CN114014807B - Preparation method of key intermediate of roxasistat - Google Patents
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- CN114014807B CN114014807B CN202111454991.7A CN202111454991A CN114014807B CN 114014807 B CN114014807 B CN 114014807B CN 202111454991 A CN202111454991 A CN 202111454991A CN 114014807 B CN114014807 B CN 114014807B
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- C07—ORGANIC CHEMISTRY
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- 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 relates to a preparation method of a key intermediate of roxasistat. The method takes m-phenoxy acetophenone derivatives and methyl propiolate as starting materials, and the m-phenoxy acetophenone derivatives and the methyl propiolate undergo cyclization reaction under the catalysis of a catalyst, so that the methyl rosinestat intermediate 1-methyl-7-phenoxy isoquinoline-3-formate is synthesized. The synthetic route simplifies the introduction mode of isoquinoline C-1 methylation, and has the characteristics of simple process, convenient operation, no need of column chromatography purification, high yield and the like.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemical synthesis, and relates to a synthesis method of a pharmaceutical intermediate, in particular to a preparation method of a key intermediate of rosixostat, namely 1-methyl-7-phenoxyisoquinoline-3-ethyl formate.
Background
The chemical name of roxasistat (Roxadustat) is:N- [ (4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline) carbonyl]The chemical structure of glycine, roxasistat (roxardustat) is as follows:
core structure of rasagile
Rosesartat (Roxadustat), a novel small molecule hypoxia inducible factor prolyl hydroxylase inhibitor (HIF-PHI) developed by FibroGen, inc. in the United states, is used clinically to treat anemia associated with chronic kidney disease and end stage renal disease. Rosxastat (Roxadustat) can affect HIF, increase hemoglobin levels, and increase iron absorption and utilization, thereby treating anemia. At present, the approval of the marketing of the Rosemasol is applied in China, japan and the European Union.
The synthetic routes of the rasagiline reported in the literature mainly comprise:
1) WO2004108681 reports the synthesis of a roxasitah intermediate and a roxasitah starting from 4-nitrophthalonitrile. The method adopts Gabriel-Colman rearrangement reaction to construct isoquinoline mother nucleus, and the used reagent is metallic sodium; part of the intermediate is purified by column chromatography; the reagent adopted for C-1 bromination is tribromooxyphosphorus oxide, and the environmental pollution is serious
2) WO2013013609 discloses a method for synthesizing a roxasistat intermediate and a roxasistat from 4-nitrophthalonitrile as a starting material. Part of intermediates synthesized by the method need to be separated by column chromatography, and are not suitable for large-scale production; the single-step yield of the methylation at the C-1 position is low; the adopted tetrakis (triphenylphosphine) palladium is a heavy metal reagent, and the price is high
3) WO2014014834 discloses the use of 5-bromoisobenzofuran-1 (3)H) -ketones as starting material, an improved process for the synthesis of a intermediate for roxasistat and also of roxasistat. In the improved method, an isoquinoline ring is constructed by adopting Claisen ester condensation;
4) EP3305769 discloses a process for the synthesis of a roxasistat intermediate and a roxasistat starting from methyl 2-bromo-4-fluorobenzoate. The method constructs an isoquinoline ring and simultaneously completes methylation at a C-1 position and hydroxylation at a C-4 position. Reagent used (Pd (OAc) 2 DPEPhos, etc.) are expensive.
5) CN 104892509 published withL-tyrosine as starting material for the synthesis of a intermediate for roxasistat and a method for the synthesis of roxasistat. The method adopts similar Pictet-Spengler reaction to construct tetrahydroisoquinoline, and then the isoquinoline parent nucleus is obtained by oxidative dehydrogenation, and simultaneously the problem of C-1 methylation of isoquinoline is solved.
6）J. Org. Chem2018, 83 (10): 15415-15425 report a process for the synthesis of a roxasistat intermediate and a roxasistat starting from 4-phenoxybenzaldehyde. The method adopts free radical reaction to cyclize to form an isoquinoline parent nucleus.
In conclusion, most of the currently reported methods for synthesizing the roxasistat are available, but the overall synthesis strategy is to construct an isoquinoline parent nucleus of the roxasistat and then carry out structural modification to obtain the roxasistat. Therefore, how to efficiently construct the parent nucleus of the Rosematarso isoquinoline is particularly critical.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and develop a m-phenoxy acetophenone derivative (the synthesis method is shown in the specification)J. Med. Chem1988,31, 1960-1964) 1 as a starting material, and carrying out cyclization reaction with methyl propiolate under the catalysis of a catalyst to synthesize a roxasistat intermediate 1-methyl-7-phenoxyisoquinoline-3-methyl formate 2. The synthetic route simplifies the introduction mode of isoquinoline C-1 methylation, and has the characteristics of simple process, convenient operation, no need of column chromatography purification, high yield and the like.
In order to achieve the purpose, the invention provides the following technical scheme:
a synthetic method for converting m-phenoxyacetophenone derivative 1 into methyl rosinestate intermediate 1-methyl-7-phenoxyisoquinoline-3-formate 2 is characterized by comprising the following steps:
synthetic route of intermediate 1-methyl-7-phenoxyisoquinoline-3-methyl formate 2 of roxasistat
M-phenoxy acetophenone derivatives 1 and methyl propiolate are subjected to cyclization reaction under the catalysis of a catalyst to obtain a rosinestat intermediate 1-methyl-7-phenoxy isoquinoline-3-methyl formate 2.
In the synthesis method, the catalyst is rhodium trichloride trihydrate, dichloro (p-methyl isopropyl phenyl) ruthenium (II) dimer and dichloro (pentamethyl cyclopentadienyl) rhodium (III) dimer.
In the synthesis method, the additives are sodium acetate, potassium acetate, silver acetate and hydrated copper acetate.
In the synthesis method, the organic solvent is methanol, tert-butyl alcohol, tert-amyl alcohol or trifluoroethanol.
In the synthesis method, the reaction temperature is reflux, and the reaction time is 24 hours.
In the synthesis method, the m-phenoxyacetophenone derivative 1: catalyst: methyl propiolate: the molar ratio of the additive is 1:2.5 Percent: 1 to 2:1 to 2.
In order to obtain the best experimental effect, in the synthesis method, the catalyst is rhodium trichloride trihydrate, dichloro (p-methyl isopropylphenyl) ruthenium (II) dimer and dichloro (pentamethyl cyclopentadienyl) rhodium (III) dimer, wherein the rhodium trichloride trihydrate is preferred.
In the synthesis method, the additives are sodium acetate, potassium acetate, silver acetate, water and copper acetate, wherein the silver acetate is preferred.
In the synthesis method, the organic solvent is methanol, tert-butyl alcohol, tert-amyl alcohol or trifluoroethanol, wherein the tert-amyl alcohol is preferred.
In the synthesis method, the m-phenoxyacetophenone derivative 1: catalyst: methyl propiolate: the preferred molar ratio of the additives is 1:2.5 Percent: 1.2:1.2.
the reaction process of the invention is as follows:
synthetic route of intermediate 1-methyl-7-phenoxyisoquinoline-3-methyl formate 2 of roxasistat
The invention takes the m-phenoxyacetophenone derivative 1 as the starting material, synthesizes the Rosemastat intermediate 1-methyl-7-phenoxyisoquinoline-3-methyl formate 2 simply and efficiently, compared with the content disclosed in the prior art, the synthetic route disclosed by the invention has short reaction steps, avoids harsh reaction conditions, does not need column chromatography purification, and realizes methylation of C-1 position while constructing isoquinoline parent nucleus. The invention focuses on the investigation of the influence of catalysts, additives, organic solvents, molar equivalents and the like on the reaction. The main difficulty of the invention lies in the selection of the catalyst, the additive and the organic solvent.
The invention discloses a method for preparing a methyl rosisoxostat intermediate 1-methyl-7-phenoxy isoquinoline-3-methyl formate 2 by using m-phenoxy acetophenone derivatives 1 and methyl propiolate as reaction substrates through cyclization reaction under the catalysis of a catalyst.
Detailed Description
The invention is described below by means of specific embodiments. Unless otherwise specified, the technical means used in the present invention are well known to those skilled in the art. In addition, the embodiments should be considered illustrative, and not restrictive, of the scope of the invention, which is defined solely by the claims. It will be apparent to those skilled in the art that various changes or modifications can be made in the components and amounts of the materials used in these embodiments without departing from the spirit and scope of the invention. The m-phenoxy acetophenone derivative 1 (see J. Med. Chem.,1988,31, 1960-1964) used as a raw material in the present invention, and m-phenoxy acetophenone, methyl propiolate, etc. are commercially available.
The preparation of a key intermediate of the invention, a roxasistat, is further illustrated below with reference to the preferred embodiments.
Example 1
2.41 g (0.01 mol) of m-phenoxyacetophenone derivative 1,0.15 g (2.5 mol%) of dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer, 1.68 g (0.02 mol) of methyl propiolate, 1.64 g (0.02 mol) of sodium acetate and 20 ml of tert-butanol were each charged into a three-necked flask equipped with a thermometer and magnetic stirrer, and the reaction was continued for 24 hours by heating to reflux after the completion of the addition. After TLC detection reaction, the reaction liquid is cooled to room temperature, 20 ml of water is added into the reaction liquid, ethyl acetate is used for extraction for 3 times, organic phases are combined, saturated sodium chloride and water are used for washing sequentially, anhydrous sodium sulfate is used for drying and concentration, the obtained concentrate is recrystallized by ethyl acetate and n-hexane, and 2.04 g of the roxasistat intermediate 1-methyl-7-phenoxyisoquinoline-3-methyl formate is obtained after drying, and the yield is 69.7%.
Example 2
2.41 g (0.01 mol) of m-phenoxyacetophenone derivative 1,0.15 g (2.5 mol%) of dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer, 1.68 g (0.02 mol) of methyl propiolate, 1.96 g (0.02 mol) of potassium acetate and 20 ml of tert-butanol were each charged into a three-necked flask equipped with a thermometer and magnetic stirrer, and the reaction was continued for 24 hours by heating to reflux after the completion of the addition. After TLC detection reaction, the reaction liquid is cooled to room temperature, 20 ml of water is added into the reaction liquid, extraction is carried out for 3 times by using ethyl acetate, organic phases are combined, saturated sodium chloride and water are sequentially used for washing, anhydrous sodium sulfate is used for drying and concentration, the obtained concentrate is recrystallized by using ethyl acetate and n-hexane, and 2.09 g of the roxasistat intermediate 1-methyl-7-phenoxyisoquinoline-3-methyl formate is obtained after drying, and the yield is 71.2%.
Example 3
2.41 g (0.01 mol) of m-phenoxyacetophenone derivative 1,0.15 g (2.5 mol%) of dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer, 1.68 g (0.02 mol) of methyl propiolate, 3.34 g (0.02 mol) of silver acetate and 20 ml of tert-butanol were each charged into a three-necked flask equipped with a thermometer and magnetic stirrer, and the reaction was continued for 24 hours by heating to reflux after the completion of the addition. After TLC detection reaction, the reaction liquid is cooled to room temperature, 20 ml of water is added into the reaction liquid, ethyl acetate is used for extraction for 3 times, organic phases are combined, saturated sodium chloride and water are used for washing sequentially, anhydrous sodium sulfate is used for drying and concentration, the obtained concentrate is recrystallized by ethyl acetate and n-hexane, and 2.44 g of the roxasistat intermediate 1-methyl-7-phenoxyisoquinoline-3-methyl formate is obtained after drying, and the yield is 83.2%.
Example 4
2.41 g (0.01 mol) of m-phenoxyacetophenone derivative 1,0.15 g (2.5 mol%) of dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer, 1.68 g (0.02 mol) of methyl propiolate, 4.00 g (0.02 mol) of hydrated copper acetate and 20 ml of tert-butanol were each introduced into a three-necked flask equipped with a thermometer and magnetic stirrer, and the reaction was continued for 24 hours by heating to reflux after the addition. After TLC detection reaction, the reaction solution is cooled to room temperature, 20 ml of water is added into the reaction solution, ethyl acetate is used for extraction for 3 times, organic phases are combined, saturated sodium chloride and water are used for washing sequentially, anhydrous sodium sulfate is used for drying and concentrating, the obtained concentrate is recrystallized by ethyl acetate and n-hexane, and 2.26 g of 1-methyl-7-phenoxyisoquinoline-3-methyl formate as a rosixastat intermediate is obtained after drying, and the yield is 77.2%.
Example 5
2.41 g (0.01 mol) of m-phenoxyacetophenone derivative 1,0.15 g (2.5 mol%) of dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer, 1.68 g (0.02 mol) of methyl propiolate, 3.34 g (0.02 mol) of silver acetate and 20 ml of methanol were each charged into a three-necked flask equipped with a thermometer and magnetically stirred, and the reaction was continued for 24 hours by heating to reflux after the completion of the addition. After TLC detection reaction, the reaction liquid is cooled to room temperature, 20 ml of water is added into the reaction liquid, ethyl acetate is used for extraction for 3 times, organic phases are combined, saturated sodium chloride and water are used for washing sequentially, anhydrous sodium sulfate is used for drying and concentration, the obtained concentrate is recrystallized by ethyl acetate and n-hexane, and 1.82 g of the roxasistat intermediate 1-methyl-7-phenoxyisoquinoline-3-methyl formate is obtained after drying, and the yield is 62.2%.
Example 6
2.41 g (0.01 mol) of m-phenoxyacetophenone derivative 1,0.15 g (2.5 mol%) of dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer, 1.68 g (0.02 mol) of methyl propiolate, 3.34 g (0.02 mol) of silver acetate and 20 ml of tert-amyl alcohol were each introduced into a three-necked flask equipped with a thermometer and magnetic stirrer, and the reaction was continued for 24 hours by heating to reflux after the addition. After TLC detection reaction, the reaction liquid is cooled to room temperature, 20 ml of water is added into the reaction liquid, ethyl acetate is used for extraction for 3 times, organic phases are combined, saturated sodium chloride and water are used for washing sequentially, anhydrous sodium sulfate is used for drying and concentration, the obtained concentrate is recrystallized by ethyl acetate and n-hexane, and 2.62 g of the roxasistat intermediate 1-methyl-7-phenoxyisoquinoline-3-methyl formate is obtained after drying, and the yield is 89.3%.
Example 7
2.41 g (0.01 mol) of m-phenoxyacetophenone derivative 1,0.15 g (2.5 mol%) of dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer, 1.68 g (0.02 mol) of methyl propiolate, 3.34 g (0.02 mol) of silver acetate and 20 ml of trifluoroethanol were each charged into a magnetically stirred three-necked flask equipped with a thermometer, and the reaction was continued for 24 hours by heating to reflux after the completion of the addition. After TLC detection reaction, the reaction liquid is cooled to room temperature, 20 ml of water is added into the reaction liquid, extraction is carried out for 3 times by using ethyl acetate, organic phases are combined, saturated sodium chloride and water are sequentially used for washing, anhydrous sodium sulfate is used for drying and concentration, the obtained concentrate is recrystallized by using ethyl acetate and n-hexane, and 2.39 g of the roxasistat intermediate 1-methyl-7-phenoxyisoquinoline-3-methyl formate is obtained after drying, and the yield is 81.7%.
Example 8
2.41 g (0.01 mol) of m-phenoxyacetophenone derivative, 1,0.065 g (2.5 mol%) of rhodium trichloride trihydrate, 1.68 g (0.02 mol) of methyl propiolate, 3.34 g (0.02 mol) of silver acetate and 20 ml of tert-amyl alcohol are respectively added into a three-neck flask which is provided with a thermometer and is magnetically stirred, the temperature is raised to reflux, and the reaction is continued for 24 hours. After TLC detection reaction, the reaction liquid is cooled to room temperature, 20 ml of water is added into the reaction liquid, ethyl acetate is used for extraction for 3 times, organic phases are combined, saturated sodium chloride and water are used for washing sequentially, anhydrous sodium sulfate is used for drying and concentration, the obtained concentrate is recrystallized by ethyl acetate and n-hexane, and 2.61 g of the roxasistat intermediate 1-methyl-7-phenoxyisoquinoline-3-methyl formate is obtained after drying, and the yield is 89.2%.
Example 9
2.41 g (0.01 mol) of m-phenoxyacetophenone derivative 1,0.15 g (2.5 mol%) of dichloro (p-methylisopropyl) ruthenium (II) dimer, 1.68 g (0.02 mol) of methyl propiolate, 3.34 g (0.02 mol) of silver acetate, 20 ml of tert-amyl alcohol were each charged into a three-necked flask equipped with a thermometer and magnetic stirrer, and the reaction was continued for 24 hours while warming to reflux. After TLC detection reaction, the reaction liquid is cooled to room temperature, 20 ml of water is added into the reaction liquid, ethyl acetate is used for extraction for 3 times, organic phases are combined, saturated sodium chloride and water are used for washing sequentially, anhydrous sodium sulfate is used for drying and concentration, the obtained concentrate is recrystallized by ethyl acetate and n-hexane, and 2.30 g of the roxasistat intermediate 1-methyl-7-phenoxyisoquinoline-3-methyl formate is obtained after drying, and the yield is 78.6%.
Example 10
2.41 g (0.01 mol) of m-phenoxyacetophenone derivative 1,0.065 g (2.5 mol%) of rhodium trichloride trihydrate, 0.84 g (0.01 mol%) of methyl propiolate, 1.67 g (0.01 mol) of silver acetate and 20 ml of tert-amyl alcohol are respectively added into a three-necked flask equipped with a thermometer and magnetically stirred, and the reaction is continued for 24 hours after the addition is finished. After TLC detection reaction, the reaction liquid is cooled to room temperature, 20 ml of water is added into the reaction liquid, ethyl acetate is used for extraction for 3 times, organic phases are combined, saturated sodium chloride and water are used for washing sequentially, anhydrous sodium sulfate is used for drying and concentration, the obtained concentrate is recrystallized by ethyl acetate and n-hexane, and 1.92 g of the roxasistat intermediate 1-methyl-7-phenoxyisoquinoline-3-methyl formate is obtained after drying, and the yield is 65.4%.
Example 11
2.41 g (0.01 mol) of m-phenoxyacetophenone derivative 1,0.065 g (2.5 mol%) of rhodium trichloride trihydrate, 1.00 g (0.012 mol) of methyl propiolate, 2.00 g (0.012 mol) of silver acetate and 20 ml of tert-amyl alcohol are respectively added into a three-neck flask which is provided with a thermometer and is magnetically stirred, the temperature is raised to reflux, and the reaction is continued for 24 hours. After TLC detection reaction, the reaction solution is cooled to room temperature, 20 ml of water is added into the reaction solution, ethyl acetate is used for extraction for 3 times, organic phases are combined, saturated sodium chloride and water are used for washing sequentially, anhydrous sodium sulfate is used for drying and concentrating, the obtained concentrate is recrystallized by ethyl acetate and n-hexane, and 2.62 g of 1-methyl-7-phenoxyisoquinoline-3-methyl formate as a rosixastat intermediate is obtained after drying, and the yield is 89.5%.
Example 12
Takes the intermediate 1-methyl-7-phenoxyisoquinoline-3-methyl formate 2 of the rosixastat as a starting material (reference literature)J. Org. Chem2018, 83 (10): 15415-15425), hydroxylation of the C-4 position is carried out by using acetic acid/hydrogen peroxide and p-methylbenzenesulfonyl chloride system, and then amidation with glycine to synthesize roxasistat, twoThe yield of step (a) was 45.7%.
The data for the assay of the intermediate 1-methyl-7-phenoxyisoquinoline-3-methyl formate of Rosemastat prepared according to the invention are shown below in example 12
1 H NMR( 400 MHz, CD 3 Cl) d: 8.49(d, J = 9.0 Hz, 1H)，7.60 - 7.28 (m, 4H)，7.26 - 7.21 (m, 1H)，7.17 - 7.12 (m, 2H)，4.07 (s, 3H)，2.91 (3, 3H).
ESI-MS(m/z) : 294.12 [M+H] + .
The results show that: the above spectroscopic data demonstrate that the product produced is the intermediate 1-methyl-7-phenoxyisoquinoline-3-carboxylic acid methyl ester of rosixastat.
It will be apparent to those skilled in the art that various changes and modifications can be made in the above embodiments without departing from the spirit and scope of the invention, and all changes and modifications that come within the meaning and range of equivalency of the claims are to be embraced within their scope. And the invention is not limited to the example embodiments set forth in the description.
Claims (1)
1. A synthetic method for converting m-phenoxy acetophenone derivatives 1 into a Rosemastat intermediate 1-methyl-7-phenoxy isoquinoline-3-methyl formate 2 is characterized in that in an organic solvent, the m-phenoxy acetophenone derivatives 1, methyl propiolate and an additive are subjected to cyclization reaction under the catalysis of a catalyst to obtain the Rosemastat intermediate 1-methyl-7-phenoxy isoquinoline-3-methyl formate 2;
wherein: m-phenoxy acetophenone derivative 1: catalyst: methyl propiolate: the molar ratio of the additive is 1:2.5 Percent: 1 to 2: 1-2;
the catalyst is rhodium trichloride trihydrate, dichloro (p-methyl isopropyl phenyl) ruthenium (II) dimer, dichloro (pentamethyl cyclopentadienyl) rhodium (III) dimer;
the additive is sodium acetate, potassium acetate, silver acetate or hydrated copper acetate;
the organic solvent is methanol, tert-butyl alcohol, tert-amyl alcohol or trifluoroethanol;
the reaction temperature is reflux, and the reaction time is 24 hours.
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