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A technology of tryptophan and hydrochloride, which is applied in the direction of organic chemistry, can solve the problems of cumbersome post-processing, violent reaction, and high cost, and achieve the effects of improving stereoselectivity, simple post-processing, and reducing risks
Active Publication Date: 2015-04-29
SUNSHINE LAKE PHARM CO LTD
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[0006] Among them, D-tryptophan methyl ester hydrochloride is prepared by refluxing D-tryptophan and thionyl chloride in methanol. This method reacts violently and uses a large amount of thionyl chloride,
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Embodiment 1D
[0026] The preparation of embodiment 1D-tryptophan methyl ester hydrochloride
[0027] Add D-tryptophan (50g) to a mixed solution of toluene (650ml) and methanol (105ml) and stir evenly, slowly add thionyl chloride (38.6g) dropwise at 0°C, and heat up to 75 After reflux reaction at ~80°C for 4 hours, the reaction is over, the reaction solution is cooled to 0°C and stirred for 2 hours, the solid precipitates, filtered, the filter cake is washed with toluene, and vacuum-dried at 50°C for 6h to obtain D-tryptophan methyl Ester hydrochloride, white powder solid. Yield 95%, HPLC purity 99%.
Embodiment 2
[0028] The preparation method of embodiment 2 compound (II)
[0029]
[0030] Into the reaction bottle, add quantitative D-tryptophan methyl ester hydrochloride (50g), compound (IV) (32.5g), acetonitrile (500ml), stir evenly, heat up to 75-85°C, reflux for 16h, HPLC detects that the reaction is progressing; after the reaction, cool down to 25±5°C, stir and crystallize for 4h; filter with suction, wash the filter cake with a small amount of acetonitrile, and dry it in vacuum at 50°C for 6-8h to obtain a white solid with a yield of 94.2%, the compound The HPLC purity of (II) was 98.175%, and the enantiomeric excess (ee%) was 99.12%.
Embodiment 3
[0031] Embodiment 3HPLC detection condition
[0032] 1. The analysis methods of central control and intermediates are as follows:
[0033]
[0034]
[0035] 2. Compound (II) chiral isomer analysis method:
[0036] Chromatographic column: CHIRAL PAK AS-H (4.6*250mm, 5μm);
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Abstract
The invention relates to an improved method of preparing a compound (II). The improved method comprises the following steps: (the formula is shown in the description) 1, mixing D-tryptophan, methanol and toluene, adding thionyl chloride dropwise, and then carrying out reaction at the temperature of 70-85 DEG C to obtain D-tryptophan ester hydrochloride, wherein the structure is shown in a formula (III):(the formula is shown in the specification); and 2, mixing the D-tryptophan ester hydrochloride, a compound (IV) and a nitrile solvent, uniformly stirring, then raising the temperature to 75-85 DEG C, and carrying out reaction, (the formula is shown in the description). The improved preparation method of the compound shown by the D-tryptophan ester hydrochloride (II) has the following beneficial effects: 1, the dosage of the thionyl chloride in the first step is greatly reduced, so that the risk and the corrosion of the reaction are lowered, the post-processing is simple, and the yield is above 90 percent; 2, in the second step, the nitrile solvent is adopted to improve the stereoselectivity, and the enantiomer extra amount (ee %) is above 99 percent.
Description
technical field [0001] The invention relates to the field of medicinal chemistry, in particular to an improved preparation method of tadalafil intermediate D-tryptophan methyl ester hydrochloride. Background technique [0002] Tadalafil, also known as (6R-12aR)-6-(1,3-benzodioxol-5-yl)-2-methyl-2,3,6,7,12,12a-hexa Hydrogenated pyrazino[1',2'-1,6]-pyrido[3,4-b]indole-1,4-dione, compound represented by formula (I), trade name "Cialis", is an oral PDE5 inhibitor for erectile dysfunction (ED). Tadalafil was launched in the U.S. in December 2003 as a once-a-day oral dosage form. It is also approved in the United States and Europe for benign prostatic hyperplasia and pulmonary hypertension. [0003] [0004] US Patent No. 5,859,006 for the first time discloses a method for preparing tadalafil by the following route. [0005] [0006] Among them, D-tryptophan methyl ester hydrochloride is prepared by refluxing D-tryptophan and thionyl chloride in methanol. This method rea...
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