CN111018838A - Synthesis method of pyrrolidinyl diaminopyrimidine oxynitride - Google Patents
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Abstract
The invention discloses a preparation method of pyrrolidinyl diaminopyrimidine oxynitride, belonging to the technical field of organic synthesis. 2, 4-diamino-6-chloropyrimidine is taken as a raw material, and the pyrrolidinyl diaminopyrimidine nitrogen oxide is obtained through continuous amination and oxidation reactions. Firstly, nucleophilic substitution amination is carried out on 2, 4-diamino-6-chloropyrimidine and tetrahydropyrrole in the presence of alkali, and acid quenching is carried out to obtain acidic aqueous solution. Then dropwise adding hydrogen peroxide in the presence of sodium tungstate for oxidation, and obtaining the pyrrolidinyl diaminopyrimidine nitrogen oxide in alkali. The method has the advantages of simple operation, mild conditions, low cost and high yield, and the obtained product has the purity of more than 99.5 percent and is suitable for large-scale production.
Description
Technical Field
The invention relates to a synthesis method of pyrrolidinyl diaminopyrimidine oxynitride, belonging to the technical field of organic synthesis.
Background
Pyrrolidinyl diaminopyrimidine nitroxide, alternative name: the Eriger is a Pyrrolidinyldiamidopyrimide oxide of formula C8H13N5The molecular weight of O is 195.22, CAS is 55921-65-8, the pyrrolidinyl diamino pyrimidine nitrogen oxide is a synthetic azapurine small molecule protein kinase inhibitor, and the azapurine small molecule protein kinase inhibitor has the effects of reducing blood pressure, treating Parkinson and the like on human bodies, can be used as a multifunctional skeleton in different compound libraries, and is widely applied to the fields of medicines, food additives and the like.
At present, the product literature has few synthesis methods, mainly comprising the following steps: the pyrrolidinyl diaminopyrimidine oxynitride is obtained by 5-step synthesis with ethyl cyanoformate as a raw material, wherein the total yield is 35%, and reference is as follows: chem.1975,40,3304.
Aiming at the defects of long steps, low yield, high cost and the like when the ethyl cyanoformate is adopted as a raw material to be subjected to a five-step synthesis route. There is therefore a need for improved process routes to accommodate the industrial scale-up process.
Disclosure of Invention
In order to overcome the technical defects, the invention adopts 2, 4-diamino-6-chloropyrimidine as a raw material, and obtains the pyrrolidinyl diaminopyrimidine nitrogen oxide through continuous nucleophilic amination and oxidation reaction. Firstly, because the activity of C6 site chlorine is stronger, nucleophilic amination is carried out on the C6 site chlorine and pyrrolidine in the presence of alkali, and an acidic aqueous solution is obtained through acid quenching. Then, in the presence of catalytic amount of sodium tungstate, hydrogen peroxide is dripped for oxidation, and the pyrrolidine diamino pyrimidine nitrogen oxide is obtained through alkali neutralization.
The invention relates to a preparation method of pyrrolidinyl diaminopyrimidine nitrogen oxide, which comprises the following reaction equation:
the method comprises the following steps:
the first step is as follows: amination reaction
Dissolving 2, 4-diamino-6-chloropyrimidine and tetrahydropyrrole in an organic solvent, reacting at 60-100 ℃ in the presence of alkali, and quenching by acid to obtain an aqueous solution of 2, 4-diamino-6-pyrrolidine pyrimidine salt;
the second step is that: oxidation reaction
Dropwise adding hydrogen peroxide into the aqueous solution of 2, 4-diamino-6-pyrrolidine pyrimidine salt in the presence of sodium tungstate for reaction, and adjusting the reaction solution to be alkaline after the reaction is finished to obtain the pyrrolidinyl diaminopyrimidine oxynitride.
Further, in the above technical solution, the organic solvent is selected from tetrahydrofuran, dioxane, 2-methyltetrahydrofuran or toluene.
Further, in the above technical solution, the base is selected from potassium tert-butoxide, sodium hydride, sodium methoxide, sodium tert-butoxide, sodium tert-amylate, and the like.
Further, in the above technical scheme, the quenching acid in the first step is selected from glacial acetic acid, trifluoroacetic acid and the like.
Further, in the above technical scheme, the pH is adjusted to 3-6 after the acid quenching in the first step.
Further, in the above technical scheme, the pH is adjusted to 2-5 after acid quenching in the second step.
Further, in the technical scheme, in the second step, the temperature of the dropping hydrogen peroxide is 10-45 ℃.
Further, in the technical scheme, in the second step, the molar ratio of the pyrrolidinyl diaminopyrimidine salt to the hydrogen peroxide is 1: 1.2-1.3.
Further, in the above technical scheme, in the second step, the molar ratio of sodium tungstate to hydrogen peroxide is 0.01-0.02: 1.
Advantageous effects of the invention
The method has the advantages of simple and convenient operation, coherent preparation, high reaction yield and low raw material price, and the purity of the obtained product can reach more than 99.5 percent, thereby being suitable for large-scale production.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
Example 1
Under the protection of nitrogen, 72.3g (0.5 mol,1eq) of 2, 4-diamino-6-chloropyrimidine, 290mL of anhydrous tetrahydrofuran and 57.7g (0.6mol,1.2eq) of sodium tert-butoxide were charged into a jacketed reaction flask. Cooling to 10 ℃, dropwise adding a tetrahydrofuran solution (50%) containing 39.2g (0.55mol,1.1eq) of pyrrolidine, heating to 65-70 ℃ after dropwise adding, stirring for reaction for 4 hours, sampling and detecting 2, 4-diamino-6-chloropyrimidine raw material residue by HPLC (high performance liquid chromatography), adding trifluoroacetic acid aqueous solution for quenching, adjusting pH to 3-4, standing for layering, washing an organic phase by water, combining water layers, and obtaining the product external standard yield: 96.3 percent. Cooling circulating water, adding 2.2g of sodium tungstate, slowly dropwise adding 78.6g (0.58mol,1.2eq) of 25% hydrogen peroxide, releasing heat, controlling the temperature to be 20-32 ℃, reacting for 3.5 hours, sampling, detecting the reaction completion, cooling the system to be 15-20 ℃, dropwise adding saturated sodium bisulfite, quenching, adding 110mL of toluene, washing, discarding, adding 30% sodium hydroxide aqueous solution to adjust the pH to be 10-11, extracting for 2 times by 250mL of 1, 2-dichloroethane, combining organic phases, concentrating under reduced pressure to be non-distillate, pulping by adopting toluene/n-heptane to be 1/3 (volume ratio), filtering, and drying to obtain the final productPyrrolidinyl diaminopyrimidine nitroxide 83.94g, HPLC: 99.6%, yield: 89.3 percent.1HNMR(400MHz,CDCl3):2.05(m,4H),2.31(t,4H), 5.69(m,1H),6.52(s,2H),6.83(s,2H).
Example 2
Under the protection of nitrogen, 72.3g (0.5 mol,1eq) of 2, 4-diamino-6-chloropyrimidine, 290mL of 2-methyltetrahydrofuran and 67.3g (0.6mol,1.2eq) of potassium tert-butoxide were charged into a jacketed reaction flask. Cooling to 10 ℃, dropwise adding a solution (50%) containing 39.2g (0.55mol,1.1eq) of pyrrolidine (2-methyltetrahydrofuran), heating to 70-80 ℃ after the dropwise adding, stirring for reaction for 4 hours, sampling and detecting by HPLC (high performance liquid chromatography) that the 2, 4-diamino-6-chloropyrimidine raw material residue is less than 1%, adding an acetic acid aqueous solution for quenching, adjusting the pH to 4-5, standing for layering, washing an organic phase by water, and detecting the external standard yield by HPLC: 95.7 percent. Cooling circulating water, adding 2.2g of sodium tungstate, slowly dropwise adding 78.6g (0.58mol,1.2eq) of 25% hydrogen peroxide, releasing heat, controlling the temperature to be 20-32 ℃, reacting for 3 hours, detecting no pyrrolidinyl diaminopyrimidine raw material by HPLC after sampling and quenching, cooling the system to be 15-20 ℃, dropwise adding saturated sodium bisulfite to quench, removing the organic phase, neutralizing the aqueous phase by using 30% sodium hydroxide aqueous solution, adjusting the pH to be 10-11, extracting for 2 times by 250mL of 1, 2-dichloroethane, combining the organic phases, concentrating under reduced pressure to be undistilled liquid, pulping by using toluene/n-heptane to be 1/3 (volume ratio), filtering, drying to obtain pyrrolidinyl diaminopyrimidine nitrogen oxide 85.3g, and performing HPLC: 99.6%, yield: 91.3 percent. When the sodium tungstate catalyst is not added, dropwise adding hydrogen peroxide at the temperature of 40-45 ℃, wherein the product yield is 80.2%, and the HPLC: 98.7 percent.
Example 3
Under the protection of nitrogen, 72.3g (0.5 mol,1eq) of 2, 4-diamino-6-chloropyrimidine, 330mL of dioxane and 32.4g (0.6mol,1.2eq) of sodium methoxide were put into a jacketed reaction flask, the temperature was reduced to 5 ℃, and a mixed solution (50%) containing 39.2g (0.55mol,1.1eq) of 1, 4-dioxane was added dropwise. Heating to 70-80 ℃ after the dropwise addition, stirring for reacting for 4 hours, sampling and detecting by HPLC (high performance liquid chromatography) that the residual of the 2, 4-diamino-6-chloropyrimidine raw material is less than 1%, adding an acetic acid aqueous solution for quenching, adjusting the pH value to 3-4, standing for layering, washing an organic phase by using water, and detecting the external standard yield by HPLC: 94.9 percent. Cooling circulating water, adding 2.2g of sodium tungstate, slowly dropwise adding 78.6g (0.58mol,1.2eq) of 25% hydrogen peroxide, releasing heat, controlling the temperature to be 20-32 ℃, reacting for 3 hours, detecting no pyrrolidinyl diaminopyrimidine raw material by HPLC after sampling and quenching, cooling the system to be 15-20 ℃, dropwise adding saturated sodium bisulfite for quenching, extracting impurities by using a small amount of 1, 2-dichloroethane, removing an organic phase, neutralizing an aqueous phase by using a 30% sodium hydroxide aqueous solution, adjusting the pH to be 10-11, extracting for 2 times by using 250mL of 1, 2-dichloroethane, combining the organic phases, concentrating under reduced pressure until the organic phase is not distilled, pulping by using toluene/n-heptane to be 1/3 (volume ratio), filtering, and drying to obtain 84.2g of pyrrolidinyl diaminopyrimidine nitrogen oxide, HPLC: 99.7%, yield: 90.9 percent.
Example 4
Under the protection of nitrogen, 72.3g (0.5 mol,1eq) of 2, 4-diamino-6-chloropyrimidine, 290mL of toluene, and 39.2g (0.55mol,1.1eq) of tetrahydropyrrole were put into a jacketed reaction flask and mixed, and sodium hydride (0.75mol,1.5eq) was put into the reaction flask in portions and stirred at room temperature for 20 minutes. Heating to 70-80 ℃ after the dropwise addition, stirring for reacting for 4 hours, sampling and detecting by HPLC (high performance liquid chromatography) that the residual of the 2, 4-diamino-6-chloropyrimidine raw material is less than 1%, adding trifluoroacetic acid aqueous solution for quenching, adjusting the pH value to 3-4, standing for layering, washing an organic phase by using water, combining aqueous phases, and detecting the external standard yield by HPLC: 95.9 percent. Cooling circulating water, adding 2.2g of sodium tungstate, slowly dropwise adding 78.6g (0.58mol,1.2eq) of 25% hydrogen peroxide, releasing heat, controlling the temperature to be 20-32 ℃, reacting for 3 hours, detecting no pyrrolidinyl diaminopyrimidine raw material by HPLC after sampling and quenching, cooling the system to be 15-20 ℃, dropwise adding saturated sodium bisulfite for quenching, extracting impurities by using a small amount of 1, 2-dichloroethane, removing an organic phase, neutralizing an aqueous phase by using a 30% sodium hydroxide aqueous solution, adjusting the pH to be 10-11, extracting for 2 times by using 250mL of 1, 2-dichloroethane, combining the organic phases, concentrating under reduced pressure until the organic phase is not distilled, pulping by using toluene/n-heptane to be 1/3 (volume ratio), filtering, and drying to obtain 86.7g of pyrrolidinyl diaminopyrimidine nitrogen oxide, which is prepared by HPLC: 99.7%, yield: 92.6 percent.
Example 5
Under the protection of nitrogen, 72.3g (0.5 mol,1eq) of 2, 4-diamino-6-chloropyrimidine, 290mL (0.55mol,1.1eq) of 2-methyltetrahydrofuran and 39.2g (0.1 eq) of tetrahydropyrrole were put into a jacketed reaction flask, and 220g of 30% sodium tert-amylate 2-methyltetrahydrofuran solution (0.6mol,1.2eq) was added dropwise. Heating to 70-80 ℃ after the dropwise addition, stirring for reacting for 4 hours, sampling and detecting by HPLC (high performance liquid chromatography) that the residual of the 2, 4-diamino-6-chloropyrimidine raw material is less than 1%, adding an acetic acid aqueous solution for quenching, adjusting the pH value to 3-4, standing for layering, washing an organic phase by using water, and detecting the external standard yield by HPLC: 96.1 percent. Cooling circulating water, adding 2.2g of sodium tungstate, slowly dropwise adding 78.6g (0.58mol,1.2eq) of 25% hydrogen peroxide, releasing heat, controlling the temperature to be 20-32 ℃, reacting for 3 hours, detecting no pyrrolidinyl diaminopyrimidine raw material by HPLC after sampling and quenching, cooling the system to be 15-20 ℃, dropwise adding saturated sodium bisulfite to quench, removing the organic phase, neutralizing the aqueous phase by using 30% sodium hydroxide aqueous solution, adjusting the pH to be 10-11, extracting for 2 times by 250mL of 1, 2-dichloroethane, combining the organic phases, concentrating under reduced pressure to be undistilled liquid, pulping by using toluene/n-heptane to be 1/3 (volume ratio), filtering, drying to obtain pyrrolidinyl diaminopyrimidine nitrogen oxide 86.5g, and performing HPLC: 99.6%, yield: 92.3 percent. Example 6:
5.06kg (35mol,1eq) of 2, 4-diamino-6-chloropyrimidine, 20kg of toluene and 4.04kg (42mol,1.2eq) of sodium tert-butoxide are charged into a 50L glass jacket reactor under the protection of nitrogen. Cooling to 10 ℃, dropwise adding 3.92kg (55mol,1.1eq) of toluene solution (50%) containing pyrrolidine, heating to 65-70 ℃ after dropwise adding, stirring for reaction for 4 hours, sampling and detecting 2, 4-diamino-6-chloropyrimidine raw material residue by HPLC (high performance liquid chromatography) until the residue is less than 1%, adding acetic acid aqueous solution for quenching, adjusting pH to 3-4, standing for layering, washing an organic phase by water, removing an organic layer, combining water layers to obtain 11.07kg of pyrrolidinyl diaminopyrimidine acetate solution, and detecting external standard content by HPLC: 30.3%, external standard yield: 95.9 percent. Putting a pyrrolidinyl diaminopyrimidine acetate solution into a jacketed reaction bottle, cooling circulating water, adding 35g of sodium tungstate, slowly dropwise adding 5.48Kg (40.3mol,1.2eq) of 25% hydrogen peroxide, discharging heat, controlling the temperature to be 20-32 ℃, reacting for 3.5 hours, after sampling and quenching, detecting no pyrrolidinyl diaminopyrimidine raw material residue by HPLC (high performance liquid chromatography), cooling the system to be 15-20 ℃, dropwise adding saturated sodium bisulfite for quenching, neutralizing by using a 30% sodium hydroxide aqueous solution, adjusting the pH to be 11-12, extracting for 2 times by using 5Kg of 1, 2-dichloroethane, combining organic phases, concentrating under reduced pressure until no liquid remains, and adding toluene: n-heptane ═ 1: 3(3V) cooling and pulping the concentrate, filtering and drying to obtain 6.08kg of pyrrolidinyl diaminopyrimidine nitrogen oxide, HPLC: 99.7%, yield: 92.8 percent.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be able to cover the technical solutions and the inventive concepts of the present invention within the technical scope of the present invention.
Claims (8)
1. A preparation method of pyrrolidinyl diaminopyrimidine nitrogen oxide is characterized in that the reaction equation is as follows:
the method comprises the following steps:
the first step is as follows: amination reaction
Dissolving 2, 4-diamino-6-chloropyrimidine and tetrahydropyrrole in an organic solvent, reacting at 60-100 ℃ in the presence of alkali, and quenching by acid to obtain an aqueous solution of 2, 4-diamino-6-pyrrolidine pyrimidine salt;
the second step is that: oxidation reaction
Dropwise adding hydrogen peroxide into the aqueous solution of 2, 4-diamino-6-pyrrolidine pyrimidine salt in the presence of sodium tungstate for reaction, and adjusting the reaction solution to be alkaline after the reaction is finished to obtain the pyrrolidinyl diaminopyrimidine oxynitride.
2. The method of claim 1 for preparing pyrrolidinyl diaminopyrimidine nitroxides, wherein: in the first step, the organic solvent is selected from tetrahydrofuran, ethyl acetate, butyl acetate or toluene.
3. The method of claim 1 for preparing pyrrolidinyl diaminopyrimidine nitroxides, wherein: in the first step, the acid-binding agent is selected from potassium tert-butoxide, sodium methoxide, sodium hydride, sodium tert-butoxide or sodium tert-amylate.
4. The method of claim 1 for preparing pyrrolidinyl diaminopyrimidine nitroxides, wherein: in the first step, the quenching acid is selected from acetic acid or trifluoroacetic acid.
5. The method of claim 1 for preparing pyrrolidinyl diaminopyrimidine nitroxides, wherein: in the first step, the molar ratio of the 2, 4-diamino-6-chloropyrimidine to the tetrahydropyrrole to the base is 1:1.1-1.2: 1.4-3.5.
6. The method of claim 1 for preparing pyrrolidinyl diaminopyrimidine nitroxides, wherein: in the second step, the temperature of the dropping hydrogen peroxide is 10-45 ℃.
7. The method of claim 1 for preparing pyrrolidinyl diaminopyrimidine nitroxides, wherein: in the second step, the molar ratio of the pyrrolidyl diaminopyrimidine salt to hydrogen peroxide is 1: 1.2-1.3.
8. The method of claim 1 for preparing pyrrolidinyl diaminopyrimidine nitroxides, wherein: in the second step, the molar ratio of sodium tungstate to hydrogen peroxide is 0.01-0.02: 1.
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| CN114315738A (en) * | 2022-01-15 | 2022-04-12 | 重庆东寰科技开发有限公司 | Preparation method of 2,4-diaminopyrimidine-3-oxide |
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Cited By (4)
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| CN112174788A (en) * | 2020-11-02 | 2021-01-05 | 浙江凯普化工有限公司 | Preparation method of 2,2,6,6-tetraethyl-3, 5-heptanedione |
| CN112174788B (en) * | 2020-11-02 | 2023-06-20 | 浙江凯普化工有限公司 | Preparation method of 2, 6-tetraethyl-3, 5-heptane dione |
| CN114315738A (en) * | 2022-01-15 | 2022-04-12 | 重庆东寰科技开发有限公司 | Preparation method of 2,4-diaminopyrimidine-3-oxide |
| CN114315738B (en) * | 2022-01-15 | 2023-08-18 | 重庆东寰科技开发有限公司 | Preparation method of 2,4-diaminopyrimidine-3-oxide |
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