CN110734443B - Preparation method of tadalafil-related substance I - Google Patents
Preparation method of tadalafil-related substance I Download PDFInfo
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- CN110734443B CN110734443B CN201911226277.5A CN201911226277A CN110734443B CN 110734443 B CN110734443 B CN 110734443B CN 201911226277 A CN201911226277 A CN 201911226277A CN 110734443 B CN110734443 B CN 110734443B
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- 229960000835 tadalafil Drugs 0.000 title claims abstract description 43
- 239000000126 substance Substances 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- IEHKWSGCTWLXFU-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C([C]4C=CC=CC4=N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 IEHKWSGCTWLXFU-IIBYNOLFSA-N 0.000 title claims abstract 10
- 239000003960 organic solvent Substances 0.000 claims abstract description 11
- 150000004965 peroxy acids Chemical class 0.000 claims abstract description 7
- 239000003513 alkali Substances 0.000 claims abstract description 5
- 238000004440 column chromatography Methods 0.000 claims abstract description 4
- 238000000746 purification Methods 0.000 claims abstract description 4
- 230000008707 rearrangement Effects 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 51
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 14
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 10
- 239000012043 crude product Substances 0.000 claims description 10
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical group CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical group [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 5
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 235000010265 sodium sulphite Nutrition 0.000 claims description 3
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical group [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 3
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 239000000203 mixture Substances 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
- FHHJDRFHHWUPDG-UHFFFAOYSA-N peroxysulfuric acid Chemical compound OOS(O)(=O)=O FHHJDRFHHWUPDG-UHFFFAOYSA-N 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract 1
- WOXKDUGGOYFFRN-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C(C4=CC=CC=C4N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 WOXKDUGGOYFFRN-IIBYNOLFSA-N 0.000 description 34
- 239000012044 organic layer Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 239000012141 concentrate Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 208000010228 Erectile Dysfunction Diseases 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 201000001881 impotence Diseases 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- -1 1, 3-benzodioxolan-5-yl Chemical group 0.000 description 2
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 2
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 102000011016 Type 5 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 2
- 108010037581 Type 5 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- XYPISWUKQGWYGX-UHFFFAOYSA-N 2,2,2-trifluoroethaneperoxoic acid Chemical compound OOC(=O)C(F)(F)F XYPISWUKQGWYGX-UHFFFAOYSA-N 0.000 description 1
- YNJSNEKCXVFDKW-UHFFFAOYSA-N 3-(5-amino-1h-indol-3-yl)-2-azaniumylpropanoate Chemical compound C1=C(N)C=C2C(CC(N)C(O)=O)=CNC2=C1 YNJSNEKCXVFDKW-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940117229 cialis Drugs 0.000 description 1
- RAABOESOVLLHRU-UHFFFAOYSA-N diazene Chemical class N=N RAABOESOVLLHRU-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 235000009200 high fat diet Nutrition 0.000 description 1
- XNFNGGQRDXFYMM-UHFFFAOYSA-N hydron;methyl 2-amino-3-(1h-indol-3-yl)propanoate;chloride Chemical compound [Cl-].C1=CC=C2C(CC([NH3+])C(=O)OC)=CNC2=C1 XNFNGGQRDXFYMM-UHFFFAOYSA-N 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 238000005502 peroxidation Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/20—Spiro-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of tadalafil related substance I. The preparation method takes tadalafil as a starting material, and the tadalafil and peroxy acid undergo oxidation reaction in an organic solvent, and the tadalafil related substance I is obtained through alkali rearrangement and column chromatography purification.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of a tadalafil related substance I.
Background
Chemical name of Tadalafil (Tadalafil): (6R,12aR) -6- (1, 3-benzodioxolan-5-yl) -2-methyl-2, 3,6,7,12,12 a-hexahydropyrazino [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione, having the following structural formula:
tadalafil, a phosphodiesterase v (PDE-5) inhibitor, was marketed in the united states in 2003 under the trade name sielier (Cialis) and is a drug used for the treatment of male Erectile Dysfunction (ED). Compared with other anti-ED medicaments, tadalafil has quick response and longest duration of efficacy, and is the only medicament which is not influenced by high fat diet and alcohol intake in the four anti-ED medicaments at present. In addition to the ED indications, tadalafil was approved for Pulmonary Arterial Hypertension (PAH) 5 months in 2009 followed by Benign Prostatic Hyperplasia (BPH) 10 months in 2011.
Tadalafil has been collected in pharmacopoeias such as USP, EP, BP, etc., EP9.0 contains nine tadalafil-related substances: A. b, C, D, E, F, G, H, I are provided. Only two documents currently report methods for preparing tadalafil-related substance I: CN109796461A reports a method for obtaining a tadalafil-related substance I through peroxidation rearrangement of tadalafil in N-halogenated diimide, glacial acetic acid, tetrahydrofuran and a water system, wherein the method has relatively long reaction time, a large amount of sodium carbonate is required for neutralizing glacial acetic acid in post-treatment, and the yield is low; the paper (qianpeng flying, "synthesis of tadalafil and related substance research [ D ], suzhou university, 2016) mentioned a process for preparing tadalafil related substance I by oxidation of D-tryptophan methyl ester hydrochloride, with a total yield of only 11.7% in 4 steps. Therefore, it is necessary to develop a synthetic method which is simple and feasible. The tadalafil related substance I has the following structural formula:
disclosure of Invention
The invention provides a preparation method of a tadalafil related substance I, which has the advantages of easily obtained raw materials, simple operation and high product purity and provides a high-quality impurity reference substance for the quality research of tadalafil.
The invention provides a preparation method of a tadalafil related substance I, which comprises the following steps:
(1) the tadalafil reacts with peroxy acid in an organic solvent 1, and is quenched by a reducing agent and concentrated to obtain a compound shown as a formula II;
(2) dissolving the compound shown in the formula II obtained in the step (1) in an organic solvent 2 to react with alkali for rearrangement, and concentrating and extracting reaction liquid to obtain crude products of tadalafil related substances I;
(3) and (3) purifying the crude product of the tadalafil related substance I obtained in the step (2) to obtain the tadalafil related substance I.
In the above preparation method, wherein the reaction of steps (1) and (2) may be monitored by TLC.
In the above preparation method, the organic solvent 1 in the step (1) is one or more of dichloromethane, chloroform, carbon tetrachloride and tetrahydrofuran, preferably, dichloromethane. The peroxy acid is peroxyacetic acid, peroxytrifluoroacetic acid, peroxybenzoic acid, 3-chloroperoxybenzoic acid or peroxysulfuric acid, and preferably is 3-chloroperoxybenzoic acid. The reducing agent is: sodium thiosulfate, sodium sulfite, or dimethyl sulfide.
In the preparation method, the reaction temperature of the reaction in the step (1) is-30-40 ℃, and the reaction is preferably 15-30 ℃; the reaction time is 5 minutes to 1.5 hours.
In the above preparation method, the organic solvent 2 in step (2) is one or more of ethanol, isopropanol, n-butanol and methanol, preferably methanol. The alkali is one or more of sodium ethoxide, sodium methoxide, sodium hydroxide and potassium hydroxide, and preferably sodium methoxide.
In the preparation method, the reaction temperature of the reaction in the step (2) is 30-85 ℃, and the reaction time is 10 minutes-2 hours.
In the above preparation method, the purification in step (3) is a column chromatography purification method, and elution is performed using a single solvent or a mixed solvent of ethyl acetate, petroleum ether, n-hexane, n-heptane, dichloromethane, methanol, and the like.
The invention has the advantages that: the preparation method of the tadalafil related substance I is brand new, raw materials are easy to obtain, the operation is simple, the product purity is high, and a high-quality impurity reference substance is provided for tadalafil quality research.
The specific implementation mode is as follows:
the invention will be further illustrated with reference to the following examples for better understanding of the contents of the invention in its version, without however limiting the invention in any way.
Example 1
A50 ml three-necked flask was charged with 10ml of dichloromethane, 390mg of tadalafil and 224mg of 3-chloroperoxybenzoic acid, reacted at room temperature for 40min, and monitored by TLC (dichloromethane/methanol, 10: 1). After the reaction, 1ml of dimethyl sulfide was added dropwise to quench, and the organic layer was concentrated to dryness under reduced pressure to obtain a concentrate (a compound represented by formula II).
The concentrate was dissolved in 20ml of 1M sodium methoxide/methanol solution, heated at reflux for 40min and monitored by TLC (dichloromethane/methanol, 10: 1). After the reaction is finished, concentrating under reduced pressure to remove the methanol, adding water/ethyl acetate for extraction, and concentrating the organic layer under reduced pressure to be dry to obtain a crude product of the tadalafil related substance I.
And (3) purifying the crude product by using a 300-400-mesh silica gel column chromatography, wherein an eluent is dichloromethane, methanol and 10:1, and the tadalafil related substance I is 310mg, the yield is 59.5%, and the HPLC purity is 96.4%.
Example 2 was carried out:
10ml of chloroform, 390mg of tadalafil and 193mg of perbenzoic acid were added to a 50ml three-necked flask, and the mixture was reacted at room temperature for 60min with TLC monitoring (dichloromethane/methanol, 10: 1). After the reaction is finished, 5ml of 5% sodium thiosulfate is dripped at 0-5 ℃ for quenching, liquid separation is carried out, 5ml of saturated sodium bicarbonate is extracted and washed in an organic layer, and the organic layer is decompressed and concentrated to be dry, so that a concentrate (the compound shown in the formula II) is obtained.
The concentrate was dissolved in 20ml of 1M sodium ethoxide/ethanol solution, heated to reflux for 60min and monitored by TLC (dichloromethane/methanol, 10: 1). After the reaction is finished, concentrating under reduced pressure to remove ethanol, adding water/ethyl acetate for extraction, and concentrating the organic layer under reduced pressure to be dry to obtain a crude product of the tadalafil related substance I.
And (3) purifying the crude product by using a 300-400-mesh silica gel column chromatography, wherein an eluent is ethyl acetate and n-hexane which is 1:1, 295mg of tadalafil related substance I is obtained, the yield is 56.7%, and the HPLC purity is 95.6%.
Example 3 of implementation:
a50 ml three-necked flask was charged with 10ml of tetrahydrofuran, 390mg of tadalafil and 336mg of peroxosulfuric acid, and reacted at room temperature for 60min with TLC monitoring (dichloromethane/methanol, 10: 1). After the reaction is finished, 5ml of 5% sodium sulfite is dripped at 0-5 ℃ for quenching, liquid separation is carried out, 5ml of saturated sodium bicarbonate is extracted and washed in an organic layer, and the organic layer is decompressed and concentrated to be dry, so as to obtain a concentrate (the compound shown in the formula II).
The concentrate was dissolved in 20ml of 1M sodium methoxide/methanol solution, heated to reflux for 40min and monitored by TLC (dichloromethane/methanol, 10: 1). After the reaction is finished, concentrating under reduced pressure to remove the methanol, adding water/ethyl acetate for extraction, and concentrating the organic layer under reduced pressure to be dry to obtain a crude product of the tadalafil related substance I.
And (3) purifying the crude product by silica gel column chromatography with 300-400 meshes, wherein an eluent dichloromethane and methanol are 10:1, so that the tadalafil related substance I is 235mg, the yield is 45.1%, and the HPLC purity is 97.0%.
The detection conditions for HPLC were as follows:
chromatographic conditions are as follows: a flow chromatography column: c8250mm X4.6 mm 5 μm packing L7
Mobile phase A: taking 1ml of trifluoroacetic acid, and adding water to dilute the trifluoroacetic acid to 1000 ml; mobile phase B of acetonitrile
Column flow rate: 1.0ml/min detection wavelength: 285nm
Sample introduction amount: 20 μ l column temperature: 40 deg.C
Diluent agent: acetonitrile-mobile phase a ═ 1:1 mobile phase: linear gradient elution:
Claims (2)
1. the preparation method of the tadalafil-related substance I comprises the following steps:
(1) the tadalafil reacts with peroxy acid in an organic solvent 1, and is quenched by a reducing agent and concentrated to obtain a compound shown as a formula II;
(2) dissolving the compound shown in the formula II obtained in the step (1) in an organic solvent 2 to react with alkali for rearrangement, and concentrating and extracting reaction liquid to obtain crude products of tadalafil related substances I;
(3) purifying the crude product of the tadalafil related substance I obtained in the step (2) by column chromatography to obtain a tadalafil related substance I; wherein the organic solvent 1 in the step (1) is dichloromethane; the peroxy acid is 3-chloroperoxybenzoic acid; the reducing agent is dimethyl sulfide; or, the organic solvent 1 in the step (1) is chloroform; the peroxy acid is peroxybenzoic acid; the reducing agent is sodium thiosulfate; alternatively, the organic solvent 1 in the step (1) is tetrahydrofuran; said peroxyacid is peroxysulfuric acid; the reducing agent is sodium sulfite;
the reaction temperature in the step (1) is 15-30 ℃;
the reaction time in the step (1) is as follows: 5 minutes to 1.5 hours;
the alkali in the step (2) is sodium methoxide; the organic solvent 2 is methanol;
the reaction temperature in the step (2): 30-85 ℃;
the reaction time in the step (2) is as follows: 10 minutes to 2 hours.
2. The preparation method according to claim 1, wherein the column chromatography purification method of step (3) is eluted using a single solvent or a mixture of any two solvents selected from ethyl acetate, petroleum ether, n-hexane, n-heptane, dichloromethane and methanol.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017165738A1 (en) * | 2016-03-25 | 2017-09-28 | The Trustees Of Columbia University In The City Of New York | Mitragynine alkaloids as opioid receptor modulators |
| CN109053724A (en) * | 2018-08-22 | 2018-12-21 | 上海青平药业有限公司 | The purification process and purposes of the preparation method and Tadalafei of a kind of impurity prepared during Tadalafei and the impurity |
| CN109796461A (en) * | 2018-12-30 | 2019-05-24 | 杭州康本医药科技有限公司 | A kind of preparation process of Tadalafei impurity I |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017165738A1 (en) * | 2016-03-25 | 2017-09-28 | The Trustees Of Columbia University In The City Of New York | Mitragynine alkaloids as opioid receptor modulators |
| CN109053724A (en) * | 2018-08-22 | 2018-12-21 | 上海青平药业有限公司 | The purification process and purposes of the preparation method and Tadalafei of a kind of impurity prepared during Tadalafei and the impurity |
| CN109796461A (en) * | 2018-12-30 | 2019-05-24 | 杭州康本医药科技有限公司 | A kind of preparation process of Tadalafei impurity I |
Non-Patent Citations (1)
| Title |
|---|
| 他达拉非的合成及有关物质研究;钱彭飞;《中国优秀硕士学位论文全文数据库》;20160115(第01期);正文第35页 * |
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