CN116082234A - Preparation method of [ (4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-formyl) amino ] acetic acid - Google Patents
Preparation method of [ (4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-formyl) amino ] acetic acid Download PDFInfo
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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 discloses a preparation method of [ (4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-formyl) amino ] acetic acid, which at least comprises the following steps: (1) esterifying the compound 3 to obtain a compound 2; (2) Ammonolysis of the compound 2 to obtain [ (4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-formyl) amino ] acetic acid; the invention has the advantages of easily obtained raw materials, no special reactions such as high temperature and high pressure, safety, easy operation, high total yield, controllable quality and low cost, and is suitable for industrial production.
Description
Technical Field
The invention relates to a preparation method of [ (4-hydroxy-1-methyl-7-phenoxy isoquinoline-3-formyl) amino ] acetic acid.
Technical Field
[ (4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-formyl) amino ] acetic acid is a novel Hypoxia Inducible Factor (HIF) -Prolyl Hydroxylase (PH) enzyme inhibitor, and is well tolerated by stabilizing HIF, inhibiting degradation, activating transcription of related genes, generating corresponding physiological reaction, moderately increasing the concentration of erythropoietin, improving the sensitivity of Erythropoietin (EPO) receptors, coordinating erythrocyte production, reducing the level of hepcidin, increasing the content and activity of transferrin receptors, promoting iron absorption and utilization, and being used for treating chronic kidney-related anemia.
In 2014, the original research of fibrinogen reports an improved route using pentabromophthalide as a starting material, the total yield is about 26% after eight steps of reactions, but palladium-carbon hydrogenation is needed in the next to last step, the requirement on equipment is high, and certain safety risk exists:
the drug group report in 2016 (CN 107954931 a) uses methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate as a starting material, and uses bromination, methylation and PyBop to condense glycine methyl ester hydrochloride, and finally hydrolyzes to obtain [ (4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-formyl) amino ] acetic acid, the total yield of four steps is 48%, the disadvantage is that the use of PyBop in the amidation step is expensive, the cost is not high, and the total yield is also general:
in view of the above, there are many routes for synthesizing the compound 1[ (4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-formyl) amino ] acetic acid, but there are still defects in industrial production, and a process route more suitable for industrial production needs to be sought for aiming at the existing process defects.
Disclosure of Invention
The invention aims to: the invention aims to solve the technical problems of providing a method which is suitable for industrial production and has mild conditions, no high temperature and high pressure and high yield [ (4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-formyl) amino ]
A method for preparing acetic acid.
The technical scheme is as follows: in order to solve the technical problems, the invention provides a preparation method of [ (4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-formyl) amino ] acetic acid, which at least comprises the following steps:
(1) Esterification of compound 3 gives compound 2:
(2) Ammonolysis of compound 2 to give [ (4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-formyl) amino ] acetic acid:
wherein R is methyl, ethyl, isopropyl, tert-butyl or n-butyl.
Wherein, the compound 2 in the step (1) is prepared by adding a condensation reagent to the compound 3 to react with an alcohol reagent, wherein the condensation reagent is selected from one of carbonyl diimidazole, sulfuric acid, thionyl chloride and acetyl chloride; the alcohol reagent is selected from one of methanol, ethanol, isopropanol, n-butanol and tert-butanol.
The specific preparation method of the compound 1 in the step (2) comprises the following steps: adding methanol or acetonitrile and sodium glycinate into the compound 2 to react completely to obtain sodium salt, and then regulating acid by acetic acid to obtain the compound 1[ (4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-formyl) amino ] acetic acid.
Wherein, the compound 3 is obtained by Suzuki coupling of the compound 4:
wherein, the compound 4 is generated by reacting the compound 5 with a halogenated reagent in a solvent:
wherein X is halogen.
The Suzuki coupling is that the compound 4 and a methylation reagent react in an organic solvent and an alkaline water solution through a catalyst to generate a crude product of the compound 3, and the crude product is crystallized and purified to obtain a pure product of the compound 3.
Wherein the organic solvent is selected from one of N, N-dimethylformamide, ethylene glycol methyl ether, toluene and N-methylpyrrolidone; the methylation reagent is selected from one of methyl boric acid, trimethyl boron and methyl boric acid isopropyl ester; the alkali is one of potassium hydroxide, potassium phosphate, potassium fluoride, potassium carbonate and potassium acetate; the catalyst is one of tetraphenylphosphine palladium, palladium acetate, diacetonitrile palladium dichloride and DPPF palladium dichloride.
Wherein the organic solvent used for crystallization and purification is selected from one of methanol, N-dimethylformamide, N-methylpyrrolidone and dimethyl sulfoxide.
Wherein the halogenated reagent is selected from one of dichloro hydantoin, dibromohydantoin, N-chlorosuccinimide, N-bromosuccinimide and N-iodosuccinimide, and the solvent is selected from one of methanol, dichloromethane and N, N-dimethylformamide.
The invention relates to a preparation method of [ (4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-formyl) amino ] acetic acid, which specifically comprises the following steps:
s1, reacting the compound 5 with a halogenated reagent in a solvent to generate a compound 4:
s2, performing Suzuki coupling on the compound 4 to obtain a compound 3:
s3, esterifying the compound 3 to obtain a compound 2:
s4, ammonolysis is carried out on the compound 2 to obtain [ (4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-formyl) amino ] acetic acid:
wherein X is halogen, R is methyl, ethyl, isopropyl, tertiary butyl and n-butyl;
when the carbonyl diimidazole is used as an esterification condensation reagent, the reaction mechanism is that an intermediate 3 and the carbonyl diimidazole undergo nucleophilic reaction, and the intermediate is further substituted in an alcohol solution to obtain a compound 2, wherein the reaction mechanism is as follows:
the beneficial effects are that: compared with the prior art, the invention has the following advantages: the invention provides a preparation method of [ (4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-formyl) amino ] acetic acid, which has the advantages of easily obtained raw materials, no special reaction such as high temperature and high pressure, safety, easy operation, high yield, controllable quality and low cost, and is suitable for industrial production.
Drawings
FIG. 1 is an HPLC chart of example 4;
FIG. 2 is a graph of the hydrogen spectrum of example 4.
Detailed Description
Example 1
3.4kg of Compound 5 was added to a 50L reactor, 17L of dichloromethane was added, 1.7kg of N-chlorosuccinimide was added, the mixture was heated to 40℃and dissolved with stirring, and reacted at 40℃for 8 hours, TLC was taken up until the reaction was completed, and 6.8L of dichloromethane was removed by concentration under reduced pressure17L of methanol is added dropwise for crystallization, the temperature is reduced to 0 ℃, the temperature is kept for 2 hours, suction filtration is carried out, 3.55kg of pure compound 4-1 is obtained by vacuum drying, the yield is 93.5%, and the HPLC purity is 99.96%. Nuclear magnetic data 1 H NMR(400MHz，CDCl 3 )δ11.76(s，1H)，8.37(d，J＝9.0Hz，1H)，7.64(d，J＝2.4Hz，1H)，7.53(dd，J＝9.0，2.4Hz，1H)，7.51-7.42(m，2H)，7.32-7.23(m，1H)，7.19-7.12(m，2H)，4.08(s，3H).
Example 2
Adding 3.52kg of compound 4-1 into a 50L reaction kettle, adding 21L of ethylene glycol methyl ether, 9kg of potassium phosphate, 18L of water, 1.3kg of methyl boric acid, 170g of DPPF palladium dichloride, replacing nitrogen for three times and protecting nitrogen in the whole course, heating to 90 ℃ for reaction for 6 hours, cooling to 50 ℃ after the reaction is finished, standing to separate out a lower aqueous phase, dropwise adding 2N hydrochloric acid to pH=2 at 50 ℃, at this time, precipitating a large amount of solids, cooling to 10 ℃ for suction filtration, air-blast drying to obtain 2.83kg of compound 3 crude product, adding the crude product into 28LN, N-dimethylformamide for heating and stirring for clearing, cooling for crystallization, cooling to 10 ℃ for suction filtration, air-blast drying to obtain 2.49kg of pure compound 3, total yield of reaction and crystallization is 79%, HPLC purity is 99.90%, nuclear magnetic data 1 H NMR(400MHz，DMSO-d 6 )δ8.45(d，J＝9.0Hz，1H)，7.79(s，1H)，7.68(d，J＝9.0Hz，1H)，7.50(t，J＝7.4Hz，2H)，7.30(d，J＝7.5Hz，1H)，7.20(d，J＝7.9Hz，2H)，2.89(s，3H).
Example 3
Adding 2.28kg of compound 3 into a 50L reaction kettle, adding into 23L of dichloromethane, adding 2.5kg of carbonyldiimidazole, heating to 40 ℃ for reflux reaction, dissolving the mixture after 4 hours, dripping 1kg of methanol and continuing to react for 1 hour, TLC until the raw materials disappear, adding 11L of water for washing twice, separating out water phase, concentrating the organic phase to obtain the compound 2-1, directly using the compound in the next step, calculating the yield according to 100%, and HPLCPurity 99.97%, nuclear magnetic data 1 H NMR(400MHz，CDCl 3 )δ11.71(s，1H)，8.45-8.39(m，1H)，7.52-7.42(m，4H)，7.26(dd，J＝13.3，5.9Hz，2H)，7.15(d，J＝7.8Hz，2H)，4.10(s，3H)，2.77(s，3H).
Example 4
Adding 24L of methanol and 2.24kg of sodium glycinate into the compound 2-1 obtained in the example 3, stirring and heating to 68 ℃ for reflux reaction for 15h, TLC until the raw materials disappear, cooling to 10 ℃ for suction filtration, drying wet products by air blast to obtain a compound 1 to obtain sodium salt, dissolving the sodium salt in 24L of water, adding 12L of isopropyl acetate for extraction twice, separating an organic phase, dropwise adding 1389g of acetic acid into an aqueous phase at 45 ℃, gradually separating out solids, cooling to room temperature for suction filtration after the dropwise adding, and drying by air blast to obtain 2.72kg of compound 1[ (4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-formyl) amino]Acetic acid yield 90%, HPLC purity 99.91% (FIG. 1), nuclear magnetic data 1 H NMR(400MHz，DMSO-d 6 ) Delta 13.30 (s, 1H), 12.82 (s, 1H), 9.10 (t, j=6.2 hz, 1H), 8.29 (d, j=9.1 hz, 1H), 7.61 (d, j=2.4 hz, 1H), 7.53 (dd, j=9.0, 2.4hz, 1H), 7.51-7.45 (m, 2H), 7.30-7.22 (m, 1H), 7.22-7.15 (m, 2H), 4.06 (d, j=6.2 hz, 2H), 2.70 (s, 3H) (fig. 2).
Example 5
295.3g of compound 5 is added into a 2L three-mouth bottle, 1.5L of methanol is added, 186g of N-bromosuccinimide is added under stirring, the temperature is raised to 68 ℃ for reflux reaction for 10h, TLC detects the disappearance of the raw materials, the temperature is reduced to 0 ℃ for heat preservation for 2h, suction filtration is carried out, 300ml of methanol is leached, a solid wet product is dried at 45 ℃ by blowing to obtain 344g of compound 4-2, the purity of HPLC is 99.93%, and the yield is 92%.
Example 6
300g of compound 4-2 is added into a 5L reaction bottle, 1.8L of toluene, 179g of potassium hydroxide, 1.5L of water, 90g of trimethylboron, 30g of tetraphenylphosphine palladium, three times of nitrogen replacement and whole nitrogen protection are added, the temperature is raised to 90 ℃ for reaction for 6 hours, the temperature is reduced to 50 ℃ after the reaction is finished, the lower water phase is separated out by standing, 2N hydrochloric acid is dropwise added at 50 ℃ until PH=2, a large amount of solids are separated out, the temperature is reduced to 10 ℃ for suction filtration, 189g of compound 3 crude product is obtained by forced draught drying, the crude product is added into 2.3L of dimethyl sulfoxide for heating, stirring and clearing, cooling and crystallization are carried out, the temperature is reduced to 20 ℃ for suction filtration, 170g of pure compound 3 is obtained by forced draught drying, the total yield of the reaction and crystallization is 72%, and the HPLC purity is 99.75%.
Example 7
150g of compound 3 is added into a 1L reaction bottle, 450ml of methanol is added, 5ml of sulfuric acid is added, the temperature is raised to 68 ℃ for reflux reaction for 8 hours, TLC is carried out until the raw materials disappear, the temperature is reduced to 0 ℃ for 2 hours, suction filtration is carried out after the temperature is kept, 50ml of methanol is leached, a wet product is dried by blowing at 45 ℃ to obtain 133g of compound 2-1, the yield is 85%, the HPLC purity is 99.07%, and nuclear magnetic data are obtained 1 H NMR(400MHz，CDCl 3 )δ11.71(s，1H)，8.45-8.39(m，1H)，7.52-7.42(m，4H)，7.26(dd，J＝13.3，5.9Hz，2H)，7.15(d，J＝7.8Hz，2H)，4.10(s，3H)，2.77(s，3H)。
Example 8
150g of compound 3 is added into a 2L reaction bottle, 1L of dichloromethane is added, 164g of carbonyldiimidazole is added for heating reflux reaction for 4 hours, 213g of isopropanol is added dropwise after dissolving, the reaction is continued for 1 hour, TLC (thin layer chromatography) is carried out until the raw materials disappear, 500ml of water is added for washing twice, the organic phase is concentrated to dryness to obtain compound 2-2, the compound is directly used in the next step, the yield is calculated according to 100%, and the HPLC purity is 99.83%.
Example 9
Adding 2.05L of methanol and 148g of sodium glycinate into the compound 2-2 obtained in the example 8, stirring and heating to 68 ℃ for reflux reaction for 15h, TLC until the raw materials disappear, cooling to 10 ℃ for suction filtration, drying wet products by air blast to obtain the sodium salt of the compound 1, dissolving the sodium salt in 1.7L of water, adding 0.8L of ethyl acetate for extraction twice, separating an organic phase, heating an aqueous phase to 45 ℃ and dropwise adding 91g of acetic acid, gradually precipitating solids, cooling to room temperature after the dropwise adding, suction filtration, and air blast drying to obtain 161g of compound 1[ (4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-formyl) amino]Acetic acid yield 90%, HPLC purity 99.91%, nuclear magnetic data 1 H NMR(400MHz，DMSO-d 6 )δ13.30(s，1H)，12.82(s，1H)，9.10(t，J＝6.2Hz，1H)，8.29(d，J＝9.1Hz，1H)，7.61(d，J＝2.4Hz，1H)，7.53(dd，J＝9.0，2.4Hz，1H)，7.51-7.45(m，2H)，7.30-7.22(m，1H)，7.22-7.15(m，2H)，4.06(d，J＝6.2Hz，2H)，2.70(s，3H)。
Claims (9)
1. A process for the preparation of [ (4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl) amino ] acetic acid, said process comprising at least the steps of:
(1) Esterification of compound 3 gives compound 2:
(2) Ammonolysis of compound 2 to give [ (4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-formyl) amino ] acetic acid:
wherein R is methyl, ethyl, isopropyl, tert-butyl or n-butyl.
2. The preparation method according to claim 1, wherein the compound 2 in the step (1) is prepared by adding a condensation reagent to the compound 3 and reacting with an alcohol reagent, wherein the condensation reagent is selected from one of carbonyl diimidazole, sulfuric acid, thionyl chloride and acetyl chloride; the alcohol reagent is selected from one of methanol, ethanol, isopropanol, n-butanol and tert-butanol.
3. The preparation method according to claim 1, wherein the specific preparation method of the compound 1 in the step (2) comprises: adding methanol or acetonitrile and sodium glycinate into the compound 2 to react completely to obtain sodium salt, and then regulating acid by acetic acid to obtain the compound 1[ (4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-formyl) amino ] acetic acid.
4. The preparation method according to claim 1, wherein the compound 3 is obtained by Suzuki coupling of the compound 4:
5. the method of claim 4, wherein compound 4 is formed by reacting compound 5 with a halogenated reagent in a solvent:
6. The preparation method of claim 4, wherein the Suzuki coupling is that the compound 4 and a methylating agent react in an organic solvent and an alkaline water solution through a catalyst to generate a crude product of the compound 3, and the crude product is crystallized and purified to obtain a pure product of the compound 3.
7. The method according to claim 6, wherein the organic solvent is one selected from the group consisting of N, N-dimethylformamide, ethylene glycol methyl ether, toluene, and N-methylpyrrolidone; the methylation reagent is selected from one of methyl boric acid, trimethyl boron and methyl boric acid isopropyl ester; the alkali is one of potassium hydroxide, potassium phosphate, potassium fluoride, potassium carbonate and potassium acetate; the catalyst is one of tetraphenylphosphine palladium, palladium acetate, diacetonitrile palladium dichloride and DPPF palladium dichloride.
8. The method according to claim 6, wherein the organic solvent used for the crystallization and purification is one selected from the group consisting of methanol, N-dimethylformamide, N-methylpyrrolidone and dimethylsulfoxide.
9. The preparation method according to claim 5, wherein the halogenated reagent is selected from one of dichlorohydantoin, dibromohydantoin, N-chlorosuccinimide, N-bromosuccinimide and N-iodosuccinimide, and the solvent is selected from one of methanol, dichloromethane and N, N-dimethylformamide.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN116803986A (en) * | 2023-06-27 | 2023-09-26 | 江苏海洋大学 | Synthesis method of roflumilast intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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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