CN107353195B - Preparation method of loxoprofen sodium ring-opening impurity - Google Patents
Preparation method of loxoprofen sodium ring-opening impurity Download PDFInfo
- Publication number
- CN107353195B CN107353195B CN201710441698.4A CN201710441698A CN107353195B CN 107353195 B CN107353195 B CN 107353195B CN 201710441698 A CN201710441698 A CN 201710441698A CN 107353195 B CN107353195 B CN 107353195B
- Authority
- CN
- China
- Prior art keywords
- stirring
- formula
- reacting
- reduced pressure
- under reduced
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 229960002373 loxoprofen Drugs 0.000 title claims abstract description 30
- 239000012535 impurity Substances 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 238000007142 ring opening reaction Methods 0.000 title claims abstract description 15
- YMBXTVYHTMGZDW-UHFFFAOYSA-N loxoprofen Chemical group C1=CC(C(C(O)=O)C)=CC=C1CC1C(=O)CCC1 YMBXTVYHTMGZDW-UHFFFAOYSA-N 0.000 title claims abstract 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 39
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 claims abstract description 30
- 239000004312 hexamethylene tetramine Substances 0.000 claims abstract description 15
- 235000010299 hexamethylene tetramine Nutrition 0.000 claims abstract description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 87
- 238000003756 stirring Methods 0.000 claims description 84
- 238000001816 cooling Methods 0.000 claims description 48
- 238000010438 heat treatment Methods 0.000 claims description 48
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 46
- 239000012044 organic layer Substances 0.000 claims description 40
- 238000010992 reflux Methods 0.000 claims description 36
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 33
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 30
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 24
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- 238000005070 sampling Methods 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 17
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 16
- 239000000126 substance Substances 0.000 claims description 15
- 239000007864 aqueous solution Substances 0.000 claims description 12
- 238000004440 column chromatography Methods 0.000 claims description 12
- 239000010410 layer Substances 0.000 claims description 12
- 238000010791 quenching Methods 0.000 claims description 12
- 235000010265 sodium sulphite Nutrition 0.000 claims description 12
- 238000000967 suction filtration Methods 0.000 claims description 12
- 238000005406 washing Methods 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 9
- 230000000171 quenching effect Effects 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims 3
- 125000001246 bromo group Chemical group Br* 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 7
- 239000003960 organic solvent Substances 0.000 abstract description 6
- 230000001590 oxidative effect Effects 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 6
- 239000007800 oxidant agent Substances 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 150000007529 inorganic bases Chemical class 0.000 abstract description 3
- 150000007522 mineralic acids Chemical class 0.000 abstract description 3
- 238000006482 condensation reaction Methods 0.000 abstract description 2
- 230000003301 hydrolyzing effect Effects 0.000 abstract description 2
- 238000006467 substitution reaction Methods 0.000 abstract description 2
- BAZQYVYVKYOAGO-UHFFFAOYSA-M loxoprofen sodium hydrate Chemical group O.O.[Na+].C1=CC(C(C([O-])=O)C)=CC=C1CC1C(=O)CCC1 BAZQYVYVKYOAGO-UHFFFAOYSA-M 0.000 description 22
- LDUYTVKPYRCKAM-UHFFFAOYSA-N 2-[2-[(2-oxocyclopentyl)methyl]phenyl]propanoic acid Chemical compound OC(=O)C(C)C1=CC=CC=C1CC1C(=O)CCC1 LDUYTVKPYRCKAM-UHFFFAOYSA-N 0.000 description 17
- 238000004128 high performance liquid chromatography Methods 0.000 description 17
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 description 16
- -1 6- (4- (1-carboxyethyl) phenyl) -5-oxohexanoic acid Chemical compound 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- 239000002253 acid Substances 0.000 description 12
- 229960004011 methenamine Drugs 0.000 description 10
- IAXYHYOWEQQFMC-UHFFFAOYSA-N 2-(4-formylphenyl)propanoic acid Chemical compound OC(=O)C(C)C1=CC=C(C=O)C=C1 IAXYHYOWEQQFMC-UHFFFAOYSA-N 0.000 description 9
- NIBFJPXGNVPNHK-UHFFFAOYSA-N 2,2-difluoro-1,3-benzodioxole-4-carbaldehyde Chemical group C1=CC(C=O)=C2OC(F)(F)OC2=C1 NIBFJPXGNVPNHK-UHFFFAOYSA-N 0.000 description 8
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 8
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 8
- 238000000034 method Methods 0.000 description 6
- 239000013558 reference substance Substances 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- HDMGAZBPFLDBCX-UHFFFAOYSA-M potassium;sulfooxy sulfate Chemical compound [K+].OS(=O)(=O)OOS([O-])(=O)=O HDMGAZBPFLDBCX-UHFFFAOYSA-M 0.000 description 2
- 238000003908 quality control method Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 229960001922 sodium perborate Drugs 0.000 description 2
- YKLJGMBLPUQQOI-UHFFFAOYSA-M sodium;oxidooxy(oxo)borane Chemical compound [Na+].[O-]OB=O YKLJGMBLPUQQOI-UHFFFAOYSA-M 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000007905 drug manufacturing Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- HLWFNAHRXUMSBM-UHFFFAOYSA-M sodium propanoate dihydrate Chemical compound O.O.C(CC)(=O)[O-].[Na+] HLWFNAHRXUMSBM-UHFFFAOYSA-M 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/16—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/16—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation
- C07C51/285—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation with peroxy-compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/373—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in doubly bound form
Abstract
The invention relates to a preparation method of loxoprofen sodium ring-opening impurities, belonging to the technical field of preparation of raw material medicines. The technical scheme of the invention is as follows: performing substitution reaction on formula I and hexamethylenetetramine in an organic solvent A, and hydrolyzing with inorganic acid to obtain a compound shown in formula II; carrying out condensation reaction on a formula II and a formula III in an organic solvent B to obtain a compound of a formula IV; and oxidizing and ring-opening the compound shown in the formula IV under the conditions of an oxidant and inorganic base to obtain loxoprofen sodium impurity shown in the formula V. The technical scheme of the invention provides a preparation method of loxoprofen sodium ring-opening impurities.
Description
Technical Field
The invention relates to a preparation method of loxoprofen sodium ring-opening impurities, belonging to the technical field of preparation of raw material medicines.
Background
Loxoprofen Sodium (Loxoprofen Sodium) having the following structural formula:
the chemical name is 2- [4- (2-oxocyclopentane-1-methyl) phenyl ] sodium propionate dihydrate, belongs to diarylpropionic acid nonsteroidal anti-inflammatory drugs, is firstly developed by Nippon Sanko corporation, is marketed in Japan in 1986, and is the first type of nonsteroidal anti-inflammatory drug to be sold in Japan.
The pharmacopoeia of various countries, regarding the quality standard of loxoprofen sodium, does not specify known impurities, and the japanese pharmacopoeia controls the related substances by Thin Layer Chromatography (TLC) technique. Improving the quality of clinical medication and reducing side effects, and is the direction of efforts of pharmaceutical workers.
With the continuous development of the analysis technology, the loxoprofen sodium quality standard is continuously upgraded, the detection of related substances is gradually replaced by a High Performance Liquid Chromatography (HPLC), and a loxoprofen sodium process impurity reference substance or a degraded impurity reference substance is required for perfecting the loxoprofen sodium quality standard.
The compound shown in the formula V is loxoprofen sodium ring-opening impurity, is a process impurity in the loxoprofen sodium synthesis process, is also the largest impurity in the original preparation (Loxonin), and can grow in loxoprofen sodium raw material medicine and preparation stability experiments, so that the qualified compound shown in the formula V is required to be used as a reference substance in daily inspection of the loxoprofen sodium raw material medicine and the preparation, and the reference substance of the compound shown in the formula V is not sold at home and must be imported. Through retrieval, no literature report about the preparation of the impurity exists, and the compound of the formula V cannot be obtained through conventional acid and alkali, oxidation and high-temperature destruction, so that a new route must be developed for directionally synthesizing the compound. Therefore, the method for synthesizing the loxoprofen sodium ring-opening impurity is of great practical significance for preparing the impurity standard product.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide a preparation method of loxoprofen sodium ring-opening impurities. And qualified impurity reference substances are provided for loxoprofen sodium bulk drug manufacturing enterprises and preparation manufacturing enterprises.
The technical scheme of the invention is as follows:
the invention provides a preparation method of loxoprofen sodium ring-opening impurities shown in a formula V, which comprises the following steps:
firstly, carrying out substitution reaction on formula I and hexamethylenetetramine in an organic solvent A, and hydrolyzing with inorganic acid to obtain a compound shown in formula II;
wherein: in the formula I, X is Cl or Br;
the mass ratio of the feed materials of the formula I to the hexamethylene tetramine is 1.0: 1.0-3.0;
the organic solvent A is selected from one of dichloromethane, chloroform, carbon tetrachloride and glacial acetic acid; preferably chloroform;
the inorganic acid is one of hydrochloric acid, sulfuric acid and phosphoric acid; hydrochloric acid is preferred.
Secondly, carrying out condensation reaction on the formula II and the formula III in an organic solvent B to obtain a compound shown in a formula IV;
wherein: the mass ratio of the fed materials in the formula II to the fed materials in the formula III is 1.0: 1.0-2.0;
the organic solvent B is selected from one of dichloromethane, chloroform, carbon tetrachloride and toluene; toluene is preferred.
And thirdly, oxidizing and opening the compound shown in the formula IV under the conditions of an oxidant and inorganic base to obtain loxoprofen sodium impurity shown in the formula V, wherein the synthetic route is shown as follows.
Wherein: the oxidant is selected from one of hydrogen peroxide, sodium perborate and potassium hydrogen persulfate composite salt; preferably hydrogen peroxide;
the mass ratio of the formula IV to the oxidant is 1.0: 2.0-3.0;
the inorganic base is selected from one of sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide; preferably sodium hydroxide;
the reaction temperature is 0-50 ℃, preferably 20-30 ℃.
Has the advantages that:
the technical scheme of the invention provides a preparation method of loxoprofen sodium ring-opening impurities, which has the advantages of simple process, simple and convenient operation, good yield, high purity and the like. The impurities exist in the loxoprofen sodium raw material medicine and the preparation, the invention can provide qualified reference substances for the quality control of the loxoprofen sodium, and has important significance for the quality control of the loxoprofen sodium raw material medicine and the preparation.
(IV) description of the drawings
FIG. 1 NMR spectrum of 2- (4-formylphenyl) propionic acid obtained in step (1) in example 1
FIG. 2 NMR spectrum of 2- (2- ((2-oxocyclopentyl) methyl) phenyl) propionic acid obtained in step (2) in example 1
FIG. 3 NMR chart of 6- (4- (1-carboxyethyl) phenyl) -5-oxohexanoic acid obtained in step (3) of example 1
The concrete embodiment (V):
example 1
Step (1): adding 80g of p-chloromethyl isopropyl benzene propionic acid (0.40 mol), 112.1g of hexamethylenetetramine (0.80 mol), 240ml of chloroform into a 500ml three-necked bottle, stirring and heating to reflux (63-65 ℃), stirring and reacting for 6h, taking a sample, completely reacting, cooling to room temperature, adding 60g of 36% concentrated hydrochloric acid, stirring and heating to reflux and reacting for 2h, cooling to room temperature, layering to obtain an organic layer, washing the organic layer with 200ml of saturated sodium carbonate aqueous solution, layering to obtain an organic layer, and concentrating under reduced pressure until the organic layer is dried to obtain 66.2g of 2- (4-formylphenyl) propionic acid as a pale yellow solid with the yield of 92.3% and the HPLC purity of 94.6%.1H-NMR (400 MHz, CDCl3)d11.31(1H, s), 9.99(1H, d),7.86 (2H, d),7.50(2H,d)，3.84(1H,q),1.56(3H,d)。
Step (2): adding 4-formyl monopropiophenoic acid (25 g, 0.14 mol), 1- (4-morpholine) cyclopentene (43 g, 0.28 mol) and toluene 150ml into a 500ml three-necked bottle, stirring and heating to reflux (115 ℃), stirring for reaction for 6h, completely reacting a sampling point plate, concentrating under reduced pressure to dryness to obtain a light yellow oily substance, adding 100ml n-hexane, stirring and crystallizing for 1h, and performing suction filtration to obtain 30g of 2- (2- ((2-oxocyclopentyl) methyl) phenyl) propionic acid as a white-like solid with the yield of 87.8% and the HPLC purity of 98.3%.1H-NMR(400 MHz, DMSO-d6) d8.35 (1H, s), 7.19(2H, d), 7.14 (2H, d), 7.10(1H, s),3.62(1H, q),3.43(2H, t),2.50(2H, t),2.40(2H, m),1.41(3H, d)。
And (3): adding 10g of 2- (2- ((2-oxocyclopentyl) methyl) phenyl) propionic acid (0.04 mol) and 50ml of ethanol into a 100ml three-necked bottle, stirring and heating to clear, cooling to below 30 ℃, dropwise adding 15g of 30% sodium hydroxide solution at below 30 ℃, after dropwise adding, cooling to 0-5 ℃, dropwise adding 10g of 30% hydrogen peroxide at 0-5 ℃, reacting for 4 hours at 25-30 ℃ after dropwise adding, adding sodium sulfite for quenching reaction, adjusting the pH to 1-2 with concentrated hydrochloric acid, concentrating under reduced pressure to dryness, adding 50ml of water, extracting the water phase with 2 x 50ml of dichloromethane for 2 times, layering to obtain a dichloromethane layer, concentrating under reduced pressure to dryness, and separating by column chromatography to obtain 8.2g of 6- (4- (1-carboxyethyl) phenyl) -5-oxohexanoic acid, wherein the yield is 72%, and the purity is 99.1%
Example 2
Step (1): adding para-bromomethyl isophenylpropionic acid (96.84 g, 0.40 mol), hexamethylenetetramine (112.1 g, 0.80 mol) and chloroform 240ml into a 500ml three-necked bottle, stirring and heating to reflux (63-65 ℃), stirring and reacting for 6h, completely reacting a sampling point plate, cooling to room temperature, adding 36% concentrated hydrochloric acid 60g, stirring and heating to reflux and reacting for 2h, cooling to room temperature, layering to obtain an organic layer, washing the organic layer with saturated sodium carbonate aqueous solution 200ml, layering to obtain an organic layer, and concentrating under reduced pressure until the 2- (4-formylphenyl) propionic acid is dried to obtain 67.56g of light yellow solid with the yield of 94.2% and the HPLC purity of 94.6%.
Step (2): adding 4-formyl monopropiophenoic acid (25 g, 0.14 mol), 1- (4-morpholine) cyclopentene (43 g, 0.28 mol) and toluene 150ml into a 500ml three-necked bottle, stirring and heating to reflux (115 ℃), stirring for reaction for 6h, completely reacting a sampling point plate, concentrating under reduced pressure to dryness to obtain a light yellow oily substance, adding 100ml n-hexane, stirring and crystallizing for 1h, and performing suction filtration to obtain 30g of 2- (2- ((2-oxocyclopentyl) methyl) phenyl) propionic acid as a white-like solid with the yield of 87.8% and the HPLC purity of 98.3%.
And (3): adding 10g of 2- (2- ((2-oxocyclopentyl) methyl) phenyl) propionic acid (0.04 mol) and 50ml of ethanol into a 100ml three-necked bottle, stirring and heating to clear, cooling to below 30 ℃, dropwise adding 15g of 30% sodium hydroxide solution at below 30 ℃, after dropwise adding, cooling to 0-5 ℃, dropwise adding 10g of 30% hydrogen peroxide at 0-5 ℃, reacting for 4 hours at 25-30 ℃ after dropwise adding, adding sodium sulfite for quenching reaction, adjusting the pH to 1-2 with concentrated hydrochloric acid, concentrating under reduced pressure to dryness, adding 50ml of water, extracting the water phase with 2 x 50ml of dichloromethane for 2 times, layering to obtain a dichloromethane layer, concentrating under reduced pressure to dryness, and separating by column chromatography to obtain 8.2g of 6- (4- (1-carboxyethyl) phenyl) -5-oxohexanoic acid, wherein the yield is 72%, and the purity is 99.1%
Example 3
Step (1): adding 80g of p-chloromethyl isopropyl benzene propionic acid (0.40 mol), 56.05g of hexamethylenetetramine (0.40 mol), and 240ml of chloroform into a 500ml three-necked bottle, stirring and heating to reflux (63-65 ℃), stirring and reacting for 6h, completely reacting a sampling point plate, cooling to room temperature, adding 60g of 36% concentrated hydrochloric acid, stirring and heating to reflux and reacting for 2h, cooling to room temperature, layering to obtain an organic layer, washing the organic layer with 200ml of saturated sodium carbonate aqueous solution, layering to obtain an organic layer, and concentrating under reduced pressure until the organic layer is dried to obtain 61.4g of 2- (4-formylphenyl) propionic acid as a light yellow solid with the yield of 85.6%. HPLC purity 94.0%.
Step (2): adding 4-formyl monopropiophenoic acid (25 g, 0.14 mol), 1- (4-morpholine) cyclopentene (43 g, 0.28 mol) and dichloromethane (150 ml) into a 500ml three-necked bottle, stirring and heating to reflux (40 ℃), stirring for reaction for 10h, completely reacting a sampling point plate, concentrating under reduced pressure to dryness to obtain a light yellow oily substance, adding 100ml n-hexane, stirring for crystallization for 1h, and performing suction filtration to obtain 28.29g of 2- (2- ((2-oxocyclopentyl) methyl) phenyl) propionic acid as an off-white solid, wherein the yield is 82.8%, and the HPLC purity is 97.6%.
And (3): adding 10g of 2- (2- ((2-oxocyclopentyl) methyl) phenyl) propionic acid (0.04 mol) and 50ml of ethanol into a 100ml three-necked bottle, stirring and heating to clear, cooling to below 30 ℃, dropwise adding 15g of 30% sodium hydroxide solution below 30 ℃, after dripping, cooling to 0-5 ℃, adding 13.54g of sodium perborate in batches at 0-5 ℃, after dripping, reacting for 4h at 25-30 ℃, adding sodium sulfite to quench, adjusting the pH to be 1-2 with concentrated hydrochloric acid, concentrating under reduced pressure to dryness, adding 50ml of water, extracting the water phase with 2 x 50ml of dichloromethane for 2 times, layering to obtain a dichloromethane layer, concentrating under reduced pressure to dryness, and separating by column chromatography to obtain 7.72g of 6- (4- (1-carboxyethyl) phenyl) -5-oxohexanoic acid, wherein the yield is 67.8%, and the purity is 98.4%
Example 4
Step (1): adding 80g of p-chloromethyl isophenylpropionic acid (0.40 mol), 168.2g of hexamethylenetetramine (0.12 mol) and 240ml of dichloromethane into a 500ml three-necked bottle, stirring and heating to reflux (40 ℃), stirring and reacting for 6h, completely reacting a sampling point plate, cooling to room temperature, adding 60g of 36% concentrated hydrochloric acid, stirring and heating to reflux and reacting for 2h, cooling to room temperature, layering to obtain an organic layer, washing the organic layer with 200ml of saturated sodium carbonate aqueous solution, layering to obtain an organic layer, and concentrating under reduced pressure until dried to obtain 65.48g of 2- (4-formylphenyl) propionic acid as a pale yellow solid with the yield of 91.3% and the HPLC purity of 94.6%.
Step (2): adding 4-formyl monopropiophenoic acid (25 g, 0.14 mol), 1- (4-morpholine) cyclopentene (21.5 g, 0.14 mol) and toluene 150ml into a 500ml three-necked bottle, stirring and heating to reflux (115 ℃), stirring for reacting for 6h, completely reacting a sampling point plate, concentrating under reduced pressure to obtain a light yellow oily substance, adding 100ml n-hexane, stirring and crystallizing for 1h, and performing suction filtration to obtain 30g of 2- (2- ((2-oxocyclopentyl) methyl) phenyl) propionic acid as a white solid with the yield of 87.8% and the HPLC purity of 98.3%.
And (3): adding 10g of 2- (2- ((2-oxocyclopentyl) methyl) phenyl) propionic acid (0.04 mol) and 50ml of ethanol into a 100ml three-necked bottle, stirring and heating to clear, cooling to below 30 ℃, dropwise adding 15g of 30% sodium hydroxide solution below 30 ℃, after dropwise adding, cooling to 0-5 ℃, dropwise adding 13.64g of 30% hydrogen peroxide at 0-5 ℃, after dropwise adding, reacting at 45-50 ℃ for 3 hours, adding sodium sulfite for quenching reaction, adjusting the pH to be 1-2 by using concentrated hydrochloric acid, concentrating under reduced pressure to be dry, adding 50ml of water, extracting the water phase with 2 x 50ml of dichloromethane for 2 times, layering to obtain a dichloromethane layer, concentrating under reduced pressure to be dry, and separating by column chromatography to obtain 7.9g of 6- (4- (1-carboxyethyl) phenyl) -5-oxohexanoic acid, wherein the yield is 69.35%, and the purity is 99.0%
Example 5
Step (1): adding 80g of p-chloromethyl isopropyl benzene propionic acid (0.40 mol), 112.1g of hexamethylenetetramine (0.80 mol) and 240ml of carbon tetrachloride into a 500ml three-necked bottle, stirring and heating to reflux (75-80 ℃), stirring and reacting for 5h, completely reacting a sampling point plate, cooling to room temperature, adding 60g of 36% concentrated hydrochloric acid, stirring and heating to reflux and reacting for 2h, cooling to room temperature, layering to obtain an organic layer, washing the organic layer with 200ml of saturated sodium carbonate aqueous solution, layering to obtain an organic layer, and concentrating under reduced pressure until the 2- (4-formylphenyl) propionic acid is dried to obtain 65.62g of light yellow solid with the yield of 91.5% and the HPLC purity of 94.2%.
Step (2): adding 4-formyl monopropiophenoic acid (25 g, 0.14 mol), 1- (4-morpholine) cyclopentene (32.25 g, 0.21 mol) and toluene 150ml into a 500ml three-necked bottle, stirring and heating to reflux (115 ℃), stirring for reacting for 6h, completely reacting a sampling point plate, concentrating under reduced pressure to obtain a light yellow oily substance, adding 100ml n-hexane, stirring and crystallizing for 1h, and performing suction filtration to obtain 28.6g of 2- (2- ((2-oxocyclopentyl) methyl) phenyl) propionic acid as a white solid with yield of 83.7% and HPLC purity of 98.0%.
And (3): adding 10g of 2- (2- ((2-oxocyclopentyl) methyl) phenyl) propionic acid (0.04 mol) and 50ml of ethanol into a 100ml three-necked bottle, stirring and heating to clear, cooling to below 30 ℃, dropwise adding 39.67g of 30% sodium carbonate solution at below 30 ℃, cooling to 0-5 ℃, dropwise adding 10g of 30% hydrogen peroxide at 0-5 ℃, reacting for 4 hours at 25-30 ℃, adding sodium sulfite to quench, adjusting the pH to be 1-2 with concentrated hydrochloric acid, concentrating under reduced pressure to dryness, adding 50ml of water, extracting the water phase with 2 x 50ml of dichloromethane for 2 times, layering to obtain a dichloromethane layer, concentrating under reduced pressure to dryness, separating by column chromatography to obtain 8.0g of 6- (4- (1-carboxyethyl) phenyl) -5-oxohexanoic acid, obtaining the yield of 70.24%, and the purity of 98.9%
Example 6
Step (1): adding 80g of p-chloromethyl isopropyl benzene propionic acid (0.40 mol), 112.1g of hexamethylenetetramine (0.80 mol) and 240ml of glacial acetic acid into a 500ml three-necked bottle, stirring and heating to reflux (63-65 ℃), stirring and reacting for 6h, completely reacting a sampling point plate, cooling to room temperature, adding 60g of 36% concentrated hydrochloric acid, stirring and heating to reflux and reacting for 2h, cooling to room temperature, layering to obtain an organic layer, washing the organic layer with 200ml of saturated sodium carbonate aqueous solution, layering to obtain an organic layer, and concentrating under reduced pressure until 64.62g of 2- (4-formylphenyl) propionic acid is obtained, wherein the yield is 90.1% and the HPLC purity is 94.0%.
Step (2): adding 4-formyl monopropiophenoic acid (25 g, 0.14 mol), 1- (4-morpholine) cyclopentene (43 g, 0.28 mol) and chloroform (150 ml) into a 500ml three-necked bottle, stirring and heating to reflux (62 ℃), stirring for reaction for 10h, completely reacting a sampling point plate, concentrating under reduced pressure to dryness to obtain a light yellow oily substance, adding 100ml n-hexane, stirring for crystallization for 1h, and performing suction filtration to obtain 29.66g of 2- (2- ((2-oxocyclopentyl) methyl) phenyl) propionic acid as an off-white solid, wherein the yield is 86.8% and the HPLC purity is 98.1%.
And (3): adding 10g of 2- (2- ((2-oxocyclopentyl) methyl) phenyl) propionic acid (0.04 mol) and 50ml of ethanol into a 100ml three-necked bottle, stirring and heating to clear, cooling to below 30 ℃, dropwise adding 15g of 30% sodium hydroxide solution at below 30 ℃, after dripping, cooling to 0-5 ℃, adding 29.72g of potassium hydrogen persulfate composite salt in batches at 0-5 ℃, after adding, reacting for 10h at 0-5 ℃, adding sodium sulfite for quenching reaction, adjusting the pH to be between 1 and 2 by using concentrated hydrochloric acid, concentrating to be dry under reduced pressure, adding 50ml of water, extracting the water phase by using 2 x 50ml of dichloromethane for 2 times, layering to obtain a dichloromethane layer, concentrating to be dry under reduced pressure, and performing column chromatography to obtain 7.69g of 6- (4- (1-carboxyethyl) phenyl) -5-oxohexanoic acid, wherein the yield is 67.5%, and the purity is 98.6%
Example 7
Step (1): adding p-chloromethyl isopropyl benzene propionic acid (80 g, 0.40 mol), hexamethylene tetramine (112.1 g, 0.80 mol) and chloroform (240 ml) into a 500ml three-necked bottle, stirring and heating to reflux (63-65 ℃), stirring and reacting for 6h, completely reacting a sampling point plate, cooling to room temperature, adding phosphoric acid (58 g), stirring and heating to reflux and reacting for 2h, cooling to room temperature, layering to obtain an organic layer, washing the organic layer with saturated sodium carbonate aqueous solution (200 ml), layering to obtain an organic layer, and concentrating under reduced pressure to dryness to obtain 64.98g of 2- (4-formylphenyl) propionic acid as a light yellow solid with the yield of 90.6% and the HPLC purity of 94.4%.
Step (2): adding 4-formyl monopropiophenoic acid (25 g, 0.14 mol), 1- (4-morpholine) cyclopentene (43 g, 0.28 mol) and carbon tetrachloride (150 ml) into a 500ml three-necked bottle, stirring and heating to reflux (77 ℃), stirring for reaction for 8h, completely reacting a sampling point plate, concentrating under reduced pressure to dryness to obtain a light yellow oily substance, adding 100ml n-hexane, stirring for crystallization for 1h, and performing suction filtration to obtain 29.1g of 2- (2- ((2-oxocyclopentyl) methyl) phenyl) propionic acid as a white-like solid, wherein the yield is 85.16%, and the HPLC purity is 98.0%.
And (3): adding 10g of 2- (2- ((2-oxocyclopentyl) methyl) phenyl) propionic acid (0.04 mol) and 50ml of ethanol into a 100ml three-necked bottle, stirring and heating to clear, cooling to below 30 ℃, dropwise adding 51.83g of 30% potassium carbonate solution at below 30 ℃, after dropwise adding, cooling to 0-5 ℃, dropwise adding 10g of 30% hydrogen peroxide at 0-5 ℃, reacting for 4h at 25-30 ℃, adding sodium sulfite for quenching reaction, adjusting the pH to be 1-2 by using concentrated hydrochloric acid, concentrating under reduced pressure to dryness, adding 50ml of water, extracting the water phase for 2 times by using 2 x 50ml of dichloromethane, layering to obtain a dichloromethane layer, concentrating under reduced pressure to dryness, and performing column chromatography to obtain 7.82g of 6- (4- (1-carboxyethyl) phenyl) -5-oxohexanoic acid, wherein the yield is 68.66%, and the purity is 98.8%
Example 8
Step (1): adding 80g of p-chloromethyl isopropyl benzene propionic acid (0.40 mol), 112.1g of hexamethylenetetramine (0.80 mol), 240ml of chloroform into a 500ml three-necked bottle, stirring and heating to reflux (63-65 ℃), stirring and reacting for 6h, completely reacting a sampling point plate, cooling to room temperature, adding 58g of concentrated sulfuric acid, stirring and heating to reflux and reacting for 2h, cooling to room temperature, layering to obtain an organic layer, washing the organic layer with 200ml of saturated sodium carbonate aqueous solution, layering to obtain an organic layer, and concentrating under reduced pressure to dryness to obtain 65.98g of 2- (4-formylphenyl) propionic acid as a pale yellow solid with the yield of 92.0% and the HPLC purity of 94.2%.
Step (2): adding 4-formyl monopropiophenoic acid (25 g, 0.14 mol), 1- (4-morpholine) cyclopentene (43 g, 0.28 mol) and toluene 150ml into a 500ml three-necked bottle, stirring and heating to reflux (115 ℃), stirring for reaction for 6h, completely reacting a sampling point plate, concentrating under reduced pressure to dryness to obtain a light yellow oily substance, adding 100ml n-hexane, stirring and crystallizing for 1h, and performing suction filtration to obtain 30g of 2- (2- ((2-oxocyclopentyl) methyl) phenyl) propionic acid as a white-like solid with the yield of 87.8% and the HPLC purity of 98.3%.1H-NMR(400 MHz, DMSO-d6) d8.35 (1H, s), 7.19(2H, d), 7.14 (2H, d), 7.10(1H, s),3.62(1H, q),3.43(2H, t),2.50(2H, t),2.40(2H, m),1.41(3H, d)。
And (3): adding 10g of 2- (2- ((2-oxocyclopentyl) methyl) phenyl) propionic acid (0.04 mol) and 50ml of ethanol into a 100ml three-necked bottle, stirring and heating to clear, cooling to below 30 ℃, dropwise adding 21g of 30% potassium hydroxide solution below 30 ℃, cooling to 0-5 ℃, dropwise adding 10g of 30% hydrogen peroxide at 0-5 ℃, reacting for 4 hours at 25-30 ℃ after dropwise adding, adding sodium sulfite for quenching reaction, adjusting the pH to 1-2 with concentrated hydrochloric acid, concentrating under reduced pressure to dryness, adding 50ml of water, extracting the water phase with 2 x 50ml of dichloromethane for 2 times, layering to obtain a dichloromethane layer, concentrating under reduced pressure to dryness, and separating by column chromatography to obtain 7.9g of 6- (4- (1-carboxyethyl) phenyl) -5-oxohexanoic acid, wherein the yield is 69.3% and the purity is 99.1%.
Claims (4)
1. A preparation method of loxoprofen sodium ring-opening impurity shown in formula V is characterized by comprising the following steps:
step (1): adding 0.40mol of a compound shown in the formula I, 0.80mol of hexamethylenetetramine and 240ml of chloroform into a 500ml three-necked bottle, stirring and heating to 63-65 ℃ for reflux, stirring and reacting for 6h, taking a sample, reacting completely, cooling to room temperature, adding 60g of 36% concentrated hydrochloric acid, stirring and heating to reflux and reacting for 2h, cooling to room temperature, layering to obtain an organic layer, washing the organic layer with 200ml of saturated sodium carbonate aqueous solution, layering to obtain an organic layer, and concentrating under reduced pressure until the organic layer is dried to obtain a compound shown in the formula II;
step (2): adding 0.14mol of a compound shown in a formula II, 0.28mol of a compound shown in a formula III and 150ml of toluene into a 500ml three-necked bottle, stirring and heating to 115 ℃ for refluxing, stirring for reacting for 6 hours, completely reacting a sampling point plate, concentrating under reduced pressure to dryness to obtain a light yellow oily substance, adding 100ml of n-hexane, stirring for crystallizing for 1 hour, and performing suction filtration to obtain a compound shown in a formula IV;
and (3): adding 0.04mol of the compound IV and 50ml of ethanol into a 100ml three-necked bottle, stirring and heating to be clear, cooling to be below 30 ℃, dropwise adding 15g of 30% sodium hydroxide solution below 30 ℃, cooling to be 0-5 ℃, dropwise adding 10g of 30% hydrogen peroxide at 0-5 ℃, reacting at 25-30 ℃ for 4 hours after dropwise adding, adding sodium sulfite to quench reaction, adjusting the pH to be-1-2 by using concentrated hydrochloric acid, concentrating to be dry under reduced pressure, adding 50ml of water, extracting the water phase for 2 times by using 2 x 50ml of dichloromethane, layering to obtain a dichloromethane layer, concentrating to be dry under reduced pressure, and separating by column chromatography to obtain the compound V.
2. A preparation method of loxoprofen sodium ring-opening impurity shown in formula V is characterized by comprising the following steps:
step (1): adding 0.40mol of a compound shown in the formula I, 0.80mol of hexamethylenetetramine and 240ml of chloroform into a 500ml three-necked bottle, stirring and heating to 63-65 ℃ for reflux, stirring and reacting for 6h, taking a sample, reacting completely, cooling to room temperature, adding 60g of 36% concentrated hydrochloric acid, stirring and heating to reflux and reacting for 2h, cooling to room temperature, layering to obtain an organic layer, washing the organic layer with 200ml of saturated sodium carbonate aqueous solution, layering to obtain an organic layer, and concentrating under reduced pressure until the organic layer is dried to obtain a compound shown in the formula II;
step (2): adding 0.14mol of a compound shown in a formula II, 0.28mol of a compound shown in a formula III and 150ml of toluene into a 500ml three-necked bottle, stirring and heating to 115 ℃ for refluxing, stirring for reacting for 6 hours, completely reacting a sampling point plate, concentrating under reduced pressure to dryness to obtain a light yellow oily substance, adding 100ml of n-hexane, stirring for crystallizing for 1 hour, and performing suction filtration to obtain a compound shown in a formula IV;
and (3): adding 0.04mol of the compound IV and 50ml of ethanol into a 100ml three-necked bottle, stirring and heating to be clear, cooling to be below 30 ℃, dropwise adding 15g of 30% sodium hydroxide solution below 30 ℃, cooling to be 0-5 ℃, dropwise adding 10g of 30% hydrogen peroxide at 0-5 ℃, reacting at 25-30 ℃ for 4 hours after dropwise adding, adding sodium sulfite to quench reaction, adjusting the pH to be-1-2 by using concentrated hydrochloric acid, concentrating to be dry under reduced pressure, adding 50ml of water, extracting the water phase for 2 times by using 2 x 50ml of dichloromethane, layering to obtain a dichloromethane layer, concentrating to be dry under reduced pressure, and separating by column chromatography to obtain the compound V.
3. A preparation method of loxoprofen sodium ring-opening impurity shown in formula V is characterized by comprising the following steps:
step (1): adding 0.40mol of a compound shown in the formula I, 0.12mol of hexamethylenetetramine and 240ml of dichloromethane into a 500ml three-necked bottle, stirring and heating to 40 ℃ for reflux, stirring and reacting for 6h, completely reacting a sampling point plate, cooling to room temperature, adding 60g of 36% concentrated hydrochloric acid, stirring and heating to reflux and reacting for 2h, cooling to room temperature, layering to obtain an organic layer, washing the organic layer with 200ml of saturated sodium carbonate aqueous solution, layering to obtain an organic layer, and concentrating under reduced pressure until the compound shown in the formula II is dried;
step (2): adding 0.14mol of a compound shown in a formula II, 0.14mol of a compound shown in a formula III and 150ml of toluene into a 500ml three-necked bottle, stirring and heating to 115 ℃ for refluxing, stirring for reacting for 6 hours, completely reacting a sampling point plate, concentrating under reduced pressure to dryness to obtain a light yellow oily substance, adding 100ml of n-hexane, stirring for crystallizing for 1 hour, and performing suction filtration to obtain a compound shown in a formula IV;
and (3): adding 0.04mol of the compound IV and 50ml of ethanol into a 100ml three-necked bottle, stirring and heating to clear, cooling to below 30 ℃, dropwise adding 15g of 30% sodium hydroxide solution below 30 ℃, cooling to 0-5 ℃, dropwise adding 13.64g of 30% hydrogen peroxide at 0-5 ℃, reacting at 45-50 ℃ for 3h after dropwise adding, adding sodium sulfite for quenching reaction, adjusting the pH to be = 1-2 by using concentrated hydrochloric acid, concentrating under reduced pressure to dryness, adding 50ml of water, extracting the water phase for 2 times by using 2 x 50ml of dichloromethane, layering to obtain a dichloromethane layer, concentrating under reduced pressure to dryness, and separating by column chromatography to obtain the compound V.
4. A preparation method of loxoprofen sodium ring-opening impurity shown in formula V is characterized by comprising the following steps:
Step (1): adding 0.40mol of a compound shown in the formula I, 0.80mol of hexamethylenetetramine and 240ml of chloroform into a 500ml three-necked bottle, stirring and heating to 63-65 ℃ for reflux, stirring and reacting for 6h, taking a sample, reacting completely, cooling to room temperature, adding 58g of concentrated sulfuric acid, stirring and heating to reflux and reacting for 2h, cooling to room temperature, layering to obtain an organic layer, washing the organic layer with 200ml of saturated sodium carbonate aqueous solution, layering to obtain an organic layer, and concentrating under reduced pressure until the compound shown in the formula II is dried;
step (2): adding 0.14mol of a compound shown in a formula II, 0.28mol of a compound shown in a formula III and 150ml of toluene into a 500ml three-necked bottle, stirring and heating to 115 ℃ for refluxing, stirring for reacting for 6 hours, completely reacting a sampling point plate, concentrating under reduced pressure to dryness to obtain a light yellow oily substance, adding 100ml of n-hexane, stirring for crystallizing for 1 hour, and performing suction filtration to obtain a compound shown in a formula IV;
and (3): adding 0.04mol of the compound IV and 50ml of ethanol into a 100ml three-necked bottle, stirring and heating to be clear, cooling to be below 30 ℃, dropwise adding 21g of 30% potassium hydroxide solution below 30 ℃, cooling to be 0-5 ℃, dropwise adding 10g of 30% hydrogen peroxide at 0-5 ℃, reacting at 25-30 ℃ for 4 hours after dropwise adding, adding sodium sulfite to quench reaction, adjusting the pH to be-1-2 by using concentrated hydrochloric acid, concentrating to be dry under reduced pressure, adding 50ml of water, extracting the water phase for 2 times by using 2 x 50ml of dichloromethane, layering to obtain a dichloromethane layer, concentrating to be dry under reduced pressure, and separating by column chromatography to obtain the compound V.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710441698.4A CN107353195B (en) | 2017-06-13 | 2017-06-13 | Preparation method of loxoprofen sodium ring-opening impurity |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710441698.4A CN107353195B (en) | 2017-06-13 | 2017-06-13 | Preparation method of loxoprofen sodium ring-opening impurity |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107353195A CN107353195A (en) | 2017-11-17 |
| CN107353195B true CN107353195B (en) | 2020-10-13 |
Family
ID=60272827
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710441698.4A Active CN107353195B (en) | 2017-06-13 | 2017-06-13 | Preparation method of loxoprofen sodium ring-opening impurity |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107353195B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111909024B (en) * | 2019-05-08 | 2022-08-02 | 金凯(辽宁)生命科技股份有限公司 | Preparation method of 4-formylbenzoic acid |
| CN113149826A (en) * | 2021-04-08 | 2021-07-23 | 台州市源众药业有限公司 | Preparation process of pelubiprofen |
| CN113387792A (en) * | 2021-07-12 | 2021-09-14 | 迪嘉药业集团有限公司 | Synthetic method of loxoprofen sodium process impurity |
| CN115850052A (en) * | 2022-12-13 | 2023-03-28 | 斯坦德药典标准物质研发(湖北)有限公司 | Preparation method of loxoprofen ring-opening impurity |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1294115A (en) * | 2000-11-07 | 2001-05-09 | 复旦大学 | Process for preparing loxoprofen sodium |
| CN106699559A (en) * | 2015-11-12 | 2017-05-24 | 浙江九洲药业股份有限公司 | Method for preparing loxoprofen sodium |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6122043A (en) * | 1984-07-10 | 1986-01-30 | Sankyo Co Ltd | Preparation of cycloalkylidenemethylphenylacetic acid derivative |
| EP2928879B1 (en) * | 2012-12-05 | 2018-02-28 | Chiesi Farmaceutici S.p.A. | Phenylethylpyridine derivatives as pde4-inhibitors and muscarinic receptor antagonists |
-
2017
- 2017-06-13 CN CN201710441698.4A patent/CN107353195B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1294115A (en) * | 2000-11-07 | 2001-05-09 | 复旦大学 | Process for preparing loxoprofen sodium |
| CN106699559A (en) * | 2015-11-12 | 2017-05-24 | 浙江九洲药业股份有限公司 | Method for preparing loxoprofen sodium |
Non-Patent Citations (2)
| Title |
|---|
| Identification of degradation products in loxoprofen sodium adhesive tapes by liquid chromatography-mass spectrometry and dynamic pressurized liquid extraction-solid-phase extraction coupled to liquid chromatography-nuclear magnetic resonance spectroscopy;Tomonori Murakami et al.;《Journal of Chromatography A》;20080827;第1208卷(第1-2期);第165页Fig.1 * |
| Synthesis of δ-Lactones. IV. 6-alkyl and 6-aralkyl δ-lactones from cyclopentanone;Akie Ijima et al.;《Chemical & Pharmaceutical Bulletin》;19730125;第21卷(第1期);第215页Scheme 1，第216页TABLE I，第218页TABLE IV，第219页倒数第3段 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107353195A (en) | 2017-11-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107353195B (en) | Preparation method of loxoprofen sodium ring-opening impurity | |
| US10662145B2 (en) | Method of synthesizing diclofenac sodium | |
| CN111892507A (en) | Synthesis method of high-purity dopamine hydrochloride | |
| EA002190B1 (en) | Process for making 2-aryl-3-aryl-5-substituted pyridines useful as cox-2 inhibitors | |
| JP6884857B2 (en) | Method for producing phenylalanine compounds | |
| Li et al. | Identification of highly potent and orally available free fatty acid receptor 1 agonists bearing isoxazole scaffold | |
| WO2019214467A1 (en) | Resolution method for axis chiral enantiomers of lesinurad | |
| CN107674027B (en) | 13C-marked pyraoxystrobin and synthetic method thereof | |
| Billman et al. | Amino Acids. IV. Amino Acids Related to Serine | |
| HUT64750A (en) | Process for the production of substituted benzoyl-benyole, biphenyl- and 2-oxazole-alcanic acid derivatives and of medical preparatives containing them | |
| JPH01156965A (en) | Thiohydantoin compound | |
| JPS6122043A (en) | Preparation of cycloalkylidenemethylphenylacetic acid derivative | |
| CN114315609A (en) | Process for preparing cis-2-aminocyclohexanol | |
| CN113620886A (en) | Preparation method of 2-substituted benzimidazole derivative | |
| US4393008A (en) | 2-Cyano-2-(3-phenoxy-phenyl)-propionic acid amide and preparation thereof | |
| JPS6044307B2 (en) | Novel O-alkylated oximes and their use as pharmaceuticals | |
| US9611217B2 (en) | Synthetic processes of carprofen | |
| JPH0567142B2 (en) | ||
| CN108383709A (en) | A kind of method that phase transfer catalysis process prepares high-purity Fenofibric Acid | |
| KR101475136B1 (en) | A green process for preparing 2-(4-formylphenyl)propionic acid in water solution | |
| CN113087655B (en) | Levobupivacaine intermediate compound | |
| JP2007246517A (en) | Process for producing optically active 5-hydroxy-3-keto ester compound | |
| CN107325075A (en) | A kind of preparation method of pomalidomide | |
| RU2015966C1 (en) | Process for preparing alkyl- (un)substituted 2-[4- (1-oxo-2- isoindolinyl) phenyl]acetic acids of nitriles thereof | |
| CN116102556A (en) | Preparation method of sitagliptin intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| TA01 | Transfer of patent application right | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20200813 Address after: 264205 Guangzhou East Road South and an East Road East, Wendeng economic and Technological Development Zone, Weihai City, Shandong Province Applicant after: Dijia Pharmaceutical Group Co.,Ltd. Applicant after: DISHA PHARMACEUTICAL GROUP Co.,Ltd. Address before: 264205 No.268 Tianrun Road, Wendeng Economic Development Zone, Weihai City, Shandong Province Applicant before: WEIHAI DISU PHARMACEUTICAL Co.,Ltd. Applicant before: DISHA PHARMACEUTICAL GROUP Co.,Ltd. |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20210610 Address after: No.1 Qingdao South Road, Weihai Economic and Technological Development Zone, Shandong Province Patentee after: Dijia Pharmaceutical Group Co.,Ltd. Address before: 264205 Wendeng economic and Technological Development Zone, Weihai City, Shandong Province Patentee before: Dijia Pharmaceutical Group Co.,Ltd. Patentee before: DISHA PHARMACEUTICAL GROUP Co.,Ltd. |
|
| CP02 | Change in the address of a patent holder | ||
| CP02 | Change in the address of a patent holder |
Address after: 264205 268 Tianrun Road, Wendeng economic and Technological Development Zone, Weihai, Shandong Patentee after: Dijia Pharmaceutical Group Co.,Ltd. Address before: No.1 Qingdao South Road, Weihai Economic and Technological Development Zone, Shandong Province Patentee before: Dijia Pharmaceutical Group Co.,Ltd. |
|
| CP03 | Change of name, title or address | ||
| CP03 | Change of name, title or address |
Address after: No. 268, Tianrun Road, Wendeng Economic and Technological Development Zone, Weihai City, Shandong Province, 264200 Patentee after: Dijia Pharmaceutical Group Co.,Ltd. Address before: 264205 268 Tianrun Road, Wendeng economic and Technological Development Zone, Weihai, Shandong Patentee before: Dijia Pharmaceutical Group Co.,Ltd. |