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Preparation method of sapropterin dihydrochloride

A technology for sapropterin hydrochloride and salt formation, which is applied in the preparation of hydrazones, the preparation of sugar derivatives, chemical instruments and methods, etc., can solve problems such as low yield and complicated operation, and achieves high yield, high purity, and reduced The effect of process and process time

Active Publication Date: 2019-05-21
北京启慧生物医药有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] In the patent WO2016189542A1, when synthesizing the intermediate DL-5, the property of the compound that can form a potassium salt is used to purify the intermediate DL-5 through a conventional method of adjusting the pH value of the aqueous solution. The operation is complicated and the yield is low

Method used

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  • Preparation method of sapropterin dihydrochloride
  • Preparation method of sapropterin dihydrochloride
  • Preparation method of sapropterin dihydrochloride

Examples

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example 1

[0037] The synthesis of example 1 DL-1:

[0038] Add DL-SMA (134g, 1.0mol), ethyl acetate 1.0L, 4-dimethylaminopyridine 24.4g to the reaction vessel in sequence, cool down to 10~15°C, add acetic anhydride (326.7g, 3.2mol) dropwise, Control the internal temperature at 15-20°C, after dropping, control the reaction temperature at 0-20°C, monitor by TLC until the reaction is complete. Post-treatment: Quench with saturated aqueous sodium carbonate solution, collect the organic phase after separation, extract the aqueous phase with ethyl acetate (500mL*2), combine the organic phases, and wash with saturated aqueous sodium carbonate solution (400mL*1), collect the organic phase The phase was spin-dried, and the ethyl acetate was recovered to obtain a pale yellow oil DL-1 (260 g), which was directly carried out to the next reaction.

example 2

[0039] The synthesis of example 2 DL-2:

[0040] Add DL-1 (260g) and 900mL water obtained in the previous reaction to the reaction vessel, add dropwise acetic acid to adjust the pH value to 3-7, then add phenylhydrazine (118.8g, 1.1mol, 1.1eq), stir and React overnight at room temperature under protection. TLC monitoring, after the reaction was completed, the reaction solution was extracted twice with ethyl acetate (500mL*2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and spin-dried to obtain a yellow oil DL-2 (340g). Proceed directly to the next reaction.

example 3

[0041] The synthetic method 1 of example 3 DL-4:

[0042] Add DL-2 (181g, 0.51mol) and 600mL of methanol into the reaction vessel, and stir until completely dissolved. Anhydrous lithium perchlorate (1.8 g, 0.187 mol) was added, and the reaction was stirred for 30 minutes. Under temperature control at 30±5°C, add DL-SMB (151 g, 0.63 mol) aqueous sodium hydroxide solution prepared in advance. Under the protection of nitrogen, the temperature was raised to reflux, and the reaction was carried out overnight, and monitored by TLC until the end of the reaction. Cool down to 10±5°C, add dropwise a solution of iodine (328g, 1.29mol) in methanol (600mL), and react at room temperature until the reaction is completed under TLC monitoring. Filter, rinse with methanol, and then wash with water, and dry the obtained solid at 50°C to constant weight to obtain light brown solid DL-4 (300g).

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PUM

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Abstract

The invention relates to a preparation method of sapropterin dihydrochloride shown as formula (I) as shown in the specification. The preparation method comprises the steps of taking 5-deoxy arabinoseas a raw material, performing acetylation reaction in the presence of acetic anhydride to form an intermediate DL-1, allowing DL-1 to react with phenylhydrazine under the catalysis of acetic acid to form an intermediate DL-2, allowing DL-2 and pyrimidylamine sulfate to give a ring closing reaction under the catalysis of anhydrous lithium perchlorate to form an intermediate DL-3, directly oxidizingDL-3 through elemental iodine without purification to form an intermediate DL-4, hydrolyzing DL-4 through potassium hydroxide to form L-biopterin (DL-5), and reducing and salifying L-biopterin through a platinum catalyst to form sapropterin dihydrochloride. The preparation method is easy and simple to operate, high in yield, low in energy consumption and suitable for industrial production, the total yield of the preparation method is greater than 70%, and the purity of a final product reaches above 99.5%.

Description

technical field [0001] The invention relates to a preparation method of Sapropterin dihydrochloride, which belongs to the field of drug synthesis. Background technique [0002] Phenylketonuria (PKU) is an autosomal recessive genetic disease. Disorders of phenylalanine metabolism due to hepatic phenylalanine hydroxylase deficiency or deficiency of tetrahydrobiopterin synthase and dihydrobiopterin reductase. At present, sapropterin hydrochloride is the only treatment drug for PKU. It is a synthetic tetrahydrobiopterin (BH4), which is the coenzyme of three aromatic amino acid hydroxylases: phenylalanine, tyrosine and tryptophan. , the use of sapropterin hydrochloride for the treatment of PKU is known as BH4 replacement therapy. [0003] Sapropterin hydrochloride, the chemical name is (6R)-2-amino-6-[(1R,2S)-1,2-dihydroxypropyl]-5,6,7,8-tetrahydro-4(1H )-pteridine dihydrochloride, the structural formula is as follows formula (I): [0004] [0005] (I) [0006] Currently,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D475/04C07H1/00C07H13/04C07C249/16C07C251/76
Inventor 刘素云李克让
Owner 北京启慧生物医药有限公司
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