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Preparation method and intermediate of isoquinoline compound

A technology for compounds and intermediates, which is applied in the field of preparation of isoquinolinic acid compounds, key intermediates of roxacus, a drug for treating chronic anemia, can solve the problems of long overall route, difficulty in process amplification, low total yield and the like, and achieve product The effect of high purity, high yield and high total yield

Active Publication Date: 2019-12-03
HANGZHOU CHEMINSPIRE TECH CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Generally speaking, the key to the method of synthesizing roxadustat lies in how to quickly prepare the key intermediate 4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline carboxylate, but the existing methods generally The route is too long, the total yield is low, and the introduction of methyl groups on the isoquinoline in the step requires the use of a noble metal catalyst, which is expensive and difficult to scale up. It is still necessary to find a method with a simple process route, low cost, and suitable for industrial production.

Method used

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  • Preparation method and intermediate of isoquinoline compound
  • Preparation method and intermediate of isoquinoline compound
  • Preparation method and intermediate of isoquinoline compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043]

[0044] Add compound formula 1 (24.02g, 100mmol) and tetrahydrofuran (120mL) into the three-necked flask, stir to dissolve, cool to -10~0°C and switch nitrogen for 3 times in vacuum, under the protection of nitrogen, methylmagnesium chloride tetrahydrofuran solution (2.0M, 55mL ) slowly drop into the reaction bottle, and keep the reaction for 2 to 4 hours after dropping. Add 1mol / L dilute hydrochloric acid (240mL) to quench the reaction at the end of the reaction, extract the aqueous phase twice with ethyl acetate (120mL), combine the organic phases and wash once with saturated brine (120mL), dry over anhydrous sodium sulfate, concentrate and use petroleum Compound 2 (21.78 g, 85%) was isolated by recrystallization from a mixed solvent of ethyl ether acetate. MS(EI)m / z=256.0 1 H NMR (400MHz, CDCl 3 )δ7.83(d, J=8.0Hz, 1H), 7.47(q, J=7.7Hz, 2H), 7.31(d, J=6.8Hz, 1H), 7.14(d, J=7.8Hz, 3H) , 7.09 (s, J=12.6Hz, 1H), 1.93 (s, 3H).

[0045] Here, methylmagnesium chlori...

Embodiment 2

[0047]

[0048] Add compound 2 (25.63g, 100mmol) and isopropanol (128mL) into a three-neck flask, add potassium carbonate (20.73g, 150mmol), stir well, add hydroxylamine hydrochloride (8.34g, 120mmol) slowly, and heat to 75-80°C React for 10-16 hours. At the end of the reaction, cool the reaction solution to 0-5°C, slowly add water to quench the reaction, remove most of the isopropanol by rotary evaporation, cool to 0-5°C for beating for 1 hour, filter, and use a mixed solvent of isopropanol and water for the crude product Compound 3 (22.79 g, 90%) was obtained by recrystallization. MS(ESI)m / z=254.1[M+H] +1 H NMR (400MHz, CDCl 3)δ8.30(d, J=8.7Hz, 1H), 7.47(t, J=7.9Hz, 2H), 7.34(dd, J=8.7, 2.3Hz, 1H), 7.29(m, J=12.6, 5.1 Hz, 1H), 7.13 (d, J=2.3Hz, 2H), 7.11 (s, 1H), 2.47 (s, 3H).

[0049] Here potassium carbonate can be replaced by sodium carbonate, potassium hydroxide or sodium hydroxide; isopropanol can be used methanol, ethanol, acetone, dichloromethane, 1,2-dichloroe...

Embodiment 3

[0051]

[0052] Add compound 3 (25.33g, 100mmol), phosphine reagent 4a (41.81g, 120mmol) and toluene (128mL) into the three-necked flask, add N,N-diisopropylethylamine (19.39g, 150mmol), heat and reflux reaction 2 ~3 days. At the end of the reaction, cool the reaction solution to 0-5°C, slowly add water (253mL) to quench the reaction, spin off most of the solvent, add ethanol (51mL), filter, and recrystallize the crude product with a mixed solvent of ethanol and petroleum ether to obtain the compound 9a (29.75 g, 92%).

[0053] Here N,N-diisopropylethylamine can be replaced by triethylamine, pyridine, 2,6-lutidine, DBU or potassium tert-butoxide; toluene can be replaced by N,N-dimethylformamide, N,N -Dimethylacetamide, N-methylpyrrolidone, DMPU, xylene or chlorobenzene instead.

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Abstract

The invention discloses a preparation method and intermediate of an isoquinoline compound. The isoquinoline compound is roxadustat, the intermediate of the roxadustat is a compound formula 2, and twonovel preparation methods of a roxadustat key intermediate 9 are developed by taking the compound formula 2 as a raw material. According to the first method, a compound 2 reacts with hydroxylamine hydrochloride to obtain an intermediate compound formula 3, and then the intermediate compound formula 3 reacts with a phosphine reagent compound formula 4 to obtain the roxadustat key intermediate compound formula 9. According to the second method, acyl chloride is prepared from the compound formula 2, then the acyl chloride and an aminomalonate ester derivative 7 are subjected to condensation and decarboxylation reaction, then a compound formula 8 is obtained, and finally, the key intermediate compound formula 9 is obtained. The two methods are high in yield, using of precious metal for catalysis is avoided, the route efficiency is greatly improved, the technological cost is lowered, generation of by products is reduced, and the purity of final finished products is improved advantageously;and a route is easy to operate, the total yield is high, the purity of obtained products is also high, the route is suitable for amplifying production, and the route is shows as the formula (please see the specifications for the formula).

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and specifically relates to a preparation method of an isoquinolinic acid compound, which is a key intermediate of Roxas, a drug for treating chronic anemia, and related intermediates. Background technique [0002] Roxadustat (FG-4592) is an oral small molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase. The drug was developed by the American non-Brogan company, and was later licensed by Astellas and AstraZeneca. Phase III clinical trials are currently underway. It is used to treat anemia associated with chronic kidney disease and end-stage renal disease. , with great market prospects. [0003] The chemical name of roxadustat is: N-[(4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline)carbonyl]glycine, and its structural formula is as follows: [0004] [0005] PCT patent WO2004108681A reports the key intermediate of roxadustat tert-butyl 4-hydroxy-1-methyl-7-phenoxy...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C51/09C07C65/34C07D217/26
CPCC07C65/34C07D217/26Y02P20/55
Inventor 郑旭春张一平
Owner HANGZHOU CHEMINSPIRE TECH CO LTD
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