CN113248432A - Novel method for preparing intermediate of roxasistat in high yield - Google Patents
Novel method for preparing intermediate of roxasistat in high yield Download PDFInfo
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- CN113248432A CN113248432A CN202110446882.4A CN202110446882A CN113248432A CN 113248432 A CN113248432 A CN 113248432A CN 202110446882 A CN202110446882 A CN 202110446882A CN 113248432 A CN113248432 A CN 113248432A
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
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Abstract
The invention discloses a preparation method of a roxasistat intermediate, which comprises the following steps: (1) reacting the compound 1 and the compound 2 in an organic solvent under the catalysis of alkali to prepare an intermediate 3; (2) reducing the intermediate 3 in an organic solvent by a reducing agent to obtain an intermediate 4; (3) the intermediate 4 reacts with a brominating reagent in an organic solvent to obtain an intermediate 5; (4) reacting the intermediate 5 with a compound 6 in an organic solvent under the catalysis of acid to obtain an intermediate 7; (5) the intermediate 7 is subjected to cyclization reaction in an organic solvent and a catalytic system to prepare an intermediate 8; (6) the intermediate 8 is reacted with a dehydrogenation reagent in an organic solvent to obtain the intermediate 9 of the rosisasetat. The preparation method of the intermediate of the roxasistat has the advantages of easily obtained raw materials, few operation steps, simple process, high reaction yield, high atom utilization rate and easiness in industrial production.
Description
Technical Field
The invention relates to a preparation method of a drug intermediate, in particular to a preparation method of a rosixastat intermediate.
Background
Rosesartat (Roxadustat), a currently developed oral Hypoxia Inducible Factor (HIF) prolyl hydroxylase inhibitor by FibroGen, Inc. in the Production of America and in cooperation with Asricon, is chemically N- [ (4-hydroxy-1-methyl-7-phenoxy-3-isoquinolyl) carbonyl ] glycine, and is used for treating chronic anemia, and is currently marketed in China and Japan.
The prior art methods for preparing roxardustat mainly include:
1. compound patent CN103435546 (application date 2013.07.15) from the original research company (fibrigen), the following scheme is shown:
the route takes 5-bromophenylphthalide as an initial raw material, and the rosisasetat is obtained through 8 steps of reaction. The purification method of the process is simple and convenient, column chromatography purification is not needed, the total yield is high (26.2%), but the price of triphenylphosphine dichloride used in the second step is higher, and the three wastes are prominent; seventhly, palladium carbon is required to be hydrogenated for deprotection, and a palladium removal step is required to be added to a product; the last step of the reaction is carried out in a pressure vessel.
2. Patent CN104024227 (application date 2012.07.23) of new drug development ltd of beijing bei mei, as shown in the following scheme:
the method takes 4-nitrophthalonitrile as a starting material, and obtains the Rosesastat through 10 steps of reaction. The route also needs more experimental steps to introduce the methyl at the 1-position of isoquinoline; step five, the by-product (isomer) is difficult to purify; purifying the products 5, 7 and 9 by column chromatography; step seven needs precious metal catalysis, and the preparation cost is relatively high; the total yield of the reaction is only (1.25%). Because the total yield is low and part of the operation steps are not suitable for industrial production.
3. Patent CN104892509A (application date 2015.06.04) by soviet minrui ltd, as shown in the following scheme:
the route takes tyrosine as a starting material and obtains the roxasistat through 6 steps of reaction. The method has the advantages of easily available raw materials and high total yield (about 20.2%). But amino substitution byproducts can be introduced in the second step, and the purification is difficult to realize; the introduction of the pentahydroxyl in the step adopts hydrogen peroxide for oxidation, and certain potential safety hazards exist in factory production.
4. Gazan and medicine patent CN106478504 (application date 2016.09.29), the following scheme is shown:
the route takes 3-bromoacetophenone as an initial raw material, and the raw material is reacted for 5 steps to obtain the roxasistat. The method has the advantages of easily available raw materials, high total reaction yield and relatively mild reaction conditions. However, diethyl carbonylmalonate is expensive and limits the use of large-scale production.
The synthesis routes are analyzed, and the synthesis methods have certain defects and are not suitable for application of industrial mass production.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide a preparation method of a rosisastat intermediate, which has the advantages of easily obtained raw materials, simple process, economy, environmental protection, safety and industrial production, and overcomes the defects in the prior art.
The technical scheme is as follows: the invention provides a preparation method of a roxasistat intermediate, which comprises the following steps:
(1) reacting the compound 1 and the compound 2 in an organic solvent under the action of a catalyst to obtain an intermediate 3;
(2) reducing the intermediate 3 in an organic solvent to obtain an intermediate 4;
(3) the intermediate 4 reacts with a brominating reagent in an organic solvent to obtain an intermediate 5;
(4) the intermediate 5 reacts with the compound 6 in an organic solvent under the catalysis of acid to obtain an intermediate 7;
(5) the intermediate 7 is subjected to cyclization reaction in an organic solvent and a catalytic system to prepare an intermediate 8;
(6) carrying out dehydrogenation reaction on the intermediate 8 in an organic solvent and a dehydrogenation reagent to obtain a intermediate 9 of the roxasistat;
wherein R is1Selected from hydrogen, potassium or sodium; r2Selected from hydrogen, methyl, ethyl, propyl, isopropyl or allyl.
In some embodiments, in the preparation method, the catalyst used in step (1) is selected from copper powder, nickel, cuprous bromide, cuprous iodide or cuprous oxide.
In some embodiments, the reducing agent used in step (2) of the preparation method is selected from sodium borohydride acetate, lithium borohydride or sodium borohydride.
In some embodiments, the preparation method, step (3), uses a brominating agent selected from hydrobromic acid, phosphorus tribromide, liquid bromine, carbon tetrabromide, or N-bromosuccinimide.
In some embodiments, the preparation method, the catalyst used in step (4), is selected from anhydrous magnesium chloride, anhydrous aluminum trichloride, anhydrous zinc chloride, p-toluenesulfonic acid, methanesulfonic acid, or trifluoroacetic acid.
In some embodiments, the catalyst used in step (5) of the preparation method is selected from anhydrous magnesium chloride, anhydrous aluminum trichloride, anhydrous zinc chloride or anhydrous ferric trichloride.
In some embodiments, the preparation method, step (6), uses a dehydrogenation reagent selected from DDQ, 1, 4-benzoquinone, chromium oxide, or iron oxide. A intermediate of rosxastat, which is intermediate 7 or intermediate 8, having the structural formula shown below:
R2selected from hydrogen, methyl, ethyl, propyl, isopropyl, allyl.
The preparation method of the intermediate of the roxasistat and the intermediate 7 comprises the following steps:
the intermediate 5 reacts with the compound 6 in an organic solvent under the catalysis of acid to obtain an intermediate 7.
The preparation method of the intermediate of the roxarstat, the intermediate 8, comprises the following steps:
and (3) carrying out cyclization reaction on the intermediate 7 in an organic solvent and a catalytic system to obtain an intermediate 8.
Has the advantages that: compared with the prior art, the preparation method has the advantages of easily available raw materials required by the reaction, simple process, capability of improving the yield to a great extent, economy, environmental protection and less byproducts, and is suitable for the requirements of safe industrialized mass production.
Detailed Description
Example 1
Preparation of intermediate 3
In a 2L reaction flask, 3-bromoacetophenone (199g, 1mol), phenol (i.e., compound 2-1, 189g, 2mol), cuprous bromide (7.17g, 0.05mol), acetylacetone (10g, 0.lmol), potassium carbonate (276g, 2mol), and N, N-dimethylformamide (1L) were added in this order. Heating to the internal temperature of 120 ℃ for reaction for 7h, cooling to room temperature, filtering, concentrating under reduced pressure, and collecting the middle fraction to obtain an intermediate 3. (171.7g, yield 81%). HPLC: 99.2%, MS M/z 213[ M + H%]+。HNMR(400M Hz,DMSO-d6)，δ3.03(s,3H)；7.17(m,3H)；7.39-7.41(m,4H)；7.85(d,1H)；15.28(br,1H)。
Example 2
Preparation of intermediate 4
To a 2L reaction flask, intermediate 3(200g, 0.94mol), sodium borohydride (17.84g, 0.47mol), and methanol (1.2L) were added in that order. Reacting at room temperature, adding water to quench the reaction after the reaction is finished, filtering, and concentrating under reduced pressure to obtain an intermediate 4. (197.8g, yield 98%). HPLC: 99.7%, MS M/z 215[ M + H%]+。HNMR(400M Hz,DMSO-d6)，δ1.49(d,3H)；4.98(m,1H)；5.17(d,1H)；7.17(m,3H)；7.39-7.41(m,4H)；7.85(d,1H)；15.28(br,1H)。
Example 3
Preparation of intermediate 5
And sequentially adding the intermediate 4(250g, 1.17mol), phosphorus tribromide (158.1g, 0.58mol) and dichloromethane (1.4L) into a 2L reaction bottle, after the reaction is finished, adding alkali water to quench the mixture for reaction, layering, washing the organic phase saturated salt once, and performing spin drying to obtain an intermediate 5. (297.7g, yield 92%). HPLC: 99.4%, MS M/z 277[ M + H ]]+。HNMR(400M Hz,DMSO-d6)，δ2.07(d,3H)；5.17(m,1H)；7.17(m,3H)；7.39-7.41(m,4H)；7.85(d,1H)；15.28(br,1H)。
Example 4
Preparation of intermediate 7
To a 2L reaction flask, intermediate 5(212g, 0.76mol), diethyl aminomalonate (i.e., compound 6-1, 133.9g, 0.76mol), p-toluenesulfonic acid (13.16g, 0.076mol), and toluene (lL) were added in that order. Heating to reflux reaction, cooling to room temperature after reaction, adding water (0.5L) for extraction, concentrating organic layer under reduced pressure to dry to obtain crude product, adding anhydrous ethanol for recrystallization to obtain intermediate 7-1(247.17g, yield)：87％)。HPLC：99.5％，MS m/z 372[M+H]+。HNMR(400M Hz,DMSO-d6)，δ1.23-1.27(m,9H)；4.01(m,1H)；4.16(m,1H)；4.24(m，4H)；4.29(m,1H)；7.17(m,3H)；7.39-7.41(m,4H)；7.85(d,1H)；15.28(br,1H)。
Example 5
Preparation of intermediate 8
A2L reaction flask is added with the intermediate 7-1(200g, 0.54mol), anhydrous magnesium chloride (5.13g, 0.054mol) and glycerol (1L), and the temperature is raised to 200 ℃ under stirring for reaction. Cooling to room temperature, adding water (1L), stirring for 30min, adding anhydrous ethanol (0.5L) to the crude product, recrystallizing, and vacuum drying to obtain intermediate 8-1(141.9g, yield 81%). HPLC: 99.7%, MS M/z 326[ M + H%]+。HNMR(400M Hz,DMSO-d6)，δ1.24(t,3H)；1.48(d,3H)；2.3(d,1H)；4.01(m，1H)；4.16(q,2H)；6.96-7.06(m,4H)；7.18(m,1H)；7.33-7.42(m,3H)；17.07(s,1H)。
Example 6
Preparation of intermediate 9
A2L reaction flask was charged with intermediate 8-1(200g, 0.61mol), DDQ (153.5g, 0.68mol), toluene (1.6L), and heated under nitrogen stirring under reflux until the reaction was complete. Cooling to room temperature, adding water (1L), quenching, stirring for 30min, concentrating, spin-drying organic phase to obtain crude product, adding acetonitrile into the crude product, pulping, washing to obtain refined product, and vacuum drying to obtain intermediate 9-1(168.9g, yield 85%). HPLC: 99.7%, MSm/z 324[ M + H ]]+。HNMR(400M Hz,DMSO-d6)，δ1.3(t,3H)；3.03(s,3H)；4.25(q,2H)；6.96-7.06(m,4H)；7.18(m,1H)；7.33-7.42(m,3H)；15.28(s,1H)。
Claims (10)
1. A preparation method of a roxasistat intermediate is characterized by comprising the following steps:
(1) reacting the compound 1 and the compound 2 in an organic solvent under the action of a catalyst to obtain an intermediate 3;
(2) reducing the intermediate 3 in an organic solvent to obtain an intermediate 4;
(3) the intermediate 4 reacts with a brominating reagent in an organic solvent to obtain an intermediate 5;
(4) the intermediate 5 reacts with the compound 6 in an organic solvent under the catalysis of acid to obtain an intermediate 7;
(5) the intermediate 7 is subjected to cyclization reaction in an organic solvent and a catalytic system to prepare an intermediate 8;
(6) carrying out dehydrogenation reaction on the intermediate 8 in an organic solvent and a dehydrogenation reagent to obtain a intermediate 9 of the roxasistat;
wherein R is1Selected from hydrogen, potassium or sodium; r2Selected from hydrogen, methyl, ethyl, propyl, isopropyl or allyl.
2. The method according to claim 1, wherein the catalyst used in step (1) is selected from copper powder, nickel, cuprous bromide, cuprous iodide, and cuprous oxide.
3. The method according to claim 1, wherein the reducing agent used in step (2) is selected from sodium borohydride acetate, lithium borohydride or sodium borohydride.
4. The process according to claim 1, wherein the brominating agent used in step (3) is selected from hydrobromic acid, phosphorus tribromide, liquid bromine, carbon tetrabromide and N-bromosuccinimide.
5. The process according to claim 1, wherein the catalyst used in the step (4) is selected from the group consisting of anhydrous magnesium chloride, anhydrous aluminum trichloride, anhydrous zinc chloride, p-toluenesulfonic acid, methanesulfonic acid and trifluoroacetic acid.
6. The process according to claim 1, wherein the catalyst used in the step (5) is selected from the group consisting of anhydrous magnesium chloride, anhydrous aluminum trichloride, anhydrous zinc chloride and anhydrous ferric trichloride.
7. The method according to claim 1, wherein the dehydrogenation reagent used in step (6) is selected from the group consisting of DDQ, 1, 4-benzoquinone, chromium oxide and iron oxide.
8. An intermediate of rosixastat which is intermediate 7 or intermediate 8 having the formula:
R2selected from hydrogen, methyl, ethyl, propyl, isopropyl, allyl.
9. The intermediate of Rosxastat according to claim 8 wherein the process for the preparation of intermediate 7 comprises the steps of:
the intermediate 5 reacts with the compound 6 in an organic solvent under the catalysis of acid to obtain an intermediate 7.
10. The intermediate of Rosxastat according to claim 8 wherein the process of preparation of intermediate 8 comprises the steps of:
and (3) carrying out cyclization reaction on the intermediate 7 in an organic solvent and a catalytic system to obtain an intermediate 8.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115594631A (en) * | 2022-10-25 | 2023-01-13 | 安徽省庆云医药股份有限公司（Cn） | Rosemastat key intermediate and preparation method of Rosemastat intermediate |
| CN116803986A (en) * | 2023-06-27 | 2023-09-26 | 江苏海洋大学 | Synthesis method of roflumilast intermediate |
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| CN104892509A (en) * | 2015-06-04 | 2015-09-09 | 苏州明锐医药科技有限公司 | Preparation method of Roxadustat |
| CN106478503A (en) * | 2016-09-29 | 2017-03-08 | 上海勋和医药科技有限公司 | The preparation method of Roxadustat intermediate |
| CN106478504A (en) * | 2016-09-29 | 2017-03-08 | 上海勋和医药科技有限公司 | The method preparing Roxadustat intermediate |
| WO2019106621A1 (en) * | 2017-12-01 | 2019-06-06 | Dr. Reddy's Laboratories Limited | Process for the preparation of roxadustat and its intermediates |
| CN111592490A (en) * | 2020-07-02 | 2020-08-28 | 浙江工业大学 | Preparation method of key intermediate of roxasistat |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104892509A (en) * | 2015-06-04 | 2015-09-09 | 苏州明锐医药科技有限公司 | Preparation method of Roxadustat |
| CN106478503A (en) * | 2016-09-29 | 2017-03-08 | 上海勋和医药科技有限公司 | The preparation method of Roxadustat intermediate |
| CN106478504A (en) * | 2016-09-29 | 2017-03-08 | 上海勋和医药科技有限公司 | The method preparing Roxadustat intermediate |
| WO2019106621A1 (en) * | 2017-12-01 | 2019-06-06 | Dr. Reddy's Laboratories Limited | Process for the preparation of roxadustat and its intermediates |
| CN111592490A (en) * | 2020-07-02 | 2020-08-28 | 浙江工业大学 | Preparation method of key intermediate of roxasistat |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115594631A (en) * | 2022-10-25 | 2023-01-13 | 安徽省庆云医药股份有限公司（Cn） | Rosemastat key intermediate and preparation method of Rosemastat intermediate |
| CN116803986A (en) * | 2023-06-27 | 2023-09-26 | 江苏海洋大学 | Synthesis method of roflumilast intermediate |
| CN116803986B (en) * | 2023-06-27 | 2024-02-06 | 江苏海洋大学 | Synthesis method of roflumilast intermediate |
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