CN113372290A - Synthetic method of drug Tafamidis - Google Patents
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- CN113372290A CN113372290A CN202110788042.6A CN202110788042A CN113372290A CN 113372290 A CN113372290 A CN 113372290A CN 202110788042 A CN202110788042 A CN 202110788042A CN 113372290 A CN113372290 A CN 113372290A
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Abstract
A synthetic method of a drug Tafamidis is provided, which takes 3-hydroxy-4-aminobenzoic acid as raw material and prepares the drug Tafamidis through esterification, amidation, cyclization and hydrolysis reaction. The method utilizes concentrated sulfuric acid and methanol to replace expensive and dangerous trimethyl silicon diazomethane to carry out methylation reaction of carboxyl; in the cyclization reaction, the dosage of the p-toluenesulfonic acid is obviously reduced; simplifies the post-reaction treatment, does not need column chromatography to purify the product in each step, obviously improves the total yield of the reaction, and is more suitable for industrial production.
Description
Technical Field
The invention belongs to the field of organic synthesis and pharmacy, and particularly relates to a synthesis method of a medicament Tafamidis.
Background
Rare diseases are also called orphan diseases, and refer to diseases with extremely low incidence rate. According to the specific conditions of the country, the countries in the world have certain differences of the identification standards of the rare diseases, China has no official standard of the rare diseases, and experts consider that the diseases with the neonatal morbidity of one ten thousandth (0.1 per thousand) or the morbidity of 50 ten thousandth (0.002 per thousand) are identified as the rare diseases, and divide the diseases into four major classes of 43 kinds, and the estimated 1000-2000 ten thousand cases exist. Transthyretin-related familial amyloidosis-polyneuropathy (TTR-FAP) is a maliciously progressing lethal chromosomal dominant hereditary rare disease first discovered in 1952 by the portentomologist Andrade. The pathogenesis of the disease is that transthyretin amyloid is abnormally deposited in tissues due to TTR gene mutation, the clinical characteristics are that progressive peripheral nerve and autonomic neuropathy and amyloid deposition of visceral organs in different degrees are taken as the characteristic, other visceral organ dysfunction such as amyloid cardiomyopathy (TTR-CM) and (or) kidney disease is often accompanied, patients generally die 7-12 years after the disease, and the prognosis is very poor. The drug Tafamidis is the only drug on the market at present for treating TTR-FAP/CM, and can effectively delay the development of nervous system symptoms of patients, thereby controlling the state of illness and improving the quality of life. The structural formula of the drug Tafamidis is shown as the following chart:
the currently reported methods for synthesizing Tafamidis, a drug, mainly include (1) the original route of the drug (Kelly j.w.;et alAngew. Chem. Int. Edit.2003, 42, 2758；Kelly J.W.; et al WO 2004056315 et al) as shown in the following figures, but this method has the following disadvantages: the reaction requires Trimethylsilyldiazomethane (TMSCHN)2) The reagent is expensive and has potential safety hazard; ② total production of reactionThe rate is only 10%, and the yield is low; ③ when preparing the intermediate 5, the product is purified by column chromatography, which limits the application of the intermediate in industrialization.
(2) Itami et al reported the synthesis of the drug Tafamidis (Itami, k.; et alChem. Eur. J. 2011, 1710113) as shown in the following figure, but this method has the following disadvantages: firstly, a potentially dangerous pyridine hydrogen fluoride solution needs to be applied; secondly, metal nickel is used as a catalyst, so that heavy metal residues can be caused; and thirdly, the multi-step reaction in the route needs to purify the product by column chromatography, so that the application of the product in industrialization is limited.
(3) Su et al reported the use of a palladium-catalyzed C-C coupling reaction as a key step to prepare a precursor of the drug Tafamidis (Su, W.; et al Chem. Commun.2012, 488964) as shown in the following figure, but this method has the following disadvantages: firstly, noble metal palladium is needed to be applied; ② the use of metallic palladium and copper as catalyst may lead to metallic residues and yield of only 43%; ③ the problem of regioselectivity, and the by-product 12 is difficult to separate from the Tafamidis precursor 5; and fourthly, the reaction needs to be separated and purified by column chromatography, so that the application of the reaction in industrialization is limited.
(4) Kumar et al reported the synthesis of precursors of Tafamidis using a copper-catalyzed direct C-H bond arylation reaction as a key step (Kumar, d.;et al Org Biomol Chem.2014, 126340) as shown in the following figure, but this method has the following disadvantages: diaryl iodides are expensive; ②The use of copper as a catalyst may result in metal residue; thirdly, the reaction needs to be separated and purified by column chromatography, so that the application of the reaction in industrialization is limited.
(5) Ji et al reported amidoxime synthesis of a benzoxazole ring under iodine stimulation as a key step to the synthesis of precursors of Tafamidis (Ji, m.; et al Eur. J. Org. Chem.2019, 7506.) as shown in the following figure, but the method has the following disadvantages: the synthesis yields of amidoxime 16 and Tafamidis precursor 17 are only 51% and 46%, respectively, and the yields are low; ② the reaction needs to be separated and purified by column chromatography, which limits the application of the reaction in industrialization.
(5) Karumanchi et al reported the synthesis of Tafamidis from 3-hydroxy-4-nitrobenzoic acid by esterification, reduction and cyclization (Karumanchi, k.;et al J. Chem. Sci. 2021,13348) as shown in the following figure, but this method has the following disadvantages: firstly, metal zinc is used as a reducing agent, which can cause metal residue; ② the total yield of the reaction is 44 percent, and the yield is lower; thirdly, 7 times of equivalent of metal zinc is needed as a reducing agent, so that the economy is poor; metal zinc and methanesulfonic acid are used as reducing agents, a large amount of muddy zinc salt is generated after the reaction is finished, severe environmental pollution is caused, and meanwhile, difficulty is brought to cleaning of instruments and pipelines, and the application of the zinc salt in industrialization is limited.
(6) Tafamidis (Tan beauty et al, 2018, CN: 108484517) is synthesized by a method for synthesizing benzoxazoles disclosed by Tan beauty et al, as shown in the following figure, but the method has the following defects: the raw material compound 20 is expensive; secondly, although the patent does not disclose the yield of the Tafamidis synthesized by the method, the yield of other analogues disclosed by the patent is 48% -52%, and the method is supposed to have low yield of the Tafamidis synthesized by the method; ③ from other disclosed similar examples, it can be known that the method needs to separate and purify the product by column chromatography, thus limiting the application in industrialization.
Therefore, a new method for synthesizing the drug Tafamidis, which has the advantages of cheap and easily available raw materials, no metal catalysis, less environmental pollution, simple product separation and purification and suitability for industrial production, is needed to be developed.
Disclosure of Invention
The invention aims to solve the technical problems that the synthesis route of the method is simple, the raw materials are cheap and easy to obtain, products in all reaction steps do not need column chromatography separation and purification, the total yield is obviously improved, the industrial production is easy to realize, and in addition, metal catalysts such as palladium, copper and the like do not need to be added in the synthesis reaction, so that possible metal residues are avoided.
In order to solve the technical problems, the invention adopts the following technical scheme:
a method for synthesizing a medicament Tafamidis, which comprises the following steps:
the method comprises the following steps: compound 1 the carboxyl group in the structure is converted to an ester group by methods known in the art to give compounds of formula I, including but not limited to the following reactions: reacting with alcohol under the catalysis of DCC and DMAP, reacting with alcohol under the catalysis of sulfuric acid or thionyl chloride or the like, or reacting with alcohol under the catalysis of anhydride and alkali; the reaction is carried out in a solvent, wherein the solvent is one or a mixed solvent of two or more of methanol, ethanol, propanol, butanol, dichloromethane, trichloromethane, carbon tetrachloride, ethyl acetate, benzene, toluene, xylene, trimethylbenzene, diethyl ether, tetrahydrofuran, 1, 2-dichloroethane, 1, 4-dioxane, dimethyl sulfoxide, N-dimethylformamide, acetonitrile and water; the reaction temperature is-40 ℃ to 150 ℃; the reaction time is 5 minutes to 120 hours; the chemical formula is as follows:
step two: carrying out amidation reaction on the compound of the formula I and a compound of a formula II to obtain a compound of a formula III, wherein the compound of the formula II is 3, 5-dichlorobenzoic acid, 3, 5-dichlorobenzoyl chloride, 3, 5-dichlorobenzoyl bromide, 3, 5-dichlorobenzoic anhydride, active 3, 5-dichlorobenzoic ester or active 3, 5-dichlorobenzamide; the dosage of the compound of the formula II is 0.5-5 times of equivalent; the reaction is carried out in a solvent, wherein the reaction solvent is one or a mixed solvent of two or more of methanol, ethanol, propanol, butanol, dichloromethane, trichloromethane, carbon tetrachloride, ethyl acetate, benzene, toluene, xylene, trimethylbenzene, diethyl ether, tetrahydrofuran, 1, 2-dichloroethane, 1, 4-dioxane, dimethyl sulfoxide, N-dimethylformamide, acetonitrile and water; the reaction is carried out under the action of a base, wherein the base is lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, lithium methoxide, sodium methoxide, lithium ethoxide, sodium tert-butoxide, potassium tert-butoxide, pyridine, triethylamine, diisopropylethylamine, triethylenediamine (DABCO), 1, 8-diazabicycloundece-7-ene (DBU), 1, 5-diazabicyclo [4.3.0] -5-nonene (DBN), tetramethylethylenediamine, 4-dimethylaminopyridine or pyridine, N-methylmorpholine; the dosage of the alkali is 1 to 20 times of equivalent; the reaction temperature is-40 ℃ to 150 ℃; the reaction time is 5 minutes to 120 hours; the chemical formula is as follows:
step three: the compound of formula III is reacted to form a compound of formula IV catalyzed by a protic or lewis acid, including but not limited to the following: p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, sulfuric acid, hydrochloric acid, phosphoric acid, and the like, lewis acids include, but are not limited to, the following compounds: boron trifluoride, zinc chloride, ferric chloride, aluminum chloride, etc.; the dosage of the protonic acid or the Lewis acid is 0.1 to 5.0 times of equivalent; the reaction is carried out in a reaction solvent, wherein the reaction solvent is one or a mixed solvent of two or more of methanol, ethanol, propanol, butanol, dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, benzene, toluene, xylene, trimethylbenzene, diethyl ether, tetrahydrofuran, 1, 2-dichloroethane, 1, 4-dioxane, dimethyl sulfoxide, N-dimethylformamide, acetonitrile and water; the reaction temperature is-40 ℃ to 150 ℃, and the reaction time is 5 minutes to 120 hours; the chemical formula is as follows:
step four: the compound of formula IV is hydrolyzed under basic or acidic conditions to form the drug Tafamidis, the base being an inorganic or organic base, including but not limited to the following compounds: lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, lithium methoxide, sodium methoxide, lithium ethoxide, sodium tert-butoxide, potassium tert-butoxide, pyridine, triethylamine, diisopropylethylamine, triethylenediamine (DABCO), 1, 8-diazabicycloundecen-7-ene (DBU), 1, 5-diazabicyclo [4.3.0] -5-nonene (DBN), tetramethylethylenediamine, 4-dimethylaminopyridine, pyridine, N-methylmorpholine; the acid is an inorganic or organic acid, including but not limited to the following compounds: p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, sulfuric acid, hydrochloric acid, phosphoric acid, boron trifluoride; the dosage of the alkali or the acid is 1 to 10 times of equivalent; the reaction is carried out in a reaction solvent, wherein the reaction solvent is one or a mixed solvent of two or more of methanol, ethanol, propanol, butanol, dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, benzene, toluene, xylene, trimethylbenzene, diethyl ether, tetrahydrofuran, 1, 2-dichloroethane, 1, 4-dioxane, dimethyl sulfoxide, N-dimethylformamide, acetonitrile and water; the reaction temperature is-40 ℃ to 100 ℃; the reaction time is 5 minutes to 120 hours; the chemical formula is as follows:
r in the compounds of formula (I), (III) and (IV)1Is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, aryl, or heteroaryl;
r in the compound of formula (II)2Is hydroxy, halogen, OR3、NR4R5Wherein R is3、R4、R5Each independently is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, aryl, or heteroaryl.
The first step is a functional group conversion reaction for converting carboxyl into ester group, and is preferably reacted with alcohol under the catalysis of sulfuric acid or thionyl chloride.
The reaction solvent of the step one is preferably methanol; the reaction temperature is preferably 50 ℃ to 90 ℃; the reaction time is preferably 2 hours to 8 hours.
The compound of formula II of step two is preferably 3, 5-dichlorobenzoyl chloride, i.e. R2Is a chlorine atom; the amount of the compound of the formula II used is preferably 1 to 1.5 equivalents.
The reaction solvent of the second step is preferably tetrahydrofuran; the base required for the reaction is preferably pyridine or triethylamine; the amount of the base used is preferably 2 to 5 times equivalent; the reaction temperature is preferably 50 ℃ to 90 ℃; the reaction time is preferably 2 hours to 8 hours.
The protonic acid or Lewis acid required for the reaction in the third step is preferably p-toluenesulfonic acid; the protonic acid or Lewis acid is preferably used in an amount of 0.1 to 3 equivalents.
The reaction solvent in the third step is preferably toluene or xylene; the reaction temperature is preferably 80 ℃ to 120 ℃ and the reaction time is preferably 2 hours to 8 hours.
The alkali or acid required by the reaction of the step four is preferably lithium hydroxide; the amount of the base or acid used is preferably 2 to 5 times equivalent.
The reaction solvent of the step four is preferably tetrahydrofuran: methanol: water = 3: 1: 1, a mixed solvent; the reaction temperature is preferably 10 ℃ to 50 ℃; the reaction time is preferably 2 hours to 8 hours.
The starting materials used in the process of the present invention may be purchased commercially or prepared according to conventional chemical synthesis methods in the art.
Compared with the prior art, the invention has the following advantages: (1) the 3-hydroxy-4-aminobenzoic acid is esterified firstly, so that the yield of each step in the synthetic route is almost improved to be quantitative, the post-reaction treatment is simplified, and the product is not required to be separated and purified by column chromatography; (2) in the esterification reaction of 3-hydroxy-4-aminobenzoic acid, the esterification reaction is carried out in a methanol solvent under the catalysis of concentrated sulfuric acid, so that compared with the esterification reaction carried out by trimethyl silicon diazomethane in the original research route, the esterification reaction is more economical, safer and more suitable for industrial production; (3) in the third reaction step, the preferable technical scheme of the invention can obtain the product with almost quantitative yield only by using 0.2 equivalent of p-toluenesulfonic acid for catalysis, while the original research route needs 2 equivalents of p-toluenesulfonic acid; (4) in the reaction step 4, a preferred technical scheme of the invention can obtain the product with almost quantitative yield only by using 2 equivalents of lithium hydroxide for catalysis, while the original research route needs to use 4 equivalents of lithium hydroxide for catalysis; (5) according to a preferable technical scheme, 3-hydroxy-4-aminobenzoic acid is used as a raw material, Tafamidis is synthesized by four-step reaction with the total yield of 94%, and the total yield of the four-step reaction in the original research route is only 10%.
Drawings
FIG. 1 is a drawing of a compound of formula Ia, prepared according to example 1 of the invention1H-NMR spectrum.
FIG. 2 shows the preparation of a compound of formula IIIa according to example 2 of the present invention1H-NMR spectrum.
FIG. 3 is a drawing of a compound of formula IVa prepared according to example 3 of the invention1H-NMR spectrum.
FIG. 4 shows Tafamidis, a compound of formula 4, prepared in accordance with the present invention1H-NMR spectrum.
Detailed Description
The present invention will be further illustrated with reference to the following specific examples, but the present invention is not limited to the following examples. The method is a conventional method unless otherwise specified. The reactants are commercially available from the open literature unless otherwise specified. In an embodiment of the present invention, it is,1the H-NMR detector is an Agilent 400 MHz nuclear magnetic resonance spectrometer.
Example 1 preparation of a Compound of formula Ia
The reaction formula is as follows:
after magnetons, compound 1 (1.531 g, 10 mmol) and methanol (31 mL) were added in this order to a clean reaction flask, concentrated sulfuric acid (3.1 mL) was slowly dropped while stirring at room temperature, and after completion of the dropping, the temperature was raised to reflux to react. TLC shows that the raw materials are completely reacted (about 4 hours), after the reaction is cooled to room temperature, saturated sodium bicarbonate solution is added into the mixture until the pH value reaches alkalinity, the mixture is filtered by diatomite, the filtrate is transferred to a separating funnel by ethyl acetate after being concentrated, the separating funnel is respectively washed by water and saturated sodium chloride solution, the organic phase is dried by anhydrous sodium sulfate and then filtered, the filtrate is concentrated and dried in vacuum to obtain 1.572 g of brown solid with the yield of 94 percent,1H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 1H), 7.29 – 7.22 (m, 2H), 6.61 – 6.56 (m, 1H), 5.41 (s, 2H), 3.72 (s, 3H)。
example 2 preparation of a Compound of formula IIIa
The reaction formula is as follows:
to a clean reaction flask were added magnetons, the compound of formula Ia (0.836 g, 5 mmol), pyridine (1.187 g, 15 mmol) and tetrahydrofuran (74 mL) in that order, thenThe compound of formula IIa (1.047 g, 5 mmol) was added with stirring at room temperature and allowed to react at room temperature after the addition was complete. TLC shows that after the raw materials are reacted (about 6 hours), the reaction solution is directly concentrated, dissolved by ethyl acetate and transferred to a separating funnel, washed by saturated sodium bicarbonate, 10% hydrochloric acid and saturated sodium chloride respectively, an organic phase is dried by anhydrous sodium sulfate and filtered, the filtrate is concentrated and dried in vacuum to obtain 1.680 g of brown solid with the yield of 99%,1H NMR (400 MHz, DMSO-d6) δ 10.33 (brs, 1H), 9.88 (brs, 1H), 7.97 (d, J = 1.8 Hz, 2H), 7.89 – 7.83 (m, 2H), 7.53 (d, J = 1.7 Hz, 1H), 7.46 (dd, J = 8.3, 1.8 Hz, 1H), 3.83 (s, 3H)。
example 3 preparation of a Compound of formula IVa
The reaction formula is as follows:
a clean reaction flask was charged with magnetons, the compound of formula IIIa (0.340 g, 1 mmol), p-toluenesulfonic acid monohydrate (0.038 g, 0.2 mmol) and toluene (8 mL) in this order, and after the addition was complete, the reaction was warmed to reflux. TLC shows that after the raw materials are reacted completely (about 12 hours), 1 mol/L sodium hydroxide solution is added into the solution after the solution is cooled to room temperature until the pH value reaches alkalinity, then a proper amount of water and ethyl acetate are added into the solution, the solution is transferred to a separating funnel, after an organic phase is separated, the organic phase is washed by saturated sodium chloride, after the organic phase is dried by anhydrous sodium sulfate, the filtration is carried out, the filtrate is concentrated and dried in vacuum, and then 0.320 g of light pink solid is obtained, the yield is 99 percent,1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 8.14 (s, 2H), 8.11 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.54 (s, 1H), 3.98 (s, 3H)。
example 4 preparation of Tafamidis
The reaction formula is as follows:
to cleanThe reaction flask of (1) was charged with magneton, the compound of formula IVa (0.141 g, 0.44 mmol), lithium hydroxide (0.021 g, 0.88 mmol), tetrahydrofuran (3.9 mL), methanol (1.3 mL) and water (1.3 mL) in this order, and reacted at room temperature after the addition. TLC shows that after the raw materials are reacted (about 12 hours), 1 mol/L hydrochloric acid solution is added into the reaction liquid until the pH value reaches acidity, then the solvent is concentrated, water and ethyl acetate are added into the residue, the mixture is transferred into a separating funnel, after an organic phase is separated, the organic phase is washed by saturated sodium chloride, after the organic phase is dried by anhydrous sodium sulfate, the filtration is carried out, the filtrate is concentrated and dried in vacuum, 0.134 g of white solid is obtained, the yield is 99 percent,1H NMR (400 MHz, DMSO-d6) δ 13.30 (brs, 1H), 8.30 – 8.23 (m, 1H), 8.19 – 8.08 (m, 2H), 8.07 – 7.99 (m, 1H), 7.98 – 7.87 (m, 2H)。
Claims (9)
1. a method for synthesizing a medicament Tafamidis is characterized by comprising the following steps: the synthesis method comprises the following steps:
the method comprises the following steps: compound 1 the carboxyl group in the structure is converted to an ester group by methods known in the art to give compounds of formula I, including but not limited to the following reactions: reacting with alcohol under the catalysis of DCC and DMAP, reacting with alcohol under the catalysis of sulfuric acid or thionyl chloride or the like, or reacting with alcohol under the catalysis of anhydride and alkali; the reaction is carried out in a solvent, wherein the solvent is one or a mixed solvent of two or more of methanol, ethanol, propanol, butanol, dichloromethane, trichloromethane, carbon tetrachloride, ethyl acetate, benzene, toluene, xylene, trimethylbenzene, diethyl ether, tetrahydrofuran, 1, 2-dichloroethane, 1, 4-dioxane, dimethyl sulfoxide, N-dimethylformamide, acetonitrile and water; the reaction temperature is-40 ℃ to 150 ℃; the reaction time is 5 minutes to 120 hours; the chemical formula is as follows:
step two: carrying out amidation reaction on the compound of the formula I and a compound of a formula II to obtain a compound of a formula III, wherein the compound of the formula II is 3, 5-dichlorobenzoic acid, 3, 5-dichlorobenzoyl chloride, 3, 5-dichlorobenzoyl bromide, 3, 5-dichlorobenzoic anhydride, active 3, 5-dichlorobenzoic ester or active 3, 5-dichlorobenzamide; the dosage of the compound of the formula II is 0.5-5 times of equivalent; the reaction is carried out in a solvent, wherein the reaction solvent is one or a mixed solvent of two or more of methanol, ethanol, propanol, butanol, dichloromethane, trichloromethane, carbon tetrachloride, ethyl acetate, benzene, toluene, xylene, trimethylbenzene, diethyl ether, tetrahydrofuran, 1, 2-dichloroethane, 1, 4-dioxane, dimethyl sulfoxide, N-dimethylformamide, acetonitrile and water; the reaction is carried out under the action of a base, wherein the base is lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, lithium methoxide, sodium methoxide, lithium ethoxide, sodium tert-butoxide, potassium tert-butoxide, pyridine, triethylamine, diisopropylethylamine, triethylenediamine (DABCO), 1, 8-diazabicycloundece-7-ene (DBU), 1, 5-diazabicyclo [4.3.0] -5-nonene (DBN), tetramethylethylenediamine, 4-dimethylaminopyridine or pyridine, N-methylmorpholine; the dosage of the alkali is 1 to 20 times of equivalent; the reaction temperature is-40 ℃ to 150 ℃; the reaction time is 5 minutes to 120 hours; the chemical formula is as follows:
step three: the compound of formula III is reacted to form a compound of formula IV catalyzed by a protic or lewis acid, including but not limited to the following: p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, sulfuric acid, hydrochloric acid, phosphoric acid, and the like, lewis acids include, but are not limited to, the following compounds: boron trifluoride, zinc chloride, ferric chloride, aluminum chloride, etc.; the dosage of the protonic acid or the Lewis acid is 0.1 to 5.0 times of equivalent; the reaction is carried out in a reaction solvent, wherein the reaction solvent is one or a mixed solvent of two or more of methanol, ethanol, propanol, butanol, dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, benzene, toluene, xylene, trimethylbenzene, diethyl ether, tetrahydrofuran, 1, 2-dichloroethane, 1, 4-dioxane, dimethyl sulfoxide, N-dimethylformamide, acetonitrile and water; the reaction temperature is-40 ℃ to 150 ℃, and the reaction time is 5 minutes to 120 hours; the chemical formula is as follows:
step four: the compound of formula IV is hydrolyzed under basic or acidic conditions to form the drug Tafamidis, the base being an inorganic or organic base, including but not limited to the following compounds: lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, lithium methoxide, sodium methoxide, lithium ethoxide, sodium tert-butoxide, potassium tert-butoxide, pyridine, triethylamine, diisopropylethylamine, triethylenediamine (DABCO), 1, 8-diazabicycloundecen-7-ene (DBU), 1, 5-diazabicyclo [4.3.0] -5-nonene (DBN), tetramethylethylenediamine, 4-dimethylaminopyridine, pyridine, N-methylmorpholine; the acid is an inorganic or organic acid, including but not limited to the following compounds: p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, sulfuric acid, hydrochloric acid, phosphoric acid, boron trifluoride; the dosage of the alkali or the acid is 1 to 10 times of equivalent; the reaction is carried out in a reaction solvent, wherein the reaction solvent is one or a mixed solvent of two or more of methanol, ethanol, propanol, butanol, dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, benzene, toluene, xylene, trimethylbenzene, diethyl ether, tetrahydrofuran, 1, 2-dichloroethane, 1, 4-dioxane, dimethyl sulfoxide, N-dimethylformamide, acetonitrile and water; the reaction temperature is-40 ℃ to 100 ℃; the reaction time is 5 minutes to 120 hours; the chemical formula is as follows:
r in the compounds of formula (I), (III) and (IV)1Is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, aryl, or heteroaryl;
r in the compound of formula (II)2Is hydroxy, halogen, OR3、NR4R5Wherein R is3、R4、R5Each independently is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, aryl, or heteroaryl.
2. The method for synthesizing the drug Tafamidis according to claim 1, wherein: the first step is a functional group conversion reaction for converting carboxyl into ester group, and is preferably reacted with alcohol under the catalysis of sulfuric acid or thionyl chloride.
3. The method for synthesizing the drug Tafamidis according to claim 1, wherein: the reaction solvent of the step one is preferably methanol; the reaction temperature is preferably 50 ℃ to 90 ℃; the reaction time is preferably 2 hours to 8 hours.
4. The method for synthesizing the drug Tafamidis according to claim 1, wherein: the compound of formula II of step two is preferably 3, 5-dichlorobenzoyl chloride, i.e. R2Is a chlorine atom; the amount of the compound of the formula II used is preferably 1 to 1.5 equivalents.
5. The method for synthesizing the drug Tafamidis according to claim 1, wherein: the reaction solvent of the second step is preferably tetrahydrofuran; the base required for the reaction is preferably pyridine or triethylamine; the amount of the base used is preferably 2 to 5 times equivalent; the reaction temperature is preferably 50 ℃ to 90 ℃; the reaction time is preferably 2 hours to 8 hours.
6. The method for synthesizing the drug Tafamidis according to claim 1, wherein: the protonic acid or Lewis acid required for the reaction in the third step is preferably p-toluenesulfonic acid; the protonic acid or Lewis acid is preferably used in an amount of 0.1 to 3 equivalents.
7. The method for synthesizing the drug Tafamidis according to claim 1, wherein: the reaction solvent in the third step is preferably toluene or xylene; the reaction temperature is preferably 80 ℃ to 120 ℃ and the reaction time is preferably 2 hours to 8 hours.
8. The method for synthesizing the drug Tafamidis according to claim 1, wherein: the alkali or acid required by the reaction of the step four is preferably lithium hydroxide; the amount of the base or acid used is preferably 2 to 5 times equivalent.
9. The method for synthesizing the drug Tafamidis according to claim 1, wherein: the reaction solvent of the step four is preferably tetrahydrofuran: methanol: water = 3: 1: 1, a mixed solvent; the reaction temperature is preferably 10 ℃ to 50 ℃; the reaction time is preferably 2 hours to 8 hours.
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| CN113735792A (en) * | 2021-09-22 | 2021-12-03 | 上海新礼泰药业有限公司 | Preparation method of chlorphenamine and intermediate thereof |
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