CN113277993B - Synthesis method of Tafamidis and derivatives thereof - Google Patents
Synthesis method of Tafamidis and derivatives thereof Download PDFInfo
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- CN113277993B CN113277993B CN202110628076.9A CN202110628076A CN113277993B CN 113277993 B CN113277993 B CN 113277993B CN 202110628076 A CN202110628076 A CN 202110628076A CN 113277993 B CN113277993 B CN 113277993B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D263/57—Aryl or substituted aryl radicals
Abstract
The invention provides a synthesis method for preparing Tafamidis and derivatives thereof from 6-amino-m-cresol and aldehyde compounds under the action of sodium periodate and potassium permanganate. In the method, the use of an acylating reagent, namely dichlorobenzoyl chloride and an esterifying reagent, namely (trimethylsilyl) diazomethane, is avoided, and the problem of environmental hazard caused by acyl chloride, diazo reagents, strong acid and strong alkali additives and the like is solved; the reaction steps are few, and the total yield is high; methoxy, halogen, trifluoromethyl, etc. are well tolerated; iodate and manganese dioxide after the reaction are insoluble in the reaction solution, can be well recovered, greatly reduces pollution caused by a reaction system, provides a more economic and environment-friendly path for synthesizing Tafamidis and derivatives thereof, and has great application value.
Description
[ field of technology ]
The invention relates to the field of organic synthesis, in particular to a synthesis method of Tafamidis and derivatives thereof.
[ background Art ]
Tafamidis is the first FDA approved drug for the treatment of cardiomyopathy caused by transthyretin-mediated amyloidosis (ATTR-CM). The drug was filed by the fei company and approved for use in the united states in 2019. According to clinical trial evaluation, the medicine reduces the death risk of patients by 30 percent, and reduces the hospitalization rate of cardiovascular related diseases of medicine users by 32 percent. Related pharmacodynamics suggests that Tafamidis can bind to the thyroxine binding site of Thyroxine Transporter (TTR) tetramer and inhibit its dissociation into monomers, thereby preventing the TTR amyloid-generating cascade.
A representative synthetic procedure for Tafamidis is to acylate 4-amino-3-hydroxybenzoic acid with dichlorobenzoyl chloride, treat the resulting product with p-toluenesulfonic acid monohydrate, esterify the resulting residue with (trimethylsilyl) diazomethane, cyclize, and finally hydrolyze to yield Tafamidis. The process has the advantages of multiple reaction steps, low total yield, greatly improved cost of the method due to the required raw materials, strong acid and alkali, additives and the like which are not easy to obtain, and great pressure on the environment. [ reference: (a) Sancar, F.J.am.Med.assoc.2019,321,2274.321. (b) Muller, M.L.; butler, j.; heicker, b.eur.j.heart fail.2020,22,39 (c) Said, g.; grippon, s.; kirkpatrick, p.; nature Publishing Group Tafamidis.2012 (d) Corazza, A.; verona, g.; waudby, c.a.; mangione, p; bingham, r.; uings, i.; canetti, d.; nocerino, p.; taylor, g.w.; pepys, m.b.j.med.chem.2019,62,8274 (e) Zhang, y; ji, m.eur.j.org.chem.2019,2019,7506. (f) Kandula, m.2013.wo 2013168014. (g) Kandula, m.2015.us 20150126567. (h) Yuan, s.; yu, b.; liu, h. -m.eur.j.med.chem.2020,112667 ]
Aiming at the defects of the method, the development of an effective method for synthesizing Tafamidis and derivatives thereof by using simple raw materials and simple reaction conditions has great significance and great application value.
[ invention ]
The invention aims to develop a method for synthesizing Tafamidis and derivatives thereof with high conversion rate by taking 6-amino-m-cresol and aldehyde compounds as raw materials under the action of oxidizing agents sodium periodate and potassium permanganate.
The invention aims at realizing the following technical scheme:
a synthesis method of Tafamidis and derivatives thereof, wherein the preparation raw materials of the Tafamidis derivatives comprise: 6-amino-m-cresol, aldehyde compound, sodium periodate (NaIO) 4 ) Potassium permanganate.
The Tafamidis derivative has the following structural formula (I):
in the structural formula, R is substituent groups at any one or more positions on a benzene ring, and each R is independently selected from H, tertiary butyl, methoxy, F, cl, br, I, trifluoromethyl, nitro and methyl formate.
In one embodiment, the aldehyde compound is selected from one of benzaldehyde, p-methoxybenzaldehyde, p-tert-butylbenzaldehyde, p-fluorobenzaldehyde, p-chlorobenzaldehyde, p-bromobenzaldehyde, p-iodobenzaldehyde, 3, 5-dichlorobenzaldehyde, p-trifluoromethylbenzaldehyde, p-nitrobenzaldehyde, and methyl p-formylbenzoate.
In one embodiment, a method for synthesizing Tafamidis and derivatives thereof is preferred, comprising the steps of:
(1) Taking 6-amino-m-cresol, aldehyde compound 1 and NaIO 4 And solvent are placed in a reaction vessel, mixed, heated and stirred for reaction, cooled to room temperature after the reaction is finished,with saturated Na 2 CO 3 Washing, extracting with ethyl acetate, concentrating under reduced pressure to remove solvent, drying, and separating crude product by column chromatography to obtain benzoxazole compound 2;
wherein the 6-amino-m-cresol, aldehyde compound and NaIO 4 The molar ratio of the components is 1 (1.8-2.2) to 1.8-2.2;
preferably, the 6-amino-m-cresol, aldehyde compound and NaIO 4 The molar ratio of the components is 1 (1.9-2.1) to 1.9-2.1;
more preferably, the 6-amino-m-cresol, aldehyde compound and NaIO 4 The molar ratio between the two is 1:2:2;
the solvent is at least one of N, N-dimethylformamide, 1, 2-dichloroethane, acetonitrile, chloroform and ethyl acetate;
the temperature of the reaction is 80-100 ℃;
preferably, the temperature of the reaction is 100 ℃;
the reaction time is 3-4h;
preferably, the reaction time is 3 hours;
the inert gas is any one or a combination of more of nitrogen, argon and helium;
(2) Collecting benzoxazole compound 2 and KMnO 4 And the solvent is placed in a reaction vessel, stirred, and then heated to boiling. Acidifying after the reaction is finished, extracting with ethyl acetate, concentrating under reduced pressure to remove a solvent, drying, and separating a crude product by column chromatography to obtain a Tafamidis derivative;
wherein the benzoxazole compound 2 and KMnO 4 The molar ratio of the two is 1 (4-6);
the solvent is a mixed solvent of pyridine and water;
the temperature of the reaction is 90-100 ℃;
the reaction time is 5-6h.
According to experimental study, the invention provides a synthesis method for preparing Tafamidis and derivatives thereof from 6-amino-m-cresol and aldehyde compounds under the action of sodium periodate and potassium permanganate. In the method, the use of an acylating reagent, namely dichlorobenzoyl chloride and an esterifying reagent, namely (trimethylsilyl) diazomethane, is avoided, and the problem of environmental hazard caused by acyl chloride, diazo reagents, strong acid and strong alkali additives and the like is solved; the reaction steps are few, and the total yield is high; methoxy, halogen, trifluoromethyl, etc. are well tolerated; iodate and manganese dioxide after the reaction are insoluble in the reaction solution, can be well recovered, greatly reduces pollution caused by a reaction system, provides a more economic and environment-friendly path for synthesizing Tafamidis and derivatives thereof, and has great application value.
[ brief description of the drawings ]
FIG. 1 is a reaction scheme for preparing Tafamidis and its derivatives.
[ detailed description ] of the invention
The synthesis method of the present invention will be further described with reference to the following synthesis examples, which should not be construed as limiting the scope of the invention.
A synthesis method of Tafamidis and derivatives thereof, wherein the preparation raw materials of the Tafamidis derivatives comprise: 6-amino-m-cresol, aldehyde compound, sodium periodate (NaIO) 4 ) Potassium permanganate.
In one embodiment, the Tafamidis derivative has the following structural formula (I):
in one embodiment, in the structural formula, R is a substituent at any one or more positions on the benzene ring, and each R is independently selected from H, t-butyl, methoxy, F, cl, br, I, trifluoromethyl, nitro, methyl formate.
In one embodiment, the aldehyde compound is selected from one of benzaldehyde, p-methoxybenzaldehyde, p-tert-butylbenzaldehyde, p-fluorobenzaldehyde, p-chlorobenzaldehyde, p-bromobenzaldehyde, p-iodobenzaldehyde, 3, 5-dichlorobenzaldehyde, p-trifluoromethylbenzaldehyde, p-nitrobenzaldehyde, and methyl p-formylbenzoate.
In one embodiment, a method for synthesizing Tafamidis and derivatives thereof is preferred, comprising the steps of:
(1) Taking 6-amino-m-cresol, aldehyde compound 1 and NaIO 4 Placing the mixture and solvent in a reaction vessel, mixing, heating and stirring for reaction, cooling to room temperature after the reaction is finished, and using saturated Na 2 CO 3 Washing, extracting with ethyl acetate, concentrating under reduced pressure to remove solvent, drying, and separating crude product by column chromatography to obtain benzoxazole compound 2;
in one embodiment, the 6-amino-m-cresol, aldehyde compound and NaIO 4 The molar ratio of the components is 1 (1.8-2.2) to 1.8-2.2;
in one embodiment, preferably, the 6-amino-m-cresol, aldehyde compound and NaIO 4 The molar ratio of the components is 1 (1.9-2.1) to 1.9-2.1;
in one embodiment, more preferably, the 6-amino-m-cresol, aldehyde compound and NaIO 4 The molar ratio between the two is 1:2:2;
in one embodiment, the solvent is at least one of N, N-dimethylformamide, 1, 2-dichloroethane, acetonitrile, chloroform, ethyl acetate;
in one embodiment, the temperature of the reaction is 80-100 ℃;
in one embodiment, preferably, the temperature of the reaction is 100 ℃;
in one embodiment, the reaction time is 3 to 4 hours;
in one embodiment, preferably, the reaction time is 3 hours;
in one embodiment, the inert gas is any one or a combination of nitrogen, argon and helium;
(2) Collecting benzoxazole compound 2 and KMnO 4 And the solvent is placed in a reaction vessel, stirred, and then heated to boiling. Acidifying after the reaction is finished, extracting with ethyl acetate, concentrating under reduced pressure to remove a solvent, drying, and separating a crude product by column chromatography to obtain a Tafamidis derivative;
in one embodiment, the benzoxazole compound 2 and KMnO 4 The molar ratio of the two is 1 (4-6);
in one embodiment, the solvent is a mixed solvent of pyridine and water;
in one embodiment, the temperature of the reaction is from 90 to 100 ℃;
in one embodiment, the reaction time is from 5 to 6 hours.
According to experimental study, the invention provides a synthesis method for preparing Tafamidis and derivatives thereof from 6-amino-m-cresol and aldehyde compounds under the action of sodium periodate and potassium permanganate. The method mainly avoids the use of strong acid, strong alkali and additives, and is specifically expressed as follows: (1) In the method, 6-amino-m-cresol and aldehyde compounds which are cheap and easy to obtain are taken as raw materials and are processed by NaIO 4 The method for synthesizing Tafamidis and derivatives thereof by two steps of oxidative condensation and potassium permanganate oxidation and methyl is realized, methoxy, halogen, trifluoromethyl and the like can be well tolerated, (2) the use of acylating agent dichlorobenzoyl chloride and esterifying agent (trimethylsilyl) diazomethane is avoided, (3) the problem of environmental hazard caused by acyl chloride, diazo agent, strong acid and alkali additive and the like is solvedThe iodate and manganese dioxide after the reaction are insoluble in the reaction solution, can be well recovered, greatly reduces the pollution caused by a reaction system, and provides a more economic and environment-friendly path for synthesizing the novel Tafamidis derivative.
The following is a specific synthesis example.
As shown in fig. 1:
synthesis example 1
Synthesis of Tafamidis
(1) Preparation of 2- (3, 5-dichlorophenyl) -6-methylbenzo [ d ]]Oxazole: 1mmol of 6-amino-m-cresol, 2mmol of 3, 5-dichlorobenzaldehyde and 2mmol of NaIO are introduced into a reactor 4 10mL EA. Continuously stirring for 5 hours at 100 ℃ under nitrogen atmosphere, stopping the reaction, cooling to room temperature, washing with saturated NaCl, extracting with ethyl acetate, concentrating under reduced pressure to remove the solvent, drying, and separating the crude product by column chromatography to obtain the target product with the yield of 91%.
(2) Synthesis of Tafamidis: then 0.4mmol of 2- (3, 5-dichlorophenyl) -6-methylbenzo [ d ]]Oxazole and 6eq KMnO 4 To a mixed solution of pyridine (0.9 mL) and water (0.6 mL). The resulting solution was stirred at room temperature for 30 minutes and heated to boiling (about 100 ℃). After the reaction was completed, the pH was adjusted to ph=2-3 using 1M HCl solution, and then the product was extracted twice with ethyl acetate and water. The organic layer was washed with 1M HCl solution to remove excess pyridine. Then using anhydrous magnesium sulfate (MgSO 4 ) The organic layer was dried and the solvent was distilled off under reduced pressure. The crude product was purified by column chromatography on silica gel using petroleum ether/ethyl acetate to give the corresponding Tafamidis in 65% yield.
Synthesis example 2
Synthesis of 2- (4-methoxyphenyl) benzo [ d ] oxazole-6-carboxylic acid
(1) Preparation of 6-methyl-2- (4-methoxyphenyl) benzo [ d ]]Oxazole: 1mmol of 6-amino-m-cresol, 2mmol of 4-methoxybenzaldehyde and 2mmol of NaIO are added into a reactor 4 10mL EA. Stirring continuously at 100deg.C under nitrogen atmosphere for 5 hr, stopping reaction, cooling to room temperature, washing with saturated NaCl, extracting with ethyl acetate, and concentrating under reduced pressure to remove solventDrying, and separating the crude product by column chromatography to obtain the target product with a yield of 87%.
(2) Synthesis of 2- (4-methoxyphenyl) benzo [ d ]]Oxazole-6-carboxylic acid: then 0.4mmol of 6-methyl-2- (4-methoxyphenyl) benzo [ d ]]Oxazole and 6eq KMnO 4 To a mixed solution of pyridine (0.9 mL) and water (0.6 mL). The resulting solution was stirred at room temperature for 30 minutes and heated to boiling (about 100 ℃). After the reaction was completed, the pH was adjusted to ph=2-3 using 1M HCl solution, and then the product was extracted twice with ethyl acetate and water. The organic layer was washed with 1M HCl solution to remove excess pyridine. Then using anhydrous magnesium sulfate (MgSO 4 ) The organic layer was dried and the solvent was distilled off under reduced pressure. Purifying the crude product by petroleum ether/ethyl acetate column chromatography on silica gel to obtain the corresponding 2- (4-methoxyphenyl) benzo [ d ]]Oxazole-6-carboxylic acid was obtained in 65% yield.
Synthesis example 3
Synthesis of 2- (4-bromophenyl) benzo [ d ] oxazole-6-carboxylic acid
(1) Preparation of 6-methyl-2- (4-bromophenyl) benzo [ d ]]Oxazole: 1mmol of 6-amino-m-cresol, 2mmol of 4-bromobenzaldehyde and 2mmol of NaIO are introduced into a reactor 4 10mL EA. Continuously stirring for 5 hours at 100 ℃ under nitrogen atmosphere, stopping the reaction, cooling to room temperature, washing with saturated NaCl, extracting with ethyl acetate, concentrating under reduced pressure to remove the solvent, drying, and separating the crude product by column chromatography to obtain the target product with the yield of 80%.
(2) Synthesis of 2- (4-bromophenyl) benzo [ d ]]Oxazole-6-carboxylic acid: then 0.4mmol of 6-methyl-2- (4-bromophenyl) benzo [ d ]]Oxazole and 6eq KMnO 4 To a mixed solution of pyridine (0.9 mL) and water (0.6 mL). The resulting solution was stirred at room temperature for 30 minutes and heated to boiling (about 100 ℃). After the reaction was completed, the pH was adjusted to ph=2-3 using 1M HCl solution, and then the product was extracted twice with ethyl acetate and water. The organic layer was washed with 1M HCl solution to remove excess pyridine. Then using anhydrous magnesium sulfate (MgSO 4 ) The organic layer was dried and the solvent was distilled off under reduced pressure. Purifying the crude product by petroleum ether/ethyl acetate column chromatography on silica gel to obtain the corresponding 2- (4-bromophenyl) benzo [ d ]]Oxazole-6-carboxylic acid in 5 yield6％。
Claims (10)
1. The synthesis method of Tafamidis and derivatives thereof is characterized in that the preparation raw materials of the Tafamidis and derivatives thereof comprise: 6-amino-m-cresol, aldehyde compound, sodium periodate and potassium permanganate, wherein the Tafamidis derivative has the following structural formula I:
；
comprises the following steps:
(1) Placing 6-amino-m-cresol 1, an aldehyde compound, sodium periodate and a solvent in a reaction container, mixing under the atmosphere of inert gas, heating and stirring for reaction to obtain a benzoxazole compound 2; the reaction formula is as follows:
；
(2) Putting the benzoxazole compound 2, potassium permanganate and a solvent into a reaction vessel, stirring, heating, and obtaining a Tafamidis derivative after the reaction is completed; the reaction formula is as follows:
；
in the structural formula, R is substituent at any one or more positions on a benzene ring, and each R is independently selected from H, tertiary butyl, methoxy, F, cl, br, I, trifluoromethyl, nitro and methyl formate.
2. The method for synthesizing Tafamidis and derivatives thereof according to claim 1, wherein the aldehyde compound is selected from one of benzaldehyde, p-tert-butylbenzaldehyde, p-methoxybenzaldehyde, p-fluorobenzaldehyde, p-chlorobenzaldehyde, p-bromobenzaldehyde, p-iodobenzaldehyde, 3, 5-dichlorobenzaldehyde, p-trifluoromethyl benzaldehyde, p-nitrobenzaldehyde and methyl p-formylbenzoate.
3. The method for synthesizing Tafamidis and derivatives thereof according to claim 1, comprising the steps of: (1) Placing 6-amino-m-cresol 1, aldehyde compound, sodium periodate and solvent in a reaction vessel, mixing under inert gas atmosphere, heating and stirring for reaction, cooling to room temperature after reaction, and using saturated Na 2 CO 3 Washing, extracting with ethyl acetate, concentrating under reduced pressure to remove solvent, drying, and separating crude product by column chromatography to obtain benzoxazole compound;
；
(2) Placing benzoxazole compound 2, potassium permanganate and a solvent into a reaction vessel, stirring, heating to boiling, acidifying after the reaction is completed, extracting with ethyl acetate, concentrating under reduced pressure to remove the solvent, drying, and separating a crude product by column chromatography to obtain a Tafamidis derivative;
。
4. the method for synthesizing Tafamidis and its derivatives according to claim 3, wherein the molar ratio of 6-amino-m-cresol, aldehyde compound and sodium periodate in the step (1) is 1 (1.8-2.2): 1.8-2.2.
5. The process for the synthesis of Tafamidis and its derivatives according to claim 3, wherein the solvent in step (1) isN,N-at least one of dimethylformamide, 1, 2-dichloroethane, acetonitrile, chloroform, ethyl acetate.
6. A process for the synthesis of Tafamidis and derivatives thereof according to claim 3, wherein the temperature of the reaction in step (1) is 100 ℃; the reaction time is 3-4 h.
7. The method of synthesizing Tafamidis and its derivatives according to claim 3, wherein the inert gas in step (1) is any one or more of nitrogen, argon and helium.
8. The method for synthesizing Tafamidis and its derivatives according to claim 3, wherein the molar ratio between the benzoxazole compound 2 and potassium permanganate in the step (2) is 1 (4-6).
9. The method for synthesizing Tafamidis and its derivatives according to claim 3, wherein the solvent in the step (2) is a mixed solvent of pyridine and water.
10. A process for the synthesis of Tafamidis and derivatives thereof according to claim 3, wherein the temperature of the reaction in step (2) is between 90 and 100 ℃; the reaction time is 5-6h.
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