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Product Details
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171596-29-5 Chemical & Physical Properties |
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Melting point |
298-300ºC |
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Boiling point |
679.1±55.0 °C at 760 mmHg |
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Density |
1.5±0.1 g/cm3 |
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Molecular Formula |
C22H19N3O4 |
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Molecular Weight |
389.404 |
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Flash Point |
364.5±31.5 °C |
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PSA |
74.87000 |
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LogP |
1.43 |
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Exact Mass |
389.137543 |
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Vapour Pressure |
0.0±2.1 mmHg at 25°C |
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Index of Refraction |
1.758 |
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Storage condition |
Hygroscopic, -20?C Freezer, Under Inert Atmosphere |
Indications and uses
171596-29-5 (or Tadalafil) was developed by American pharmaceutical company Lilly. It is used to treat erectile dysfunction and belongs to a second generation of PDE5 inhibitors. Studies show that 171596-29-5 works very quickly, taking effect in around 15-20 minutes, and has a prolonged effect that can last for up to 36 hours. T1/2 is 17.5h.
Clinical Research
Tadalafil is a prescription drug approved for the treatment of erectile dysfunction (ED) and pulmonary arterial hypertension (PAH). Numerous clinical trials have been conducted to evaluate the safety and efficacy of tadalafil in these indications.
In patients with erectile dysfunction, tadalafil has been shown to be effective in a dose-dependent manner, with doses of 10 mg, 20 mg, and 40 mg demonstrating significant improvements in erectile function compared to placebo. The most common adverse events associated with tadalafil therapy include headache, flushing, nasal congestion, and rhinitis.
In patients with pulmonary arterial hypertension, clinical trials have demonstrated that tadalafil improves exercise capacity, pulmonary hemodynamics, and quality of life compared to placebo. The most common adverse events associated with tadalafil therapy in this population include headache, flushing, and nasal congestion.
Mechanism of action
The mechanism of action for Tadalafil is primarily based on its modulation of the cyclic guanosine monophosphate (cGMP) pathway. cGMP is a key intracellular second messenger that mediates a variety of physiological processes, including smooth muscle relaxation and erectile function. Tadalafil is a selective phosphodiesterase type 5 (PDE5) inhibitor, which means it blocks the breakdown of cGMP by PDE5 enzymes, leading to an accumulation of cGMP in the corpus cavernosum (the spongy tissue in the penis). This increase in cGMP potentiates the smooth muscle relaxation required for penile erection, allowing for normal sexual performance. Additionally, Tadalafil may also have beneficial effects on the central nervous system, as it can enhance male libido and potency through activation of central dopamine receptors.
The invention provides a preparation method of tadalafil, and relates to the technical field of medicines. The preparation method comprises the steps of taking D-cis-carboline hydrochloride as an initial raw material, carrying out acylating chlorination reaction on the D-cis-carboline hydrochloride and chloroacetyl chloride under the action of an acid-binding agent, carrying out primary refining on an obtained chloroacetylate intermediate crude product, carrying out aminolysis cyclization reaction on the obtained high-purity chloroacetylate intermediate and methylamine, adding a pulping solvent into the obtained tadalafil crude product for pulping, carrying out solid-liquid separation, washing the obtained solid product, and drying to obtain the high-purity tadalafil. Moreover, the D-cis-carline hydrochloride raw material is cheap, easy to obtain and stable in quality, the D-cis-carline hydrochloride raw material is used as a starting raw material, the production period of tadalafil is short, and the production cost is low.
The invention discloses a preparation method of tadalafil. According to the method, a compound I is adopted as a starting material, the tadalafil is obtained through condensation, Fisher indole synthesis reaction, Pictet-Spengler reaction, acylation and ring closing in sequence, and dangerous reagents (n-butyllithium and the like) are not used during ring closing. The reaction route is simple, the reaction condition is mild, the purity is high, the cost is relatively low, the operation is simple and convenient, and industrial production is easy.
The invention belongs to the technical field of medicines, and particularly relates to a production process of a tadalafil bulk drug. The production process of the tadalafil bulk drug comprises the following steps: A1, carrying out an esterification reaction on methanol and D-tryptophan to obtain an intermediate I; A2, performing a condensation reaction on the intermediate I and heliotropin to obtain an intermediate II; A3, performing an acylation reaction on the intermediate II and chloroacetyl chloride to obtain an intermediate III; and A4, carrying out a cyclization reaction on the intermediate III and monomethylamine to obtain the tadalafil bulk drug. According to the method, a reaction path is reasonably selected, and meanwhile, the process details of each reaction step are deeply optimized, so high purity and yield of a product of each step of reaction can be obtained, the prepared tadalafil bulk drug is low in cost and good in stability, the economical efficiency of the whole reaction path is improved, and production cost is reduced.
![(6R,12aR)-6-(3,4-dihydroxyphenyl)-2-methyl-2,3,6,7,12,12a-hexahydropyrazino[1',2'-1,6]-pyrido[3,4-b]indole-1,4-dione](/upload/2023/1\d920477d-0a1e-45e7-95c6-1ff6506fc820.png)
(6R,12aR)-6-(3,4-dihydroxyphenyl)-2-methyl-2,3,6,7,12,12a-hexahydropyrazino[1',2'-1,6]-pyrido[3,4-b]indole-1,4-dione
1,1-dibromomethane
![(6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione](/upload/2023/1\5fa36582-24f0-412c-8a23-9b1a2452c274.png)
(6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione
| Conditions | Yield |
|---|---|
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With sodium hydroxide; In N,N-dimethyl-formamide; at 60 ℃; for 6h;
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95% |
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With caesium carbonate; In N,N-dimethyl-formamide; at 80 ℃; for 8h;
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93% |
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With caesium carbonate; In N,N-dimethyl-formamide; at 80 ℃; for 8h;
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93% |
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With caesium carbonate; In N,N-dimethyl-formamide; at 80 ℃; for 8h;
|
93% |
![(1R,3R)-methyl-1,2,3,4-tetrahydro-2-(2-(benzyl(methyl)amino)acetyl)-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate](/upload/2023/1\ca82e20e-4d92-4608-9922-676499d310de.png)
(1R,3R)-methyl-1,2,3,4-tetrahydro-2-(2-(benzyl(methyl)amino)acetyl)-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate
(6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione
| Conditions | Yield |
|---|---|
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With hydrogen; Raney Ni; In ISOPROPYLAMIDE; at 80 ℃; for 22h; under 2280.15 Torr; Product distribution / selectivity;
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94% |
methylamine
methyl (1R,3R)-1-(3,4-methylenedioxyphenyl)-2-chloroacetyl-2,3,4,9-tetrahydro-9H-pyrido[3,4-b]indol-3-carboxylate
1-benzo[1,3]dioxol-5-yl-2-{[(9H-fluoren-9-ylmethoxycarbonyl)-methyl-amino]-acetyl}-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid methyl ester
(1R,3R)-1-(benzo[d][1,3]dioxol-5-yl)-2-(2-chloroacetyl)-N-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxamide
11-benzo[1,3]dioxol-5-yl-3-methyl-2,3,4a,11-tetrahydro-10H-3,10,11a-triaza-benzo[b]fluorene-1,4,5-trione
(6R,12aS)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione
3-((2-(benzo[d][1,3]dioxole-5-carbonyl)-1H-indol-3-yl)methyl)-1-methylpiperazine-2,5-dione
C10H12O3*C22H19N3O4
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