CN107973796B - Preparation method of tadalafil isomer - Google Patents
Preparation method of tadalafil isomer Download PDFInfo
- Publication number
- CN107973796B CN107973796B CN201711295146.3A CN201711295146A CN107973796B CN 107973796 B CN107973796 B CN 107973796B CN 201711295146 A CN201711295146 A CN 201711295146A CN 107973796 B CN107973796 B CN 107973796B
- Authority
- CN
- China
- Prior art keywords
- isomer
- tadalafil
- preparation
- organic base
- polar solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- IEHKWSGCTWLXFU-IIBYNOLFSA-N tadalafil Chemical class 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 6
- 229960000835 tadalafil Drugs 0.000 claims abstract description 11
- 150000007530 organic bases Chemical class 0.000 claims abstract description 10
- 239000002798 polar solvent Substances 0.000 claims abstract description 10
- 230000006340 racemization Effects 0.000 claims abstract description 8
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical group CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 12
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 abstract description 13
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 abstract description 10
- 238000000746 purification Methods 0.000 abstract description 6
- 229960004799 tryptophan Drugs 0.000 abstract description 5
- 238000000034 method Methods 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- WOXKDUGGOYFFRN-IIBYNOLFSA-N tadalafil Chemical class 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 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 229940125782 compound 2 Drugs 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- SATCULPHIDQDRE-UHFFFAOYSA-N piperonal Chemical compound O=CC1=CC=C2OCOC2=C1 SATCULPHIDQDRE-UHFFFAOYSA-N 0.000 description 6
- 229940125904 compound 1 Drugs 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- 238000012827 research and development Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000000010 aprotic solvent Substances 0.000 description 3
- 239000012320 chlorinating reagent Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- LFETXMWECUPHJA-UHFFFAOYSA-N methanamine;hydrate Chemical compound O.NC LFETXMWECUPHJA-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 238000012954 risk control Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940117229 cialis Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- ANSXAPJVJOKRDJ-UHFFFAOYSA-N furo[3,4-f][2]benzofuran-1,3,5,7-tetrone Chemical compound C1=C2C(=O)OC(=O)C2=CC2=C1C(=O)OC2=O ANSXAPJVJOKRDJ-UHFFFAOYSA-N 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- -1 stirred for 10min Chemical compound 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of tadalafil isomers, belonging to the technical field of drug synthesis. The preparation method comprises the steps of placing tadalafil in an aprotic strong polar solvent, and performing partial racemization by using an organic base to obtain an isomer I; taking L-tryptophan as a raw material, and completely synthesizing to obtain an isomer II through four steps of reaction; placing the isomer II in an aprotic strong polar solvent, and performing partial racemization by using an organic base to obtain an isomer III; and the structures of the three isomers are confirmed. The preparation method provided by the invention has the advantages of simple process, high yield, simple post-treatment and easy purification.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a preparation method of tadalafil isomers.
Background
Tadalafil (Tadalafil), chemical name: (6R,12aR) -6- (1, 3-benzodioxol-5-yl) -2-methyl-2, 3,6,7,12,12 a-hexahydropyrazino [1 ', 2': 1,6] pyrido [3,4-b ] indole-1, 4-dione, developed by American Provisions under the trade name of Hizili (Cialis), 11 months 2002, Tadalafil from Gift Inc. obtained from the European Union approved for the treatment of ED, first marketed in 2 months 2003 in various countries, such as the United kingdom, Sweden, Denmark, Germany and Australia; 11 months 2003, Tadalafil was approved by the FDA in the united states for the treatment of ED; on month 7, 2007, approval for PMDA in japan was obtained for marketing.
The structural formula is shown as formula 1-1:
the molecular structure of tadalafil has 2 chiral centers and contains 3 isomers, wherein one enantiomer II and two diastereomers I and III are shown as formulas 1-2:
structural formula of Tadalafil isomer of formula 1-2
The three isomers are particularly critical in the development and verification of tadalafil medicaments, play an important role in the whole isomer risk control, and can powerfully help the completion of research and development and production. However, the existing preparation method for the isomers has the problems of low yield, difficult purification, complex process and the like, and can not well meet the requirements of research and development and reference substances.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide a preparation method of tadalafil isomer, which has the advantages of simple process, high yield, simple post-treatment and easy purification.
In order to solve the problems, the technical scheme adopted by the invention is as follows:
a preparation method of tadalafil isomer I comprises the step of carrying out partial racemization on tadalafil and an aprotic strong polar solvent under the condition of an organic base to obtain the isomer I, wherein the formula is shown as follows:
preferably, the aprotic strongly polar solvent is one or a mixture of any two or more of DMF, DMSO and NMP.
Preferably, the organic base is one or a mixture of more than two of DMAP, DBU and triethylamine.
The invention also provides a preparation method of the tadalafil isomer II, which comprises the following steps:
firstly, mixing L-tryptophan and a chlorinating agent for esterification reaction to obtain a compound 1;
secondly, reacting the compound 1 with 3, 4-methylene dioxybenzaldehyde under the condition of an aprotic solvent to obtain a compound 2;
thirdly, reacting the compound 2 with chloroacetyl chloride under the condition of anhydrous tetrahydrofuran to obtain a compound 3;
fourthly, reacting the compound 3 with acetonitrile and methylamine aqueous solution to obtain an isomer II;
the synthetic route is as follows:
preferably, in the first step of reaction, the chlorinating agent is one or a mixture of two of oxalyl chloride and thionyl chloride.
Preferably, in the second step of reaction, the aprotic solvent is one or a mixture of any two or more of acetonitrile, DMF and THF.
Preferably, in the third step of reaction, the dropping temperature of the chloracetyl chloride is-5-10 ℃.
Preferably, in the fourth step of reaction, the concentration of the methylamine water solution is preferably 30-40%.
The invention also provides a preparation method of the tadalafil isomer III, which comprises the step of carrying out partial racemization on the isomer II and an aprotic strong polar solvent under the condition of organic base to obtain the isomer III, wherein the isomer III is shown as the following formula:
preferably, the aprotic strongly polar solvent is one or a mixture of any two or more of DMF, DMSO and NMP; the organic base is one or a mixture of more than two of DMAP, DBU and triethylamine.
Compared with the prior art, the invention has the beneficial effects that:
according to the invention, the isomer I is obtained by partial racemization purification of tadalafil, the isomer II is obtained by total synthesis of 4 steps with L-tryptophan as a raw material, the isomer III is obtained by partial racemization purification of the isomer II, the preparation processes can be monitored by HPLC and are easy to control, and the structures of the three isomers are confirmed, so that the obtained isomer has high optical purity, meets the requirements of research and development and comparison products, can effectively help research and development and production completion, and is beneficial to isomer risk control. The preparation method has simple and reliable process, high yield, simple post-treatment and easy purification.
Detailed Description
The present invention will be described in further detail with reference to specific embodiments.
All reagents and starting materials used in the following examples are commercially available.
Example 1: preparation of tadalafil isomer I
Tadalafil (3.9g, 0.01mol) was added to 40mL dimethylformamide, stirred for 10min, DMAP (1.2g, 0.01mol) was added, reacted at 80 ℃ for 6h, cooled to room temperature, crystallized for 1h, filtered, washed with acetone, and vacuum dried to give isomer I3.1 g, with a yield of 79.5%.
MS：m/z(％)＝390.5(M+H+)；
1HNMR(DMSO-d6，400MHz)δ：2.85(s,3H)，2.96(m,1H)，3.27(dd,1H)，4.05(d,1H)，4.09(dd,1H)，4.26(d,1H)，6.01(dd,2H)，6.62(dd,1H)，6.77(d,1H)，6.84(s,2H)，6.88(d,1H)，7.02(m,1H)，7.02(m,1H)，7.32(d,1H)，7.51(d,1H)，11.07(s,1H)。
Example 2: preparation of tadalafil isomer II
The synthetic route for tadalafil isomer II is shown below:
the first step of reaction: mixing L-tryptophan and a chlorinating agent for esterification reaction
Adding 100mL of anhydrous methanol and L-tryptophan (10g, 0.05mol), slowly dropwise adding thionyl chloride (7.1g, 0.06mol) at room temperature, keeping the temperature at 50 ℃ for reaction for 3 hours after the addition is finished, adding 100mL of isopropyl ether after the reaction is finished, cooling to 0-5 ℃, growing crystals for 1 hour, filtering, washing with isopropyl ether, and drying in vacuum to obtain 10.5g of compound 1, wherein the yield is 105%.
The second step of reaction: reacting compound 1 with 3, 4-methylene dioxybenzaldehyde under the condition of aprotic solvent
Adding anhydrous THF80mL, compound 1(10g, 0.04mol) and 3, 4-methylene dioxybenzaldehyde (6g, 0.04mol), refluxing for 10h, cooling to room temperature, cooling to 0-5 ℃, growing crystals for 1h, filtering, washing with THF, and vacuum drying to obtain 13.5g of compound 2 with the yield of 135%.
The third step of reaction: reacting compound 2 with chloroacetyl chloride under the condition of anhydrous tetrahydrofuran
Adding 100mL of anhydrous tetrahydrofuran, a compound 2(11.6g, 0.03mol) and triethylamine (3g, 0.03mol), cooling to 0-5 ℃, slowly dropwise adding chloroacetyl chloride (3.4g, 0.03mol), heating to room temperature to react for 2h after the dropwise adding is finished, concentrating a half solvent under reduced pressure, growing crystals at room temperature for 1h, filtering, washing with tetrahydrofuran, and drying in vacuum to obtain 11.0g of a compound 3, wherein the yield is 94.8%.
And a fourth step of reaction: reaction of Compound 3 with aqueous acetonitrile and methylamine
Adding 90mL of acetonitrile and a compound 2(8.5g, 0.02mol), slowly dropwise adding 20mL of methylamine water solution at room temperature, keeping the temperature at 50 ℃ for reaction for 3h, reducing the temperature to room temperature, decompressing and concentrating about one third of the solvent, stirring at room temperature for crystal growth for 1h, filtering, washing with acetonitrile, and performing vacuum drying to obtain 6.8g of an isomer II with the yield of 80%.
MS：m/z(％)＝390.5(M+H+)；
1HNMR(DMSO-d6，400MHz)δ：2.93(s,3H)，2.99(m,1H)，3.52(dd,1H)，3.94(d,1H)，4.18(dd,1H)，4.39(dd,1H)，5.92(s,2H)，6.14(s,1H)，6.78(m,2H)，6.87(s,1H)，7.00(m,1H)，7.06(m,1H)，7.30(d,1H)，7.54(d,1H)，11.01(s,1H)。
Example 3: preparation of tadalafil isomer III
Adding the isomer II (3.9g, 0.01mol) into 40mL of dimethylformamide, stirring for 10min, adding DMAP (1.2g, 0.01mol), reacting at 80 ℃ for 6h, cooling to room temperature, growing crystals for 1h, filtering, washing with acetone, and drying in vacuum to obtain the isomer III 3.0g, wherein the yield is 76.9%.
MS：m/z(％)＝390.5(M+H+)；
1HNMR(DMSO-d6，400MHz)δ：2.86(s,3H)，2.95(m,1H)，3.27(dd,1H)，4.04(d,1H)，4.09(dd,1H)，4.25(d,1H)，6.01(d,2H)，6.62(dd,1H)，6.77(d,1H)，6.84(s,1H)，6.87(d,1H)，7.03(m,1H)，7.02(m,1H)，7.11(m,1H)，7.32(d,1H)，7.51(d,1H)，11.04(s,1H)。
The above embodiments are only preferred embodiments of the present invention, and the protection scope of the present invention is not limited thereby, and any insubstantial changes and substitutions made by those skilled in the art based on the present invention are within the protection scope of the present invention.
Claims (2)
1. A preparation method of tadalafil isomer is characterized by comprising the following steps: carrying out partial racemization on tadalafil and an aprotic strong polar solvent under the condition of an organic base to obtain an isomer I, which is shown as the following formula:
wherein the aprotic strongly polar solvent is DMF; the organic base is DMAP.
2. A preparation method of tadalafil isomer is characterized by comprising the following steps: carrying out partial racemization on the isomer II and an aprotic strong polar solvent under the condition of organic base to obtain an isomer III; isomers II and III are each represented by the following formula:
wherein the aprotic strongly polar solvent is DMF; the organic base is DMAP.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711295146.3A CN107973796B (en) | 2017-12-08 | 2017-12-08 | Preparation method of tadalafil isomer |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711295146.3A CN107973796B (en) | 2017-12-08 | 2017-12-08 | Preparation method of tadalafil isomer |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107973796A CN107973796A (en) | 2018-05-01 |
| CN107973796B true CN107973796B (en) | 2020-05-26 |
Family
ID=62009503
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711295146.3A Active CN107973796B (en) | 2017-12-08 | 2017-12-08 | Preparation method of tadalafil isomer |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107973796B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2692764C1 (en) * | 2019-04-26 | 2019-06-27 | Общество с ограниченной ответственностью "Балтфарма" | Method of producing tadalafil |
| CN111253399A (en) * | 2020-03-30 | 2020-06-09 | 苏州弘森药业股份有限公司 | Production process of tadalafil raw material medicine |
| CN113214251B (en) * | 2021-04-30 | 2024-06-11 | 湖北丽益医药科技有限公司 | Preparation method of tadalafil intermediate impurity |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103772384A (en) * | 2014-01-23 | 2014-05-07 | 苏州大学 | Preparation method of tadalafil |
-
2017
- 2017-12-08 CN CN201711295146.3A patent/CN107973796B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103772384A (en) * | 2014-01-23 | 2014-05-07 | 苏州大学 | Preparation method of tadalafil |
Non-Patent Citations (2)
| Title |
|---|
| Alain Daugan et al.The Discovery of Tadalafil: A Novel and Highly Selective PDE5 Inhibitor. 2: 2,3,6,7,12,12a-hexahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione Analogues.《J. Med. Chem.》.2003,第46卷 * |
| The Discovery of Tadalafil: A Novel and Highly Selective PDE5 Inhibitor. 2: 2,3,6,7,12,12a-hexahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione Analogues;Alain Daugan et al;《J. Med. Chem.》;20030917;第46卷;4533-4542 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107973796A (en) | 2018-05-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2698245C (en) | Process and intermediates for preparing integrase inhibitors | |
| CN107973796B (en) | Preparation method of tadalafil isomer | |
| CN104341370B (en) | Preparation method of cetilistat | |
| KR20170016754A (en) | New method for preparation of chromanone derivatives | |
| CN114644612B (en) | Preparation method of benzodiazepine nerve inhibitor intermediate compound | |
| EP3527556B1 (en) | Method for preparing deuterated imidazole diketone compound | |
| CN106749335A (en) | A kind of preparation method and application of halo oxygen cephalo-type intermediate | |
| CN102516133A (en) | Preparation method of methanesulfonic acid derivative | |
| CN107722007B (en) | Preparation method of apixaban impurity | |
| CN109134510A (en) | Prepare 2- amino -5-CBZ-4, the new method of 5,6,7- tetrahydro-thiazoles simultaneously [5,4-C] pyridine | |
| CN114560862A (en) | Synthesis method of pyrrolo [1,2-A ] quinoxaline-4 (5H) -ketone and derivative thereof | |
| CN115536634A (en) | Synthetic method of apatamide | |
| CN113402512A (en) | Preparation method of benzoxazine-4-one derivative | |
| CN101787035A (en) | Preparation method of 7-aminocephalo-5-mercapto-1-methyltetrazole | |
| TWI845992B (en) | A method for preparing a hepatitis B virus nucleocapsid inhibitor | |
| CN100408577C (en) | Process for the preparation of imidazo (1, 2-A) pyridine-3-acetamides | |
| CN116135845B (en) | A preparation method of telmisartan intermediate | |
| CN109970643A (en) | A kind of green synthesis method of tetrahydroacridine compound under the promotion of iodine anion | |
| CN105037374B (en) | Preparation method of N-butyl-9H-pyrido[4,5-b]indole-2-carboxamide | |
| CN113999200B (en) | A synthesis method of thiodiazaspiro compound, intermediate thereof and synthesis method thereof | |
| CN118812458B (en) | Synthesis method of 2-mercaptobenzothiazole derivatives | |
| CN104418805B (en) | Dabigatran etexilate intermediate as well as preparation method and application thereof | |
| CN112480142B (en) | A kind of preparation method of 9-defluoro-9-methylpiperazine levofloxacin impurity | |
| CN109810112B (en) | A kind of preparation method of indolo[2,1-a]phthalazine derivative | |
| WO2016034150A1 (en) | Method for preparing bosutinib and crystal thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |