CN110684025A - Preparation method of tadalafil - Google Patents
Preparation method of tadalafil Download PDFInfo
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- CN110684025A CN110684025A CN201911039962.7A CN201911039962A CN110684025A CN 110684025 A CN110684025 A CN 110684025A CN 201911039962 A CN201911039962 A CN 201911039962A CN 110684025 A CN110684025 A CN 110684025A
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- 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 the field of chemical synthesis, and particularly relates to a preparation method of tadalafil. According to the method, piperic acid acyl chloride and the like which are easy to obtain are used as raw materials, the prepared intermediate 1 and sarcosine are subjected to amidation reaction, high-purity tadalafil can be prepared in a high yield under specific reaction conditions, the whole synthesis process is divided into two steps, the tadalafil can be prepared in a one-pot boiling mode, and compared with the prior art, the method has the advantages that the complex reaction steps are obviously reduced, the operation is simple, and the method is suitable for large-scale industrial production of tadalafil.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis. More particularly, it relates to a preparation method of tadalafil.
Background
Tadalafil is a selective, reversible inhibitor of cyclic guanosine monophosphate (cGMP) specific phosphodiesterase 5(PDE5) and is approved by the FDA for marketing in the united states as a drug for the treatment of Male Erectile Dysfunction (MED) in 2003. Recent clinical research shows that tadalafil can also be used for treating pulmonary hypertension, and has wide application prospect. Compared with similar medicines of sildenafil or vardenafil, tadalafil has the advantages of high activity, quick response, long drug effect, small side effect and the like, and is a hot spot of research and development.
At present, the prior art mainly uses D-tryptophan methyl ester, D-tryptophan methyl ester hydrochloride, D-tryptophan and NαReacting Boc-D-tryptophan serving as a raw material with piperonal or analogues thereof, and preparing tadalafil through a series of synthetic steps. For example, US2009312548 discloses a method for preparing tadalafil, which comprises condensing D-tryptophan with piperonal by methyl thionyl chloride esterification, then grafting chloroacetyl chloride, and cyclizing with methylamine to obtain tadalafil. However, piperonal adopted by the method is not easy to obtain as a tubular medicament, and reagents such as thionyl chloride, chloroacetyl chloride, methylamine and the like have the problems of high toxicity, flammability, explosiveness, serious environmental pollution and the like.
To solve the above problems, Wupulhua et al disclose a synthetic route for tadalafil:
in the synthetic route, D-tryptophan methyl ester hydrochloride is condensed with piperic acid acyl chloride to prepare a compound 9, a compound 10 is prepared under the action of Lawson reagent, methyl iodide reflux and sodium borohydride reduction cyclization are carried out to obtain a compound 7 (an intermediate 1), the yield is 62.5%, then triethylamine catalytic condensation and methylamine ethanol cyclization reaction are carried out on the compound and chloroacetyl chloride to prepare a final product tadalafil, and the yield is 66.4% (Wupul, Xieypeng. tadalafil synthetic route diagram [ J ]. Chinese journal of pharmaceutical chemistry, 2015,25(05): 407-. Although the method avoids using tubular raw materials such as piperonal, toxic and harmful reagents such as thionyl chloride and the like, the method has various steps, is easy to generate various byproducts, has low yield of each step, and finally has the total yield of only 25.9 percent, and is not suitable for actual production due to the fact that the Lawson reagent used in the reaction process is smelly.
Therefore, the tadalafil preparation method which avoids the use of controlled and toxic and harmful reagents, has simple steps, high yield and good purity is urgently needed.
Disclosure of Invention
The invention aims to solve the technical problems of overcoming the defects and shortcomings of complicated steps, low yield and the like of commonly used tubular and toxic and harmful reagents in the reaction in the prior art, and providing the tadalafil preparation method which avoids the use of the tubular and toxic and harmful reagents, and has simple steps, high yield and good purity.
The above purpose of the invention is realized by the following technical scheme:
a preparation method of tadalafil comprises the following reaction route:
the method specifically comprises the following steps:
s1, dissolving D-tryptophan methyl ester hydrochloride and piperic acid acyl chloride in an aprotic organic solvent, adding trifluoroacetic acid, stirring and reacting for 8-12 h at 30-45 ℃ under the protection of nitrogen, adding sodium triacetoxyborohydride, and continuing to react for 2-4 h to obtain a reaction solution containing an intermediate 1;
s2, adding sarcosine and triethylamine into the reaction liquid containing the intermediate 1 obtained in the step S1, stirring for 15-25 min at 20-35 ℃, slowly dropwise adding N, N' -dicyclohexylcarbodiimide, adding 4-dimethylaminopyridine, carrying out mixed reaction for 7-8 h, cooling to 2-5 ℃, adding an alkaline reagent, carrying out reflux reaction for 8-10 h, carrying out post-treatment, and separating to obtain tadalafil;
in the step S1, the mass ratio of the D-tryptophan methyl ester hydrochloride to the trifluoroacetic acid is 1 (0.02-0.5);
in the step S2, the alkaline reagent is selected from one of triethylamine, N-diisopropylethylamine, magnesium methoxide, sodium hydroxide and potassium hydroxide.
Wherein, the reaction mechanism of the step s1 may be:
firstly, carrying out Friedel-crafts acylation reaction on D-tryptophan methyl ester hydrochloride and piperic acid acyl chloride under the action of a trace acid catalyst trifluoroacetic acid, then carrying out Schiff base reaction, and adding sodium triacetoxyborohydride for further reductive amination to form an intermediate 1, wherein the imine compound is unstable. The whole reaction process is completed in one step, no intermediate product needs to be separated, the reaction process is controlled by adding sodium triacetoxyborohydride, and the intermediate 1 can be prepared by one-step reaction.
Lewis acid (such as aluminum trichloride) is usually adopted for catalysis in the Friedel-crafts acylation reaction, but the catalysts are easy to generate hydroxide colloid in the reaction process, can cover the surface of reactants to influence the reaction process, and are easy to block filter paper and difficult to filter; moreover, in order to ensure the normal running of the friedel-crafts-acylation reaction, a large amount of metal halide is generally added, which is relatively high in cost. The applicant surprisingly found in practice that a catalytic amount of protonic acid trifluoroacetic acid is adopted, and a Friedel-crafts reaction and a Schiff base reaction can be simultaneously catalyzed without adding other reagents, the protonic acid trifluoroacetic acid can react to form an imine compound within a certain time, and an intermediate 1 obtained after reduction has high yield and purity and accords with the idea of green chemistry.
In the step S2, the invention adopts sarcosine and the intermediate 1 to carry out amidation reaction, then carries out reflux reaction to carry out aminolysis reaction under the condition of alkaline reagent, can obtain high-yield tadalafil by controlling the conditions of alkaline reagent, reflux temperature and the like, and solves the problems of low reaction rate, long reaction time, low yield and the like of reaction adopting sarcosine ester hydrochloride or sarcosine ester.
Preferably, in the step S1, the mass ratio of the D-tryptophan methyl ester hydrochloride to the trifluoroacetic acid is 1 (0.05-0.2).
More preferably, in step S1, the mass ratio of the D-tryptophan methyl ester hydrochloride to the trifluoroacetic acid is 1: 0.05. Applicants found in practice that the yield of intermediate 1 was higher when the mass ratio of D-tryptophan methyl ester hydrochloride to trifluoroacetic acid was 1: 0.05.
Preferably, in the step S1, the reaction temperature is 30-40 ℃.
More preferably, in step s1, the temperature of the reaction is 30 ℃. The applicant found in practice that the yield of intermediate 1 was higher when the temperature of the reaction was 30 ℃.
Further, in the step S2, the temperature of the reflux reaction is 50-80 ℃.
Preferably, in the step S2, the temperature of the reflux reaction is 60-80 ℃.
More preferably, in step s2, the temperature of the reflux reaction is 80 ℃. The applicant found in practice that the yield of tadalafil was higher when the temperature of the reflux reaction was 80 ℃.
Preferably, in step s2, the basic reagent is selected from one of triethylamine, N-diisopropylethylamine, and magnesium methoxide.
More preferably, in step s2, the alkaline reagent is magnesium methoxide. The applicant has found in practice that the yield of tadalafil is higher when the alkaline agent is magnesium methoxide.
Furthermore, in the step S1, the mass ratio of the D-tryptophan methyl ester hydrochloride to the sodium triacetoxyborohydride is 1 (1-5).
Preferably, in the step S1, the mass ratio of the D-tryptophan methyl ester hydrochloride to the sodium triacetoxyborohydride is 1 (3-5).
More preferably, in step S1, the mass ratio of the D-tryptophan methyl ester hydrochloride to the sodium triacetoxyborohydride is 1: 3.
Further, in the step S2, the mass ratio of the intermediate 1 to the alkaline reagent is 1 (1-3).
Preferably, in the step S2, the mass ratio of the intermediate 1 to the alkaline reagent is 1 (1-2).
More preferably, in step s2, the mass ratio of the intermediate 1 to the alkaline agent is 1: 1.5.
Furthermore, in the step S2, the temperature of the mixing reaction is 20-35 ℃.
Preferably, in the step S2, the temperature of the mixing reaction is 30-35 ℃.
More preferably, in step s2, the temperature of the mixing reaction is 30 ℃.
In step S2, the mass ratio of the intermediate 1, N' -dicyclohexylcarbodiimide and 4-dimethylaminopyridine is 1 (1-3) to 0.005-0.02.
Preferably, in the step S2, the mass ratio of the intermediate 1, the N, N' -dicyclohexylcarbodiimide and the 4-dimethylaminopyridine is 1 (2-3) to (0.01-0.02).
More preferably, in step S2, the mass ratio of the intermediate 1, N' -dicyclohexylcarbodiimide and 4-dimethylaminopyridine is 1:2: 0.01.
Further, in steps s1 and s2, the aprotic organic solvent is selected from one of tetrahydrofuran, toluene, dichloromethane, N-dimethylformamide, acetonitrile, and dimethyl sulfoxide.
Preferably, in the steps s1. and s2, the aprotic organic solvent is tetrahydrofuran.
The invention has the following beneficial effects:
according to the preparation method of tadalafil, the easily obtained piperic acid acyl chloride and the like are used as raw materials, the prepared intermediate 1 and sarcosine are subjected to amidation reaction, the high-purity tadalafil can be prepared in a high yield under specific reaction conditions, the whole synthesis process is only divided into two steps, the tadalafil can be prepared in a one-pot boiling mode, compared with the prior art, the complex reaction steps are obviously reduced, the operation is simple, and the preparation method is suitable for large-scale industrial production of tadalafil.
Drawings
Fig. 1 is a synthetic route diagram for the tadalafil preparation method of the present invention.
FIG. 2 is a hydrogen spectrum of tadalafil prepared in example 1 of the present invention.
FIG. 3 is a mass spectrum of tadalafil prepared in example 1 of the present invention.
FIG. 4 is a high performance liquid chromatogram of tadalafil prepared in example 1 of the present invention.
Detailed Description
The invention is further described with reference to the drawings and the following detailed description, which are not intended to limit the invention in any way. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.
Unless otherwise indicated, reagents and materials used in the following examples are commercially available.
The synthetic route of the tadalafil preparation method is as follows:
example 1 preparation of tadalafil
The tadalafil is prepared and separated by the following method:
s1, dissolving 9.34g D-tryptophan methyl ester hydrochloride and 8.12g piperic acid acyl chloride in 300mL redistilled tetrahydrofuran, adding 0.14mL trifluoroacetic acid, stirring and reacting at 30 ℃ for 10h under the protection of nitrogen, adding 23.30g sodium triacetoxyborohydride, continuing to react for 3h, and after the reaction is monitored by a TLC plate, obtaining 300mL tetrahydrofuran solution containing 12.33g of intermediate 1;
s2, adding 3.41g of sarcosine and 3.23g of triethylamine into the tetrahydrofuran solution containing 12.33g of the intermediate 1 obtained in the step S1, stirring for 20min at 30 ℃, slowly dropwise adding 30mL of tetrahydrofuran solution containing 13.16g N, N' -dicyclohexylcarbodiimide, after the dropwise adding is finished for 30min, adding 0.04g of 4-dimethylaminopyridine, mixing and reacting for 7h at 30 ℃, cooling the reaction solution to 4 ℃ after the reaction is finished, adding 7 wt% of methanol solution containing 4.13g of magnesium methoxide, heating to 80 ℃, carrying out reflux reaction for 9h, monitoring the reaction by a TLC plate, cooling to room temperature, adding 15g of kieselguhr, mixing and filtering, recovering and washing solid residues, concentrating the filtrate under reduced pressure to about 30mL, adding 100mL of deionized water, extracting twice by using 200mL of ethyl acetate, combining organic phases, and performing organic phase extractionRecrystallizing for 4 times, and vacuum drying the solid at 25 deg.C to obtain 11.24g tadalafil with yield of 90.54%, purity of 100.00%, ESI (M/z) [ M + H ]]+：390.1463，[M+Na]+：412.1279。
Example 2 influence of trifluoroacetic acid addition, temperature, solvent on intermediate 1 yield
Reference example 1 preparation of tadalafil except that in step s1, intermediate 1 was prepared using different amounts of trifluoroacetic acid added, temperatures, solvents and the yield of the resulting intermediate 1 was calculated. Specific trifluoroacetic acid addition, temperature, solvent and experimental results are shown in table 1.
TABLE 1 influence of trifluoroacetic acid addition, temperature, solvent on intermediate 1 yield
As can be seen from table 1:
(1) in the step S1, under the same conditions of reaction temperature and solvent, when the mass ratio of D-tryptophan methyl ester hydrochloride to trifluoroacetic acid is 1 (0.05-0.2), the yield of the intermediate 1 is over 75 percent, the yield is higher, and when the yield is beyond the range, the yield of the intermediate 1 is remarkably reduced to be below 50 percent;
(2) in the step S1, under the condition that the quantity ratio of substances is the same as that of a reagent, the yield of the prepared intermediate 1 is reduced along with the rise of the reaction temperature, wherein when the reaction temperature is 30-40 ℃, the yield can reach more than 70%;
(3) in step S1. of the present invention, under the condition of the same mass ratio and temperature, different solvents are selected to also have a certain influence on the yield of the intermediate 1, wherein, when the solvent is tetrahydrofuran, the yield is the highest. EXAMPLE 3 Effect of alkaline reagent, reflux reaction temperature, aprotic organic solvent on Tadalafil yield
Reference example 1 preparation of tadalafil, except that, in step s2, tadalafil was prepared using different alkaline reagents, reflux reaction temperature, aprotic organic solvent, and the yield of the obtained tadalafil was calculated. Specific alkaline reagents, reflux reaction temperature, aprotic organic solvents and experimental results are shown in table 2.
TABLE 2 influence of alkaline reagent, reflux reaction temperature, aprotic organic solvent on Tadalafil yield
As can be seen from table 2:
(1) in the step S2, under the same temperature and solvent conditions, except that potassium carbonate can only prepare a trace amount of tadalafil, a certain amount of tadalafil can be prepared by using other alkaline reagents; wherein the yield of tadalafil prepared from magnesium methoxide is highest;
(2) in the step S2, a certain amount of tadalafil can be prepared at the reflux reaction temperature of 50-80 ℃ under the condition of the same alkaline reagent and solvent, but the reflux reaction temperature has a certain influence on the yield of tadalafil, wherein the yield of tadalafil is highest when the reflux reaction temperature is 80 ℃;
(3) in the step S2, under the same alkaline reagent and temperature conditions, different solvents are selected to also have certain influence on the yield of tadalafil, wherein the yield is highest when the solvent is tetrahydrofuran. Experimental example 1 detection of Tadalafil by Hydrogen Spectroscopy, Mass Spectroscopy and high Performance liquid chromatography
And (3) carrying out hydrogen spectrum, mass spectrum and high performance liquid chromatography detection on the tadalafil prepared in the example 1 to obtain a graph 2-4.
The detection method of the high performance liquid chromatography comprises the following steps:
an appropriate amount of tadalafil prepared in example 1 was precisely weighed, and according to 0512 high performance liquid chromatography in the fourth general rule of the pharmacopoeia of China (2015 edition), octadecylsilane chemically bonded silica was used as a filler, the detection wavelength was set to 285nm, the flow rate was set to 1.0ml/min, the sample amount was 10 μ l, 0.1% trifluoroacetic acid was used as a mobile phase A, acetonitrile was used as a mobile phase B, gradient elution was performed according to the conditions in Table 3, and the chromatogram was recorded.
TABLE 3 high performance liquid chromatography gradient elution conditions
As can be seen from FIG. 4, the time to peak of tadalafil was 24.141 min.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (10)
1. The preparation method of tadalafil is characterized by comprising the following reaction route:
the method specifically comprises the following steps:
s1, dissolving D-tryptophan methyl ester hydrochloride and piperic acid acyl chloride in an aprotic organic solvent, adding trifluoroacetic acid, stirring and reacting for 8-12 h at 30-45 ℃ under the protection of nitrogen, adding sodium triacetoxyborohydride, and continuing to react for 2-4 h to obtain a reaction solution containing an intermediate 1;
s2, adding sarcosine and triethylamine into the reaction liquid containing the intermediate 1 obtained in the step S1, stirring for 15-25 min at 20-35 ℃, slowly dropwise adding N, N' -dicyclohexylcarbodiimide, adding 4-dimethylaminopyridine, carrying out mixed reaction for 7-8 h, cooling to 2-5 ℃, adding an alkaline reagent, carrying out reflux reaction for 8-10 h, carrying out post-treatment, and separating to obtain tadalafil;
in the step S1, the mass ratio of the D-tryptophan methyl ester hydrochloride to the trifluoroacetic acid is 1 (0.02-0.5);
in the step S2, the alkaline reagent is selected from one of triethylamine, N-diisopropylethylamine, magnesium methoxide, sodium hydroxide and potassium hydroxide.
2. The process according to claim 1, wherein in step S1, the mass ratio of D-tryptophan methyl ester hydrochloride to trifluoroacetic acid is 1 (0.05 to 0.2).
3. The method according to claim 1, wherein in step S1, the reaction temperature is 30 to 40 ℃.
4. The preparation method according to claim 1, wherein in step S2, the temperature of the reflux reaction is 50-80 ℃.
5. The method according to claim 1, wherein in step S2, the basic reagent is one selected from triethylamine, N-diisopropylethylamine, and magnesium methoxide.
6. The preparation method according to claim 1, wherein in step S1, the mass ratio of D-tryptophan methyl ester hydrochloride to sodium triacetoxyborohydride is 1 (1-5).
7. The preparation method according to claim 1, wherein in step S2, the mass ratio of the intermediate 1 to the alkaline reagent is 1 (1-3).
8. The preparation method according to claim 1, wherein in step S2, the temperature of the mixing reaction is 20-35 ℃.
9. The method according to claim 1, wherein in step S2, the amount ratio of the intermediate 1, N' -dicyclohexylcarbodiimide, and 4-dimethylaminopyridine is 1 (1-3) to (0.005-0.02).
10. The preparation method according to claim 1, wherein in steps s1 and s2, the aprotic organic solvent is one selected from tetrahydrofuran, toluene, dichloromethane, N-dimethylformamide, acetonitrile and dimethyl sulfoxide.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111721874A (en) * | 2020-06-28 | 2020-09-29 | 南京赛尔健生物技术有限公司 | HPLC method for separating tadalafil and chiral isomer thereof |
| CN115184531A (en) * | 2021-04-07 | 2022-10-14 | 浙江康恩贝制药股份有限公司 | Method for simultaneously determining contents of 3 impurities in tadalafil |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007052283A1 (en) * | 2005-10-31 | 2007-05-10 | Alembic Limited | An improved process for preparing tadalafil and its intermediate |
| WO2007100387A3 (en) * | 2005-11-03 | 2008-03-06 | Reddys Lab Ltd Dr | Process for preparing tadalafil |
| CN101155809A (en) * | 2005-04-12 | 2008-04-02 | 特瓦制药工业有限公司 | Preparation of tadalafil intermediates |
| CN103772384A (en) * | 2014-01-23 | 2014-05-07 | 苏州大学 | Preparation method of tadalafil |
| CN105524062A (en) * | 2015-12-31 | 2016-04-27 | 湖南千金湘江药业股份有限公司 | A synthetic method of tadalafil |
| CN106810554A (en) * | 2017-01-14 | 2017-06-09 | 山东裕欣药业有限公司 | A kind of preparation method of Tadalafei compound |
| CN106977516A (en) * | 2017-03-02 | 2017-07-25 | 山东裕欣药业有限公司 | A kind of preparation method of Tadalafei |
-
2019
- 2019-10-29 CN CN201911039962.7A patent/CN110684025B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101155809A (en) * | 2005-04-12 | 2008-04-02 | 特瓦制药工业有限公司 | Preparation of tadalafil intermediates |
| WO2007052283A1 (en) * | 2005-10-31 | 2007-05-10 | Alembic Limited | An improved process for preparing tadalafil and its intermediate |
| WO2007100387A3 (en) * | 2005-11-03 | 2008-03-06 | Reddys Lab Ltd Dr | Process for preparing tadalafil |
| CN103772384A (en) * | 2014-01-23 | 2014-05-07 | 苏州大学 | Preparation method of tadalafil |
| CN105524062A (en) * | 2015-12-31 | 2016-04-27 | 湖南千金湘江药业股份有限公司 | A synthetic method of tadalafil |
| CN106810554A (en) * | 2017-01-14 | 2017-06-09 | 山东裕欣药业有限公司 | A kind of preparation method of Tadalafei compound |
| CN106977516A (en) * | 2017-03-02 | 2017-07-25 | 山东裕欣药业有限公司 | A kind of preparation method of Tadalafei |
Non-Patent Citations (2)
| Title |
|---|
| ANNA SPINDLER等: "Synthesis and Investigation of Tetrahydro-β-carboline Derivatives as Inhibitors of the Breast Cancer Resistance Protein (ABCG2)", 《J. MED. CHEM》 * |
| 钱彭飞: "他达拉非的合成工艺及有关物质研究", 《苏州大学硕士学位论文》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111721874A (en) * | 2020-06-28 | 2020-09-29 | 南京赛尔健生物技术有限公司 | HPLC method for separating tadalafil and chiral isomer thereof |
| CN115184531A (en) * | 2021-04-07 | 2022-10-14 | 浙江康恩贝制药股份有限公司 | Method for simultaneously determining contents of 3 impurities in tadalafil |
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