Preparation method of l-erythro-type biopterin compound

A biopterin, compound technology, applied in the fields of drug combination, organic chemistry, metabolic diseases, etc., can solve the problems of poor selectivity, many impurities, poor solubility, etc.

Active Publication Date: 2022-03-11
SHANGHAI FOREFRONT PHARMA CO LTD
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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 needs to be condensed into acetal by using L-rhamnose and ethanethiol with strong odor, complicated operation and pollution 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
[0012] According to the current technology, most of the process improvement of L-erythro-biopterin compounds in the world is still in the preparation of 5-deoxy-L-arabinose, especially the use of other reagents to replace mercaptans to reduce odor and pollution; there is no significant progress on the condensation of 5-deoxy-L-arabinose derivatives and TAP, and the raw materials are expensive, the route is long, and the yield is low, resulting in high production costs and low safety performance, which cannot meet the requirements of modern pharmaceutical industry production. need

Method used

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  • Preparation method of l-erythro-type biopterin compound
  • Preparation method of l-erythro-type biopterin compound
  • Preparation method of l-erythro-type biopterin compound

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preparation example Construction

[0192] Wherein, the definition of each substituent is as above, and will not be repeated here. The preparation method of L-erythrotype biopterin compound shown in formula (I) comprises the following steps:

[0193] (1) compound shown in formula (VI) and Carry out Sonogashira reaction, make the compound shown in formula (V);

[0194] (2) compound shown in formula (V) is through catalytic hydrogenation, makes the compound shown in formula (IIa);

[0195] (3) The compound shown in formula (IIa) is subjected to dihydroxylation reaction to obtain the compound shown in formula (IV);

[0196] (4) compound shown in formula (IV) is through cyclization reaction, makes the compound shown in formula (I-1), and the compound shown in formula (I-1) is hydrolyzed, makes the L- shown in formula (I) Erythro-biopterin compounds.

[0197] In the above (1)-(4), the specific introduction of each reaction is as above, and will not be repeated here.

[0198] understandable when R 4 for-COOR 5...

Embodiment 1

[0222]

[0223] Weigh 200mg compound 8, 11mg CuI, 10mg PdCl 2 , 30mg PPh 3 Place in a 25mL three-neck flask, and add 5mL of acetonitrile. 0.7 mL of triethylamine and 1.1 mL of propyne (1M in THF) were added under stirring at room temperature, and the reaction was stirred for 16 h. 10 mL of water was added to quench the reaction, the layers were separated, and the organic layer was dried and concentrated to obtain 163 mg of crude compound 6, which was used in the next reaction. IR (cm -1 )ν3400, 2226, 1647, 1487, 1192; 1 H NMR (400MHz, DMSO-d 6 )δ8.26(s,1H),7.54(s,2H),2.01(s,3H), 13 C NMR (101MHz, DMSO) δ155.61, 150.33, 128.08, 115.71, 111.16, 88.27, 76.62, 4.18. HRMS m / z (ESI+) C 8 h 7 N 4 + requires: 159.0667; found: 159.0671.

[0224]

[0225] Add 62mg Na to 10mL MeOH and stir until complete reaction, then add 226mg guanidine hydrochloride N 2 Protected, stirred at room temperature for 5min. The insoluble matter in the system was filtered, and 163 mg of com...

Embodiment 2

[0240]

[0241] Disperse 200 mg of compound 5 in 5 mL of an aqueous solution containing 50 mg of NaOH, heat to 78 ° C, stir for 1 h, add acetic acid dropwise to neutralize the system to pH = 5-6, filter the precipitated solid, and wash with methanol to obtain compound 5-1 (152mg, purity 98%, yield 76%);

[0242] Dissolve 152mg of compound 5-1 in a combined solution of 5mL MeOH / DCM=1 / 1, stir well to dissolve, add 100mg of Lindlar Pd, replace H 2 (1 atm) stirred at room temperature for 3 days. After filtering the catalyst, the solvent was concentrated to obtain compound 3 (150mg, purity 95%, yield 93%); 1 H NMR (500MHz, DMSO) δ12.3(s, 1H), 8.53(s, 1H), 6.49(s, 2H), 2.04(s, 3H). 13 C NMR (125MHz, DMSO) δ161.85, 156.13, 150.79, 148.55, 136.37, 127.07, 92.12, 85.24, 4.59. HRMS m / z (ESI+) C 9 h 10 N 5 o + requires:203.2050,found:203.2051

[0243]

[0244] Compound 3 is subjected to a dihydroxylation reaction, including the following methods:

[0245] 1) Sharpless asymm...

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Abstract

The invention relates to a preparation method of L-erythrotype biopterin compounds. Wherein, the L-erythrotype biopterin compound has the structure shown in formula (I), and the L-erythrotype biopterin compound shown in formula (I) is mainly represented by formula (II) or formula (III) The compound with the structure shown is prepared through a dihydroxylation reaction; the preparation method of the L-erythro-type biopterin compound has high production efficiency, low cost, and is green and environmentally friendly, and is suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of medicine preparation, in particular to a preparation method of L-erythrotype biopterin compounds. 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)-pteridinone (BH4), which is an essential coenzyme in hydroxylation reaction and oxygenase in organisms, is the most important coenzyme of nitric oxide synthase (NOS), and its hydrochloride (i.e. dihydrochloride sapyl Pterin, whose structural formula is formula (I-3)) 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 in formula (I-1). [0005] [0006] Therefore, how to safely...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D475/04A61P3/00
CPCC07D475/04A61P3/00
Inventor 不公告发明人
Owner SHANGHAI FOREFRONT PHARMA CO LTD
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