CN109988167A - A kind of preparation method of Tadalafei - Google Patents
A kind of preparation method of Tadalafei Download PDFInfo
- Publication number
- CN109988167A CN109988167A CN201711468018.4A CN201711468018A CN109988167A CN 109988167 A CN109988167 A CN 109988167A CN 201711468018 A CN201711468018 A CN 201711468018A CN 109988167 A CN109988167 A CN 109988167A
- Authority
- CN
- China
- Prior art keywords
- tadalafei
- compound
- added
- preparation
- methylamine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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
Abstract
The invention belongs to pharmaceutical technology fields, and in particular to a kind of preparation method of Tadalafei.The preparation method includes: (1R; 3R) -1; 2; 3,4- tetrahydro -2- chloracetyl -1- (3,4- methylenedioxyphenyl) -9H- pyridos [3; 4-b] temperature control in thionyl chloride reacts indole -3-carboxylic acid methyl ester (compound A) with methylamine water solution; centrifugation after purified water crystallization is added to obtain Tadalafei, without recrystallization, organic solvent residual meets standards of pharmacopoeia.This method greatly improves Tadalafei yield, and easy operation reduces the dosage of organic solvent, reduces purification process, is suitable for industrialized production.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of preparation method of Tadalafei.
Background technique
Tadalafei (tadalafil), chemical name: (6R-12aR) -6- (1,3- benzo two dislikes cyclopentadienyl -5- base) -2- methyl -
2,3,6,7,12,12a- hexahydro pyrazine simultaneously [1', 2'-1,6]-pyrido [3,4-b] indoles -1,4- diketone；Molecular weight:
389.41；Molecular formula: C22H19N3O4；Structural formula is as follows:
Tadalafei (Tadalafi) is a kind of PDE5 inhibitor, is initially researched and developed by GlaxoSmithKline PLC company (GSK),
And then transfer ICOS company, after developed jointly by ICOS and Li Lai (EliLillv).Ratify through FDA within 2003, as controlling
The drug for treating male erectile dysfunction (MED) lists in the U.S..Another clinical application for finding the drug later is to control
Treat pulmonary hypertension.Compared with similar drugs, have selectivity high, long half time, patient has bigger independence etc. excellent
Point.
The current synthetic method reported in the literature for preparing Tadalafei is mostly prepared using D-trp, piperonal as raw material,
D-trp generates D-trp methyl esters through over-churning, then with piperonal through Pickett-Shi Penggele (Pictet-Spengler)
Cyclization generates cis--1, and 3-two replace click wave quinoline intermediate, obtains (1R, 3R)-using the amidation of 2 secondary amino groups
1,2,3,4- tetrahydro -2- chloracetyl -1- (3.4- methylenedioxyphenyl) -9-H- pyrido (3,4-b) indole -3-carboxylic acid's first
Ester intermediate (compound A), compound A, which replaces finally by methylamine and is condensed closed loop, obtains product Tadalafei.Wherein change
The step for closing object A and methylamine reaction generation product mainly uses the tetrahydrofuran solution of methylamine or the methanol solution of methylamine adding
It is reacted in the case where heat to reflux, in addition CN03818238.6 discloses the side that compound A reacts in tetrahydrofuran with methylamine
Method.Above-mentioned preparation method is primarily present following problem: (1) reaction condition is not mild, needs to heat and be reacted, can make body
Enantiomter (compound B) amount increases in system, causes the product isomers exceeded, the USP requirement impurity must not mistake
0.10%；(2) there is contaminant overstandard in crude product, need to pass through polishing purification；(3) process operation is too complicated, needs concentration,
After product processing time is long, obtained product colour is deep, is unfavorable for quality control；(4) organic solvent is not easy in the product obtained
Control, especially with the reagent containing tetrahydrofuran, tetrahydrofuran is more than medicine song standard in obtained product, make it difficult into
Row industrialized production
In terms of the purification of Tadalafei crude product, United States Patent (USP) 5859006, which is disclosed through flash chromatography, to be purified then in first
The method crystallized in alcohol, Tadalafei crude product need to carry out many additional purification steps, for example, repeatedly extract, crystallization and/
Or flash chromatography to remove synthesis after be present in the impurity in compound, and wherein crystallize the dosage of the methanol of needs
Very big-about 220 times weight ratios, therefore the purification step industrial cost is high, workers with long time purifies that he reaches with methanol in industrial production
It draws and non-contact and imbedibility is be easy to cause to be poisoned.
CN101128463A also discloses a kind of Tadalafei in certain solvent: C2-C6 fatty alcohol and ketone or nitrile and hydroxyl
Carry out the method for crystallization purifying in the solution of the mixture of solvent, similarly exists and need a large amount of organic solvent and temperature etc.
The not mild problem of condition.And the yield of both methods, all in 40%-80%, yield is relatively low, and it is cumbersome, it is unsuitable for
Industrialized production.
Patent CN104262340B also discloses a kind of Tadalafei and reacts and purify in N,N-dimethylformamide
Method, but n,N-Dimethylformamide itself is easy to remain in Tadalafei, medicine Qu Yaoqiu n,N-Dimethylformamide residual
0.088%, therefore the undesirable dangerous of Tadalafei quality prepared by the technique must not be crossed.
Summary of the invention
In order to solve the above technical problems, the present invention provides a kind of preparation method of Tadalafei, the preparation methods
Product including obtaining needs to refine, and greatly improves Tadalafei yield, and easy operation reduces the use of organic solvent
Amount is suitable for industrialized production.
The present invention is achieved by the following technical solution: by (1R, 3R) -1,2,3,4- tetrahydro -2- chloracetyl -
1- (3,4- methylenedioxyphenyl) -9H- pyrido [3,4-b] indole -3-carboxylic acid methyl ester (abbreviation compound A) and dimethyl
Stirring and dissolving in reaction flask is added in sulfoxide, and 40% methylamine water solution is added, and continues to be stirred to react 3h, water is added dropwise, it is solid that white is precipitated
Body；Centrifugation, is dried under reduced pressure after drying, obtains white powder Tadalafei crude solid；
Compared with prior art, the beneficial effects of the present invention are:
(1) in the preparation of Tadalafei crude product, by the way that the side of pure water crystallization is added dropwise after reaction using dimethyl sulfoxide as solvent
Formula can effectively remove methylamine,
(2) reaction temperature is mild, close to reacting at room temperature, can effectively reduce energy consumption,
(3) it does not need to refine after Tadalafei preparation, obtained product quality meets USP standard, reduces purifying behaviour
Make, production cost be effectively reduced,
(4) dimethyl sulfoxide content is lower than 0.5% in the Tadalafei obtained, meets standards of pharmacopoeia.
Figure of description:
Fig. 1: the XRD spectrum of 1 Tadalafei of embodiment.
Specific embodiment
Elaborate below to the embodiment of the present invention: the present embodiment carries out under the premise of the technical scheme of the present invention
Implement, gives detailed embodiment and process, single protection scope of the present invention is not limited to following embodiments.
Embodiment 1
(1) by 300g (0.703mol) compound A(HPLC purity: 98.6%) being added in reaction flask and stir with 900ml dimethyl sulfoxide
Dissolved clarification is mixed, 218.4g (2.812mol) 40% methylamine water solution is added, 20-30 DEG C is continued to be stirred to react 2-3h, and compound A is anti-
It should finish, the pure water of 2100ml is added dropwise, ex vivo is precipitated；It filters, the ethanol rinse of 100ml is added in filter cake, and 75 DEG C of decompressions are dry after draining
It is dry, obtain 276.0g white powder Tadalafei crude solid, yield 92.0%, HPLC:99.94%, largest single impurity
0.04%；HPLC method is the related substance method of USP.
Embodiment 2
(1) by 300g (0.703mol) compound A(HPLC purity: 98.5%) being added in reaction flask and stir with 750ml dimethyl sulfoxide
Dissolved clarification is mixed, 191.1g (2.460mol) 40% methylamine water solution is added, 20-30 DEG C is continued to be stirred to react 2-3h, and compound A is anti-
It should finish, the pure water of 1800ml is added dropwise, ex vivo is precipitated；It filters, the ethanol rinse of 120ml is added in filter cake, and 75 DEG C of decompressions are dry after draining
It is dry, obtain 281.1g white powder Tadalafei crude solid, yield 93.7%, HPLC:99.92%, largest single impurity
0.05%；HPLC method is the related substance method of USP.
Comparative example 1
It is prepared referring to patent CN03818238.6 step 4 method:
By 86g (0.201mol) compound A(HPLC purity: 98.5%), being added in tetrahydrofuran 430ml, obtained mixture exists
Heated under nitrogen is to 30 to 55 DEG C, stirring.Obtained solution is filtered to remove insoluble matter, by 78.2g (1.0 at 5 to 25 DEG C
Mol) 40% methylamine water solution is added in solution, and obtained mixture exists, and continues to be stirred to react at 30-55 DEG C anti-to compound A
It should finish.Reaction is finished, and system is cooled to 0 to 30 DEG C, 244ml isopropanol and 175ml water is added, the hydrochloric acid of 12M is then added
With excessive methylamine in 67ml, it is 7 that mother, which reaches pH,.After distilling substantially completely removal tetrahydrofuran, solution 260ml isopropyl
Pure and mild 75ml water process is cooled to 0 DEG C, and stirring is filtered after 2 hours, is eluted with 50% cold aqueous isopropanol, and product subtracts at 80 DEG C
It press dry dry, obtains 69.8g pale yellow powder shape Tadalafei crude solid, yield 89.0%, HPLC:99.52%, largest single impurity
0.14%；.
HPLC method is the related substance method of USP:
Chromatographic condition:
Solution is prepared and (notes: must not use ultrasonic treatment in the solution process for preparation under this)
Mixed solvent: acetonitrile: isopropanol=50:50(V/V)；
Dilution and blank solution: 0.1% trifluoroacetic acid aqueous solution: acetonitrile=50:50(V/V)；
The detection method of dissolvent residual (tetrahydrofuran and dimethyl sulfoxide):
Solution is prepared
Dilution and blank solution: DMF
Dissolvent residual detection is carried out using the Tadalafei that the above method prepares embodiment 1,2 and comparative example 1, as a result such as
Under:
Dissolvent residual content and product colour testing result in Tadalafei prepared by the present invention
Claims (5)
1. a kind of preparation method of Tadalafei, which is characterized in that
By (1R, 3R) -1,2,3,4- tetrahydro -2- chloracetyl -1- (3,4- methylenedioxyphenyl) -9H- pyrido [3,4-
B] stirring and dissolving in reaction flask is added in indole -3-carboxylic acid methyl ester (compound A) and dimethyl sulfoxide, 40% methylamine water solution is added,
Continue to be stirred to react, until less than 0.10%, water is added dropwise in compound, white solid is precipitated；Centrifugation, is dried under reduced pressure after drying, obtains white
Powdered Tadalafei crude solid.
2. a kind of method for preparing Tadalafei as described in claim 1, characterized in that described with the meter of using of compound A
The dosage of dimethyl sulfoxide is 2-10 g/g.
3. a kind of method for preparing Tadalafei as described in claim 1, characterized in that described in terms of the quality of compound A
The additional amount of 40% methylamine water solution is 0.4-1.5 g/g.
4. a kind of method for preparing Tadalafei as described in claim 1, characterized in that described in terms of the quality of compound A
The additional amount of water is 2-10g/g.
5. a kind of method for preparing Tadalafei as described in claim 1, characterized in that the compound A is reacted with methylamine
Temperature is 20-40 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711468018.4A CN109988167A (en) | 2017-12-29 | 2017-12-29 | A kind of preparation method of Tadalafei |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711468018.4A CN109988167A (en) | 2017-12-29 | 2017-12-29 | A kind of preparation method of Tadalafei |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109988167A true CN109988167A (en) | 2019-07-09 |
Family
ID=67108289
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711468018.4A Pending CN109988167A (en) | 2017-12-29 | 2017-12-29 | A kind of preparation method of Tadalafei |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109988167A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111072662A (en) * | 2019-12-23 | 2020-04-28 | 成都锦华药业有限责任公司 | Method for preparing tadalafil I-type crystal |
| 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 |
| CN113880837A (en) * | 2021-11-04 | 2022-01-04 | 昆明源瑞制药有限公司 | Preparation method of tadalafil |
-
2017
- 2017-12-29 CN CN201711468018.4A patent/CN109988167A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111072662A (en) * | 2019-12-23 | 2020-04-28 | 成都锦华药业有限责任公司 | Method for preparing tadalafil I-type crystal |
| 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 |
| CN113880837A (en) * | 2021-11-04 | 2022-01-04 | 昆明源瑞制药有限公司 | Preparation method of tadalafil |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| NO317304B1 (en) | Tetrahydropyridoetere | |
| CN109988167A (en) | A kind of preparation method of Tadalafei | |
| CA2788774A1 (en) | Crystalline forms of sodium 4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5h-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoate | |
| CN105732622A (en) | Preparation method of apixaban | |
| CN113061138A (en) | Triazole [5,4-d ] pyrimidone tricyclic compound and preparation method and application thereof | |
| CN107778223B (en) | Preparation method of betrixaban maleate | |
| CN102911176A (en) | Preparation method of pemetrexed disodium | |
| CN115403521A (en) | Synthesis method of lomefloxacin hydrochloride intermediate | |
| CN106749258B (en) | Method for purifying ertapenem sodium | |
| CN101541798B (en) | Process for production of mirtazapine | |
| CA2368815A1 (en) | Novel synthesis and crystallization of piperazine ring-containing compounds | |
| CN100516046C (en) | Synthesizing process of quinolone main cycle compound | |
| CN106146512A (en) | The preparation method of Buddhist nun is replaced according to Shandong | |
| WO2019029554A1 (en) | Sulfonamide derivative, preparation method thereof, and use of same in medicine | |
| FI110777B (en) | Process for selectively obtaining a 3/2-hydrate of 7- [7- (S) -amino-5-azaspiro [2.4] heptan-5-yl] -8-chloro-6-fluoro-1 - [(1R, 2S) -2-fluorocyclopropyl] -4-oxo-1,4-dihydroquinoline-3-carboxylic acid | |
| CN115160321A (en) | Vardenafil analogue and synthetic method and application thereof | |
| AU2010251385B2 (en) | Novel solid materials of {[2S, 5R,8S,11S)-5-benzyl-11-(3-guanidino-propyl)-8-isopropyl-7-methyl-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid} and methods for obtaining them | |
| CN106432195B (en) | Method for preparing (R) -2- (2-methylpyrrolidine-2-yl) -1H-benzimidazole-4-formamide | |
| CN104557877A (en) | Avanafil intermediate as well as preparation method and application thereof | |
| CN109912605B (en) | Purification method of pemetrexed intermediate | |
| CN107739328B (en) | Preparation method of key intermediate 1 for synthesizing barretinib | |
| US20030088094A1 (en) | Novel synthesis and crystallization of piperazine ring-containing compounds | |
| CN103265559A (en) | Substituted tricyclo-quinone compounds, and preparation method and application thereof | |
| CN110183446A (en) | A kind of new impurity of Moxifloxacin and its preparation method and use | |
| KR20140140398A (en) | A synthetic method of high purity mirtazapine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20190709 |
|
| WD01 | Invention patent application deemed withdrawn after publication |