WO2009144734A1 - Process for preparation of tadalafil - Google Patents
Process for preparation of tadalafil Download PDFInfo
- Publication number
- WO2009144734A1 WO2009144734A1 PCT/IN2008/000339 IN2008000339W WO2009144734A1 WO 2009144734 A1 WO2009144734 A1 WO 2009144734A1 IN 2008000339 W IN2008000339 W IN 2008000339W WO 2009144734 A1 WO2009144734 A1 WO 2009144734A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- methyl
- pyrido
- indole
- tertahydro
- carboxylate
- 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.)
- Ceased
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Definitions
- the invention encompasses process for the preparation of Tadalafil in pure form higher yields under optimized conditions.
- Tadalafil is a potent and selective inhibitor of the cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase enzyme, PDE5.
- cGMP cyclic guanosine monophosphate
- PDE5 cyclic guanosine monophosphate
- Tadalafil is known chemically as (6R, 12aR)-6-(1,3-benzodioxol-5-yl)-
- WO 95/19978, WO 2005/068464, WO 2005/116030 report a processes for the preparation of tadalafil by reacting (6R,12aR)-methyl-1,2,3,4-tertahydro- 2-chloroacetyl-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxyl- ate in methanol with methylamine.
- WO 2004/011463 process for preparation of tadalafil by reacting (6R,12aR)-methyl-1,2,3,4-tertahydro-2-chloroacetyl-1-(3,4-methylenedioxy- phenyI)-9H-pyrido[3,4-b]indole-3-carboxylate in tetrahydrofuran with methyl amine.
- Tadalafil obtained by this method is contaminated with tetrahydrofuran solvent. It has been found that it is difficult to remove solvent traces from tadalafil.
- tadalafil can be obtained in high purity when (6R,12aR)-methyl-1 ,2,3,4-tertahydro-2-chloroacetyl-1-(3,4- methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate is reacted with methylamine in methanol in specific quantities for a specific reaction time.
- a process for preparing tadalafil in high purity there is provided a process for preparing tadalafil in high purity.
- a process for preparing tadalafil which comprises reacting (6R,12aR)-methyl- 1,2,3,4-tertahydro-2-chloroacetyl-1 -(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b] indole-3-carboxylate with 3 to 12 moles of methylamine per mole of (6R,12aR)- methyl-1,2,3,4-tertahydr-2- chloroacetyM-1-(3,4-methylenedioxyphenyl)-9H- pyrido[3,4-b]indoIe-3-carboxylate in 15 - 20 times by volume of alcohol solvent with respect to (6R,12aR)-methyl-1 ,2,3,4-tertahydro-2-chloroacetyl-1-(3,4- methylenedioxyphenyl)-9H-pyrido
- the alcohol is used, in 7 to 11 moles of methylamine with respect to (6R,12aR)-methyl-1 ,2,3,4-tertahydro-2-chloroacetyl-1-(3,4-methylene- dioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate.
- the alcohol may be single alcohol or a mixture of alcohol, Preferbly the alcohol is selcted from methanol, ethanol and isopropanol, More preferably the alcohol may be methanol.
- a process for preparing (6R, 12aR)-methyl-1 ,2,3,4-tertahydro-2-chloroacetyl-1-(3,4 -methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate which comprises: a) Reacting D-Tryptophan methyl ester with pipernal to give (1 R,3R)- methyl-1,2,3,4-tertahydro-1-(3,4-methyIenedioxyphenyl)-9H-pyrido[3,4-b] indole-3-carboxylate (cis isomer) and (1S,3R)-methyl-1 ,2,3,4-terta- hydro-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indoIe-3- carboxylate (trans isomer) b) Adding aqueous HCI to
- HPLC High performance liquid chromatography
- Buffer Dissolve 8.64gm of Sodiumlaurylsulphate and 3.5 ml of orthophospharic acid in 1000 ml of double distilled water. Adjust pH to 2.5 with NaOH.
- Solvent B BUFFER: CAN (30:70)
- Test solution preparation Dissolve 5 mg of the substance in 10 ml of diluent.
- reaction mass was cooled to 25 - 30oC and stirred at this temperature for one hour. Filtered the material and washed the solid obtained with methanol and dried to get pure tadalafil [Yield: 4.3 gm; HPLC purity 99.98%].
- the reaction mass was cooled to 25oC and added methylene dichloride (1000 ml) and pH adjusted to 9.0 with 1N sodium hydroxide solution. Then the methylene dichloride layer was separated and washed the methylene dichloride layer with water, dried the methylene dichloride layer with sodium sulphate and filtered. To the methylene dichloride layer was added (32 gm) trimethyl amine and the mass cooled to OoC. To the cooled mass was slowly added chloroacetyl chloride (36 gm). The reaction mass was maintained for 2 hours at 0 - 5oC, the reaction completion was checked by HPLC.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
It has been found that tadalafil can be obtained in high purity when (6R,12aR)-methyl-1,2,3,4-tertahydro-2-chloroacetyL-1-(3,4-methylenedioxy- phenyl)-9H-pyrido[3,4-b]indole-3-carboxylate is reacted with methylamine in methanol in specific quantities for a specific reaction time. It has also been found that (6R,12aR)-methyl-1,2,3,4-tertahydro-2-chloroacetyl-1-(3,4-methylenedioxy- phenyl)-9H-pyrido[3,4-b]indole-3-carboxylate, the key intermediate in the preparation of tadalafil, may be obtained in higher yield from D-Tryptophan methyl ester without isolationg intermediate as solid.
Description
PROCESS FOR PREPARATION OF TADALAFIL
FIELD OF THE INVENTION
The invention encompasses process for the preparation of Tadalafil in pure form higher yields under optimized conditions.
BACKGROUND OF THE INVENTION
Tadalafil is a potent and selective inhibitor of the cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase enzyme, PDE5. The inhibition of PDE5 increases the amount of cGMP, resulting in smooth muscle relaxation and increased blood flow. Tadalafil and its therapeutic use are disclosed in patent publication WO 95/19978.
Tadalafil is known chemically as (6R, 12aR)-6-(1,3-benzodioxol-5-yl)-
2,3,6,7,12,12a-hexahydro-2-methylpyrazino[1l,2':1 ,6]pyrido[3,4-b]indole-1 ,4- dione and the chemical structure is :
The process for the preparation of tadalafil described in WO 95/19978, WO 96/38131, WO 02/36593, WO 2004/011463, WO 2005/0116030, WO 2005/068464, WO 2006/091975, WO 2006/0258865 and WO 2006/110893.
WO 95/19978, WO 2005/068464, WO 2005/116030 report a processes for the preparation of tadalafil by reacting (6R,12aR)-methyl-1,2,3,4-tertahydro- 2-chloroacetyl-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxyl- ate in methanol with methylamine.
WO 2004/011463 process for preparation of tadalafil by reacting (6R,12aR)-methyl-1,2,3,4-tertahydro-2-chloroacetyl-1-(3,4-methylenedioxy-
phenyI)-9H-pyrido[3,4-b]indole-3-carboxylate in tetrahydrofuran with methyl amine. Tadalafil obtained by this method is contaminated with tetrahydrofuran solvent. It has been found that it is difficult to remove solvent traces from tadalafil.
It has been found that under the set quantities of methanol and methyl amine used in the prior art the reaction between (6R,12aR)-methyl-1 ,2,3,4- tertahydro-2-chloroacetyl-1-(3,4-methylenedioxyphenyl)-9 H-pyrido[3,4-b]indole- 3-carboxylate and methylamine the tadalafil obtained contains higher amounts of diastereomeric impurities. We have found that tadalafil can be obtained in high purity when (6R,12aR)-methyl-1 ,2,3,4-tertahydro-2-chloroacetyl-1-(3,4- methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate is reacted with methylamine in methanol in specific quantities for a specific reaction time.
(6R, 12aR)-methyl-1 ,2,3,4-tertahydro-2-chloroacetyl-1 -(3,4-methylene dioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate (II) is a key intermediate for preparation of tadalafil. The preparation (6R,12aR)-methyl-1,2,3,4-tertahydro-2- chloroacetyl-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4~b]indole-3-carboxylate is disclosed in WO 95/19978, WO 96/38131, WO 02/36593, WO 2004/011463, WO 2005/0116030, WO 2005/068464, WO 2006/091975, WO 2006/0258865 and WO 2006/110893. The preparation of the key intermediate:
According to known process (1R,3R)-methyl-1,2,3,4-tertahydro-1-(3,4- methyIenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate is isolated as a solid before converting into (6R,12aR)-methyl-1,2,3,4-tertahydro-2-chloroacetyl- 1 -(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate. We have found that high yields of (6R,12aR)-methyl-1,2,3,4-tertahydro-2-chloroacetyl~1- (3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxyIate results when (1R,3R)-methyl-1,2,3,4-tertahydro-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4- b]indole-3-carboxylate is made to react with chloroacetyl chloride without isolating (1 R,3R)-methyl-1 ,2,3,4-tertahydro-1-(3,4-metriylenedioxyphenyl)-9H- pyrido[3,4-b]indole-3-carboxylate as solid.
Thus, according to one object of the present invention there is provided a process for preparing tadalafil in high purity.
According to another object of the present invention, there is provided an improved process for preparing (6R,12aR)-methyl-1 ,2,3,4-tertahydro-2- chloroacetyl-1-(3,4-methyIenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxyIate in high yield.
DETAILED DESCRIPTION OF THE INVENTION According to one aspect of the present invention there is provided a process for preparing tadalafil which comprises reacting (6R,12aR)-methyl- 1,2,3,4-tertahydro-2-chloroacetyl-1 -(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b] indole-3-carboxylate with 3 to 12 moles of methylamine per mole of (6R,12aR)- methyl-1,2,3,4-tertahydr-2- chloroacetyM-1-(3,4-methylenedioxyphenyl)-9H- pyrido[3,4-b]indoIe-3-carboxylate in 15 - 20 times by volume of alcohol solvent with respect to (6R,12aR)-methyl-1 ,2,3,4-tertahydro-2-chloroacetyl-1-(3,4- methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate by weight for 1 hour to 3 hours 30 minutes.
Preferably the alcohol is used, in 7 to 11 moles of methylamine with respect to (6R,12aR)-methyl-1 ,2,3,4-tertahydro-2-chloroacetyl-1-(3,4-methylene- dioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate.
The alcohol may be single alcohol or a mixture of alcohol, Preferbly the alcohol is selcted from methanol, ethanol and isopropanol, More preferably the alcohol may be methanol.
According to another aspect of the present invention there is provided a process for preparing (6R, 12aR)-methyl-1 ,2,3,4-tertahydro-2-chloroacetyl-1-(3,4 -methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate which comprises: a) Reacting D-Tryptophan methyl ester with pipernal to give (1 R,3R)- methyl-1,2,3,4-tertahydro-1-(3,4-methyIenedioxyphenyl)-9H-pyrido[3,4-b] indole-3-carboxylate (cis isomer) and (1S,3R)-methyl-1 ,2,3,4-terta- hydro-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indoIe-3- carboxylate (trans isomer) b) Adding aqueous HCI to the reaction mass obtain in step (a) without separating (1 R,3R)-methyl-1 ,2,3,4-tertahydro-1-(3,4-methylenedioxy- phenyI)-9H-pyrido[3,4-b]indole-3-carboxylate (cis isomer) and (1S,3R)- methyl-1,2,3,4-tertahydro-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4- b]indole-3-carboxylate (trans isomer)
c) Stirring for 8 to 10 hours of the reaction mass of step (b) at 50 - 100ºC d) Extracting (1 R,3R)-methyI-1 ,2,3,4-tertahydro-1-(3,4-methylenedioxy- phenyl)-9H-pyrido[3,4-b]indole-3-carboxylate into methylene dichloride from step (c) e) Reacting the solution obtained in step (d) with chloroacetyl chloride, and f) The isolating (6R,12aR)-methyl-1 ,2,3,4-tertahydro-2-chloroacetyl-1-(3,4- methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate.
High performance liquid chromatography (HPLC) conditions for reaction monitoring and final sample analysis
Column: ZORBAX RX-C8 250 X 4.6mm, 5μm
Buffer: Dissolve 8.64gm of Sodiumlaurylsulphate and 3.5 ml of orthophospharic acid in 1000 ml of double distilled water. Adjust pH to 2.5 with NaOH.
Mobile phase: Solvent A: BUFFER: CAN (60:40)
Solvent B: BUFFER: CAN (30:70)
Diluent: Solvent A
Test solution preparation: Dissolve 5 mg of the substance in 10 ml of diluent.
Temperature: Ambient
Detector: 285 nm
Flow rate: 1.0 ml/min
Injection volume: 20 μl
Run Time: 30 minutes
Examples Example 1
To a stirred suspension of (6R,12aR)-methyl-1,2,3,4-tertahydro-2-chloro acetyl-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate (5 gm) in methanol (75 ml) was added methanolic methylamine (7.4 ml, 26% methylamine in methanol by weight/volume) at 25 - 30ºC, the reaction mass was heated to 50 - 60° ! C and maintained at this temperature for 3 hours. The reaction mass was monitored by HPLC for the completion of the reaction. After the reaction was completed, the reaction mass was cooled to 25 - 30ºC and
stirred at this temperature for one hour. Filtered the material and washed the solid obtained with methanol and dried to get pure tadalafil [Yield: 4.3 gm; HPLC purity 99.98%].
Example 2
To a stirred suspension of (6R,12aR)-methyl-1,2,3,4-tertahydro-2-chloro acetyl-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate (5 gm) in methanol (75 ml) was added methanolic methylamine (16.4 ml, 26% methylamine in methanol by weight/volume) at 25 - 30ºC and maintained at 55° - 60ºC for 1 hour. The reaction mass was monitored by HPLC for the completion of the reaction. After the reaction was completed, the reaction mass was cooled to 25ºC and maintained at 25ºC for one hour. Filtered the material and washed the solid obtained with methanol and dried to get pure tadalafil [Yield: 4.3 gm; HPLC purity: 99.97%].
Example 3
To a stirred solution of methyl ester D-tryptophan (100 gm) in methylene dichloride (2000 ml), piperanal (50 gm) and trifluoroacetic acid (154 gm) are added at 25ºC. The reaction mass was heated to reflux and maintained for 9 hours at reflux temperature and the reaction completion was checked by HPLC. The reaction mass was cooled to 25 - 30ºC, the reaction mass was washed with water and distilled out methylene dichloride completely to obtained residue. To the residue was added (800 ml) 1 N HCI, heated the mass to 60 - 65ºC, maintained for 10 hours and checked the reaction completion by HPLC. The reaction mass was cooled to 25ºC and added methylene dichloride (1000 ml) and pH adjusted to 9.0 with 1N sodium hydroxide solution. Then the methylene dichloride layer was separated and washed the methylene dichloride layer with water, dried the methylene dichloride layer with sodium sulphate and filtered. To the methylene dichloride layer was added (32 gm) trimethyl amine and the mass cooled to OºC. To the cooled mass was slowly added chloroacetyl chloride (36 gm). The reaction mass was maintained for 2 hours at 0 - 5ºC, the reaction completion was checked by HPLC. Distilled out methylene dichloride added water (100 ml) and isopropyl alcohol (300 ml), maintained for 2 hours at 25ºC, filtered the material, washed the solid separated with aqueous isopropyl alcohol
and dried to get the (6R,12aaRJ-methyl-1,2,3,4-tertahydro-2-chloroacetyl-1-(3,4- methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate (chloroacetyl compound) [Yield: 103 gm] .
Claims
Claims:
1) A process for the preparation of tadalafil (I) which comprises, reacting (6R,12aR)-methyI-1 ,2,3,4-tertahydro-2-chloroacetyl-1-(3,4-methyIenedioxy~ phenyl)-9H-pyrido[3,4-b]indole-3-carboxylate with 3 to 12 moles of methylamine per mole of (6R,12aR)-methyl-1 ,2,3,4-tertahydro-2-chloroacetyl-1-(3,4- methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate in 15 - 20 times by volume of alcohol solvent with respect to (6R,12aR)-methyl-1 ,2,3,4-tertahydro-2- chloroacetyl-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate by weight for 1 hour to 3 hours 30 minutes.
2) The process according to claim 1, the moles of methyl amine used is 7 to 11 per mole of (6R,12aR)-methyl-1,2,3,4-tertahydro-2-chloroacetyl-1(-(3,4- methylene dioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate.
3) The process according to claim 1 , the moles of methyl amine used is 7 to 8 per mole of (6R,12aR)-methyl-1 ,2,3,4-tertahydro-2-chloroacetyl-1-(3,4- methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate and reaction . is carried out for 3 hours to 3 hours 30 minutes.
4) The process according to claim 1 , the moles of methyl amine used is 9 to 11 per mole of (6R,12aR)-methyl-1 ,2,3,4-tertahydro-2-chloroacetyl-1-(3,4- methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate and reaction is carried out for 1 hour to 1 hour 30 minutes.
5) The process according to claim 1 , where in the alcohol solvent is selected from the group comprising of methanol, ethanol, isopropyl alcohol and a mixture thereof.
6) The process according to claim 5, the solvent is selected from methanol.
7) The process for preparing (6R, 12aR)-methyI-1 ,2,3,4-tertahydro-2-chloro acetyl-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate which comprises: a) Reacting D-Tryptophan methyl ester with pipernal to give (1 R,3R)- methyl-1,2,3,4-tertahydro-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b] indole-3-carboxylate (cis isomer) and (1S,3R)-methyl-1 ,2,3,4-terta- hydro-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indoIe-3- carboxylate (trans isomer) b) Adding aqueous HCI to the reaction mass obtain in step (a) without separating (1 R,3R)-methyl-1 ,2,3,4-tertahydro-1-(3,4-methylenedioxy- phenyl)-9H-pyrido[3,4-b]indole-3-carboxylate (cis isomer) and (1S,3R)- methyl-1 ,2,3,4-tertahydro-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4- b]indole-3-carboxylate (trans isomer) c) Stirring for 8 to 10 hours of the reaction mass of step (b) at 50 - 100ºC d) Extracting (1 R,3R)-methyl-1 ,2,3,4-tertahydro-1-(3,4-methylenedioxy- phenyl)-9H-pyrido[3,4-b]indole-3-carboxyIate into methylene dichloride from step (c) e) Reacting the solution obtained in step (d) with chloroacetyl chloride, and f) The isolating (6R,12aR)-methyl-1 ,2,3,4-tertahydro-2-chloroacetyl-1-(3,4- methylenedioxyphenyI)-9H-pyrido[3,4-b]indole-3-carboxylate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IN2008/000339 WO2009144734A1 (en) | 2008-05-28 | 2008-05-28 | Process for preparation of tadalafil |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IN2008/000339 WO2009144734A1 (en) | 2008-05-28 | 2008-05-28 | Process for preparation of tadalafil |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2009144734A1 true WO2009144734A1 (en) | 2009-12-03 |
Family
ID=41376662
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2008/000339 Ceased WO2009144734A1 (en) | 2008-05-28 | 2008-05-28 | Process for preparation of tadalafil |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2009144734A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012107549A1 (en) | 2011-02-10 | 2012-08-16 | Interquim, S.A. | PROCESS FOR OBTAINING COMPOUNDS DERIVED FROM TETRAHYDRO-ß-CARBOLINE |
| CN104151313A (en) * | 2014-07-13 | 2014-11-19 | 浙江华海药业股份有限公司 | Method for purifying Tadalafil intermediate |
| 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 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005068464A2 (en) * | 2003-12-15 | 2005-07-28 | Cadila Healthcare Limited | Process for preparing tadalafil and its intermediates |
-
2008
- 2008-05-28 WO PCT/IN2008/000339 patent/WO2009144734A1/en not_active Ceased
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005068464A2 (en) * | 2003-12-15 | 2005-07-28 | Cadila Healthcare Limited | Process for preparing tadalafil and its intermediates |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012107549A1 (en) | 2011-02-10 | 2012-08-16 | Interquim, S.A. | PROCESS FOR OBTAINING COMPOUNDS DERIVED FROM TETRAHYDRO-ß-CARBOLINE |
| US8829023B2 (en) | 2011-02-10 | 2014-09-09 | Interquim, S.A. | Process for obtaining compounds derived from tetrahydro-β-carboline |
| CN104151313A (en) * | 2014-07-13 | 2014-11-19 | 浙江华海药业股份有限公司 | Method for purifying Tadalafil intermediate |
| CN104151313B (en) * | 2014-07-13 | 2019-04-09 | 浙江华海药业股份有限公司 | A kind of method of purifying tadalafil intermediate |
| RU2692764C1 (en) * | 2019-04-26 | 2019-06-27 | Общество с ограниченной ответственностью "Балтфарма" | Method of producing tadalafil |
| WO2020218941A1 (en) | 2019-04-26 | 2020-10-29 | Obshestvo S Ogranichennoy Otvetstvennostuy "Baltfarma" | Tadalafil synthesis method |
| 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 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US6943255B2 (en) | Process for imidazo[4,5-c]pyridin-4-amines | |
| EP1539752B1 (en) | Preparation of 1h-imidazo[4,5-c]quinolin-4-amines via novel imidazo[4,5-c]quinolin-4-cyano and 1h-imidazo[4,5-c]quinolin-4-carboxamide intermediates | |
| US20130012712A1 (en) | Method for preparing disubstituted piperidine and intermediates | |
| EP3212620B1 (en) | Process for the preparation of apixaban and intermediates thereof | |
| JP6114881B2 (en) | Compound of “3- (5-substitutedoxy-2,4-dinitro-phenyl) -2-oxo-propionic ester”, process and use thereof | |
| EP3142997A1 (en) | Methods of producing compounds from 5-(halomethyl)furfural | |
| WO2009144734A1 (en) | Process for preparation of tadalafil | |
| US20110105751A1 (en) | Conversion of tryptophan into beta-carboline derivatives | |
| WO2005068464A2 (en) | Process for preparing tadalafil and its intermediates | |
| US7223863B2 (en) | Process for preparing Tadalafil and its intermediate | |
| US20100137592A1 (en) | Process for preparing purine derivative | |
| CN114907365B (en) | Influenza virus inhibitor and application thereof | |
| EP1812435A2 (en) | Preparation of tadalafil intermediates | |
| JP2011522042A (en) | Method for producing tadalafil | |
| Josephrajan et al. | Synthesis and antimicrobial studies of some acridinediones and their thiourea derivatives | |
| US8871932B2 (en) | Process for the preparation of tadalafil | |
| EP2004644A1 (en) | Process for the preparation of tadalafil | |
| US20110087024A1 (en) | process for the preparation of paliperidone intermediates | |
| AU2002244711B2 (en) | Method for purifying 20(S)-camptothecin | |
| KR20070102719A (en) | Synthesis method of tadalafil | |
| KR20140128318A (en) | Method for stereoselective synthesis of 1,4-protected 9-hydroxy-5-oxo-1,4-diaza-spiro [5.5] undecanes | |
| KR20220106766A (en) | Method for preparing tofacitinib and its intermediates | |
| HRP990013A2 (en) | A process for preparing naphthyridinones and its intermediates | |
| WO2006046096A2 (en) | A polymorphic form of narwedine and its use in the synthesis of galantamine | |
| EP2970143A1 (en) | Process for preparing alkyl esters of 4-(5-(bis(2-hydroxyethyl) amino)-1-methyl-1h-benzo[d]imidazol-2-yl)butyric acid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 08776677 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 08776677 Country of ref document: EP Kind code of ref document: A1 |