CN109516933B - Preparation method of silodosin intermediate - Google Patents
Preparation method of silodosin intermediate Download PDFInfo
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- CN109516933B CN109516933B CN201811269403.0A CN201811269403A CN109516933B CN 109516933 B CN109516933 B CN 109516933B CN 201811269403 A CN201811269403 A CN 201811269403A CN 109516933 B CN109516933 B CN 109516933B
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- trifluoroethoxy
- phenoxy
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- PNCPYILNMDWPEY-QGZVFWFLSA-N silodosin Chemical compound N([C@@H](CC=1C=C(C=2N(CCCO)CCC=2C=1)C(N)=O)C)CCOC1=CC=CC=C1OCC(F)(F)F PNCPYILNMDWPEY-QGZVFWFLSA-N 0.000 title claims abstract description 34
- 229960004953 silodosin Drugs 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 92
- -1 2- [2- (2,2, 2-trifluoroethoxy) phenoxy ] ethyl Chemical group 0.000 claims abstract description 40
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical compound OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 claims abstract description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Natural products CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 17
- 235000019441 ethanol Nutrition 0.000 claims abstract description 17
- WGHPWLUYIPUQOJ-UHFFFAOYSA-N 2-(2-hydroxyethoxy)benzaldehyde Chemical compound OCCOC1=CC=CC=C1C=O WGHPWLUYIPUQOJ-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 13
- 238000007027 Dakin phenol oxidation reaction Methods 0.000 claims abstract description 12
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims abstract description 12
- KMTRUDSVKNLOMY-UHFFFAOYSA-N Ethylene carbonate Chemical compound O=C1OCCO1 KMTRUDSVKNLOMY-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims abstract description 11
- 238000006266 etherification reaction Methods 0.000 claims abstract description 11
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims abstract description 11
- HOJMCBMXHWZNKX-UHFFFAOYSA-N 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCOC1=CC=CC=C1OCC(F)(F)F HOJMCBMXHWZNKX-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 6
- 238000005886 esterification reaction Methods 0.000 claims abstract description 4
- 150000002148 esters Chemical group 0.000 claims abstract 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 39
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 22
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 230000035484 reaction time Effects 0.000 claims description 9
- 238000005809 transesterification reaction Methods 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 6
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 claims description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 5
- NDKBVBUGCNGSJJ-UHFFFAOYSA-M benzyltrimethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)CC1=CC=CC=C1 NDKBVBUGCNGSJJ-UHFFFAOYSA-M 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 150000002978 peroxides Chemical class 0.000 claims description 3
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 2
- XCRBXWCUXJNEFX-UHFFFAOYSA-N peroxybenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1 XCRBXWCUXJNEFX-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 27
- 230000015572 biosynthetic process Effects 0.000 abstract description 20
- 238000003786 synthesis reaction Methods 0.000 abstract description 20
- 230000007613 environmental effect Effects 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 238000010907 mechanical stirring Methods 0.000 description 16
- 238000001914 filtration Methods 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- 239000000126 substance Substances 0.000 description 12
- 239000005457 ice water Substances 0.000 description 10
- 238000001035 drying Methods 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 6
- 239000012295 chemical reaction liquid Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 4
- 235000019345 sodium thiosulphate Nutrition 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 4
- RKOUFQLNMRAACI-UHFFFAOYSA-N 1,1,1-trifluoro-2-iodoethane Chemical compound FC(F)(F)CI RKOUFQLNMRAACI-UHFFFAOYSA-N 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 2
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 2
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 2
- 238000006193 diazotization reaction Methods 0.000 description 2
- LHGVFZTZFXWLCP-UHFFFAOYSA-N guaiacol Chemical compound COC1=CC=CC=C1O LHGVFZTZFXWLCP-UHFFFAOYSA-N 0.000 description 2
- 231100000086 high toxicity Toxicity 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- BFCFYVKQTRLZHA-UHFFFAOYSA-N 1-chloro-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1Cl BFCFYVKQTRLZHA-UHFFFAOYSA-N 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- 238000010960 commercial process Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229960001867 guaiacol Drugs 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/64—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of functional groups containing oxygen only in singly bound form
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of a silodosin intermediate, which relates to the technical field of pharmaceutical chemistry synthesis and comprises the following steps: carrying out ester exchange reaction on salicylaldehyde and ethylene carbonate to obtain 2- (2-hydroxyethoxy) benzaldehyde; then obtaining 2- (2-hydroxyethoxy) sodium phenolate through Dakin oxidation reaction; then carrying out etherification reaction with trifluoroethanol to obtain 2- [2- (2,2, 2-trifluoroethoxy) phenoxy ] ethyl alcohol; finally, the intermediate 2- [2- (2,2, 2-trifluoroethoxy) phenoxy ] ethyl methanesulfonate of silodosin is obtained through esterification reaction with methanesulfonyl chloride. The invention has novel and short synthetic route, and can prepare the target product only by four steps of reaction. The method has the advantages of cheap and easily-obtained raw materials and reagents, environmental protection, mild and controllable reaction conditions, convenient and simple operation, good purity of the prepared silodosin intermediate, high yield, suitability for industrial production, wide prospect and industrial application value.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemistry synthesis, in particular to a preparation method of a silodosin intermediate.
Background
Silodosin (silodosin), chemically known as 2, 3-dihydro-1- (3-hydroxypropyl) -5- [ (2R) -2- [2- [2- (2,2, 2-trifluoroethoxy) phenoxy ] ethylamino ] propyl ] -1H-indole-7-carboxamide, is an α 1A receptor antagonist developed by Kissei pharmaceutical company, first marketed in japan in 5 months of 2006 and approved by FDA in 10 months of 2008, officially marketed in the united states under the trade name of uri. Silodosin is used clinically to treat symptoms associated with Benign Prostatic Hyperplasia (BPH) or hypertrophy.
[2- (2,2, 2-trifluoroethoxy) phenoxy ] ethyl methanesulfonate (1) is an important intermediate of silodosin, and the following routes are mainly used for the synthesis of (1).
The first synthetic route is as follows: european patent EP600675 reports a synthetic route to [2- (2,2, 2-trifluoroethoxy) phenoxy ] ethyl methanesulfonate (1) starting from guaiacol, which is etherified with trifluoroiodoethane, demethylated with boron tribromide, etherified with ethyl bromoacetate, reduced with lithium aluminum hydride, and finally esterified with methanesulfonyl chloride to give [2- (2,2, 2-trifluoroethoxy) phenoxy ] ethyl methanesulfonate (1).
The route has multiple steps, and uses expensive trifluoroiodoethane with poor stability, boron tribromide with high toxicity and corrosivity and lithium aluminum hydride with high risk, so that the route has high cost, difficult control and high risk and is difficult to realize industrial production.
The second synthetic route is as follows: chinese Chemical letters.200819 (1): 59-60, reports a novel synthetic route of [2- (2,2, 2-trifluoroethoxy) phenoxy ] ethyl methanesulfonate (1), which uses o-nitrochlorobenzene as a starting material, and obtains o-hydroxy trifluoroethyl ether by trifluoroethanol etherification, palladium-carbon nitro reduction, diazotization and hydrolysis, and can be used for further preparing silodosin intermediate.
The route avoids using expensive trifluoroiodoethane in the first route, but needs nitro reduction and diazotization hydrolysis, has low yield and explosion danger, and makes the route difficult to realize industrial large-scale production.
The third synthetic route is as follows: chinese patent CN102320996 reports a synthetic route which can obtain a target compound by only two steps, and uses catechol as a starting material to obtain [2- (2,2, 2-trifluoroethoxy) phenoxy ] ethyl methanesulfonate through two transesterification reactions.
The route is very perfect, novel and short in steps, but because the reaction has selectivity problems, the side reactions of the system are more, so that the good separation is difficult to realize, and the ideal result cannot be obtained after several attempts. Making the route difficult to implement in commercial processes.
In conclusion, the synthesis of silodosin intermediate [2- (2,2, 2-trifluoroethoxy) phenoxy ] ethyl methanesulfonate is difficult to store due to expensive raw materials and poor stability, and reagents used in the reaction have high toxicity; or because of low yield, a reaction with high risk and difficult control is adopted; or the product purity is poor due to poor reaction selectivity, so that the separation and purification are difficult. Therefore, a synthetic route which has the advantages of cheap and easily obtained raw materials, convenient and simple operation, novel route, environmental protection and high yield is found, and has wide prospect.
Disclosure of Invention
Based on the technical problems in the background art, the invention provides a preparation method of a silodosin intermediate, which has the advantages of novel route, cheap and easily-obtained reaction raw materials, environmental protection, convenient and simple operation, high yield and high purity of the prepared silodosin intermediate.
The invention provides a preparation method of a silodosin intermediate, which comprises the following synthetic route:
the method comprises the following steps:
performing transesterification on S1, salicylaldehyde (formula II) and ethylene carbonate to obtain 2- (2-hydroxyethoxy) benzaldehyde (formula III);
s2, carrying out Dakin oxidation reaction on 2- (2-hydroxyethoxy) benzaldehyde (formula III) to obtain 2- (2-hydroxyethoxy) sodium phenolate (formula IV);
s3, carrying out etherification reaction on 2- (2-hydroxyethoxy) sodium phenolate (formula IV) and trifluoroethanol to obtain 2- [2- (2,2, 2-trifluoroethoxy) phenoxy ] ethyl alcohol (formula V);
s4, 2- [2- (2,2, 2-trifluoroethoxy) phenoxy ] ethyl alcohol (formula V) and methanesulfonyl chloride are subjected to esterification reaction to obtain silodosin intermediate 2- [2- (2,2, 2-trifluoroethoxy) phenoxy ] ethyl methanesulfonate (formula I).
Preferably, in S1, the molar ratio of salicylaldehyde to ethylene carbonate is 1: 1-1.5, preferably 1: 1.1; preferably, the reaction temperature of the transesterification reaction is 110-130 ℃, the reaction time is 7-10h, preferably the reaction temperature is 120 ℃, and the reaction time is 8 h.
Preferably, in S1, the solvent for the transesterification reaction is one or more of N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, and N-methylpyrrolidone, preferably N, N-dimethylformamide; preferably, the catalyst for the transesterification reaction is one or more of sodium carbonate, potassium carbonate, cesium carbonate, preferably potassium carbonate.
Preferably, in S2, the Dakin oxidation reaction is carried out at a temperature of 30-70 ℃ for 1-4 h.
Preferably, in S2, the peroxide used in the Dakin oxidation reaction is one or more of hydrogen peroxide, peracetic acid, tert-butyl hydroperoxide, oxone, m-chloroperoxybenzoic acid and peroxybenzoic acid, preferably hydrogen peroxide; preferably, the alkaline reagent used in the Dakin oxidation reaction is one or more of sodium hydroxide, potassium hydroxide, trimethyl benzyl ammonium hydroxide and tetramethyl amino hydroxide, and sodium hydroxide is preferred.
Preferably, in S3, the molar ratio of sodium 2- (2-hydroxyethoxy) phenolate to trifluoroethanol is 1: 1.5-2.5; preferably 1: 2.
preferably, in S3, the reaction temperature of the etherification reaction is 60-160 ℃, and the reaction time is 8-16 h; the reaction temperature is preferably 110 ℃ and the reaction time is 12 h.
Preferably, in S3, the solvent for the etherification reaction is one or more of N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, and N-methylpyrrolidone, preferably N, N-dimethylformamide.
Preferably, in S4, the molar ratio of 2- [2- (2,2, 2-trifluoroethoxy) phenoxy ] ethyl alcohol to methanesulfonyl chloride is 1: 1.2-4.
The invention also provides a silodosin intermediate prepared by the method.
Has the advantages that: the invention discloses a preparation method of a silodosin intermediate, which has a novel route and a short synthetic route, and can prepare a target product only by four-step reaction. The method has the advantages of cheap and easily-obtained raw materials and reagents, environmental protection, mild and controllable reaction conditions, convenient and simple operation, good purity of the prepared silodosin intermediate, high yield, suitability for industrial production, wide prospect and industrial application value, and the purity of the product obtained in each step can reach more than 96%.
Detailed Description
Examples
The invention provides a preparation method of a silodosin intermediate, which comprises the following synthetic route:
the method comprises the following steps:
performing transesterification on S1, salicylaldehyde (formula II) and ethylene carbonate to obtain 2- (2-hydroxyethoxy) benzaldehyde (formula III);
s2, carrying out Dakin oxidation reaction on 2- (2-hydroxyethoxy) benzaldehyde (formula III) to obtain 2- (2-hydroxyethoxy) sodium phenolate (formula IV);
s3, carrying out etherification reaction on 2- (2-hydroxyethoxy) sodium phenolate (formula IV) and trifluoroethanol to obtain 2- [2- (2,2, 2-trifluoroethoxy) phenoxy ] ethyl alcohol (formula V);
s4, 2- [2- (2,2, 2-trifluoroethoxy) phenoxy ] ethyl alcohol (formula V) and methanesulfonyl chloride are subjected to esterification reaction to obtain silodosin intermediate 2- [2- (2,2, 2-trifluoroethoxy) phenoxy ] ethyl methanesulfonate (formula I).
It should be noted that, in the above steps S1-S4, other auxiliary steps for collecting the product, increasing the yield, increasing the purity of the product, removing impurities, etc. may be added, such as common auxiliary means of filtration, washing, extraction, purification, drying, etc.
The technical solution of the present invention will be described in detail below with reference to specific examples.
Example 1
The invention provides a preparation method of a silodosin intermediate, which comprises the following steps:
s1 Synthesis of 2- (2-hydroxyethoxy) benzaldehyde (formula III)
200g (1.64mol, 1.0eq) of salicylaldehyde participating in the reaction, 145g (1.64mol, 1.0eq) of ethylene carbonate, 535g (1.64mol, 1.0eq) of cesium carbonate, 600mL of dimethyl sulfoxide and 600mL of N-methylpyrrolidone are sequentially added into a 2000mL four-neck flask with mechanical stirring, the temperature is raised to 130 ℃ under the protection of nitrogen, the temperature is kept for reaction for 10 hours, the HPLC raw material is sampled and completely converted, the reaction system is cooled to room temperature, and the filtration is carried out. The filtrate was poured into 1000mL of ice water, extracted with 500mL x 3 of ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate to give 200g of pale yellow oil with 73.3% yield and 97.8% purity.
S2 Synthesis of sodium 2- (2-hydroxyethoxy) phenolate (formula IV)
Under the protection of nitrogen, 166g (1.0mol, 1.0eq) of 2- (2-hydroxyethoxy) benzaldehyde and 1000mL (1.0mol, 1.0eq) of 1.0M potassium hydroxide which are involved in the reaction are sequentially added into a 2000mL four-neck flask with mechanical stirring, 300g (1.0mol, 1.0eq) of 30% tert-butyl hydroperoxide is slowly dropped into the flask under mechanical stirring, the reaction temperature is controlled to be not higher than 20 ℃, the temperature is raised to 30 ℃ after dropping is finished, the reaction is continued for 1 hour, the reaction is monitored by HPLC, after the raw materials are completely converted, the raw materials are quenched by sodium thiosulfate, the pH value is adjusted to about 5 by dilute hydrochloric acid, the raw materials are extracted by ethyl acetate, the oily materials are obtained by concentration, the oily materials are poured into a 1.0M sodium hydroxide aqueous solution, the pH value is adjusted to about 10, the mixture is stirred for 30 minutes, and the mixture is concentrated under reduced pressure to obtain 146g of off-white solid, the yield is 82.
S3 Synthesis of 2- [2- (2,2, 2-trifluoroethoxy) phenoxy ] ethyl alcohol (formula V)
Under the protection of nitrogen, 132g (0.75mol, 1.0eq) of sodium 2- (2-hydroxyethoxy) phenolate and 104g (0.75mol, 1.0eq) of potassium carbonate, 113g (1.13mol, 1.5eq) of trifluoroethanol, which are involved in the reaction, are sequentially added into a 2000mL four-necked flask with mechanical stirring, the temperature is raised to 60 ℃ for heat preservation and reaction for 8 hours, the reaction progress is monitored by HPLC, after the raw materials are completely converted, the mixture is cooled to room temperature, the reaction liquid is filtered, the filtrate is poured into 1000mL of ice water, the mixture is extracted by 500mL of 3 ethyl acetate, anhydrous sodium sulfate is dried, the dry light black oily substance is concentrated, and the colorless viscous liquid 143g is obtained by reduced pressure distillation, the yield is 80.8%, and the purity is 98.0%.
Synthesis of S4, 2- [2- (2,2, 2-trifluoroethoxy) phenoxy ] ethyl methanesulfonate (formula I)
In a 3000mL four-necked flask equipped with a mechanical stirrer, 129g (0.55mol, 1.0eq) of 2- [2- (2,2, 2-trifluoroethoxy) phenoxy ] ethyl alcohol, 67g (0.66mol, 1.2eq) of triethylamine, and 1000mL of dichloromethane were sequentially added to reduce the temperature of the reaction system to about 0 ℃ under an ice salt bath, and 75g (0.66mol, 1.2eq) of methanesulfonyl chloride dissolved in 500mL of dichloromethane was slowly added dropwise while controlling the temperature of the reaction system to be not higher than 20 ℃. After the dropwise addition, removing the deicing salt bath, heating to reflux reaction for 3 hours, cooling to room temperature, filtering to remove triethylamine hydrochloride, washing the filtrate with 1000ml of 3 saturated sodium carbonate, drying with anhydrous sodium sulfate, filtering, concentrating the dried gray oily substance under reduced pressure, adding 400g of isopropanol, stirring at 0 ℃ for crystallization for 6 hours, filtering, and drying in vacuum to obtain 150g of white solid, wherein the melting point is 39-42 ℃, the yield is 86.7%, and the purity is 98.0%.
Example 2
The invention provides a preparation method of a silodosin intermediate, which comprises the following steps:
s1 Synthesis of 2- (2-hydroxyethoxy) benzaldehyde (formula III)
200g (1.64mol, 1.0eq) of salicylaldehyde participating in the reaction, 217g (2.46mol, 1.5eq) of ethylene carbonate, 679g (4.92mol, 3.0eq) of potassium carbonate and 1000mL of N, N-dimethylacetamide are sequentially added into a 2000mL four-neck flask with mechanical stirring, the temperature is raised to 110 ℃ under the protection of nitrogen, the reaction is kept for 7 hours, the HPLC raw material is sampled and completely converted, the reaction system is cooled to room temperature, and the mixture is filtered. The filtrate was poured into 1000mL of ice water, extracted with 500mL x 3 of ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate to give 216g of pale yellow oil with 79.1% yield and 98.0% purity.
S2 Synthesis of sodium 2- (2-hydroxyethoxy) phenolate (formula IV)
Under the protection of nitrogen, 200g (1.2mol, 1.0eq) of 2- (2-hydroxyethoxy) benzaldehyde to be reacted, 100g (0.6mol, 0.5eq) of trimethyl benzyl ammonium hydroxide and 1200mL (1.2mol, 1.0eq) of 1.0M sodium hydroxide are sequentially added into a 2000mL four-neck flask with mechanical stirring, 547g (2.16mol, 1.8eq) of 30% peracetic acid is slowly dropped into the flask under mechanical stirring, the temperature of the reaction is controlled to be not higher than 20 ℃, the flask is heated to 70 ℃ after dropping, the reaction is continued for 4 hours, the HPLC monitors the reaction, the raw materials are quenched by sodium thiosulfate after complete conversion, the pH is adjusted to about 5 by dilute hydrochloric acid, the raw materials are extracted by ethyl acetate, oil is obtained by concentration, the oily matter is poured into 1.0M sodium hydroxide aqueous solution, the pH is adjusted to about 10, after stirring for 30 minutes, the oily matter is concentrated by decompression, the off-white solid is obtained by concentration, the yield is 88.7%, and the purity is 96.7%.
S3 Synthesis of 2- [2- (2,2, 2-trifluoroethoxy) phenoxy ] ethyl alcohol (formula V)
Under the protection of nitrogen, 176g (1.0mol, 1.0eq) of sodium 2- (2-hydroxyethoxy) phenolate participating in the reaction, 414g (3.0mol, 3.0eq) of potassium carbonate, 250g (2.5mol, 2.5eq) of trifluoroethanol, 400mL of N-methylpyrrolidone and 1000mL of N, N-dimethylformamide are added in sequence into a 2000mL four-neck flask with mechanical stirring, the temperature is raised to 160 ℃, the reaction is kept for 16 hours, the reaction process is monitored by HPLC, after the raw materials are completely converted, the reaction liquid is cooled to room temperature, the reaction liquid is filtered, the filtrate is poured into 1000mL of ice water, and then the ice water is extracted by 500mL of ethyl acetate of 3, dried by anhydrous sodium sulfate, a dry black light oily substance is concentrated, and the colorless viscous liquid is obtained by reduced pressure distillation, the yield is 89.8%, and the purity is 98.4%.
Synthesis of S4, 2- [2- (2,2, 2-trifluoroethoxy) phenoxy ] ethyl methanesulfonate (formula I)
200g (0.85mol, 1.0eq) of 2- [2- (2,2, 2-trifluoroethoxy) phenoxy ] ethyl alcohol, 155g (1.53mol, 1.8eq) of triethylamine and 2400mL of dichloromethane which are involved in the reaction were sequentially added to a 5000mL four-necked flask equipped with a mechanical stirrer, and the temperature of the reaction system was lowered to about 0 ℃ under an ice salt bath, and 388g (3.4mol, 4.0eq) of methanesulfonyl chloride dissolved in 1000mL of dichloromethane was slowly added dropwise while controlling the temperature of the reaction system to be not higher than 20 ℃. After the dropwise addition, removing the deicing salt bath, heating to reflux reaction for 4 hours, cooling to room temperature, filtering to remove triethylamine hydrochloride, washing the filtrate with 1000ml of 3 saturated sodium carbonate, drying with anhydrous sodium sulfate, filtering, concentrating the dried gray oily substance under reduced pressure, adding 400g of isopropanol, stirring at 0 ℃ for crystallization for 6 hours, filtering, and drying in vacuum to obtain 247g of white solid, wherein the melting point is 39-42 ℃, the yield is 92.5%, and the purity is 98.3%.
Example 3
The invention provides a preparation method of a silodosin intermediate, which comprises the following steps:
s1 Synthesis of 2- (2-hydroxyethoxy) benzaldehyde (formula III)
200g (1.64mol, 1.0eq) of salicylaldehyde participating in the reaction, 188g (2.13mol, 1.3eq) of ethylene carbonate, 680g (2.46mol, 3.0eq) of potassium carbonate and 1000mL of N, N-dimethylformamide are sequentially added into a 2000mL four-neck flask with mechanical stirring, the temperature is raised to 120 ℃ under the protection of nitrogen, the reaction is kept for 9 hours, the HPLC raw material is sampled and completely converted, the reaction system is cooled to the room temperature, and the mixture is filtered. The filtrate was poured into 1000mL of ice water, extracted with 500mL x 3 of ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate to give 214g of pale yellow oil with a yield of 78.4% and a purity of 98.2%.
S2 Synthesis of sodium 2- (2-hydroxyethoxy) phenolate (formula IV)
Under the protection of nitrogen, 200g (1.2mol, 1.0eq) of 2- (2-hydroxyethoxy) benzaldehyde and 1440mL (1.44mol,1.2eq) of 1.0M sodium hydroxide which are involved in the reaction are sequentially added into a 2000mL four-neck flask with mechanical stirring, 205g (1.8mol,1.5eq) of 30% hydrogen peroxide is slowly dropped into the flask with mechanical stirring, the reaction temperature is controlled to be not higher than 20 ℃, the temperature is raised to 50 ℃ after the dropping is finished, the reaction is continued for 3 hours, the reaction is monitored by HPLC, after the raw materials are completely converted, the raw materials are quenched by sodium thiosulfate, the pH value is adjusted to about 5 by dilute hydrochloric acid, the raw materials are extracted by ethyl acetate, the raw materials are concentrated to obtain oily substances, the oily substances are poured into a 1.0M sodium hydroxide aqueous solution, the pH value is adjusted to about 10, the mixture is stirred for 30 minutes, and the mixture is concentrated to obtain 192g of off-white solid, the yield is.
S3 Synthesis of 2- [2- (2,2, 2-trifluoroethoxy) phenoxy ] ethyl alcohol (formula V)
Under the protection of nitrogen, 176g (1.0mol, 1.0eq) of sodium 2- (2-hydroxyethoxy) phenolate, 276g (2.0mol, 2.0eq) of potassium carbonate, 220g (2.2mol, 2.2eq) of trifluoroethanol and 1200mL of N, N-dimethylformamide which are involved in the reaction are sequentially added into a 2000mL four-neck flask with mechanical stirring, the temperature is raised to 80 ℃ for heat preservation and reaction is carried out for 10 hours, the reaction progress is monitored by HPLC, after the raw materials are completely converted, the reaction liquid is cooled to room temperature, the reaction liquid is filtered, the filtrate is poured into 1000mL of ice water, the ice water is extracted by 500mL of ethyl acetate of 3, anhydrous sodium sulfate is dried, dry light black oily matter is concentrated, and the colorless viscous liquid 207g, the yield is 87.7 percent and the purity is 98.0 percent are obtained by reduced pressure distillation.
Synthesis of S4, 2- [2- (2,2, 2-trifluoroethoxy) phenoxy ] ethyl methanesulfonate (formula I)
In a 3000mL four-necked flask equipped with a mechanical stirrer, 200g (0.85mol, 1.0eq) of 2- [2- (2,2, 2-trifluoroethoxy) phenoxy ] ethyl alcohol, 112g (1.1mol, 1.5eq) of triethylamine, and 2000mL of dichloromethane were sequentially added to react, and the temperature of the reaction system was lowered to about 0 ℃ in an ice salt bath, and 194g (1.7mol, 2.0eq) of methanesulfonyl chloride dissolved in 500mL of dichloromethane was slowly added dropwise while controlling the temperature of the reaction system to be not higher than 20 ℃. After the dropwise addition, removing the deicing salt bath, heating to reflux reaction for 5 hours, cooling to room temperature, filtering to remove triethylamine hydrochloride, washing the filtrate by 1000ml of 3 saturated sodium carbonate, drying by anhydrous sodium sulfate, filtering, concentrating the dried gray oily substance under reduced pressure, adding 400g of isopropanol, stirring at 0 ℃ for crystallization for 6 hours, filtering, and drying in vacuum to obtain 245g of white solid, wherein the melting point is 39-42 ℃, the yield is 91.7%, and the purity is 98.2%.
Example 4
The invention provides a preparation method of a silodosin intermediate, which comprises the following steps:
s1 Synthesis of 2- (2-hydroxyethoxy) benzaldehyde (formula III)
200g (1.64mol, 1.0eq) of salicylaldehyde participating in the reaction, 159g (1.8mol, 1.1eq) of ethylene carbonate, 340g (2.46mol, 1.5eq) of potassium carbonate and 1000mL of N, N-dimethylformamide are sequentially added into a 2000mL four-neck flask with mechanical stirring, the temperature is raised to 120 ℃ under the protection of nitrogen, the reaction is kept for 8 hours, the HPLC raw material is sampled and completely converted, the reaction system is cooled to the room temperature, and the mixture is filtered. The filtrate was poured into 1000mL of ice water, extracted with 500mL x 3 of ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate to give 216g of pale yellow oil with 79.1% yield and 98.2% purity.
S2 Synthesis of sodium 2- (2-hydroxyethoxy) phenolate (formula IV)
Under the protection of nitrogen, 200g (1.2mol, 1.0eq) of 2- (2-hydroxyethoxy) benzaldehyde and 1440mL (1.44mol,1.2eq) of 1.0M sodium hydroxide which are involved in the reaction are sequentially added into a 2000mL four-neck flask with mechanical stirring, 164g (1.44mol,1.2eq) of 30% hydrogen peroxide is slowly dropped under mechanical stirring, the reaction temperature is controlled to be not higher than 20 ℃, after the dropping is finished, the temperature is raised to 30 ℃ for continuous reaction for 2 hours, the reaction is monitored by HPLC, after the raw materials are completely converted, the raw materials are quenched by sodium thiosulfate, the pH value is adjusted to about 5 by dilute hydrochloric acid, the raw materials are extracted by ethyl acetate, the raw materials are concentrated to obtain oily substances, the oily substances are poured into a 1.0M sodium hydroxide aqueous solution, the pH value is adjusted to about 10, after the stirring is carried out for 30 minutes, the raw materials are concentrated to obtain 192g of off-white solid, the yield is 90..
S3 Synthesis of 2- [2- (2,2, 2-trifluoroethoxy) phenoxy ] ethyl alcohol (formula V)
Under the protection of nitrogen, 176g (1.0mol, 1.0eq) of sodium 2- (2-hydroxyethoxy) phenolate participating in the reaction, 207g (1.5mol, 1.5eq) of potassium carbonate, 200g (2.0mol, 2.0eq) of trifluoroethanol and 1200mL of N, N-dimethylformamide were added in sequence to a 2000mL four-neck flask equipped with mechanical stirring, the temperature was raised to 110 ℃ and the reaction was kept for 12 hours, the reaction progress was monitored by HPLC, after the conversion of the raw materials was completed, the reaction solution was cooled to room temperature, the reaction solution was filtered, the filtrate was poured into 1000mL of ice water, and then extracted with 500mL of ethyl acetate of 3, dried over anhydrous sodium sulfate, concentrated to a dry light black oily substance, and distilled under reduced pressure to obtain 210g of colorless viscous liquid with yield of 89.0% and purity of 98.4%.
Synthesis of S4, 2- [2- (2,2, 2-trifluoroethoxy) phenoxy ] ethyl methanesulfonate (formula I)
In a 3000mL four-necked flask equipped with a mechanical stirrer, 200g (0.85mol, 1.0eq) of 2- [2- (2,2, 2-trifluoroethoxy) phenoxy ] ethyl alcohol, 129g (1.27mol, 1.5eq) of triethylamine, and 2000mL of dichloromethane were sequentially added to the reaction system, and the temperature of the reaction system was lowered to about 0 ℃ in an ice salt bath, and 145g (1.27mol, 1.5eq) of methanesulfonyl chloride dissolved in 500mL of dichloromethane was slowly added dropwise while controlling the temperature of the reaction system to be not higher than 20 ℃. After the dropwise addition, removing an ice salt bath, heating to reflux reaction for 4 hours, cooling to room temperature, filtering to remove triethylamine hydrochloride, washing the filtrate by 1000ml of 3 saturated sodium carbonate, drying by anhydrous sodium sulfate, filtering, concentrating the dried gray oily substance under reduced pressure, adding 400g of isopropanol, stirring at 0 ℃ for crystallization for 6 hours, filtering, and drying in vacuum to obtain 246g of white solid, wherein the melting point is 39-42 ℃, the yield is 92.1%, and the purity is 98.4%.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.
Claims (8)
1. The preparation method of the silodosin intermediate is characterized in that the synthetic route is as follows:
the method comprises the following steps:
performing transesterification on S1, salicylaldehyde (formula II) and ethylene carbonate to obtain 2- (2-hydroxyethoxy) benzaldehyde (formula III);
s2, carrying out Dakin oxidation reaction on 2- (2-hydroxyethoxy) benzaldehyde (formula III) to obtain 2- (2-hydroxyethoxy) sodium phenolate (formula IV);
s3, carrying out etherification reaction on 2- (2-hydroxyethoxy) sodium phenolate (formula IV) and trifluoroethanol to obtain 2- [2- (2,2, 2-trifluoroethoxy) phenoxy ] ethyl alcohol (formula V);
s4, 2- [2- (2,2, 2-trifluoroethoxy) phenoxy ] ethyl alcohol (formula V) and methanesulfonyl chloride are subjected to esterification reaction to obtain silodosin intermediate 2- [2- (2,2, 2-trifluoroethoxy) phenoxy ] ethyl methanesulfonate (formula I);
in S1, the molar ratio of salicylaldehyde to ethylene carbonate is 1: 1-1.5; the reaction temperature of the ester exchange reaction is 110-130 ℃, and the reaction time is 7-10 h; the solvent for ester exchange reaction is one or more of N, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone; the catalyst of the ester exchange reaction is one or more of sodium carbonate, potassium carbonate and cesium carbonate;
in S2, the reaction temperature of Dakin oxidation reaction is 30-70 ℃, and the reaction time is 1-4 h; peroxide used in the Dakin oxidation reaction is one or more of hydrogen peroxide, peracetic acid, tert-butyl hydroperoxide, oxone, m-chloroperoxybenzoic acid and peroxybenzoic acid; the alkaline reagent used in the Dakin oxidation reaction is one or more than one of sodium hydroxide, potassium hydroxide, trimethyl benzyl ammonium hydroxide and tetramethyl amino hydroxide;
in S3, the molar ratio of the sodium 2- (2-hydroxyethoxy) phenolate to the trifluoroethanol is 1: 1.5-2.5; the reaction temperature of the etherification reaction is 60-160 ℃, and the reaction time is 8-16 h;
in S4, the molar ratio of 2- [2- (2,2, 2-trifluoroethoxy) phenoxy ] ethyl alcohol to methanesulfonyl chloride was 1: 1.2-4.
2. The method for preparing silodosin intermediate according to claim 1, wherein the molar ratio of salicylaldehyde to ethylene carbonate in S1 is 1: 1.1; the reaction temperature of the ester exchange reaction is 120 ℃, and the reaction time is 8 h.
3. The process for producing a silodosin intermediate as claimed in claim 1 or 2, wherein the solvent for the transesterification reaction in S1 is N, N-dimethylformamide; the catalyst for the transesterification reaction was potassium carbonate.
4. The process for producing a silodosin intermediate as claimed in claim 1 or 2, wherein the peroxide used in the Dakin oxidation reaction in S2 is hydrogen peroxide; the alkaline reagent used in the Dakin oxidation reaction is sodium hydroxide.
5. The method for preparing silodosin intermediate according to claim 1 or 2, wherein the molar ratio of sodium 2- (2-hydroxyethoxy) phenolate to trifluoroethanol in S3 is 1: 2.
6. the method for preparing silodosin intermediate according to claim 1 or 2, wherein the reaction temperature of the etherification reaction in S3 is 110 ℃ and the reaction time is 12 hours.
7. The process of claim 1 or 2, wherein the solvent for the etherification reaction in S3 is one or more selected from N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, and N-methylpyrrolidone.
8. The process for producing a silodosin intermediate as claimed in claim 1 or 2, wherein the solvent for the etherification reaction in S3 is N, N-dimethylformamide.
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