CN109776415B - Preparation method of Roxadustat intermediate - Google Patents

Abstract

The invention discloses a preparation method of a Roxadustat intermediate (A), which is characterized in that the synthetic route is as follows:

Description

Preparation method of Roxadustat intermediate

Technical Field

The invention belongs to the field of synthesis of medical compounds, and particularly relates to a synthesis method of a new medicament roxadustat intermediate for treating anemia of CKD patients.

Background

Anemia is a disease very common to CKD patients, and morbidity and mortality are very high in both dialysis and non-dialysis CKD patients. CKD can develop in any age, more common in the elderly, with approximately 1.195 million CKD patients in china. The number of CKD people receiving dialysis in china exceeds 40 million and rapidly increases in two-digit increments, so that there is an increasing demand for anti-anemia therapy. Roxadustat is a hypoxia inducible factor prolyl hydroxylase (HIF-PH) inhibitor, which inhibits ubiquitination degradation of HIF and helps the body produce more red blood cells. Hypoxia Inducible Factor (HIF) is a protein that can respond to changes in oxygen levels in the cellular environment and can induce erythropoiesis to meet the body's demand for oxygen. FG-4592 aids in the production of red blood cells through the body's natural oxygen sensing and response system, acting through a mechanism similar to the body's natural response to high altitude (hypoxic) environments.

In fig. 10, 18 of 2017, CFDA has received a class 1 new drug, roxidustat, submitted by china incorporated fable-bon (china) pharmaceutical technology development ltd, for the treatment of anemia in dialysis-dependent chronic kidney disease patients (DD-CKD) and dialysis-independent chronic kidney disease patients (NDD-CKD).

The current methods for preparing roxardustat mainly comprise:

1) the synthetic route of the compound patent of FibroGen in the original research is shown as follows (CN102977015B)

2) The Zhejiang Beida pharmaceutical industry Co Ltd improves the synthesis method of the original compound patent, and the specific synthetic route is as follows (CN104024227B),

3) a new synthetic route was proposed by the original research FibroGen company to prepare Roxadustat (CN103435546A)

4) The synthesis route published by Suzhou Mingrui medicine science and technology Limited is as follows (CN104892509A)

5) Shanghai Xun and medicine science and technology Limited company proposed a new method for preparing the intermediate of Roxadustat (CN106478503A)

Analysis of the above-mentioned Roxadustat synthetic route shows that routes 1 and 2 require multi-step reactions to introduce methyl group at position 1 on the isoquinoline ring, and that the introduction process requires noble metal catalysis and an ultralow temperature method, so that the preparation cost is high, and large-scale production is not easy to achieve. The second step in the route 3 uses thionyl chloride, which can generate HCl and sulfur dioxide polluting the environment in the reaction process, increasing the environmental protection cost. The final step of hydrogenation and deesterification for introducing methyl needs to be completed by high-pressure hydrogenation under the catalysis of palladium-carbon. This requires special hydrogenation equipment, and the preparation cost is high, which is not favorable for large-scale production. Route 4, introduced by the direct preparation of the isoquinoline ring, is prone to produce an N-substituted by-product during the second reaction with bromobenzene, which presents difficulties in subsequent purification. In the fifth step, the method introduces hydroxyl on the isoquinoline ring by using hydrogen peroxide for oxidation. The hydrogen peroxide has larger potential safety hazard in industrial production.

As can be seen from the above synthetic route, the difficulty in preparing Roxadustat is the synthesis of the key intermediate, 4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline carboxylate A (see formula below).

Route 5 provides a new method for the synthesis of intermediate a, an improvement over the original route 3, avoiding high pressure hydrogenation reactions, but still using thionyl chloride.

Disclosure of Invention

In order to solve the technical problems, the invention further improves the scheme 3, provides a new method for synthesizing the intermediate A, avoids using thionyl chloride and high-pressure hydrogenation reaction, and reduces reaction steps. The method provided by the invention has the advantages of simple process, economy, environmental protection, no need of thionyl chloride, avoidance of high-pressure hydrogenation reaction, energy conservation, environmental protection and cost reduction.

The scheme provided by the invention is as follows:

a preparation method of a Roxadustat intermediate (A) comprises the following synthetic route:

specifically, the preparation method of the roxardustat intermediate (a) comprises the following steps:

(1) taking p-phenoxy phenol as a raw material, and obtaining a compound (I) through acetylation reaction;

(2) under the action of aluminum trichloride, acetyl in the compound (I) is transferred to generate a compound (II);

(3) condensing and dehydrating the compound (II) and methyl carbazate to obtain a compound (III);

(4) oxidizing the compound (III) by an oxidant of lead tetraacetate or diacetyloxy iodobenzene to obtain a compound (IV);

(5) condensing and dehydrating the compound (IV) and glycine methyl ester to obtain imine (V);

(6) imine (V) is treated with a strong base to form intermediate (A).

In the step (6), the strong base is MOR, wherein M is Li, Na and K; r is C₁-C₆Straight or branched chain alkyl.

The invention has the beneficial effects that:

the invention improves the route 3, provides a new method for synthesizing the intermediate A, has simple synthetic route and less reaction steps, avoids using thionyl chloride and high-pressure hydrogenation reaction, reduces pollution and requirements on reaction equipment, saves energy, reduces emission and reduces production cost.

Detailed Description

The invention will be further illustrated with reference to specific examples, to which the present invention is not at all restricted.

A preparation method of a Roxadustat intermediate (A) comprises the following synthetic route:

specifically, the preparation method of the roxardustat intermediate (a) comprises the following steps:

(1) taking p-phenoxy phenol as a raw material, and obtaining a compound (I) through acetylation reaction;

(2) under the action of aluminum trichloride, acetyl in the compound (I) is transferred to generate a compound (II);

(3) condensing and dehydrating the compound (II) and methyl carbazate to obtain a compound (III);

(4) oxidizing the compound (III) by an oxidant to obtain a compound (IV);

(5) condensing and dehydrating the compound (IV) and glycine methyl ester to obtain imine (V);

(6) imine (V) is treated with a strong base to form intermediate (A).

The oxidant in the step (4) is lead tetraacetate or diacetoxy iodobenzene.

In the step (6), the strong base is MOR, wherein M is Li, Na and K; r is C₁-C₆Straight or branched chain alkyl.

Example 1

(1) Synthesis of Compound I:

4-Phenoxyphenol (25g, 0.134mol) was placed in a three-necked flask and 150ml DCM was added. After stirring well triethylamine (27.12g, 0.268mol) was added and cooled. Acetic anhydride (27.36g, 0.268mol) was added at 0 ℃ and the temperature was controlled below 10 ℃. After addition, stir at room temperature overnight. Filter and wash the solid with DCM. The organic phase was washed successively with water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was passed through a silica gel pad, the solvent was removed under reduced pressure and dried under vacuum to give a pale yellow liquid, compound I.

¹HNMR(400MHz)：(CDCl₃)7.37(2H，m)，7.07(7H，m),2.33(3H,s).

(2) Synthesis of Compound II:

compound I (6.4g, 28.3mmol) and 8ml of chlorobenzene were added to a reaction flask, and after stirring well, aluminum trichloride (7.55g, 56.6mmol) was added. The mixture was heated under reflux until the starting material disappeared, cooled to room temperature, and quenched by the slow addition of 2N hydrochloric acid. Adding ethyl acetate, washing the organic phase with 2N HCl, water and salt solution in turn, drying with anhydrous sodium sulfate, removing the solvent under reduced pressure, and separating and purifying the residue by column chromatography to obtain the compound II.

¹HNMR(400MHz)：(CDCl₃)11.98(1H,s),7.34(1H,d),7.25(2H,m),7.15(1H,dd),7.01(1H, m),6.91(1H,d),6.87(2H,m),2.50(3H,s).

(3) Synthesis of Compound III:

compound II (4.5g, 19.72mmol) and 30ml acetonitrile were added to a reaction flask, and after stirring well, ethyl carbazate (1.78g, 19.72mmol) was added. Reflux was heated until compound II disappeared, cooled to room temperature and the solvent was removed under reduced pressure. The solid was recrystallized from ethanol to give compound III as a white solid.

¹HNMR(400MHz)：(CDCl₃)12.24(1H,s),8.90(1H,s,br),7.30(2H,m),7.16(1H,s), 7.05(1H,m),6.99(2H,m),6.93(2H,m),3.91(3H,s),2.23(3H,s).

(4) Synthesis of compound IV:

into a reaction flask were added compound III (2.1g, 7.0mmol) and 15ml THF. While stirring at room temperature, lead tetraacetate (6.21g, 14.0mmol) was added in portions, and stirring was carried out overnight after the addition was completed. Filter and wash the solid with THF. THF was removed under reduced pressure and the residue was isolated by column chromatography to give compound IV as a white solid.

¹HNMR(400MHz)：(CDCl₃)7.89(1H,d),7.41(2H,m),7.26(1H,s),7.07(2H,m),6.99(1H, dd),6.86(1H,d),3.88(3H,s),2.51(3H,s).

(5) Synthesis of Compound A:

to a reaction flask were added glycine methyl ester hydrochloride (1.5g, 12.0mmol) and 30ml of toluene, and triethylamine (4ml) was added with stirring and stirred at room temperature overnight. Filtration and transfer of the filtrate to another reaction flask and add compound IV (1.6g, 6.0 mmol). The temperature was reduced to 0 ℃ and 0.5ml of a tetrahydrofuran solution of boron trifluoride was added, followed by stirring at room temperature overnight. Adding water to quench the reaction, washing the organic phase with saturated sodium bicarbonate water solution, water and brine in sequence, and drying with anhydrous sodium sulfate. After filtration and removal of the solvent under reduced pressure, the residue was dissolved in 15ml of methanol, cooled to 0 ℃ and sodium methoxide (0.5g, 9mmol) was added portionwise and, after completion of addition, stirred at room temperature overnight. Concentrating under reduced pressure to dryness, adding mixed solution of water and acetic acid, and stirring for 2 hr. Filtering, washing and vacuum drying to obtain the compound A.

¹HNMR(400MHz)：(DMSO-d₆)8.28(1H,m),7.47(4H,m),7.25(1H,dd),7.16(2H,m), 3.93(3H,s),2.58(3H,s).

The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any modification, equivalent replacement, and improvement made by those skilled in the art within the technical scope of the present invention should be included in the scope of the present invention.

Claims (4)

1. A preparation method of a Roxadustat intermediate (A) is characterized in that the synthetic route is as follows:

。

2. a process for the preparation of roxxadustat intermediate (a) as claimed in claim 1, comprising the steps of:

(1) taking p-phenoxy phenol as a raw material, and obtaining a compound (I) through acetylation reaction;

(2) under the action of aluminum trichloride, acetyl in the compound (I) is transferred to generate a compound (II);

(3) condensing and dehydrating the compound (II) and methyl carbazate to obtain a compound (III);

(4) oxidizing the compound (III) by an oxidant of lead tetraacetate or diacetyloxy iodobenzene to obtain a compound (IV);

(5) condensing and dehydrating the compound (IV) and glycine methyl ester to obtain imine (V);

(6) imine (V) is treated with a strong base to form intermediate (A).

3. The method of claim 2, wherein: the temperature of acetylation reaction in the step (1) is 0-room temperature.

4. The method of claim 2, wherein: in the step (6), the strong base is MOR, wherein M is Li, Na and K; r is C₁-C₆Straight or branched chain alkyl.