolyl) phenyl] sulfonyl] propionamide (chemical combination shown in Q
Object) synthesis
Reaction equation is as follows:
Feed ratio:
Technical process:
300mL methylene chloride is added into reaction flask, ice bath is cooled to 0 DEG C, be added 31.g L compound represented,
11.96g propionyl chloride and 13.13g triethylamine react at room temperature 1h, monitor fully reacting, and the stirring of 300mL water is added, separates organic
Layer, is successively respectively washed twice with water and saturated common salt water washing, and anhydrous sodium sulfate is dry, concentration, concentrate ethyl acetate and
Petroleum ether (2:5) recrystallization, crosses liquation crystalline substance, filtering, and filtration cakes torrefaction obtains 34.2g white solid, yield 92.4%, purity
99.5%.
1H NMR(400MHz,d6- DMSO): δ 0.88 (t, J=7.6Hz, 3H), 2.18 (q, J=7.6Hz, 2H), 2.52
(s, 3H), 7.25 (m, 6H), 7.68 (m, 2H), 8.16 (dd, J=7.6Hz, J=1.2Hz, 1H), 11.85 (s, 1H)
The synthesis of 5 3- of embodiment (5- methyl 4-phenyl -3- isoxazolyl) benzsulfamide (compound shown in formula K)
The synthesis of S1:K-2 compound represented
Reaction equation is as follows:
Feed ratio:
Technical process:
15.1g K-1 compound represented is dissolved in 200mL methanol, 71.76g hydroxylamine hydrochloride and 22.79g are dissolved in
Aqueous solution is formed in 20mL water to be added in reaction solution, after 33 DEG C of reaction 2h, removes methanol under reduced pressure, 200mL water is added, is extracted with ether
It taking three times, merges organic phase, saturated common salt is washed twice, and anhydrous sodium sulfate dries, filters, filtrate concentration, and it is dry, obtain 14.12g
Solid, yield 85.1%.
The synthesis of S2:K-3 compound represented
Reaction equation is as follows:
Feed ratio:
Technical process:
16.6g K-2 compound represented is dissolved in 200mL DMF, 14.497g NCS is added portionwise at 2 DEG C, adds
To finish, 40 DEG C of reaction 6h, after completion of the reaction, remove DMF under reduced pressure, water stirring is added, methylene chloride extracts three times, merge organic phase,
Organic phase washed with water and saturated common salt washing, anhydrous sodium sulfate dry, filter, and are concentrated, obtain 16.96g solid, yield
84.8%.The synthesis of S3:K-4 compound represented
Reaction equation is as follows:
Feed ratio:
Technical process:
21.4g K-3, III compound represented of 11.6g formula and 5.05g triethylamine are added in 300mL toluene, are passed through
Nitrogen pours into ice water after completion of the reaction in 72 DEG C of reaction 3h, and aqueous layer with ethyl acetate extraction, anhydrous sodium sulfate is dry, dense
Contracting is chromatographed with petroleum ether and ethyl acetate (10:3) column, obtains 21.74g white solid, yield 77.6%.
The synthesis of S4:K-5 compound represented
Reaction equation is as follows:
Feed ratio:
Technical process:
28g Q-4 compound represented and 300mL methanol are added in hydrogen reaction kettle, 2.52g is added after nitrogen displacement
The palladium carbon that palladium mass percent is 5%, is passed through hydrogen, reacts in 85 DEG C, after reaction, palladium carbon recycling is recovered by filtration,
Filtrate concentration, it is dry, obtain 23.31g solid, yield 93.24%.
The synthesis of S5:K-6 compound represented
Reaction equation is as follows:
Feed ratio:
Technical process:
25g K-5 compound represented and 50mL concentrated hydrochloric acid are sequentially added into reaction flask, 0 DEG C is cooled under stirring, are delayed
The slow 300mL that is added contains 7.038g NaNO2Acetic acid, 0 DEG C of temperature control, finish, react 1h after, obtain diazonium salt solution；By 50mL
Toluene is cooled to 0 DEG C, and 10mL acetic acid is added in storage temperature, and 10 DEG C of temperature control are passed through sulfur dioxide gas to being saturated, and 0.3082g is added
Stannous chloride, stirring, obtains sulfur dioxide solution；Diazonium salt solution is slowly added dropwise into sulfur dioxide solution, control reaction
Temperature is 0 DEG C, after completion of the reaction, removes acetic acid, and water layer is extracted with dichloromethane three times, merges organic phase, is concentrated, dry, is obtained
24.98g white solid, yield 75.0%.
The synthesis of S6:3- (5- methyl 4-phenyl -3- isoxazolyl) benzsulfamide (K compound represented)
Reaction equation is as follows:
Feed ratio:
Technical process:
Under ice-water bath, 50mL methylene chloride, stirring are added into reaction flask, system vacuumizes displacement ammonia, is at
33.3g K-6 compound represented is dissolved in 250mL methylene chloride by the ammonia environment of 1.5 atmospheric pressure, then instills reaction
It in bottle, is stirred to react, after fully reacting, methylene chloride is evaporated off, 37% aqueous hydrochloric acid solution 100mL is added dropwise into reaction flask, stir,
Crystallization, filtering, filter cake is dissolved in 200mL methylene chloride, wash the pH to 7 of organic layer with 10% sodium carbonate liquor, then with water with
Saturated sodium chloride solution respectively washes twice, and anhydrous sodium sulfate dries, filters, and is concentrated to give 28.31g white solid, yield 90.2%,
Purity 99.4%.
1H NMR(400MHz,d6- DMSO): δ 2.50 (s, 3H), 7.24 (m, 2H), 7.40 (m, 6H), 7.56 (t, J=
8.0Hz, 1H), 7.88 (dt, J=8.0Hz, J=1.6Hz, 1H), 8.00 (t, J=1.6Hz, 1H)
Embodiment 6N- [[3- (5- methyl 4-phenyl -3- isoxazolyl) phenyl] sulfonyl] propionamide (chemical combination shown in N
Object) synthesis
Reaction equation is as follows:
Feed ratio:
Technical process:
300mL methylene chloride is added into reaction flask, ice bath is cooled to 0 DEG C, be added 31.4g K compound represented,
12.88g propionyl chloride and 14.14g triethylamine react at room temperature 1h, monitor fully reacting, and the stirring of 300mL water is added, separates organic
Layer, is successively respectively washed twice with water and saturated common salt water washing, and anhydrous sodium sulfate is dry, concentration, concentrate ethyl acetate and
Petroleum ether (2:5) recrystallization, crosses liquation crystalline substance, filtering, and filtration cakes torrefaction obtains 34.57g white solid, yield 93.4%, purity
99.3%.
1H NMR(400MHz,d6- DMSO): δ 0.88 (t, J=7.2Hz, 3H), 2.20 (q, J=7.2Hz, 2H), 2.50
(s, 3H), 7.23 (dd, J=7.6Hz, J=1.6Hz, 2H), 7.42 (m, 3H), 7.63 (m, 2H), 7.93 (s, 1H), 7.97
(td, J=7.6Hz, J=1.6Hz, 1H), 12.11 (s, 1H)
Embodiment 7N- [[4- (5- methyl 4-phenyl -3- isoxazolyl) phenyl] sulfonyl] propionamide (chemical combination shown in R
Object) synthesis
The synthesis of S1:R-2 compound represented
Reaction equation is as follows:
Feed ratio:
Technical process:
15.1g R-1 compound represented is dissolved in 200mL methanol, 71.07g hydroxylamine hydrochloride and 22.26g are dissolved in
Aqueous solution is formed in 20mL water to be added in reaction solution, after 35 DEG C of reaction 2h, removes methanol under reduced pressure, 200mL water is added, is extracted with ether
It taking three times, merges organic phase, saturated common salt is washed twice, and anhydrous sodium sulfate dries, filters, filtrate concentration, and it is dry, obtain 14.22g
Solid, yield 85.7%.
The synthesis of S2:R-3 compound represented
Reaction equation is as follows:
Feed ratio:
Technical process:
16.6g R-2 compound represented is dissolved in 200mL DMF, 14.497g NCS is added portionwise at 0 DEG C, adds
To finish, 35 DEG C of reaction 6h, after completion of the reaction, remove DMF under reduced pressure, water stirring is added, methylene chloride extracts three times, merge organic phase,
Organic phase washed with water and saturated common salt washing, anhydrous sodium sulfate dry, filter, and are concentrated, obtain 16.92g solid, yield
84.6%.The synthesis of S3:R-4 compound represented
Reaction equation is as follows:
Feed ratio:
Technical process:
21.2g R-3, III compound represented of 11.6g formula and 5.05g triethylamine are added in 300mL toluene, are passed through
Nitrogen pours into ice water after completion of the reaction in 75 DEG C of reaction 3h, and aqueous layer with ethyl acetate extraction, anhydrous sodium sulfate is dry, dense
Contracting is chromatographed with petroleum ether and ethyl acetate (10:3) column, obtains 22.01g white solid, yield 78.6%.
The synthesis of S4:R-5 compound represented
Reaction equation is as follows:
Feed ratio:
Technical process:
28g R-4 compound represented and 300mL methanol are added in hydrogen reaction kettle, 2.38g is added after nitrogen displacement
The palladium carbon that palladium mass percent is 5%, is passed through hydrogen, reacts in 85 DEG C, after reaction, palladium carbon recycling is recovered by filtration,
Filtrate concentration, it is dry, obtain 23.28g solid, yield 93.1%.
The synthesis of S5:R-6 compound represented
Reaction equation is as follows:
Feed ratio:
Technical process:
25g R-5 compound represented and 50mL concentrated hydrochloric acid are sequentially added into reaction flask, 0 DEG C is cooled under stirring, are delayed
The slow 300mL that is added contains 7.107g NaNO2Acetic acid, 0 DEG C of temperature control, finish, react 1h after, obtain diazonium salt solution；By 50mL
Toluene is cooled to 0 DEG C, and 10mL acetic acid is added in storage temperature, and 10 DEG C of temperature control are passed through sulfur dioxide gas to being saturated, and 0.3216g is added
Stannous chloride, stirring, obtains sulfur dioxide solution；Diazonium salt solution is slowly added dropwise into sulfur dioxide solution, control reaction
Temperature is 0 DEG C, after completion of the reaction, removes acetic acid, and water layer is extracted with dichloromethane three times, merges organic phase, is concentrated, dry, is obtained
25.3g white solid, yield 76.0%.
The synthesis of compound shown in S6:R-7
Reaction equation is as follows:
Feed ratio:
Technical process:
Under ice-water bath, 50mL methylene chloride, stirring are added into reaction flask, system vacuumizes displacement ammonia, is at
33.3g R-6 compound represented is dissolved in 250mL methylene chloride by the ammonia environment of 1.5 atmospheric pressure, then instills reaction
It in bottle, is stirred to react, after fully reacting, methylene chloride is evaporated off, 37% aqueous hydrochloric acid solution 100mL is added dropwise into reaction flask, stir,
Crystallization, filtering, filter cake is dissolved in 200mL methylene chloride, wash the pH to 7 of organic layer with 10% sodium carbonate liquor, then with water with
Saturated sodium chloride solution respectively washes twice, and anhydrous sodium sulfate dries, filters, and is concentrated to give 28.41g white solid, yield 90.5%.
S7:N- [[4- (5- methyl 4-phenyl -3- isoxazolyl) phenyl] sulfonyl] propionamide (R compound represented)
Synthesis
Reaction equation is as follows:
Feed ratio:
Technical process:
300mL methylene chloride is added into reaction flask, ice bath is cooled to 0 DEG C, be added 31.g R-7 compound represented,
11.96g propionyl chloride and 13.13g triethylamine react at room temperature 1h, monitor fully reacting, and the stirring of 300mL water is added, separates organic
Layer, is successively respectively washed twice with water and saturated common salt water washing, and anhydrous sodium sulfate is dry, concentration, concentrate ethyl acetate and
Petroleum ether (2:5) recrystallization, crosses liquation crystalline substance, filtering, and filtration cakes torrefaction obtains 34.43g white solid, yield 93.1%, purity
99.7%.
1H NMR(400MHz,d6- DMSO): δ 0.88 (t, J=7.2Hz, 3H), 2.23 (q, J=7.2Hz, 2H), 2.49
(s, 3H), 7.23 (dd, J=7.6Hz, J=1.6Hz, 2H), 7.41 (m, 3H), 7.57 (s, 1H), 7.59 (d, J=1.6Hz,
1H),7.90(s,1H),7.92(s,1H),12.14(s,1H).
Claims (10)
1. a kind of synthetic method of Parecoxib Sodium Isomeric impurities, which is characterized in that the structure of Parecoxib Sodium Isomeric impurities is such as
Shown in formula one and formula two, the synthetic method includes the following steps:
1): I compound represented of formula is reacted shown in production IV in the presence of alkali with formula II or III compound represented of formula
Compound；
2): IV compound represented of formula is through V compound represented of reduction reaction production；
3): V compound represented of formula passes through VI compound represented of diazotising and sulfonylation production；
4): VI compound represented of formula is by Parecoxib Sodium Isomeric impurities shown in amino substitution reaction production one；
5): compound described in formula one is different by Parecoxib Sodium shown in acylation reaction production two occurs under alkaline condition
Structure impurity；
Reaction equation is as follows:
Wherein, R1And R2It is not simultaneously H and NO2, R3 and R4 are not H and NH simultaneously2, R5And R6It is not simultaneously H and SO2Cl, R7And R8
It is not simultaneously H and SO2NH2, R9It is not simultaneously C with R2H5CONHSO2。
2. synthetic method as described in claim 1, which is characterized in that the synthetic method of I compound represented of formula includes as follows
Step:
11) compound described in X-1 and hydroxylamine hydrochloride generate X-2 compound represented in the presence of alkali；
12) X-2 compound represented I compound represented of production after chlorination；
Reaction equation is as follows:
3. synthetic method as described in claim 1, which is characterized in that the synthetic method of II compound represented of formula is as follows:
J-1 compound represented and acetic anhydride II compound represented of production in the presence of alkali；
Reaction equation is as follows:
4. synthetic method as described in claim 1, which is characterized in that the alkali is sodium ethoxide or triethylamine, is changed shown in formula I
It closes object, formula II or III compound represented of formula and the molar ratio of alkali is 1.05-1.1:1:0.2-0.5.
5. synthetic method as described in claim 1, which is characterized in that reducing agent used in step 2) reduction reaction is palladium quality point
The mass ratio of the palladium carbon that number is 5%, IV compound represented of formula and palladium carbon is 1:0.1-0.08.
6. synthetic method as described in claim 1, which is characterized in that diazotising specific method described in step 3) is V institute of formula
The compound and concentrated hydrochloric acid and sodium nitrite shown generates diazonium compound, and diazonium compound reacts production VI with sulfide, copper chloride
Compound represented.
7. synthetic method as claimed in claim 6, which is characterized in that V compound represented, sodium nitrite and chlorine are cuprous
Molar ratio is 1:1.01-1.03:0.022-0.024.
8. synthetic method as described in claim 1, which is characterized in that the acylating reagent of the step 5) acylation reaction is propionyl
Chlorine, alkali used are triethylamine, and the molar ratio of compound, propionyl chloride and alkali described in formula one is 1:1.3-1.5:1.3-1.5.
9. synthetic method as claimed in claim 2, which is characterized in that mole of X-1 compound represented, hydroxylamine hydrochloride and alkali
Than for 1:1.03-1.05:2.1-2.2, the alkali is sodium bicarbonate；Preferably, the chlorination reagent of chlorination is N- chloro fourth
The molar ratio of imidodicarbonic diamide, X-2 compound represented and chlorination reagent is 1:1.08-1.1.
10. synthetic method as claimed in claim 3, which is characterized in that mole of J-1 compound represented, acetic anhydride and alkali
Than for 1:5:0.6, the alkali is N- methylimidazole.
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| CN111153865A (en) * | 2020-01-19 | 2020-05-15 | 上海臣邦医药科技股份有限公司 | Parecoxib sodium substituted impurity and preparation method thereof |
| CN113773270A (en) * | 2021-08-06 | 2021-12-10 | 四川新开元制药有限公司 | Synthesis method of parecoxib sodium impurity |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104557754A (en) * | 2015-01-04 | 2015-04-29 | 成都克莱蒙医药科技有限公司 | Synthesis method for parecoxib sodium impurity |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104557754A (en) * | 2015-01-04 | 2015-04-29 | 成都克莱蒙医药科技有限公司 | Synthesis method for parecoxib sodium impurity |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111153865A (en) * | 2020-01-19 | 2020-05-15 | 上海臣邦医药科技股份有限公司 | Parecoxib sodium substituted impurity and preparation method thereof |
| CN113773270A (en) * | 2021-08-06 | 2021-12-10 | 四川新开元制药有限公司 | Synthesis method of parecoxib sodium impurity |
| CN113773270B (en) * | 2021-08-06 | 2024-05-31 | 四川新开元制药有限公司 | Synthesis method of 3- (5-methyl-4-phenylisoxazole-3-yl) benzenesulfonamide |
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