CN109988121B - Preparation method of acotiamide derivative - Google Patents
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- CN109988121B CN109988121B CN201910350282.0A CN201910350282A CN109988121B CN 109988121 B CN109988121 B CN 109988121B CN 201910350282 A CN201910350282 A CN 201910350282A CN 109988121 B CN109988121 B CN 109988121B
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- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Abstract
The invention discloses a preparation method of acotiamide derivatives, belongs to the field of compound preparation, and provides a synthesis method of novel drug molecule acotiamide derivatives, which is reasonable in process design, high in yield and convenient and controllable in operation process. The synthesis of the acotiamide derivative is realized by taking 2-aminothiazole-4-formate as a raw material and carrying out seven-step reaction. The preparation method provided by the invention has the advantages of reasonable process design, strong operability, mild reaction conditions, high yield and capability of realizing industrial production. The acotiamide derivative prepared by the invention provides important basis for scientific evaluation of the quality, safety and efficiency of the acotiamide. And the acotiamide derivative has good pharmacological activity, can be developed into a new medicine for treating functional dyspepsia, and has important application value.
Description
Technical Field
The invention belongs to the field of compound preparation, and particularly relates to a preparation method of acotiamide derivatives.
Background
Acotiamide is the first approved therapeutic agent for functional dyspepsia in the world. Functional Dyspepsia (FD), also known as dyspepsia, is a group of clinical syndromes of organic diseases which have uncomfortable symptoms such as epigastric pain, epigastric distension, early satiety, eructation, inappetence, nausea, vomiting and the like and cause the symptoms after examination and exclusion. Symptoms may persist or recur, with a course of disease of more than one month or cumulatively more than twelve weeks over the past twelve months. FD is one of the most common functional gastrointestinal diseases in clinical practice. Dyspepsia symptoms are more common and significantly reduce the quality of life of patients, most of whom have Functional Dyspepsia (FD). According to survey data, the dyspepsia symptoms of common people in western countries are close to 40%, and the life quality is remarkably reduced. A small part of people are caused by gastric ulcer and can be treated by radically treating helicobacter pylori, about 20 percent of symptomatic people belong to gastroesophageal reflux diseases and can be effectively treated by a proton pump inhibitor, but most of dyspepsia people belong to FD, and the treatment of FD is still challenging at present.
Acotiamide was first developed by Zeria new drugs Industrial Co., ltd, japan, and then introduced by Astellas pharmaceutical industry together with Zeria pharmaceutical industry in Japan. The acotiamide tablet is a novel muscarinic M1, M2 antagonist and an adenosine A1 receptor antagonist, is suitable for postprandial fullness, epigastric flatulence and early satiety caused by functional dyspepsia, and can promote gastric motility, improve gastric accommodation disorder and enhance fundus distension.
A plurality of clinical studies in Japan, such as breath test, ultrasonic test, TQT test and the like, prove that the product can obviously improve FD symptoms, has high safety, can still maintain the improvement effect after stopping taking the medicine, and is not easy to form drug resistance after a plurality of times of administration.
With the progress of the times and the improvement of the technological level, people have more sufficient understanding on the importance of scientific evaluation of the quality, safety, efficacy and the like of the medicine before the medicine is marketed, wherein the control of impurities contained in the medicine is closely related to the quality of the medicine. Impurities are often associated with drug safety and in a few cases also with efficacy. Therefore, controlling impurity levels is becoming increasingly appreciated by medical workers in the course of drug development and research. However, no report is found on the synthesis method of the acotiamide derivative.
Disclosure of Invention
The invention provides a preparation method of acotiamide derivatives, solves the defects of the prior art, and provides a synthesis method of novel drug molecule acotiamide derivatives, which has reasonable process design, high yield and convenient and controllable operation process.
In order to realize the purpose, the invention adopts the following technical scheme:
a preparation method of acotiamide derivatives comprises the following steps:
(1) Dissolving 2-aminothiazole-4-formic ether II in a polar aprotic solvent, adding 1.0 to 3.0 equivalent of alkali, and then cooling to 0 to 20 DEG CAdding 1.0 to 2.0 equivalent of R under the condition 1 X, stirring for 4 to 8 hours at room temperature to obtain a compound III;
(2) Dissolving the compound III obtained in the step (1) in an organic solution, adding 1.0 to 8.0 equivalent of inorganic base, stirring for 2 hours at the temperature of 20-80 ℃, and then acidifying, purifying and separating to obtain a compound IV;
(3) Dissolving the compound IV obtained in the step (2) in a nonpolar solvent, adding 1.0 to 2.0 equivalents of a condensation reagent in an ice bath, and reacting at room temperature for 18 to 20 hours to obtain a compound V;
(4) Dissolving the compound V obtained in the step (3) in an organic solvent, adding 1.0 to 2.0 equivalent of the compound VI and 1.0 to 3.0 equivalent of organic base, and reacting at 20-80 ℃ overnight to obtain a compound VII;
(5) Taking the compound VII obtained in the step (4) to obtain a compound VIII after deprotection in acid;
(6) Reacting the compound X with 1.0 to 2.0 equivalent of a condensing agent to obtain a compound IX;
(7) And (4) reacting the compound VIII obtained in the step (5) with 1.0 to 2.0 equivalents of a compound IX to obtain a compound I, namely the acotiamide derivative.
In the above step, the polar aprotic solvent in step (1) is dimethyl sulfoxide, dimethylformamide, dimethylacetamide, acetonitrile, pyridine or tetrahydrofuran, the base is sodium hydride, sodium hydroxide, potassium hydroxide, lithium bis (trimethylsilyl) amide, potassium, triethylamine or pyridine, and R is 1 X is triphenylchloromethane, benzyl chloride, benzyl bromide, DMT or vinyl bromide, and the formate in the 2-aminothiazole-4-formic ether is methyl ester, ethyl ester, benzyl ester or allyl ester; in the step (2), the alcohol is methanol, ethanol or isopropanol, and the inorganic base is sodium hydroxide, potassium hydroxide, lithium hydroxide or potassium carbonate; the organic solvent in the step (3) is dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile, dimethyl sulfoxide or N, N-dimethylformamide, and the condensing agent is DCC (dicyclohexylcarbodiimide), HOBT (1-hydroxybenzotriazole), EDCI (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride) or CDI (N, N' -carbonyldiimidazole); in step (4)The organic solvent is dimethylformamide, dimethyl sulfoxide or acetonitrile, and the organic base is triethylamine, trimethylamine, diisopropylethylamine, pyridine or heteronitrogen bicyclic ring; in the step (5), the acid is dilute hydrochloric acid, trifluoroacetic acid, formic acid, dilute phosphoric acid or dilute sulfuric acid; the condensing agent in the step (6) is DCC (dicyclohexylcarbodiimide), HOBT (1-hydroxybenzotriazole), EDCI (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride) or CDI (N, N' -carbonyldiimidazole).
Has the advantages that: the acotiamide derivative prepared by the invention provides an important basis for scientific evaluation of the quality, safety and efficiency of acotiamide, and the acotiamide derivative has good pharmacological activity, can be developed for treating functional dyspepsia, and has important application value.
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FIG. 1 is a flow chart of the preparation process of acotiamide derivatives of the present invention.
Detailed Description
The invention is described in detail below with reference to the following figures and specific examples:
example 1
As shown in fig. 1, the preparation method of acotiamide derivative specifically comprises the following steps:
(1) Dissolving 30.00g (174 mmol) of 2-aminothiazole-4-formic ether II in 300mL of dimethyl sulfoxide, adding 24mL of pyridine, adding 58.28g (209 mmol) of triphenylchloromethane at 20 ℃, stirring at room temperature for 8 hours, concentrating and filtering to obtain 70g of a compound III, wherein the yield is 100%;
(2) Taking 70g of compound III, suspending in 240 mL of ethanol, adding 160mL of 3N NaOH solution, reacting for 2 hours at room temperature, adding dilute hydrochloric acid to adjust the pH value to 4-5, performing suction filtration, and drying to obtain 63g of white solid compound IV, wherein the yield is 97%;
(3) Dissolving 63g (164 mmol) of compound IV in 600 mL of dichloromethane, adding 22.5g (164 mmol) of HOBT (HOBT) under the condition of ice bath, reacting at room temperature for 20 hours, performing suction filtration, washing with n-hexane after suction filtration, and performing vacuum drying to obtain 58g of yellow solid compound V, wherein the yield is 70.3%;
(4) Dissolving 58g (115 mmol) of the compound V in 500 mL of dimethylformamide, adding 19.8 g of the compound VI, adding 17.5g of triethylamine, reacting at 40 ℃ for 10 hours, concentrating, and purifying by column chromatography to obtain 50g of a light yellow solid compound VII with the yield of 80%;
(5) Dissolving 4.8g (8.9 mmol) of a compound VII in 24mL of trifluoroacetic acid for reacting for 2 hours at room temperature, adding water, adjusting the pH value with sodium bicarbonate, extracting with dichloromethane, and spin-drying to obtain 2.6g of a compound VIII with the yield of 99.9%;
(6) Taking 5.0 g (23 mmol) of the compound X, dissolving in 50mL of dichloromethane, adding HOBT3.21g (23 mmol) and EDCI4.8 g (23 mmol), reacting for 2h at room temperature, filtering and drying to obtain about 6.2g of a white solid compound IX, wherein the yield is 79.7%;
(7) Dissolving 2.91g (9 mmol) of compound VIII and 4.83g (14 mmol) of compound IX in dimethylformamide, adding 1.48g of triethylamine, reacting at 70 ℃ for two days, concentrating, recrystallizing with methanol to obtain 3g of white-like solid compound I (98.83% HPLC), i.e. acotiamide derivative, of which the chemical name is ethyl 2- (2, 4, 5-trimethoxybenzamido) thiazole-4-formamido) thiazole-4-carboxylic ester, the molecular weight is 492.52, and the molecular formula is C 20 H 20 N 4 O 7 S 2 The yield is 62.5 percent, 1 H NMR (400 MHz, DMSO-d6): δ 12.4（s, 1H）, δ 11.53 (s, 1H), δ 8.34 (s, 1H), δ 8.13 (s, 1H), δ 7.49 (s, 1H), δ 6.89 (s, 1H), δ 4.31 (q, 2H), δ 4.08 (s, 3H),δ 3.93 (s, 3H), δ 3.79 (s, 3H),δ 1.31 (t, 3H) . MS:493.1[M-H] + ，515.1[M-Na] + 。
example 2
As shown in fig. 1, the preparation method of acotiamide derivatives specifically comprises the following steps:
(1) Dissolving 3.00g (17.4 mmol) of 2-aminothiazole-4-formic ether II in 30mL of dimethyl sulfoxide, adding 3mL of pyridine, adding 5.8g (20.9 mmol) of triphenylchloromethane at 20 ℃, stirring at room temperature for 8 hours, concentrating and filtering to obtain 6g of a compound III, wherein the yield is 85.7%;
(2) Suspending a compound III (7 g, 17 mmol) in ethanol (24 mL), adding 16mL of 3N NaOH solution, reacting at room temperature for 2 hours, adding dilute hydrochloric acid to adjust the pH value to 4-5, performing suction filtration, and drying to obtain 6g of a white solid compound IV with the yield of 93%;
(3) Dissolving 6g (16 mmol) of compound IV in 60mL of dichloromethane, adding 2.3 g (16 mmol) of HOBT (N-hydroxyben-ethyl-N-hydroxyben-ethyl) under the ice bath condition, reacting at room temperature for 20 hours, performing suction filtration, washing with n-hexane after suction filtration, and performing vacuum drying to obtain 6g of yellow solid compound V, wherein the yield is 72%;
(4) Dissolving 20g (40 mmol) of a compound V in 40 mL of dimethylformamide, adding 7 g of a compound VI, adding 8g of triethylamine, reacting at 40 ℃ for 10 hours, concentrating, and purifying by column chromatography to obtain 15g of a light yellow solid compound VII with the yield of 72%;
(5) Dissolving VII4.8g (8.9 mmol) of compound in 24mL of trifluoroacetic acid, reacting for 2h at room temperature, adding water, adjusting the pH value with sodium bicarbonate, extracting with dichloromethane, and spin-drying to obtain 2.5g of compound VIII with the yield of 94%;
(6) Taking 5.0 g (23 mmol) of the compound X, dissolving in 50mL of dichloromethane, adding HOAt3.21g (23 mmol) and EDCI4.8 g (23 mmol), reacting at room temperature for 4h, filtering and drying to obtain about 5g of a white solid compound IX, wherein the yield is 64%;
(7) Dissolving 2.91g (9 mmol) of compound VIII and 4.83g (14 mmol) of compound IX in dimethylformamide, adding 1.48g of triethylamine, reacting at 80 ℃ for two days, concentrating, and recrystallizing with methanol to obtain 3.5g of white-like solid compound I (98.83% HPLC), i.e. acotiamide derivative, with chemical name of ethyl 2- (2, 4, 5-trimethoxybenzamido) thiazole-4-formamido) thiazole-4-carboxylic ester, molecular weight of 492.52 and molecular formula C 20 H 20 N 4 O 7 S 2 The yield is 62.5 percent, 1 H NMR (400 MHz, DMSO-d6): δ 12.4（s, 1H）, δ 11.53 (s, 1H), δ 8.34 (s, 1H), δ 8.13 (s, 1H), δ 7.49 (s, 1H), δ 6.89 (s, 1H), δ 4.31 (q, 2H), δ 4.08 (s, 3H),δ 3.93 (s, 3H), δ 3.79 (s, 3H),δ 1.31 (t, 3H) . MS:493.1[M-H] + ，515.1[M-Na] + 。
example 3
As shown in fig. 1, the preparation method of acotiamide derivative specifically comprises the following steps:
(1) Dissolving 30.00g of 2-aminothiazole-4-formic ether II in 300mL of dimethylformamide, adding 24mL of triethylamine, adding 58.28g of benzyl chloride at 20 ℃, stirring for 8 hours at room temperature, concentrating and filtering to obtain 70g of a compound III, wherein the yield is 96%;
(2) Taking 70g of compound III, suspending in 240 mL of methanol, adding 160mL of KOH solution, reacting at room temperature for 2 hours, adding dilute hydrochloric acid to adjust the pH value to 4-5, performing suction filtration, and drying to obtain 63g of white solid compound IV, wherein the yield is 97%;
(3) Dissolving 63g of compound IV in 600 mL of tetrahydrofuran, adding 22.5g of EDCI under the ice bath condition, reacting for 20 hours at room temperature, performing suction filtration, washing with n-hexane after suction filtration, and performing vacuum drying to obtain 58g of yellow solid compound V, wherein the yield is 70.3%;
(4) Dissolving 58g (115 mmol) of the compound V in 500 mL of dimethyl sulfoxide, adding 19.8 g of the compound VI, adding 17.5g of diisopropylethylamine, reacting at 40 ℃ for 10 hours, concentrating, and purifying by column chromatography to obtain 50g of a light yellow solid compound VII with the yield of 80%;
(5) Dissolving 4.8g of a compound VII in 24mL of formic acid, reacting for 2 hours at room temperature, adding water, adjusting the pH value with sodium bicarbonate, extracting with dichloromethane, and spin-drying to obtain 2.6g of a compound VIII with the yield of 99.9%;
(6) Dissolving 5.0 g of the compound X in 50mL of dichloromethane, adding 3.21g of DCC3 and 4.8g of CDI, reacting at room temperature for 2 hours, filtering and drying to obtain about 6.2g of a white solid compound IX, wherein the yield is 79.7%;
(7) Dissolving VIII2.91g and IX 4.83g in dimethylformamide, adding triethylamine 1.48g, reacting at 70 deg.C for two days, concentrating, recrystallizing with methanol to obtain 3g white solid compound I (98.83% HPLC), i.e. acotiamide derivative, whose chemical name is ethyl 2- (2, 4, 5-trimethoxybenzamido) thiazole-4-carboxamido) thiazole-4-carboxylate, molecular weight is 492.52, and molecular formula is C 20 H 20 N 4 O 7 S 2 The yield is 62.5 percent, 1 H NMR (400 MHz, DMSO-d6): δ 12.4（s, 1H）, δ 11.53 (s, 1H), δ 8.34 (s, 1H), δ 8.13 (s, 1H), δ 7.49 (s, 1H), δ 6.89 (s, 1H), δ 4.31 (q, 2H), δ 4.08 (s, 3H),δ 3.93 (s, 3H), δ 3.79 (s, 3H),δ 1.31 (t, 3H) . MS:493.1[M-H] + ，515.1[M-Na] + 。
example 4
As shown in fig. 1, the preparation method of acotiamide derivative specifically comprises the following steps:
(1) Dissolving 10g of 2-aminothiazole-4-formic ether II in 100mL of acetonitrile, adding 10mL of lithium potassium bis (trimethylsilyl) amide, adding 20g of vinyl bromide at 20 ℃, stirring at room temperature for 8 hours, concentrating and filtering to obtain 23g of a compound III, wherein the yield is 96%;
(2) Taking 23g of a compound III, suspending the compound III in 100mL of isopropanol, adding 55mL of lithium hydroxide solution, reacting at room temperature for 2 hours, adding dilute hydrochloric acid to adjust the pH value to 4-5, performing suction filtration, and drying to obtain 20g of a white solid compound IV, wherein the yield is 95%;
(3) Dissolving 20g of compound IV in 200mL of dimethyl sulfoxide, adding 8g of DCC under the ice bath condition, reacting at room temperature for 20 hours, performing suction filtration, washing with n-hexane after suction filtration, and performing vacuum drying to obtain 16g of yellow solid compound V with the yield of 68%;
(4) Dissolving 16g of a compound V in 200mL of acetonitrile, adding 6.5 g of a compound VI, adding 6g of pyridine, reacting at 40 ℃ for 10 hours, concentrating, and purifying by column chromatography to obtain 16g of a light yellow solid compound VII with the yield of 79%;
(5) Dissolving 4.8g of a compound VII in 24mL of dilute hydrochloric acid, reacting for 2h at room temperature, adding water, adjusting the pH value with sodium bicarbonate, extracting with dichloromethane, and spin-drying to obtain 2.6g of a compound VIII with the yield of 99.9%;
(6) Dissolving 5.0 g of the compound X in 50mL of dichloromethane, adding 3.21g of DCC3 and 4.8g of CDI, reacting at room temperature for 2 hours, filtering and drying to obtain about 6.2g of a white solid compound IX, wherein the yield is 79.7%;
(7) The compound VIII2.91g and the compound IX 4.83g were dissolved in dimethylformamide, 1.48g of triethylamine was added, and after two days at 70 ℃, the reaction mixture was concentrated and recrystallized from methanol to obtain 3g of a white-like solid compound I (98.83% HPLC), i.e., acotiamide derivative.
Example 5
As shown in fig. 1, the preparation method of acotiamide derivative specifically comprises the following steps:
(1) Dissolving 10g of 2-aminothiazole-4-formic ether II in 100mL of tetrahydrofuran, adding 10mL of sodium hydride, adding 20g of DMT at 20 ℃, stirring at room temperature for 8 hours, concentrating and filtering to obtain 23g of a compound III, wherein the yield is 96%;
(2) Taking 23g of a compound III, suspending the compound III in 100mL of isopropanol, adding 55mL of potassium carbonate solution, reacting at room temperature for 2 hours, adding dilute hydrochloric acid to adjust the pH value to 4-5, performing suction filtration, and drying to obtain 20g of a white solid compound IV with the yield of 95%;
(3) Dissolving 20g of compound IV in 200mLN, N-dimethylformamide, adding 8g of CDI under ice bath condition, reacting at room temperature for 20 hours, performing suction filtration, washing with n-hexane after suction filtration, and performing vacuum drying to obtain 16g of yellow solid compound V, wherein the yield is 68%;
(4) Dissolving 16g of a compound V in 200mL of acetonitrile, adding 6.5 g of a compound VI, adding 6g of heteronitrogen bicyclic ring, reacting at 40 ℃ for 10 hours, concentrating, and purifying by column chromatography to obtain 16g of a light yellow solid compound VII with the yield of 79%;
(5) Dissolving 4.8g of a compound VII in 24mL of diluted phosphoric acid, reacting for 2h at room temperature, adding water, adjusting the pH value with sodium bicarbonate, extracting with dichloromethane, and spin-drying to obtain 2.6g of a compound VIII with the yield of 99.9%;
(6) Dissolving 5.0 g of the compound X in 50mL of dichloromethane, adding 3.21g of DCC3 and 4.8g of CDI, reacting at room temperature for 2 hours, filtering and drying to obtain about 6.2g of a white solid compound IX, wherein the yield is 79.7%;
(7) Compound viii2.91g and compound IX 4.83g were dissolved in dimethylformamide, 1.48g triethylamine was added, and after two days of reaction at 70 ℃, concentration was carried out, and recrystallization was carried out with methanol to obtain 3g of off-white solid compound I (98.83% HPLC), i.e., acotiamide derivative.
Example 6
As shown in fig. 1, the preparation method of acotiamide derivatives specifically comprises the following steps:
(1) Dissolving 15g of 2-aminothiazole-4-formic ether II in 150mL of pyridine, adding 15mL of sodium hydroxide, adding 15g of benzyl bromide at 20 ℃, stirring at room temperature for 8 hours, concentrating and filtering to obtain 16g of a compound III, wherein the yield is 94%;
(2) Taking 16g of a compound III, suspending the compound III in 80mL of ethanol, adding 45mL of potassium carbonate solution, reacting at room temperature for 2 hours, adding dilute hydrochloric acid to adjust the pH value to 4-5, performing suction filtration, and drying to obtain 15g of a white solid compound IV, wherein the yield is 95%;
(3) Dissolving 15g of compound IV in 150mL of dichloroethane, adding 6g of EDCI under the ice bath condition, reacting at room temperature for 20 hours, then carrying out suction filtration, washing with n-hexane after suction filtration, and carrying out vacuum drying to obtain 12g of yellow solid compound V, wherein the yield is 68%;
(4) Dissolving 12g of a compound V in 150mL of acetonitrile, adding 5.5 g of a compound VI, adding 6g of trimethylamine, reacting at 40 ℃ for 10 hours, concentrating, and purifying by column chromatography to obtain 16g of a light yellow solid compound VII with the yield of 79%;
(5) Dissolving 4.8g of a compound VII in 24mL of dilute sulfuric acid, reacting for 2 hours at room temperature, adding water, adjusting the pH value with sodium bicarbonate, extracting with dichloromethane, and spin-drying to obtain 2.6g of a compound VIII with the yield of 99.9%;
(6) Taking 5.0 g of the compound X, dissolving in 50mL of dichloromethane, adding DCC3.21g and CDI4.8 g, reacting at room temperature for 2 hours, filtering and drying to obtain about 6.2g of a white solid compound IX, wherein the yield is 79.7%;
(7) 2.6g of compound VIII2 and 6.2g of compound IX6 are dissolved in dimethylformamide, 2.48g of triethylamine is added, after reaction for two days at 70 ℃, concentration is carried out, and recrystallization is carried out with methanol, 3g of off-white solid compound I (98.83% HPLC), namely acotiamide derivative is obtained.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
1. A preparation method of acotiamide derivatives is characterized by comprising the following steps:
(1) Dissolving 2-aminothiazole-4-formic ether II in polar aprotic solvent, adding 1.0-3.0 equivalent of alkali,adding 1.0-2.0 equivalent of R at the temperature of 0-20 DEG C 1 X, stirring at room temperature for 4 to 8 hours to obtain a compound III
(2) Dissolving the compound III obtained in the step (1) in alcohol, adding 1.0-8.0 equivalent of inorganic base, stirring for 2h at 20-80 ℃, and then obtaining a compound IV through acidification, purification and separation
(3) Dissolving the compound IV obtained in the step (2) in a nonpolar solvent, adding 1.0-2.0 equivalent of a condensation reagent in ice bath, and reacting at room temperature for 18-20 hours to obtain a compound V
(4) Dissolving the compound V obtained in the step (3) in an organic solvent, adding 1.0-2.0 equivalent of the compound VI and 1.0-3.0 equivalent of organic base, and reacting at 20-80 ℃ overnight to obtain a compound VII
(5) Taking the compound VII obtained in the step (4) to obtain a compound VIII after deprotection under an acidic condition
(6) Reacting the compound X with 1.0-2.0 equivalent of condensing agent at room temperature to obtain a compound IX
(7) Dissolving the compound VIII obtained in the step (5) and 1.0-2.0 equivalent of the compound IX in dimethylformamide, adding triethylamine, and reacting for two days to obtain a compound I, namely the acotiamide derivative
2. The process for producing acotiamide derivative according to claim 1, wherein the polar aprotic solvent in step (1) is dimethyl sulfoxide, dimethylformamide, dimethylacetamide, acetonitrile, pyridine or tetrahydrofuran.
3. The process for producing acotiamide derivative according to claim 1, wherein the base in the step (1) is sodium hydride, sodium hydroxide, potassium hydroxide, lithium bistrimethylsilyl amide, lithium potassium bistrimethylsilyl amide, triethylamine or pyridine.
4. The process for producing acotiamide derivative according to claim 1, wherein R in the step (1) 1 X is triphenylchloromethane, benzyl chloride, benzyl bromide, DMT or vinyl bromide.
5. The process for producing acotiamide derivatives according to claim 1, wherein the formate in the 2-aminothiazole-4-carboxylic acid ester in the step (1) is methyl ester, ethyl ester, benzyl ester or allyl ester.
6. The process for producing acotiamide derivative according to claim 1, wherein the alcohol in the step (2) is methanol, ethanol or isopropanol, and the inorganic base is sodium hydroxide, potassium hydroxide, lithium hydroxide or potassium carbonate.
7. The process for producing acotiamide derivative according to claim 1, wherein the organic solvent in the step (3) is dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile, dimethyl sulfoxide or N, N-dimethylformamide.
8. The process for producing acotiamide derivative according to claim 1, wherein the condensing agent in the step (3) and the step (6) is DCC, HOBT, EDCI or CDI.
9. The process for producing acotiamide derivatives according to claim 1, wherein the organic solvent in the step (4) is dimethylformamide, dimethylsulfoxide or acetonitrile; the organic base is triethylamine, trimethylamine, diisopropylethylamine, pyridine or azabicyclo.
10. The process for producing acotiamide derivative according to claim 1, wherein the acid in the step (5) is dilute hydrochloric acid, trifluoroacetic acid, formic acid, dilute phosphoric acid or dilute sulfuric acid.
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| CN1184471A (en) * | 1995-05-18 | 1998-06-10 | 泽里新药工业株式会社 | Aminothiazole derivatives, drug containing the same and intermediate in the production of the compounds |
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