CN111269192A - Synthesis method of 5-hydroxymethyl tetrazole and derivatives thereof - Google Patents
Synthesis method of 5-hydroxymethyl tetrazole and derivatives thereof Download PDFInfo
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- CN111269192A CN111269192A CN202010113533.6A CN202010113533A CN111269192A CN 111269192 A CN111269192 A CN 111269192A CN 202010113533 A CN202010113533 A CN 202010113533A CN 111269192 A CN111269192 A CN 111269192A
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- C07—ORGANIC CHEMISTRY
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- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
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Abstract
The invention provides a synthesis method of 5-hydroxymethyl tetrazole and derivatives thereof, which takes a carboxylic ester or aldehyde compound protected by Trt as a raw material to react to obtain the 5-hydroxymethyl tetrazole derivatives; the whole synthesis route has good step repeatability, mild operation conditions and high safety, and is favorable for large-scale production and industrialized popularization; the post-treatment does not produce toxic waste liquid containing cyanide ions, has no pollution to the environment, reduces the safety level and the production cost of production, is beneficial to the application of green and environment-friendly industrial production, and has wide application prospect.
Description
Technical Field
The invention relates to the technical field of organic compound synthesis, in particular to a method for synthesizing 5-hydroxymethyl tetrazole and derivatives thereof.
Background
The 5-hydroxymethyl tetrazole and the derivative thereof comprise hydroxyl and a plurality of nitrogen active sites, and are important intermediate compounds for synthesizing a plurality of novel pharmaceutical compounds containing nitrogen heteroatoms. The structure of the 5-hydroxymethyl tetrazole and the derivative thereof is shown as the following formula:
at present, the synthesis method of 5-hydroxymethyl tetrazole and derivatives thereof in the prior published documents is the cyclization reaction of tetrazole through sodium cyanide and sodium azide. Sodium cyanide and sodium azide are both highly toxic products, and sodium azide is also an explosive product, so the synthetic method of 5-hydroxymethyl tetrazole and derivatives thereof disclosed in the prior art has the defects of great danger, harsh reaction conditions, poor operation safety, generation of cyanide ion-containing waste liquid in post-treatment, no environmental protection and the like. In addition, the 5-hydroxymethyl tetrazole derivative prepared by carrying out the cyclization reaction of tetrazole with sodium cyanide and sodium azide is only suitable for synthesizing part of the 5-hydroxymethyl tetrazole derivative, and the universality is poor.
Therefore, the technical personnel in the field are dedicated to develop a synthesis method of 5-hydroxymethyl tetrazole and derivatives thereof, aiming at solving the defects of the synthesis method of the compounds in the prior art.
Disclosure of Invention
The invention aims to solve the technical problems that in the prior art, the synthesis method of the 5-hydroxymethyl tetrazole and the derivative thereof has harsh reaction conditions, high risk, high toxicity and explosive property and poor operation safety. Is not beneficial to the environmental protection.
In order to realize the purpose, the invention provides a method for synthesizing 5-hydroxymethyl tetrazole and derivatives thereof, the structures of the 5-hydroxymethyl tetrazole and the derivatives thereof are shown as the following formula A,
wherein R is1、R2Each independently selected from hydrogen, C1-C10 alkyl;
when R is1、R2When hydrogen is not used at the same time, the synthetic method route of the 5-hydroxymethyl tetrazole and the derivative thereof is shown as the following scheme I:
route I:
wherein R is3Selected from hydrogen, alkoxy;
the specific operation steps are as follows:
step 1, cooling a compound A-1 and a Grignard reagent A-2 in the presence of an organic solvent to perform nucleophilic addition reaction, and performing post-treatment to obtain a compound A-3;
step 2, adding an acid reagent and a mixed solvent into the compound A-3, reacting at normal temperature to remove the Trt protecting group, and performing post-treatment to obtain a target product 5-hydroxymethyl tetrazole and a derivative thereof (formula A);
when R is1、R2And when the hydrogen is simultaneously used, the synthetic method route of the 5-hydroxymethyl tetrazole and the derivative thereof is shown as a route II:
route II:
wherein R is3Selected from hydrogen, alkoxy;
the specific operation steps are as follows:
step 1, cooling the compound A-1 in the presence of a reducing agent and an organic solvent for reduction reaction, and carrying out post-treatment to obtain a compound A-3;
step 2, adding an acid reagent and a mixed solvent into the compound A-3, reacting at normal temperature to remove the Trt protecting group, and performing post-treatment to obtain a target product 5-hydroxymethyl tetrazole and a derivative thereof (formula A);
further, said R1、R2Each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, cyclobutyl, cyclopentyl, cyclohexyl;
further, said R3Selected from hydrogen, methoxy, ethoxy;
according to the synthesis method of the 5-hydroxymethyl tetrazole and the derivative thereof, the organic solvent is selected from tetrahydrofuran, dioxane and diethyl ether;
according to the synthesis method of the 5-hydroxymethyl tetrazole and the derivative thereof, the reducing agent is lithium aluminum hydride, sodium borohydride and lithium borohydride;
according to the synthesis method of the 5-hydroxymethyl tetrazole and the derivative thereof, the cooling temperature is 0-5 ℃;
according to the synthesis method of the 5-hydroxymethyl tetrazole and the derivative thereof, acid in the acid reagent is hydrochloric acid, sulfuric acid and nitric acid;
further, the acid reagent is an organic solvent solution with the acid molar concentration of 4 mol/L;
according to the synthesis method of the 5-hydroxymethyl tetrazole and the derivative thereof, the mixed solvent is a mixture of two of acetonitrile, diethyl ether, tetrahydrofuran, dioxane, dichloromethane, chloroform and carbon tetrachloride;
according to the synthesis method of the 5-hydroxymethyl tetrazole and the derivative thereof, the molar ratio of the compound A-1 to the Grignard reagent A-2 is 1: 1.5-1: 3;
according to the synthesis method of the 5-hydroxymethyl tetrazole and the derivative thereof, the molar ratio of the compound A-1 to the reducing agent is 1: 1.5-1: 3;
according to the synthesis method of the 5-hydroxymethyl tetrazole and the derivative thereof, the weight-volume ratio (g: mL) of the compound A-1 to the organic solvent is 1: 20-1: 60;
according to the synthesis method of the 5-hydroxymethyl tetrazole and the derivative thereof, the weight-volume ratio (g: mL) of the compound A-3 to the acid reagent is 1: 5-1: 20;
according to the synthesis method of the 5-hydroxymethyl tetrazole and the derivative thereof, the weight-volume ratio (g: mL) of the compound A-3 to the mixed solvent is 1: 10-1: 30;
according to the preferred embodiment of the synthesis method of 5-hydroxymethyl tetrazole and derivatives thereof, the route I is specifically operated as follows:
adding the compound A-1 and the Grignard reagent A-2 into a tetrahydrofuran solvent, cooling to 0-5 ℃ in an ice bath under an inert gas environment, stirring for reaction for 1-3 hours, and carrying out post-treatment to obtain a compound A-3;
adding a dichloromethane solvent into the compound A-3, then adding a dioxane solution of an acid reagent, stirring for 1-3 hours at normal temperature, and carrying out aftertreatment to obtain a target product 5-hydroxymethyl tetrazole and a derivative thereof (formula A);
according to the preferred embodiment of the synthesis method of 5-hydroxymethyl tetrazole and the derivative thereof, the route II is specifically operated as follows:
adding the compound A-1 and a reducing agent into a tetrahydrofuran solvent, cooling the reaction liquid to 0-5 ℃ in an ice bath, stirring for reaction for 1-3 hours, and carrying out aftertreatment to obtain a compound A-3;
adding a dichloromethane solvent into the compound A-3, then adding a dioxane solution of an acid reagent, stirring for 1-3 hours at normal temperature, and carrying out aftertreatment to obtain a target product 5-hydroxymethyl tetrazole and a derivative thereof (formula A);
according to a preferred embodiment of the method for synthesizing 5-hydroxymethyl tetrazole and the derivative thereof, when R is3When the compound is ethoxy, the compound A-1 is prepared by taking 5-ethyl formate tetrazole as a raw material and reacting with triphenylchloromethane (TrtCl);
according to a preferred embodiment of the method for synthesizing 5-hydroxymethyl tetrazole and the derivative thereof, when R is3When the hydrogen is contained, the compound A-1 is prepared by taking 5-ethyl formate tetrazole as a raw material, firstly reacting with triphenylchloromethane (TrtCl), and then reducing; or is prepared by oxidizing 2-Trt-5-hydroxymethyl tetrazole serving as a raw material;
according to the preferred embodiment of the synthesis method of the 5-hydroxymethyl tetrazole and the derivative thereof, the molar ratio of the compound A-1 to the Grignard reagent A-2 is 1: 1.5;
according to the preferred embodiment of the synthesis method of the 5-hydroxymethyl tetrazole and the derivative thereof, the molar ratio of the compound A-1 to the Grignard reagent A-2 is 1: 2;
according to the preferred embodiment of the synthesis method of the 5-hydroxymethyl tetrazole and the derivative thereof, the molar ratio of the compound A-1 to the Grignard reagent A-2 is 1: 3;
according to a preferred embodiment of the synthesis method of the 5-hydroxymethyl tetrazole and the derivative thereof, the molar ratio of the compound A-1 to the reducing agent is 1: 1.5;
according to a preferred embodiment of the synthesis method of the 5-hydroxymethyl tetrazole and the derivative thereof, the molar ratio of the compound A-1 to the reducing agent is 1: 2;
according to a preferred embodiment of the synthesis method of the 5-hydroxymethyl tetrazole and the derivative thereof, the molar ratio of the compound A-1 to the reducing agent is 1: 3;
according to a preferred embodiment of the synthesis method of the 5-hydroxymethyl tetrazole and the derivative thereof, the weight-to-volume ratio (g: mL) of the compound A-1 to the organic solvent is 1: 24;
according to the preferable embodiment of the synthesis method of the 5-hydroxymethyl tetrazole and the derivative thereof, the weight volume ratio (g: mL) of the compound A-1 to the organic solvent is 1: 32;
according to the preferable embodiment of the synthesis method of the 5-hydroxymethyl tetrazole and the derivative thereof, the weight volume ratio (g: mL) of the compound A-1 to the organic solvent is 1: 52;
according to a preferred embodiment of the synthesis method of the 5-hydroxymethyl tetrazole and the derivative thereof, the weight-to-volume ratio (g: mL) of the compound A-1 to the organic solvent is 1: 59;
according to a preferred embodiment of the synthesis method of the 5-hydroxymethyl tetrazole and the derivative thereof, the weight-to-volume ratio (g: mL) of the compound A-3 to the acid reagent is 1: 8.5;
according to a preferred embodiment of the synthesis method of the 5-hydroxymethyl tetrazole and the derivative thereof, the weight-to-volume ratio (g: mL) of the compound A-3 to the acid reagent is 1: 11;
according to the preferable embodiment of the synthesis method of the 5-hydroxymethyl tetrazole and the derivative thereof, the weight volume ratio (g: mL) of the compound A-3 to the acid reagent is 1: 16;
according to the preferable embodiment of the synthesis method of the 5-hydroxymethyl tetrazole and the derivative thereof, the weight volume ratio (g: mL) of the compound A-3 to the acid reagent is 1: 20;
according to a preferred embodiment of the synthesis method of the 5-hydroxymethyl tetrazole and the derivative thereof, the weight-to-volume ratio (g: mL) of the compound A-3 to the mixed solvent is 1: 11;
according to the preferable embodiment of the synthesis method of the 5-hydroxymethyl tetrazole and the derivative thereof, the weight volume ratio (g: mL) of the compound A-3 to the mixed solvent is 1: 14;
according to a preferred embodiment of the synthesis method of the 5-hydroxymethyl tetrazole and the derivative thereof, the weight-to-volume ratio (g: mL) of the compound A-3 to the mixed solvent is 1: 20;
according to the preferable embodiment of the synthesis method of the 5-hydroxymethyl tetrazole and the derivative thereof, the weight volume ratio (g: mL) of the compound A-3 to the mixed solvent is 1: 26;
according to a preferred embodiment of the method for synthesizing 5-hydroxymethyltetrazole and derivatives thereof, the inert gas environment is a nitrogen environment;
the technical parameter characteristics in the above preparation method of the present invention can be combined at will.
In the above-mentioned operations, the post-treatment includes, but is not limited to, quenching with a quenching agent, stirring, extraction, liquid or solid transfer, water washing, alkali washing, acid washing, filtration, ultrafiltration, cyclic ultrafiltration, dilution, concentration, drying, purification, lyophilization, etc., or one or more of water quenching, stirring, extraction, liquid or solid transfer, water washing, alkali washing, acid washing, filtration, ultrafiltration, cyclic ultrafiltration, dilution, concentration, drying, purification, lyophilization, etc.
In a preferred embodiment of the present invention, the quenching with a quenching agent is a process of adding a quenching agent to the reaction solution to stop the reaction from proceeding to the right;
the quenching agent is saturated ammonium chloride aqueous solution and Na2SO4·10H2O, aqueous sodium thiosulfate solution or water;
in a preferred embodiment of the invention, the extraction solvent is dichloromethane, ethyl acetate, or diethyl ether;
in a preferred embodiment of the present invention, the filtration refers to a process of separating solids and liquids in a reaction solution, or a process of separating solids and liquids in a post-treatment operation; the filtration comprises common filtration and separation and centrifugal separation; wherein, the common filtration separation includes but is not limited to filtration using filter cloth, membrane filtration, and diatomite filtration;
in a preferred embodiment of the present invention, the water washing, alkali washing and acid washing include, but are not limited to, the use of saturated aqueous ammonium chloride solution, saturated aqueous sodium bicarbonate solution, 5% aqueous potassium carbonate solution, saturated brine;
in a preferred embodiment of the present invention, the drying comprises anhydrous sodium sulfate drying, vacuum drying of the filtrate;
in a preferred embodiment of the present invention, the concentration refers to a process of removing a liquid solvent, including concentration under reduced pressure, concentration under normal pressure, low-temperature spin-drying, etc.;
the steps, solvents, reagents, filtration, drying, concentration, extraction, separation and the like in the synthesis method of the 5-hydroxymethyl tetrazole and the derivatives thereof can be combined/separated at will, and the purpose of the invention can be achieved.
The room temperature is 15 ~ 30 ℃.
According to the synthesis method of the 5-hydroxymethyl tetrazole and the derivative thereof, the 5-hydroxymethyl tetrazole derivative (formula A) is obtained by using the carboxylic ester or aldehyde compound protected by Trt as a raw material through reaction, no toxic and explosive chemical hazardous substances are used in the whole synthesis method, the reaction conditions are mild, and the operation safety is high; the method has good repeatability of route steps, high conversion rate and yield, good universality and suitability for workshop amplification operation, can be applied to the synthesis of 5-hydroxymethyl tetrazole derivatives with various substituent structures; the post-treatment does not generate toxic waste liquid containing cyanide ions, is green and environment-friendly, has no pollution to the environment, reduces the safety level and the production cost of production, is beneficial to the application of green and environment-friendly industrial production, and has wide application prospect.
Detailed Description
The following describes preferred embodiments of the present invention to make the technical contents thereof clearer and easier to understand. The invention may be embodied in many different forms of embodiments, which are intended to be illustrative only, and the scope of the invention is not intended to be limited to the embodiments shown herein.
If there is an experimental method not specified specific conditions, it is usually carried out according to conventional conditions, such as the relevant instructions or manuals.
Example 1 preparation of 2-Trt-5-Ethyl formate tetrazole
To a 100mL three-necked flask, into which a stirrer was placed in advance and a thermometer was placed, was added anhydrous DMF (60mL), and 5-ethyl formate tetrazole (2.84g), K2CO3(5.52g) and TrtCl (6.12g), the reaction flask was replaced with nitrogen three times, the mixture was stirred at room temperature overnight, after completion of the reaction, the reaction solution was extracted into a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the combined organic phase solutions were washed with a saturated aqueous ammonium chloride solution and a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered and dried, and purified to obtain 2-Trt-5-ethyl formate tetrazole (white solid, 4.0g, yield 52%).
Example 2 preparation of 2-Trt-5-hydroxymethyl tetrazole
To a 100mL round-bottomed flask, into which a stirrer was placed in advance, was added 2-Trt-5-ethyl formate tetrazole (2.1g,5.47mmol) and anhydrous tetrahydrofuran (50mL), and under ice-bath conditions, lithium aluminum hydride (416mg,10.94mmol) was further added, and the reaction was stirred for 60 minutes under ice-bath conditions. After the reaction is completed, Na is added2SO4The reaction was quenched by 10H2O (2.1 g). Filtering, decompressing and rotary steaming to obtain the 2-Trt-5-hydroxymethyl tetrazole (1.4g of white solid, yield 75%).
Example 3 preparation of 5-hydroxymethyl tetrazole
To a 50mL round-bottomed flask into which a stirrer had been placed in advance were added 2-Trt-5-hydroxymethyltetrazole (150mg,0.44mmol) and DCM (1mL), and at room temperature, a 4M HCl/dioxane (3mL) solution was added, followed by stirring at room temperature for 60 minutes. After completion of the reaction, the solvent was removed by rotary evaporation under reduced pressure, and H was added to the residue2O (10mL), washing the aqueous phase with diethyl ether, and lyophilizing the aqueous phase in vacuo to give 5-hydroxymethyltetrazole (40 mg of yellow solid, 93% yield);
the structure NMR detection of the obtained 5-hydroxymethyl tetrazole is carried out, and the detection result is as follows:
1H NMR(400MHz,DMSO-d6):δ4.80(s,2H)。
the detection result shows that the synthesized compound 5-hydroxymethyl tetrazole has a correct structure.
Example 4 preparation of 2-Trt-5-aldehyde tetrazole
After the reaction was completed, the reaction solution was quenched with 20% aqueous sodium thiosulfate, extracted with ethyl acetate, the combined organic phase solutions were washed with saturated sodium bicarbonate solution and brine, and the organic phase was dried over anhydrous sodium sulfate, filtered and dried by spin-drying. The residue was purified by column chromatography to give 2-Trt-5-formyltetrazole (720mg of white solid, yield 51%).
Performing structural NMR detection on the obtained 2-Trt-5-aldehyde tetrazole, wherein the detection result is as follows:
1H NMR(400MHz,DMSO-d6)δ10.15(s,1H)，7.44-7.41(m，9H),7.08-7.05(m，6H)。
the detection result shows that the synthesized compound 2-Trt-5-aldehyde tetrazole has correct structure.
Example 5 preparation of 2-Trt-5- (1-cyclopropyl) hydroxymethyltetrazole
2-Trt-5-aldehyde tetrazole (720mg, 2.12mmol) and anhydrous tetrahydrofuran (20mL) were added to a 50mL three-necked flask into which a stirrer was placed in advance, the flask was replaced with nitrogen gas three times, the reaction was placed in an ice bath, a 1mol/L cyclopropyl magnesium bromide tetrahydrofuran solution (3.2mL,3.18mmol) was added, and the reaction was stirred for 1 hour under ice bath. After the reaction was completed, the reaction mixture was quenched with a saturated aqueous solution of ammonium chloride in an ice bath, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered and dried. After concentration, the mixture is separated and purified by column chromatography to obtain 2-Trt-5- (1-cyclopropyl) hydroxymethyl tetrazole (540 mg of yellow solid, yield 68%).
Structural NMR detection is carried out on the obtained 2-Trt-5- (1-cyclopropyl) hydroxymethyl tetrazole, and the detection result is as follows:
1H NMR(400MHz,DMSO-d6)δ7.19-7.15(m，9H),6.80-6.76(m，6H)，4.10(d，J＝7.6Hz，1H)，1.08-1.05(m，1H)，0.29-0.26(m，1H)，0.18-0.12(m，2H)，0.00--0.01(m，1H)。
the detection result shows that the synthesized compound 2-Trt-5- (1-cyclopropyl) hydroxymethyl tetrazole has a correct structure.
Example 6 preparation of 5- (1-cyclopropyl) hydroxymethyltetrazole
To a 50mL round-bottomed flask, into which a stirrer was placed in advance, was added 2-Trt-5- (1-cyclopropyl) hydroxymethyltetrazole (191mg,0.50mmol) and DCM (1mL), and at room temperature, a 4M HCl/dioxane (3mL) solution was added, followed by stirring at room temperature for 60 minutes. After completion of the reaction, the solvent was removed by rotary evaporation under reduced pressure, and H was added to the residue2The aqueous phase was washed with diethyl ether and lyophilized to give 5- (1-cyclopropyl) hydroxymethyltetrazole (68 mg of yellow solid, 96% yield).
The 5- (1-cyclopropyl) hydroxymethyl tetrazole obtained above is subjected to structure NMR detection, and the detection result is as follows:
1H NMR(400MHz,DMSO-d6)δ4.10(d，J＝7.2Hz，1H)，1.24-1.18(m，1H)，0.51-0.42(m，3H)，0.38-0.34(m，1H).
the detection result shows that the synthesized compound 5- (1-cyclopropyl) hydroxymethyl tetrazole has a correct structure.
Example 7 preparation of 2-Trt-5- (1, 1-dimethyl) hydroxymethyltetrazole
To a 50mL three-necked flask into which a stirrer was placed in advance, 2-Trt-5-ethyl formate tetrazole (384mg, 1.00mmol) and THF (20mL) were added, the reaction flask was replaced with nitrogen gas three times, the reaction was placed in an ice bath, 3M methyl magnesium bromide (1.0mL,3.0mmol) was added, and the reaction was stirred for 1 hour under ice bath. After the reaction is completed, saturated ammonium chloride aqueous solution is added in ice bath for quenching, ether extraction is carried out, the organic phase is dried by anhydrous sodium sulfate and then filtered and dried to obtain 2-Trt-5- (1, 1-dimethyl) hydroxymethyl tetrazole (366 mg of yellow solid, 99 percent of yield).
Example 8 preparation of 5- (1, 1-dimethyl) hydroxymethyltetrazole
To a 50mL round-bottomed flask into which a stirrer had been placed in advance were added 2-Trt-5- (1, 1-dimethyl) hydroxymethyltetrazole (365mg,0.99mmol) and DCM (1mL), and at room temperature, a 4M HCl/dioxane (4mL) solution was added and stirred at room temperature for 60 minutes. After completion of the reaction, the solvent was removed by concentration, and H was added to the residue2The aqueous phase was washed with diethyl ether and lyophilized in vacuo to give 5- (1, 1-dimethyl) hydroxymethyltetrazole (120 mg of yellow solid, 95% yield).
The 5- (1, 1-dimethyl) hydroxymethyl tetrazole obtained above is subjected to structure NMR detection, and the detection result is as follows:
1H NMR(400MHz,DMSO-d6)δ1.54(s,6H)。
the detection result shows that the synthesized compound 5- (1, 1-dimethyl) hydroxymethyl tetrazole has a correct structure.
Example 9 preparation of 2-Trt-5- (1-methyl) hydroxymethyltetrazole
To a 50mL three-necked flask into which a stirrer was placed in advance, 2-Trt-5-aldehyde tetrazole (340mg, 1.00mmol) and anhydrous tetrahydrofuran (20mL) were added, the reaction flask was replaced with nitrogen gas three times, the reaction was placed in an ice bath, 3M methyl magnesium bromide (0.5mL,1.5mmol) was added, and the reaction was stirred for 1 hour under ice bath. After the reaction was completed, the reaction mixture was quenched with a saturated aqueous solution of ammonium chloride in an ice bath, extracted with ether, the organic phase was dried over anhydrous sodium sulfate, and the filtrate was dried by spinning to obtain 2-Trt-5- (1-methyl) hydroxymethyltetrazole (350mg of yellow solid, yield 98%).
Example 10 preparation of 5- (1-methyl) hydroxymethyltetrazole
To a 50mL round-bottomed flask, into which a stirrer was placed in advance, was added 2-Trt-5- (1-methyl) hydroxymethyltetrazole (350mg,0.98mmol) and DCM (1mL), and at room temperature, a 4M HCl/dioxane (3mL) solution was added, followed by stirring at room temperature for 60 minutes. After completion of the reaction, the solvent was spin-dried, and H was added to the residue2O, the aqueous phase was washed with diethyl ether and lyophilized in vacuo to give 5- (1-methyl) hydroxymethyltetrazole (95 mg as a yellow solid, 85% yield).
The 5- (1-methyl) hydroxymethyl tetrazole obtained above is subjected to structure NMR detection, and the detection result is as follows:
1H NMR(400MHz,DMSO-d6)δ5.08(q,J＝6.4Hz，1H)，1.48(d,J＝6.8Hz，3H)
the detection result shows that the synthesized compound 5- (1-methyl) hydroxymethyl tetrazole has a correct structure.
Purity detection is carried out on the 5-hydroxymethyl tetrazole derivative obtained in the embodiments 3, 6, 8 and 10, and the detection result shows that the purity of the 5-hydroxymethyl tetrazole derivative (formula A) obtained in the embodiments 3, 6, 8 and 10 is more than 95%;
in conclusion, the 5-hydroxymethyl tetrazole derivative (formula A) obtained in the embodiment of the invention has the advantages of correct structure, high purity, low impurity content and excellent quality.
The 5-hydroxymethyl tetrazole derivative (formula A) obtained by the method in other embodiments and technical schemes of the invention has similar beneficial effects as described above.
The invention is not limited to the foregoing embodiments. The invention extends to any novel feature or any novel combination of features disclosed in this specification and any novel method or process steps or any novel combination of features disclosed.
Claims (10)
1. A method for synthesizing 5-hydroxymethyl tetrazole and derivatives thereof is characterized in that the structures of the 5-hydroxymethyl tetrazole and the derivatives thereof are shown as the following formula A,
wherein R is1、R2Each independently selected from hydrogen, C1-C10 alkyl;
when R is1、R2When hydrogen is not used at the same time, the synthetic method route of the 5-hydroxymethyl tetrazole and the derivative thereof is shown as the following scheme I:
route I:
wherein R is3Selected from hydrogen, alkoxy;
the specific operation steps are as follows:
step 1, cooling a compound A-1 and a Grignard reagent A-2 in the presence of an organic solvent to perform nucleophilic addition reaction, and performing post-treatment to obtain a compound A-3;
step 2, adding an acid reagent and a mixed solvent into the compound A-3, reacting at normal temperature to remove the Trt protecting group, and performing post-treatment to obtain a target product 5-hydroxymethyl tetrazole and a derivative thereof;
when R is1、R2And when the hydrogen is simultaneously used, the synthetic method route of the 5-hydroxymethyl tetrazole and the derivative thereof is shown as a route II:
route II:
wherein R is3Selected from hydrogen, alkoxy;
the specific operation steps are as follows:
step 1, cooling the compound A-1 in the presence of a reducing agent and an organic solvent for reduction reaction, and carrying out post-treatment to obtain a compound A-3;
and 2, adding an acid reagent and a mixed solvent into the compound A-3, reacting at normal temperature to remove the Trt protecting group, and performing post-treatment to obtain a target product 5-hydroxymethyl tetrazole and a derivative thereof.
2. The method of claim 1,
the R is1、R2Each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, cyclobutyl, cyclopentyl, cyclohexyl;
the R is3Selected from hydrogen, methoxy, ethoxy.
3. The method of claim 1,
the reducing agent is lithium aluminum hydride, sodium borohydride or lithium borohydride;
the acid in the acid reagent is hydrochloric acid, sulfuric acid and nitric acid;
the acid reagent is an organic solvent solution with the acid molar concentration of 4 mol/L.
4. The method of claim 1,
the molar ratio of the compound A-1 to the Grignard reagent A-2 is 1: 1.5-1: 3;
the molar ratio of the compound A-1 to the reducing agent is 1: 1.5-1: 3;
the weight-volume ratio of the compound A-1 to the organic solvent is 1: 20-1: 60.
5. The method of claim 1,
the weight-volume ratio of the compound A-3 to the acid reagent is 1: 5-1: 20;
the weight-volume ratio of the compound A-3 to the mixed solvent is 1: 10-1: 30.
6. The method of claim 1,
the specific operation of the route I is as follows:
adding the compound A-1 and the Grignard reagent A-2 into a tetrahydrofuran solvent, cooling to 0-5 ℃ in an ice bath under an inert gas environment, stirring for reaction for 1-3 hours, and carrying out post-treatment to obtain a compound A-3;
adding a dichloromethane solvent into the compound A-3, then adding a dioxane solution of an acid reagent, stirring for 1-3 hours at normal temperature, and carrying out aftertreatment to obtain a target product 5-hydroxymethyl tetrazole and a derivative thereof (formula A).
7. The method of claim 1,
the specific operation of the route II is:
adding the compound A-1 and a reducing agent into a tetrahydrofuran solvent, cooling the reaction liquid to 0-5 ℃ in an ice bath, stirring for reaction for 1-3 hours, and carrying out aftertreatment to obtain a compound A-3;
adding a dichloromethane solvent into the compound A-3, then adding a dioxane solution of an acid reagent, stirring for 1-3 hours at normal temperature, and carrying out aftertreatment to obtain a target product 5-hydroxymethyl tetrazole and a derivative thereof (formula A).
8. The method of claim 1,
when R is3And when the compound is ethoxy, the compound A-1 is prepared by taking 5-ethyl formate tetrazole as a raw material and reacting with triphenylchloromethane (TrtCl).
9. The method of claim 1,
when R is3When the hydrogen is contained, the compound A-1 is prepared by taking 5-ethyl formate tetrazole as a raw material, firstly reacting with triphenylchloromethane (TrtCl), and then reducing; or prepared by oxidizing 2-Trt-5-hydroxymethyl tetrazole serving as a raw material.
10. 5-hydroxymethyl tetrazole and derivatives thereof synthesized by the method of any one of claims 1 to 9, wherein the purity of the 5-hydroxymethyl tetrazole and derivatives thereof is greater than 95%.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999051590A1 (en) * | 1998-04-03 | 1999-10-14 | Boehringer Ingelheim Pharma Kg | Substituted indolinones as kinase inhibitors |
| CN1918137A (en) * | 2004-02-18 | 2007-02-21 | 阿斯利康(瑞典)有限公司 | Tetrazole compounds and their use as metabotropic glutamate receptor antagonists |
| CN101535272A (en) * | 2006-11-06 | 2009-09-16 | 格林代克斯联合股份公司 | Method for preparing medetomidine and its salts |
| CN104955454A (en) * | 2012-08-27 | 2015-09-30 | 凯莫森特里克斯股份有限公司 | Antagonists of chemokine receptors |
-
2020
- 2020-02-25 CN CN202010113533.6A patent/CN111269192A/en not_active Withdrawn
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999051590A1 (en) * | 1998-04-03 | 1999-10-14 | Boehringer Ingelheim Pharma Kg | Substituted indolinones as kinase inhibitors |
| CN1918137A (en) * | 2004-02-18 | 2007-02-21 | 阿斯利康(瑞典)有限公司 | Tetrazole compounds and their use as metabotropic glutamate receptor antagonists |
| CN101535272A (en) * | 2006-11-06 | 2009-09-16 | 格林代克斯联合股份公司 | Method for preparing medetomidine and its salts |
| CN104955454A (en) * | 2012-08-27 | 2015-09-30 | 凯莫森特里克斯股份有限公司 | Antagonists of chemokine receptors |
Non-Patent Citations (3)
| Title |
|---|
| ADAM W. SLEDESKI ET AL.: "A Convergent Synthesis of an LTD4 Antagonist， RG12525", 《TETRAHEDRON LETTERS》 * |
| DUNCAN J. WARDROP ET AL.: "Dehydrative Fragmentation of 5-Hydroxyalkyl-1H-tetrazoles: A Mild Route to Alkylidenecarbenes", 《ORGANIC LETTERS》 * |
| 二异丁基氢化铝: "《当代有机合成方法》", 31 March 2006, 华东理工大学出版社 * |
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