CN118164846A - Synthesis method of dexketoprofen, intermediate and application thereof - Google Patents
Synthesis method of dexketoprofen, intermediate and application thereof Download PDFInfo
- Publication number
- CN118164846A CN118164846A CN202211583566.2A CN202211583566A CN118164846A CN 118164846 A CN118164846 A CN 118164846A CN 202211583566 A CN202211583566 A CN 202211583566A CN 118164846 A CN118164846 A CN 118164846A
- Authority
- CN
- China
- Prior art keywords
- dexketoprofen
- cav
- reaction
- compound
- methanol
- 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.)
- Pending
Links
- 229960002783 dexketoprofen Drugs 0.000 title claims abstract description 32
- DKYWVDODHFEZIM-NSHDSACASA-N dexketoprofen Chemical compound OC(=O)[C@@H](C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-NSHDSACASA-N 0.000 title claims abstract description 32
- 238000001308 synthesis method Methods 0.000 title claims abstract description 6
- 238000000034 method Methods 0.000 claims abstract description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 15
- -1 2- (3-bromophenyl) -2-phenyl-1, 3-dioxolane Chemical compound 0.000 claims abstract description 10
- 239000011734 sodium Substances 0.000 claims abstract description 10
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 10
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 8
- UCKZQZDVQVFOHP-UHFFFAOYSA-N bromo propanoate Chemical compound CCC(=O)OBr UCKZQZDVQVFOHP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 230000002378 acidificating effect Effects 0.000 claims abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 29
- 238000006243 chemical reaction Methods 0.000 claims description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 5
- GFHNAMRJFCEERV-UHFFFAOYSA-L cobalt chloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].[Cl-].[Co+2] GFHNAMRJFCEERV-UHFFFAOYSA-L 0.000 claims description 5
- 238000002425 crystallisation Methods 0.000 claims description 5
- 230000008025 crystallization Effects 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 238000010189 synthetic method Methods 0.000 claims 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 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 239000011777 magnesium Substances 0.000 claims description 3
- 229910052749 magnesium Inorganic materials 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 239000012535 impurity Substances 0.000 claims description 2
- 239000008186 active pharmaceutical agent Substances 0.000 claims 1
- 229940088679 drug related substance Drugs 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000012071 phase Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 238000001914 filtration Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000005191 phase separation Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000004321 preservation Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 208000002193 Pain Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 230000036407 pain Effects 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- MONMFXREYOKQTI-REOHCLBHSA-N (2s)-2-bromopropanoic acid Chemical compound C[C@H](Br)C(O)=O MONMFXREYOKQTI-REOHCLBHSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 238000011914 asymmetric synthesis Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 230000006340 racemization Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 208000006820 Arthralgia Diseases 0.000 description 1
- 206010058019 Cancer Pain Diseases 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- 208000034656 Contusions Diseases 0.000 description 1
- 208000005171 Dysmenorrhea Diseases 0.000 description 1
- 206010013935 Dysmenorrhoea Diseases 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 206010018634 Gouty Arthritis Diseases 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- 206010024453 Ligament sprain Diseases 0.000 description 1
- 208000004550 Postoperative Pain Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 208000010040 Sprains and Strains Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 208000005298 acute pain Diseases 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000009519 contusion Effects 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000004371 toothache Diseases 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for synthesizing dexketoprofen, an intermediate and application thereof. The synthesis method comprises the steps of reacting 2- (3-bromophenyl) -2-phenyl-1, 3-dioxolane with S-2-sodium bromopropionate to generate a compound CAV-71-2 with chiral centers; the compound CAV-71-2 is deprotected under acidic conditions to produce dexketoprofen. In addition, the invention also provides a compound CAV-71-2 and application thereof in synthesizing intermediates of the dexketoprofen.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a method for synthesizing dexketoprofen, an intermediate compound CAV-71-2 thereof and application thereof.
Background
Dexketoprofen is a nonsteroidal anti-inflammatory drug with anti-inflammatory, analgesic, antipyretic effects, the mechanism of action of which may be related to inhibition of prostaglandin synthesis; is suitable for treating mild and moderate pains of different etiologies, such as joint pain of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, gouty arthritis, etc., and various acute and chronic pains such as dysmenorrhea, toothache, postoperative pain, cancer pain, acute sprain or soft tissue contusion pain, general pain caused by common cold and fever, etc.
Dexketoprofen (dexketoprofen), chemical name α -methyl-3-benzoyl-phenylacetic acid, has the following specific structural formula:
Dexketoprofen is a chiral compound, and the current methods for preparing dexketoprofen mainly comprise an asymmetric synthesis method and a racemization resolution method. The asymmetric synthesis method and the racemization resolution method have more complicated synthesis routes and more severe conditions.
Disclosure of Invention
The inventor develops a dextro-ketoprofen synthesis route with simple operation, which is shown as follows:
The synthetic method ensures that the dexketoprofen process route has the characteristics of reduced steps, easy operation and economy.
The invention aims to provide a novel method for synthesizing dexketoprofen.
It is another object of the present invention to provide an intermediate compound.
It is another object of the present invention to provide the use of an intermediate compound for the synthesis of dexketoprofen.
In an embodiment of the invention, the invention provides a method for synthesizing dexketoprofen, comprising the following steps:
(1) 2- (3-bromophenyl) -2-phenyl-1, 3-dioxolane reacts with magnesium scraps to prepare a format reagent, and then reacts with S-2-sodium bromopropionate to obtain a compound CAV-71-2;
(2) And (3) deprotecting the compound CAV-71-2 obtained in the step (1) under an acidic condition to obtain the dexketoprofen.
In the above-mentioned method for preparing dexketoprofen of the present invention, the step (1) is performed in an organic solvent selected from one of tetrahydrofuran, diethyl ether and 2-methyltetrahydrofuran, preferably tetrahydrofuran.
In the method for preparing dexketoprofen according to the present invention, the step (1) is performed in the presence of a catalyst, and the catalyst may be cobalt chloride hexahydrate.
In the preparation method of the dexketoprofen, the reaction with S-2-bromopropionic acid sodium in the step (1) is carried out at a low temperature, and the reaction temperature is optionally-10-0 ℃.
In the preparation method of the dexketoprofen, the step (1) further comprises acidification with a dilute acid such as dilute hydrochloric acid (e.g. 2N hydrochloric acid) after the reaction with the S-2-bromopropionic acid sodium is completed; more preferably, the method further comprises the steps of sequentially adding alkali to form salt, and then acidifying and dissociating; here, the base used for the salt formation is sodium carbonate, potassium carbonate, or sodium hydroxide, preferably potassium carbonate.
In the method for preparing dexketoprofen according to the present invention, the reaction in the step (2) is performed in a hydrophilic organic solvent selected from one of methanol, ethanol, 1, 4-dioxane and tetrahydrofuran, preferably methanol.
In the method for preparing dexketoprofen according to the present invention, the acidic condition of the step (2) means to use one selected from concentrated hydrochloric acid and trifluoroacetic acid, preferably concentrated hydrochloric acid.
In the method for preparing dexketoprofen according to the present invention, the reaction in the step (2) further comprises a step of solvent crystallization, preferably, the crystallization solvent is selected from one of methanol, ethanol and isopropanol, and preferably, methanol.
In a second aspect, the present invention provides the compound CAV-71-2
In a third aspect, the invention provides the use of compound CAV-71-2 as an intermediate in a process route for synthesizing dexketoprofen, and as an impurity reference in quality study or control of dexketoprofen bulk drug.
Detailed Description
For the purpose of illustrating the embodiments of the present invention, the following examples of implementation are provided. These examples are illustrative only and are not intended to limit the scope of the invention.
In some examples, the invention provides a method for preparing dexketoprofen, comprising the steps of:
(1) After the Grignard reaction is initiated by iodine, the residual 2- (3-bromophenyl) -2-phenyl-1, 3-dioxolane is dripped, and the reaction is carried out for 1-6 hours while maintaining the temperature until the reaction is finished, the mol ratio of 2- (3-bromophenyl) -2-phenyl-1, 3-dioxolane to magnesium chips is 1:1, after the reaction is finished, the temperature is reduced to-10 ℃ to 0 ℃, cobalt chloride hexahydrate is added between-10 ℃ and 0 ℃, S-2-sodium bromopropionate is added in batches, the mol ratio of the raw materials to the S-2-sodium bromopropionate is 1:0.95-1.2, the reaction is carried out for 1-4 hours at the temperature of 10 ℃, 2N hydrochloric acid is dripped at the temperature of less than 10 ℃, the reaction is carried out for 2 hours, the filtration, ethyl acetate leaching residues, phase separation is carried out, the ethyl acetate extraction aqueous phase is carried out, the anhydrous sodium sulfate is combined, the drying is carried out, and the concentrated solvent is removed. Adding toluene and 10% potassium carbonate solution into the concentrate, heating to 70-90 ℃ and stirring for 0.5-3h, carrying out phase separation while the mixture is hot, adding 10% potassium carbonate solution into the organic phase, heating to 70-90 ℃ and stirring for 0.5-3h, carrying out phase separation while the mixture is hot, merging the water phases, carrying out free crystallization under the condition that the pH of hydrochloric acid is less than 2-3, stirring for 10-60min, and drying at 50-60 ℃ to obtain the intermediate cell CAV-71-2.
(2) Reflux-reacting the intermediate CAV-71-2 obtained in the step (1) with concentrated hydrochloric acid for 1-6h in methanol at a mass-volume ratio of 1/(0.9-2), adding dichloromethane and water after the reaction is finished, stirring, separating phases, washing an organic phase with water, drying with anhydrous sodium sulfate, filtering, concentrating to remove a solvent, crystallizing with alcohol, filtering, and drying at 50-60 ℃ to obtain the dexketoprofen.
Example 1
To a 100ml dry four-necked flask, 0.18g of magnesium turnings, one particle of iodine was added and stirred. A solution of about 1/5 of 2.00g of 2- (3-bromophenyl) -2-phenyl-1, 3-dioxolan in tetrahydrofuran (10 ml) was added dropwise thereto under nitrogen, and the mixture was reacted at 45-55℃with reddish brown to brown. After initiation, the remaining solution of 2- (3-bromophenyl) -2-phenyl-1, 3-dioxolane in tetrahydrofuran was added dropwise under heat preservation. And (3) carrying out heat preservation reaction for 2 hours, and finishing the reaction of the raw materials.
Cooling to-10 ℃. 0.0004g of cobalt chloride hexahydrate was added. 1.16g S-2-sodium bromopropionate is added in portions at the temperature of less than 0 ℃. The reaction is carried out for 2h at 0 ℃. After the reaction of the raw materials, dropwise adding 10ml of 2N hydrochloric acid at the temperature of less than 10 ℃, stirring for 2 hours, filtering, leaching filter residues with 5ml of ethyl acetate, separating phases of the filtrate, extracting the water phase with 20ml of ethyl acetate, combining the organic phases, drying with anhydrous sodium sulfate, filtering, and concentrating at 50 ℃ to remove the solvent. Adding 20ml of toluene, 10ml of 10% potassium carbonate solution, heating to 80 ℃, preserving heat for 1h, separating phases while the organic phase is hot, adding 10ml of 10% potassium carbonate solution, heating to 80 ℃, preserving heat for 1h, separating phases, combining aqueous phases, adjusting pH to 2.0 with 6N hydrochloric acid, filtering, and drying at 50 ℃. 0.98g of a white solid was obtained in 50% yield.
Example 2
To a 100ml dry four-necked flask, 0.48g of magnesium turnings, one particle of iodine was added and stirred. A solution of about 1/5 of 2- (3-bromophenyl) -2-phenyl-1, 3-dioxolan in tetrahydrofuran (30 ml) was added dropwise thereto under nitrogen, and the mixture was reacted at 45-55℃with reddish brown to brown. After initiation, the remaining solution of 2- (3-bromophenyl) -2-phenyl-1, 3-dioxolane in tetrahydrofuran was added dropwise under heat preservation. And (3) carrying out heat preservation reaction for 3 hours, and finishing the reaction of the raw materials.
Cooling to-10 ℃. 0.0012g of cobalt chloride hexahydrate was added. 3.48g S-2-sodium bromopropionate is added in portions at the temperature of less than 0 ℃. The reaction is carried out for 3h at 0 ℃. After the reaction, 30ml of 2N hydrochloric acid is added dropwise under the condition of the temperature of less than 10 ℃, the mixture is stirred for 2 hours, filtered, and the filter residue is leached by 15ml of ethyl acetate, the filtrate is split, the water phase is extracted by 60ml of ethyl acetate, the organic phases are combined, dried by anhydrous sodium sulfate, filtered, and the solvent is removed by concentration at 50 ℃. 60ml of toluene, 30ml of 10% potassium carbonate solution are added, the temperature is raised to 80 ℃, the mixture is kept for 1h, the phases are separated while the mixture is hot, 10ml of 10% potassium carbonate solution are added to the organic phase, the temperature is raised to 80 ℃, the reaction is kept for 1h, the phases are separated, the aqueous phase is combined, 6N hydrochloric acid is used for adjusting the PH value to be 2.0, the filtration is carried out, and the mixture is dried at 50 ℃. 3.23g of a white solid was obtained in 55.1% yield.
Preparation of dexketoprofen
Example 3
To a dry four-necked flask, 0.50g of 71A-3,5.00ml of methanol and 0.50ml of hydrochloric acid were added and stirred. And heating and refluxing for 2 hours. After the reaction of the raw materials is completed, 10ml of dichloromethane and 20ml of water are added, stirring is carried out for 30min, phase separation is carried out, an organic phase is washed by 10ml of water, dried by anhydrous sodium sulfate, filtered, concentrated to remove the solvent at 50 ℃,3ml of methanol is crystallized, and dried at 55 ℃. 0.37g of white solid is obtained in 86.85% yield.
Example 4
To a dry four-necked flask, 0.90g of 71A-3,5.00ml of methanol and 1.0ml of hydrochloric acid were added and stirred. And heating and refluxing for reaction for 3 hours. After the reaction of the raw materials is completed, 20ml of dichloromethane and 36ml of water are added, stirring is carried out for 30min, phase separation is carried out, an organic phase is washed by 16ml of water, dried by anhydrous sodium sulfate, filtered, concentrated to remove the solvent at 50 ℃,6ml of methanol is crystallized, and dried at 55 ℃. 0.65g of a white solid was obtained in 84.7% yield.
Claims (9)
1. A method for synthesizing dexketoprofen comprises the following steps:
(1) 2- (3-bromophenyl) -2-phenyl-1, 3-dioxolane reacts with magnesium scraps to prepare a format reagent, and then reacts with S-2-sodium bromopropionate to obtain a compound CAV-71-2;
(2) And (3) deprotecting the compound CAV-71-2 obtained in the step (1) under an acidic condition to obtain the dexketoprofen.
2. The synthetic method of claim 1, wherein step (1) is performed in an organic solvent selected from one of tetrahydrofuran, diethyl ether and 2-methyltetrahydrofuran, preferably tetrahydrofuran.
3. The synthetic method of claim 1, wherein step (1) is performed in the presence of a catalyst, optionally cobalt chloride hexahydrate.
4. The synthetic method of claim 1, wherein the reaction with sodium S-2-bromopropionate in step (1) is performed at a low temperature, optionally-10 ℃ to 0 ℃.
5. The synthesis method according to any one of claims 1 to 4, wherein the reaction of step (2) is carried out in a hydrophilic organic solvent selected from one of methanol, ethanol, 1, 4-dioxane, tetrahydrofuran, preferably methanol.
6. The synthesis method according to any one of claims 1 to 4, wherein the acidic condition of step (2) means the use of one selected from concentrated hydrochloric acid and trifluoroacetic acid, preferably concentrated hydrochloric acid.
7. The synthesis method according to claim 1, wherein the reaction of step (2) further comprises a step of solvent crystallization after completion, preferably the crystallization solvent is selected from one of methanol, ethanol and isopropanol, preferably methanol.
8. Compound CAV-71-2
9. Use of the compound CAV-71-2 of claim 8 as an intermediate in a process route for synthesizing dexketoprofen, or as an impurity reference in quality study or control of dexketoprofen drug substance.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211583566.2A CN118164846A (en) | 2022-12-10 | 2022-12-10 | Synthesis method of dexketoprofen, intermediate and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211583566.2A CN118164846A (en) | 2022-12-10 | 2022-12-10 | Synthesis method of dexketoprofen, intermediate and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN118164846A true CN118164846A (en) | 2024-06-11 |
Family
ID=91345966
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211583566.2A Pending CN118164846A (en) | 2022-12-10 | 2022-12-10 | Synthesis method of dexketoprofen, intermediate and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN118164846A (en) |
-
2022
- 2022-12-10 CN CN202211583566.2A patent/CN118164846A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2013026391A1 (en) | Synthesis method of azoxystrobin and exclusive intermediate in the synthesis thereof | |
| CN115850286B (en) | Vitamin Bei Gelong intermediate and preparation method thereof | |
| CN112500361A (en) | Preparation method of (S) -4-phenyl-2-oxazolidinone | |
| CN118164846A (en) | Synthesis method of dexketoprofen, intermediate and application thereof | |
| CN111662245A (en) | Synthesis method of ethyl-3-oxylidene-1-oxa-4-azaspiro [5.5] undecane-9-formic acid ester | |
| CN103087090B (en) | Synthetic method of 2-dipalmitoyl-sn-glycero-3-phosphoethanolamine | |
| CN111943862A (en) | Preparation method of heart failure resistant drug Entresto key component Shakuba koji | |
| CN100387586C (en) | Synthesis method of chiral 2-amino-1- (6-fluoro-3, 4-dihydrobenzopyranyl) ethanol | |
| CN112645813B (en) | Preparation method of (R) -3-cyclohexene carboxylic acid | |
| CN111269094B (en) | Preparation method of 2-bromo-1, 3-dimethoxybenzene | |
| CN107857710A (en) | A kind of preparation method of antiepileptic Pregabalin | |
| CN109265385B (en) | Synthesis process of chiral catalyst | |
| CN109651234B (en) | Synthesis method of donepezil hydrochloride | |
| CN113816837A (en) | Synthesis method of 4,4' -dimethoxy triphenylchloromethane | |
| CN113234447A (en) | Preparation method of biphenyl liquid crystal material | |
| CN112125790A (en) | Synthesis method of 7-chloro-1-naphthaldehyde | |
| CN112062740B (en) | Synthesis method of (R) -4-propyl dihydrofuran-2-ketone | |
| CN111217709A (en) | Preparation method of (1-fluorocyclopropyl) methylamine hydrochloride | |
| CN115448858B (en) | Efficient synthesis process of 2-chloroethyl sodium sulfonate | |
| CN111138293B (en) | Method for synthesizing ibutilide fumarate intermediate by using microchannel reactor | |
| CN110483360B (en) | Synthesis method of alfaprost alcohol | |
| CN118561748B (en) | Method for preparing 2-amino-4-chloro-5-nitropyridine | |
| CN112125864B (en) | Synthesis method of 1,1 '-diamino-5, 5' -bitetrazole | |
| JP5083753B2 (en) | Novel process for producing 4,5-dimethyl- [1,3] diselenol-2-thelone | |
| CN105712905B (en) | A kind of method that cleaning prepares high-purity methane sulfonic acid copper |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication |