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Intermediate for preparing L-red biopterin compound and preparation method thereof

A technology of intermediates and compounds, applied in the field of intermediates and preparations of L-erythro-type biopterin compounds, can solve problems affecting quality, poor selectivity, pollution, etc., and achieve easy storage and transportation, and easy quality control , requiring a wide range of effects

Pending Publication Date: 2022-02-22
SHANGHAI FOREFRONT PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] However, there are major defects in this industrial route: 1) The synthesis of the key intermediate 5-deoxy-L-arabinose requires the condensation of L-rhamnose and ethanethiol with a strong odor to form acetal, which is complicated to operate and pollutes Seriously, it is no longer used in industry; 2) The intermediate 5-deoxy-L-arabinose itself is unstable and cannot be stored for a long time. Most of them are oils, and they are all unstable, so it is necessary to use the crude product to push all the way from C to L-erythrobiopterin, which makes the process difficult to control quality and carry out GMP production; 4) adopt 5-deoxy-L-arabinose Derivatives are condensed with 2,4,5-triamino-6-hydroxypyrimidine (TAP) to prepare L-erythro-biopterin, which has poor selectivity, many impurities and low yield; 5) the generated L-erythro-biopterin , because of its extremely poor solubility in common solvents and extremely difficult purification, its quality directly and negatively affects the quality of subsequent hydrogenation to prepare sapropterin hydrochloride
Further research found that although the construction of chiral centers by dihydroxylation can greatly reduce the difficulty of separation of chiral products, if high-purity products are required, column separation and other means are still required, which is not conducive to industrial production

Method used

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  • Intermediate for preparing L-red biopterin compound and preparation method thereof
  • Intermediate for preparing L-red biopterin compound and preparation method thereof
  • Intermediate for preparing L-red biopterin compound and preparation method thereof

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preparation example Construction

[0106] The present invention also provides the preparation method of above-mentioned intermediate, comprises the following steps:

[0107] Mix the compound to be resolved, the first reagent, the second reagent and an aprotic solvent, heat to reflux, and after the reaction is completed, crystallize to obtain the intermediate of the structure shown in formula (IVa-1) or formula (IVa-2); wherein , the compound to be resolved is a mixture of formula (IVa) and formula (IVa');

[0108]

[0109] Understandably, the reaction process of above-mentioned reaction should not be interpreted as limitation of the present invention, and above-mentioned reaction can make to be resolved compound and the first reagent reaction generation formula (IVa-3) and the structure shown in formula (IVa-4) earlier The mixture, and then the mixture of the structures shown in formula (IVa-3) and formula (IVa-4) is reacted with a second reagent to prepare an intermediate of the structure shown in formula (...

Embodiment 1

[0179]

[0180] Take 10g (50mmol) compound 8, CuI 475mg (2.5mmol), PdCl 2 (440mg 2.5mmol), TPP 1.3g (5mmol), TEA (25.3g 250mmol) and propyne 55mL (1M), dissolved in 250mL of acetonitrile, stirred at room temperature for 16h, HPLC detection of raw materials completely converted to products, add 100mLH 2 O washed, separated, the aqueous phase was extracted with 25mL x3 EA, the oil phase was collected, Na 2 SO 4 After drying, column chromatography (EA:Heptane=3:1) obtained compound 6, 7.8 g of yellow crystals, with a yield of 98.7%.

[0181]

[0182] Take 2g (12.5mmol) of compound 6, put it in a hydrogenation kettle, add 20mL 2-MeTHF to dissolve it, add 20mg of Lindlar Pd, replace the H 2 And pressurize 0.2MPa, stir at room temperature, monitor the reaction by HPLC until the raw material just disappears, filter Lindlar Pd, and concentrate, column chromatography (EA:Heptane=1:3) to obtain compound 5a, yellow crystal 1.9g. IR (cm -1 )ν3401, 3202, 2222, 1644, 1492, 1515, 1...

Embodiment 2

[0197] The preparation of 4a and 4b racemate mixture is with embodiment 1;

[0198]

[0199] Dissolve 100mg of the racemic mixture of 4a and 4b in 5mL of acetonitrile, add 117mg of isopropyl borate at the same time, and stir at reflux for 30min. 93.4 mg of L-phenylalaninol was dissolved in acetonitrile and added to the reaction system. Continue to reflux for about 15 minutes, a precipitate occurs, and the precipitate is filtered to obtain 72 mg of product 9a as white crystals with a chemical purity of 99% and a diastereomer ratio (dr) 9a:9b=99.2:0.8.

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Abstract

The invention relates to an intermediate for preparing an L-red biopterincompound and a preparation method thereof, wherein the intermediate has a structure shown as a formula (IVa-1), a formula (IVa-2), a formula (IVa-3) or a formula (IVa-4), and the formulas (IVa-1), (IVa-2), (IVa-3) and (IVa-4) are defined in the specification. According to the invention, the intermediate and the preparation method thereof effectively realize the effects of one-pot resolution and purification, are simple and convenient to operate, can greatly reduce the production cost, and are particularly suitable for preparing L-red biopterin compounds.

Description

technical field [0001] The invention relates to the technical field of medicine preparation, in particular to an intermediate for preparing L-erythro biopterin compounds and a preparation method thereof. Background technique [0002] Formula (I) indicates that L-erythro-biopterin compounds are important intermediates of most drugs at present, especially sapropterin drugs. For example: (R)-2-amino-6-[(1R,2S)-1,2-dihydroxypropyl]-5,6,7,8-tetrahydro-4 (3H) represented by formula (Ib) -pteridone (BH4), which is an essential coenzyme in hydroxylation reactions and oxygenases in organisms, is the most important coenzyme of nitric oxide synthase (NOS), and its hydrochloride (i.e. sapropterin dihydrochloride , whose structural formula is formula (Ic)) has been approved by many countries for the treatment of phenylketonuria. [0003] [0004] And the main method of synthesizing sapropterin dihydrochloride at present is to obtain by hydrogenation reduction of the compound shown i...

Claims

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Application Information

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IPC IPC(8): C07F5/04C07D475/04C07D241/26C07B57/00
CPCC07F5/04C07D475/04C07D241/26C07B57/00C07B2200/07
Inventor 不公告发明人
Owner SHANGHAI FOREFRONT PHARMA CO LTD
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