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A technology of tadalafil and its synthesis method, which is applied in the direction of organic chemistry, can solve the problems of flammability, high toxicity, environmental pollution, etc., and achieve the effect of simple reaction method, convenient operation, and serious environmental pollution
Active Publication Date: 2016-02-24
ZHEJIANG YONGNING PHARMA
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[0006] Although there are many synthetic routes for tadalafil at present, they basically use thionyl chloride, chloroacetyl chloride, and methylamine. These reagents have problems such as serious environmental pollution, high toxicity, and inflammability and explosion.
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Embodiment 1
[0032] 200ml of tetrahydrofuran, 20g of D-tryptophan, 7.7g of methylaminoacetonitrile, 38.2g of EDC·HCl and 1g of 4-dimethylaminopyridine were added to a 1L three-necked flask, and the reaction was stirred at room temperature for 5 hours. After the reaction is complete, add 300ml of ethyl acetate and 300ml of water, stir and separate the layers, add 200ml of saturated sodium chloride to the ethyl acetate layer, stir and wash, let stand and separate the layers, and distill the ethyl acetate layer under reduced pressure at 30°C to a volume of about 200ml , adding 700ml of petroleum ether to crystallize, filter, and vacuum-dry at 40°C to obtain 22.25g of compound III. HPLC purity 98%, yield 91%. 1 HNMR (500MHz, DMSO), δ: 3.27-3.38(m, 2H), 3.09(s, 3H), 3.91(s, 1H), 4.16(t, 1H), 6.98(t, 1H), 7.07(t, 1H), 7.25(d, J=2Hz, 1H), 7.35(d, J=8Hz, 1H), 7.50(d, J=8Hz, 1H), 8.76(s, 2H), 11.19(s, 1H); MS(m / z): 257.1[M+1] + .
Embodiment 2
[0034] According to the operation of Example 1, the influence of solvent and reaction temperature on the yield of compound III was investigated, and the results are shown in Table 1.
[0035] Table 1: Effect of solvent and reaction temperature on the yield of compound Ⅲ
[0036]
[0037]
Embodiment 3
[0039] Add 200ml of isopropanol, 20g of compound III and 12.3g of piperonal into a 250ml three-necked flask, heat to reflux, and stir to react for 20 hours. After the reaction was complete, the temperature was lowered to room temperature and stirred for one hour. After filtering and rinsing with ice isopropanol, 27.6 g of compound V was obtained after vacuum drying. (HPLC purity 98.5%, yield 94%. 1 HNMR (500MHz, DMSO), δ: 3.32(d, J=8Hz, 2H), 3.21(s, 3H), 3.93(s, 2H), 4.66(m, 1H), 5.91(s, 1H), 6.07( s, 2H), 7.01-7.12(m, 5H), 7.31(d, J=8Hz, 1H), 7.54(d, J=8Hz, 1H), 10.37(s, 1H), 10.79(s, 1H); MS(m / z): 389.1[M+1] + .
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Abstract
The invention relates to a synthetic method for a compound in the technical field of medicine and chemical engineering, and particularly relates to a novel synthetic method for tadalafil. The synthetic method comprises the steps of: 1) condensing an initial raw material which is D-tryptophan (I) and methylamino acetonitrile (II) or salt thereof to obtain a compound as shown in a formula III; 2) carrying out Pictet-Spengler cyclization reaction on the compound as shown in the formula III and heliotropin and carrying out crystallization to obtain a compound as shown in a formula V; and 3) hydrolyzing the compound V under an acidic or alkaline condition by cyano and then condensing the compound to obtain the target product tadalafil (VI). The formula is shown in the description. In the synthetic method provided by the invention, chemical raw materials which are great in toxicity, severe in environmental pollution and flammable and combustible such as thionyl chloride, chloroacetyl chloride, methylamine and the like. The novel synthetic method for tadalafil provided by the invention is simple in reaction method, convenient to operate and high in yield.
Description
technical field [0001] The invention relates to a synthesis method of compounds in the technical field of medicine and chemical engineering, in particular to a synthesis method of tadalafil. Background technique [0002] The chemical name of tadalafil is (6R-12aR)-6-(1,3-benzodioxol-5-yl)-2-methyl-2,3,6,7,12,12a - Hexahydropyrazino[1',2'-1,6]-pyrido[3,4-b]indole-1,4-dione, the structural formula is as follows: [0003] [0004] Tadalafil is a phosphodiesterase type V (PDE5) inhibitor. When sexual stimulation leads to the local release of nitric oxide, PDE5 is inhibited by tadalafil, which increases the level of cyclic guanosine monophosphate in the cavernous body of the penis, which leads to Smooth muscles relax and blood flows into the penile tissue, producing an erection. The compound was originally developed by GlaxoSmithKline and subsequently transferred to ICOS, and later jointly developed by ICOS and Eli Lilly. Approved by the FDA in 2003, tadalafil was listed in...
Claims
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