CN114644589A - Preparation method of compound N- [ (4-hydroxy-1-methyl-3-isoquinolyl) carbonyl ] -glycine - Google Patents
Preparation method of compound N- [ (4-hydroxy-1-methyl-3-isoquinolyl) carbonyl ] -glycine 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 belongs to the field of organic synthesis, and particularly discloses a preparation method of a compound N- [ (4-hydroxy-1-methyl-3-isoquinolyl) carbonyl ] -glycine, which comprises the steps of firstly reducing carbon-carbon double bonds of 2-vinyl methyl benzoate by palladium-carbon/hydrogen to obtain a compound of a formula A2; halogenating the compound of formula A2 with N-bromosuccinimide to obtain a brominated product compound of formula A3; reacting the compound of formula A3 with a sulfonamide to provide a compound of formula a 4; cyclizing the compound of the formula A4 by taking potassium tert-butoxide as base to obtain a compound of a formula A5; acylation of the compound of formula a5 with glycine gives the final product compound of formula a 6. Compared with the prior art, the synthesis preparation method provided by the invention reduces the synthesis steps, and has the advantages of convenience in operation, safety in production, high yield and lower cost.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of a compound N- [ (4-hydroxy-1-methyl-3-isoquinolyl) carbonyl ] -glycine.
Background
The roxasistat belongs to 4-hydroxyisoquinoline derivatives, is a novel Hypoxia Inducible Factor (HIF) -Prolyl Hydroxylase (PH) enzyme inhibitor, inhibits the degradation of the HIF by stabilizing the HIF, activates the transcription of related genes, generates corresponding physiological reaction, moderately increases the concentration of erythropoietin, improves the sensitivity of Erythropoietin (EPO) receptors, coordinates the generation of red blood cells, reduces the level of hepcidin, increases the content and activity of transferrin receptors, promotes the absorption and utilization of iron, and has good tolerance.
The compound N- [ (4-hydroxy-1-methyl-3-isoquinolinyl) carbonyl ] -glycine belongs to 4-hydroxyisoquinoline derivatives, and is a structural analogue of the roxasistat. Only two documents, namely Methods of screening for agents for the purpose of the present treatment of postmenopausal vacuolar alkaline aberration by analysis of effects on marker gene expression (WO 2006099610) and Preparation of isoquinoline compounds and the use of a mediating hypoxia absorbent factor and a mediating endogeneous erythropoetin (WO 2004108681), are currently involved.
According to patent WO 2004108681, the existing synthetic route is as follows:
the route is long and complicated, ten steps of reaction are needed to finally synthesize the target product compound of the formula A6, and the yield is low, so the invention provides a new synthetic route.
Disclosure of Invention
The invention aims to provide a method for preparing N- [ (4-hydroxy-1-methyl-3-isoquinolyl) carbonyl ] -glycine, which has the advantages of fewer reaction steps, convenient operation, safe production, high yield and lower cost aiming at the defects in the prior art
The specific object of the invention can be achieved by the following measures:
a process for producing N- [ (4-hydroxy-1-methyl-3-isoquinolinyl) carbonyl ] -glycine, characterized by comprising the steps of: taking 2-vinyl methyl benzoate as a raw material, and obtaining a product through reduction reaction, halogenation reaction, coupling reaction, cyclization reaction and acylation reaction, wherein the specific reaction route is as follows:
wherein the reducing agent adopted in the reduction reaction is one or more of palladium carbon/hydrogen, sodium borohydride or lithium aluminum hydride. A process for the preparation of N- [ (4-hydroxy-1-methyl-3-isoquinolinyl) carbonyl ] -glycine comprising the following steps:
a) the method comprises the following steps Reducing the carbon-carbon double bond of the compound of formula A1 with palladium-carbon/hydrogen to obtain a compound of formula A2;
b) the method comprises the following steps Halogenating the compound of formula A2 with N-bromosuccinimide to obtain a brominated product compound of formula A3;
c) the method comprises the following steps Reacting a compound of formula A3 with a sulfonamide to provide a compound of formula a 4;
d) the method comprises the following steps Cyclizing the compound of the formula A4 under the action of potassium tert-butoxide to obtain a compound of a formula A5;
e) the method comprises the following steps Acylation of the compound of formula A5 with glycine affords the final compound of formula A6.
The reaction process is as follows:
in the step a), one preferable scheme is as follows: the compound of formula A1 is subjected to reduction reaction with 10% palladium carbon and hydrogen in methanol solvent at room temperature under vacuum condition, and the carbon-carbon double bond is reduced by 10% palladium carbon and hydrogen to obtain the compound of formula A2.
In step a), the molar ratio of the compound of formula A1 to the selected 10% Pd/C may be 1: 0.1-1: 0.5.
one specific operation of step a) is as follows: a compound according to formula a 1: the molar ratio of 10% Pd/C was 1: 0.35 weigh compound of formula A1 and 10% Pd/C in a round bottom flask, sealed, evacuated, and mixed according to formula A1: the mass volume ratio of the solvent is 1: 10-1: 20 adding a solvent methanol, introducing hydrogen into a bottle, reacting for 4 hours under the condition of room temperature while stirring, detecting by thin layer chromatography, cooling the system to room temperature after the reaction is finished, extracting the reaction system by using an organic solvent ethyl acetate, washing by using a saturated sodium chloride solution, collecting an organic phase, and drying the organic phase by using anhydrous Na2SO 4. Concentrating the dried organic phase, purifying by column chromatography with petroleum ether as mobile phase, and concentrating to obtain compound A2 as transparent oily product.
In the step b), one preferable scheme is as follows: and carrying out halogenation reaction on the compound of the formula A2, N-bromosuccinimide and a catalyst at 80 ℃ in a nitrogen atmosphere to obtain the compound of the formula A3.
In the step b), the solvent can be carbon tetrachloride, the catalyst is azobisisobutyronitrile, and the molar ratio of the compound A2 to the N-bromosuccinimide to the azobisisobutyronitrile is 1: (0.75-1.15): (0.05-0.2).
One specific operation of step b) is as follows: the molar ratio of the compound represented by the formula A2 to N-bromosuccinimide and azobisisobutyronitrile is 1: 1.15: 0.05 weigh the three reagents into a sealed vial, sparge with nitrogen to protect, and compound according to formula A2: the mass volume ratio of the solvent is 1: 10-1: 20 adding carbon tetrachloride solvent, and refluxing and stirring at 80 ℃ for reaction for 2 h. Detecting by thin layer chromatography, cooling the system to room temperature after the reaction is finished, extracting the reaction system by using an organic solvent ethyl acetate, washing by using a saturated sodium chloride solution, collecting an organic phase, and drying the organic phase by using anhydrous Na2SO 4. The dried organic phase is concentrated and then purified by column chromatography with petroleum ether and ethyl acetate as mobile phases, petroleum ether: ethyl acetate 200: product point at 1 hour and concentrate to give the compound of formula a3 as a pale yellow oily product.
In the step c), one preferable scheme is as follows: the compound of the formula A3, sulfonamide and alkali, wherein the alkali can be potassium carbonate, sodium carbonate, calcium carbonate, cesium carbonate and barium carbonate, the solvent is one or more of DMF, acetonitrile, NMP and acetone, and the sulfonylation reaction is carried out at 30-70 ℃ to obtain the compound of the formula A3.
In a preferable scheme, potassium carbonate is selected as the base in the step c), potassium iodide is added for catalytic reaction, one or more of DMF, acetonitrile, NMP and acetone are selected as the solvent, and the reaction temperature is 30-70 ℃.
In a preferable scheme, the base in the step c) is potassium carbonate, potassium iodide is added to catalyze the reaction, the selected solvent is acetonitrile, and the reaction temperature is 50 ℃.
One specific operation of step c) is as follows: a compound according to formula a 3: sulfonamide: the molar ratio of alkali is 1: 1.2: 5 weigh compound into round bottom flask, compound according to formula a 3: the mass volume ratio of the solvent is 1: 10 adding solvent, heating to 50 ℃, and stirring for reaction overnight. Detecting by thin layer chromatography, cooling the system to room temperature after the reaction is finished, extracting the reaction system by using an organic solvent ethyl acetate, washing by using a saturated sodium chloride solution, collecting an organic phase, and drying the organic phase by using anhydrous Na2SO 4. The dried organic phase is concentrated and then purified by column chromatography with petroleum ether and ethyl acetate as mobile phases, petroleum ether: ethyl acetate 80: product point at 1 hour and concentrate to give the compound of formula a4 as a pale yellow oily product.
In the step d), one preferable scheme is as follows: dissolving the compound of the formula A4 in a solvent DMF, adding strong base while stirring, heating and stirring for cyclization reaction.
In a preferable scheme, the base used in the cyclization reaction in the step d) is potassium tert-butoxide, and the reaction temperature is 30-50 ℃.
One specific operation of step d) is as follows: the compound of formula A4 is weighed to dissolve in a mass to volume ratio of 1: 10 in DMF, a compound according to formula a 4: the molar ratio of potassium tert-butoxide is 1: 2, weighing potassium tert-butoxide, adding the potassium tert-butoxide into the system under stirring, heating to 40 ℃ for reaction, and stirring for reaction for 3 hours. Detecting by thin layer chromatography, cooling the system to room temperature after the reaction is finished, adding dilute hydrochloric acid to adjust the system to acidity, extracting with organic solvent ethyl acetate, washing with saturated sodium chloride solution, collecting an organic phase, and drying the organic phase with anhydrous Na2SO 4. The dried organic phase is concentrated and then purified by column chromatography with petroleum ether and ethyl acetate as mobile phases, petroleum ether: ethyl acetate 50: product point at 1 hour and concentrate to give the compound of formula a5 as a yellow solid product.
In the step e), one preferable scheme is as follows: the compound of formula A5 and glycine are reacted at high temperature under the action of sodium methoxide.
In the step e), during feeding, the sodium methoxide is selected from a methanol solution of sodium methoxide, a reaction solvent is selected from methanol, and the temperature can be selected from high temperature of 100-120 ℃.
The specific operation of step e) is as follows: according to the formula A5 compound to glycine molar ratio of 1: 3, weighing the reactant, placing the reactant in a sealed tube, and reacting the compound according to the formula A5 and sodium methoxide according to the molar ratio of 1: 2 adding sodium methoxide in methanol to obtain a compound of formula a 5: the mass volume ratio of the solvent is 1: adding methanol solvent in the amount of 10, sealing, and stirring at 110 ℃ for reaction overnight. Detecting by thin layer chromatography, cooling the system to room temperature after the reaction is finished, adding water-soluble clear solution into the system, extracting by ethyl acetate, collecting a water phase, adding diluted hydrochloric acid to adjust the collected water phase to be acidic, and separating out solids. And (3) carrying out suction filtration on the system, washing impurities out of a filter cake by using methanol and acetone, and collecting the filter cake, namely the compound shown as the formula A6, wherein the product is a light brown solid.
Drawings
FIG. 1 is a nuclear magnetic spectrum of N- [ (4-hydroxy-1-methyl-3-isoquinolinyl) carbonyl ] -glycine prepared in example 5.
Detailed Description
EXAMPLES 1-1 preparation and characterization of Compounds of formula A2
Weighing 3.5g of compound of formula A1 and 583mg of 10% Pd/C, placing in a round-bottom flask, sealing, vacuumizing the flask, adding 35mL of solvent methanol, introducing hydrogen into the flask, stirring and reacting for 4h at room temperature, detecting by thin layer chromatography, cooling the system to room temperature after the reaction is finished, extracting the reaction system with organic solvent ethyl acetate, washing with saturated sodium chloride solution, collecting an organic phase, and using anhydrous Na as the organic phase2And drying the SO 4. The dried organic phase was concentrated and then purified by column chromatography using petroleum ether as the mobile phase and concentrated to give formula a2 in 96% yield as a clear oil.
Nuclear magnetic data for a compound of formula a 2:1H NMR(500MHz,Chloroform-d)δ7.83(dd,J＝7.5,1.8Hz,1H),7.47–7.36(m,2H),7.14(ddt,J＝7.6,2.8,1.0Hz,1H),3.89(s,2H),2.82(qd,J＝7.2,1.0Hz,2H),1.19(t,J＝7.2Hz,3H).
EXAMPLES 1-2 preparation and characterization of Compounds of formula A3
Weighing 2.1g of a compound of a formula A2, 1.68mg of N-bromosuccinimide and 40mg of azobisisobutyronitrile, placing the mixture in a sealed bottle, introducing nitrogen for protection, adding 30mL of solvent-dried carbon tetrachloride, and carrying out reflux stirring reaction for 2h at 80 ℃. Detecting by thin layer chromatography, cooling the system to room temperature after the reaction is finished, extracting the reaction system by using an organic solvent ethyl acetate, washing by using a saturated sodium chloride solution, collecting an organic phase, and drying the organic phase by using anhydrous Na2SO 4. The dried organic phase is concentrated and then purified by column chromatography with petroleum ether and ethyl acetate as mobile phases, petroleum ether: ethyl acetate 200: the product was obtained at 1 hour and concentrated to give formula a3 in 94% yield, which appeared as a pale yellow oil.
Nuclear magnetic data for a compound of formula a 3:1H NMR(500MHz,Chloroform-d)δ7.86(dd,J＝7.6,1.6Hz,1H),7.50–7.41(m,2H),7.40(td,J＝7.5,1.6Hz,1H),5.26(qd,J＝6.8,0.9Hz,1H),3.89(s,2H),1.95(d,J＝6.8Hz,3H).
EXAMPLES 1-3 preparation and characterization of Compounds of formula A4
1g of the compound of formula A3, 870mg of sulfonamide, 2g of potassium carbonate and 740mg of potassium iodide were weighed out and placed in a round-bottomed flask, 20mL of acetonitrile as a solvent was added, and the mixture was heated to 50 ℃ and stirred to react overnight. Detecting by thin layer chromatography, cooling the system to room temperature after the reaction is finished, extracting the reaction system by using an organic solvent ethyl acetate, washing by using a saturated sodium chloride solution, collecting an organic phase, and drying the organic phase by using anhydrous Na2SO 4. The dried organic phase is concentrated and then purified by column chromatography with petroleum ether and ethyl acetate as mobile phases, petroleum ether: ethyl acetate 80: product point at 1 hour and concentrate to give the compound of formula a4 in 89% yield, which appears as a pale yellow solid.
Nuclear magnetic data for a compound of formula a 4:1H NMR(500MHz,Chloroform-d)δ7.83(dd,J＝7.7,1.6Hz,1H),7.69–7.62(m,2H),7.56–7.50(m,1H),7.54–7.43(m,2H),7.37–7.31(m,2H),4.96(qd,J＝6.1,0.9Hz,1H),4.41(d,J＝12.3Hz,1H),4.03(d,J＝12.3Hz,1H),3.90(s,2H),3.73(s,2H),2.43(d,J＝0.9Hz,3H),1.47(d,J＝6.2Hz,3H).
EXAMPLES 1-4 preparation and characterization of Compounds of formula A5
Weighing 1g of the compound of the formula A4, dissolving in 20mL of DMF solvent, adding 450mg of potassium tert-butoxide into the system under stirring, heating to 40 ℃ for reaction, and stirring for reaction for 3 h. Detecting by thin layer chromatography, cooling the system to room temperature after the reaction is finished, adding dilute hydrochloric acid to adjust the system to acidity, extracting with organic solvent ethyl acetate, washing with saturated sodium chloride solution, collecting an organic phase, and drying the organic phase with anhydrous Na2SO 4. The dried organic phase is concentrated and then purified by column chromatography with petroleum ether and ethyl acetate as mobile phases, petroleum ether: ethyl acetate 50: the product was taken off at 1 hour and concentrated to give the compound of formula a5 in 92% yield, which appeared as a yellow solid.
Nuclear magnetic data for a compound of formula a 5:1H NMR(500MHz,Chloroform-d)δ8.10(dd,J＝7.9,1.5Hz,1H),7.86(dd,J＝7.7,1.5Hz,1H),7.50(td,J＝7.9,1.4Hz,1H),7.42(td,J＝7.8,1.3Hz,1H),3.91(s,2H),2.94(s,2H).
EXAMPLES 1-5 preparation and characterization of Compounds of formula A6
500mg of the compound represented by the formula A5, 380mg of glycine and 11mg of sodium methoxide were weighed out and placed in a sealed tube, and 12mL of a methanol solution was added thereto, sealed and placed at 110 ℃ for reaction with stirring overnight. Detecting by thin layer chromatography, cooling the system to room temperature after the reaction is finished, adding water-soluble clear liquid into the system, extracting by ethyl acetate, collecting a water phase, and adding diluted hydrochloric acid to adjust the collected water phase to acid.
Claims (10)
1. A process for the preparation of the compound N- [ (4-hydroxy-1-methyl-3-isoquinolinyl) carbonyl ] -glycine, characterized in that it comprises the following steps: taking 2-vinylmethyl benzoate as a raw material, and obtaining a product through reduction reaction, halogenation reaction, coupling reaction, cyclization reaction and acylation reaction, wherein the specific reaction route is as follows:
2. the method for preparing N- [ (4-hydroxy-1-methyl-3-isoquinolinyl) carbonyl ] -glycine as claimed in claim 1, wherein the reducing agent used in the reduction reaction is one or more of palladium on carbon/hydrogen, sodium borohydride or lithium aluminum hydride.
3. A process for the preparation of N- [ (4-hydroxy-1-methyl-3-isoquinolinyl) carbonyl ] -glycine according to claim 1, characterized by the fact that it comprises the following steps:
a) the method comprises the following steps Reducing the carbon-carbon double bond of the compound of the formula A1 by palladium-carbon/hydrogen to obtain a compound of a formula A2;
b) the method comprises the following steps Halogenating the compound of formula A2 with N-bromosuccinimide to obtain a brominated product compound of formula A3;
c) the method comprises the following steps Reacting a compound of formula A3 with a sulfonamide to provide a compound of formula a 4;
d) the method comprises the following steps Cyclizing the compound of the formula A4 by taking potassium tert-butoxide as base to obtain a compound of a formula A5;
e) the method comprises the following steps Acylation of the compound of formula A5 with glycine affords the final compound of formula A6.
The reaction process is as follows:
4. the process according to claim 3, wherein during the reaction of step a), the molar ratio of the compound of formula A1 to the chosen 10% Pd/C is 1: 0.1-1: 0.5, preferably 1: 0.35.
5. the process according to claim 3 or 4, wherein during the reaction in step b), azobisisobutyronitrile is added as a catalyst, and the molar ratio of the compound of formula A2 to N-bromosuccinimide and azobisisobutyronitrile is 1: (0.75-1.15): (0.05-0.2).
6. The method according to claim 3 or 5, wherein during the reaction in step c), the reaction solvent is one or more selected from DMF, acetonitrile, NMP and acetone, preferably acetonitrile.
7. The process according to claim 3 or 6, characterized in that during the reaction in step c), the reaction temperature is 30 to 70 ℃, preferably 50 ℃.
8. The method according to claim 3 or 7, wherein the reaction temperature during the step d) is 30-50 ℃, preferably 40 ℃.
9. The method according to claim 3 or 8, wherein in the reaction process of step e), a methanol solution of sodium methoxide is used as an alkali condition, and the reaction is carried out at a high temperature and in a sealing manner, wherein the reaction temperature is 80-120 ℃.
10. The method according to claim 3 or 8, wherein the reaction in step e) is carried out under high temperature and sealed conditions with a methanol solution of sodium methoxide as a base, and the reaction temperature is 110 ℃.
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| CN1816527A (en) * | 2003-06-06 | 2006-08-09 | 菲布罗根有限公司 | Nitrogen-containing heteroaryl compounds and their use in increasing endogenous erythropoietin |
| CN103435546A (en) * | 2012-07-16 | 2013-12-11 | 菲布罗根有限公司 | Method for preparing isoquinoline compounds |
| WO2017161555A1 (en) * | 2016-03-25 | 2017-09-28 | 沈阳三生制药有限责任公司 | Intermediate for compounding 5-hydroxyl-1,7-naphthyridine compound substituted by aryl or heteroaryl, and preparation method therefor |
| CN111499514A (en) * | 2019-01-31 | 2020-08-07 | 连云港润众制药有限公司 | Preparation method of intermediate of roxasistat |
| WO2020173860A1 (en) * | 2019-02-26 | 2020-09-03 | Bayer Aktiengesellschaft | Fused bicyclic heterocycle derivatives as pesticides |
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2020
- 2020-12-17 CN CN202011501994.7A patent/CN114644589A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1816527A (en) * | 2003-06-06 | 2006-08-09 | 菲布罗根有限公司 | Nitrogen-containing heteroaryl compounds and their use in increasing endogenous erythropoietin |
| CN103435546A (en) * | 2012-07-16 | 2013-12-11 | 菲布罗根有限公司 | Method for preparing isoquinoline compounds |
| WO2017161555A1 (en) * | 2016-03-25 | 2017-09-28 | 沈阳三生制药有限责任公司 | Intermediate for compounding 5-hydroxyl-1,7-naphthyridine compound substituted by aryl or heteroaryl, and preparation method therefor |
| CN108884047A (en) * | 2016-03-25 | 2018-11-23 | 沈阳三生制药有限责任公司 | For synthesizing the intermediate and preparation method thereof for the 5- hydroxyl -1,7- naphthyridine compounds being optionally substituted aryl or heteroaryl |
| CN111499514A (en) * | 2019-01-31 | 2020-08-07 | 连云港润众制药有限公司 | Preparation method of intermediate of roxasistat |
| WO2020173860A1 (en) * | 2019-02-26 | 2020-09-03 | Bayer Aktiengesellschaft | Fused bicyclic heterocycle derivatives as pesticides |
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