Preparation method of R-9-(2-phosphoric acid methoxy propyl) adenine

Abstract

The invention discloses a preparation method of R-9-(2-phosphoric acid methoxy propyl) adenine, which comprises the following specific implementation processes: taking (R)-1-(6-amino-9H-purine-9-yl) propan-2-ol and (bis (benzyloxy) phosphoryl) methyl 4-methyl benzene sulfonate as initial raw materials, adding a solvent and alkali, replacing for three times by using nitrogen, stirring and reacting for 7-14 hours at 60-100 DEG C, after the reaction is finished, separating and purifying to obtain the R-9-(2-phosphoric acid methoxy propyl) adenine. Performing reduced pressure distillation to remove the solvent to obtain a brown yellow oily liquid, adding ethyl acetate, stirring, filtering to obtain a yellow filtrate, adding water into the filtrate for extraction and liquid separation, collecting an organic layer, adding anhydrous sodium sulfate, filtering, and performing rotary evaporation to remove ethyl acetate to obtain a yellow oily product; and finally, carrying out hydrogenation in an autoclave to obtain R-9-(2-phosphoric acid methoxy propyl) adenine. The invention designs a novel synthesis method, the hydrogenation yield of an autoclave is 94-98%, the total yield is 65-72%, and compared with the yield of 59.1% in the existing synthesis route, the yield is improved.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemical synthesis, and specifically relates to a method for preparing R-9-(2-methoxypropyl phosphate) adenine. Background Art

[0002] Tenofovir, R-9-(2-methoxypropyl phosphate) adenine (PMPA) is an important pharmaceutical intermediate, which can be further synthesized into (R)-9-(2-methoxypropyl phosphate) adenine di(isopropyloxycarbonyloxymethyl) ester fumarate, which directly binds to the natural deoxyribose substrate, inhibits viral polymerase, inserts into DNA to prevent its extension, and terminates the DNA chain, thereby achieving the purpose of inhibiting HIV and HBV viruses. The molecular formula of R-9-(2-methoxypropyl phosphate) adenine is C9H 14 N5O4P, relative molecular mass is 287.08, molecular structure formula is:

[0003]

[0004] The existing method for preparing R-9-(2-methoxypropyl phosphate) adenine is: (R)-1-(6-amino-9H-purin-9-yl) propan-2-ol is used as a raw material, and R-9-(2-methoxypropyl phosphate) adenine is generated through two steps of hydroxyl alkylation and ester hydrolysis. The reaction equation is as follows:

[0005]

[0006] The reaction yield of this method is not high, and the total yield of the two steps is 59.1%. At the same time, hydrobromic acid or hydrochloric acid is used in the second step of hydrolysis, and the post-processing reaction steps are complicated and cause great pollution to the environment. Summary of the invention

[0007] In view of the above problems, the object of the present invention is to provide a method for preparing R-9-(2-methoxypropyl phosphate)adenine.

[0008] The specific technical solutions are as follows:

[0009] A preparation method of R-9-(2-methoxypropyl phosphate) adenine comprises the following steps: using (R)-1-(6-amino-9H-purine-9-yl) propan-2-ol and (bis(benzyloxy)phosphoryl)methyl 4-methylbenzenesulfonate as starting materials, adding a solvent and a base, replacing with nitrogen three times, stirring and reacting at 60-100° C. for 7-14 hours, after the reaction is completed, removing the solvent by reduced pressure distillation to obtain a brown-yellow oily liquid, adding ethyl acetate, stirring, and filtering to obtain a yellow filtrate, adding water to the filtrate for extraction and separation, collecting the organic layer, adding anhydrous sodium sulfate, filtering, and removing ethyl acetate by rotary evaporation to obtain a yellow oily product, and finally hydrogenating in an autoclave to obtain R-9-(2-methoxypropyl phosphate) adenine. The reaction equation is as follows:

[0010]

[0011] Furthermore, the added solvent is dimethyl sulfoxide, N-methylpyrrolidone or N,N-dimethylformamide, and the base is magnesium tert-butoxide, sodium carbonate, potassium carbonate or cesium carbonate.

[0012] Further, the molar ratio of (R)-1-(6-amino-9H-purin-9-yl)propan-2-ol to (bis(benzyloxy)phosphoryl)methyl 4-methylbenzenesulfonate is 1:1-3.

[0013] Furthermore, the molar ratio of (R)-1-(6-amino-9H-purin-9-yl)propan-2-ol to the base is 1:2-4.

[0014] Furthermore, the mass ratio of the solvent to (R)-1-(6-amino-9H-purin-9-yl)propan-2-ol is 30-40:1.

[0015] Furthermore, a solvent and a catalyst need to be added during the autoclave hydrogenation process, the solvent is water, ethanol, methanol, a mixed solution of methanol and water, or a mixed solution of ethanol and water, the catalyst is Pd / C, the mass ratio of the solvent to (R)-(((1-(6-amino-9H-purine-9-yl)propan-2-yl)oxy)methyl)phosphonic acid dibenzyl ester and the solution is 18-30:1, the reaction temperature is 30-40°C, the reaction time is 12-16h, the hydrogen pressure is 1Mpa, and the amount of the catalyst (Pd / C) is 20% of the mass of (R)-(((1-(6-amino-9H-purine-9-yl)propan-2-yl)oxy)methyl)phosphonic acid dibenzyl ester.

[0016] Furthermore, the molar ratio of (R)-1-(6-amino-9H-purine-9-yl)propan-2-ol and (bis(benzyloxy)phosphoryl)methyl 4-methylbenzenesulfonate is 1:1.5, the molar ratio of (R)-1-(6-amino-9H-purine-9-yl)propan-2-ol and base is 1:3, the reaction temperature is 70°C, and the reaction time is 9 hours.

[0017] The beneficial effects of the present invention are:

[0018] 1) The present invention designs a new synthesis method, the high pressure autoclave hydrogenation yield is between 94% and 98%, and the total yield is between 65% and 72%, which is higher than the yield of 59.1% of the existing synthesis route;

[0019] 2) The present invention adopts high pressure autoclave hydrogenation to avoid the problem of serious environmental pollution caused by the use of hydrobromic acid or hydrochloric acid in the traditional hydrolysis route. DETAILED DESCRIPTION

[0020] The present invention will be further described below in conjunction with embodiments, but the protection scope of the present invention is not limited thereto.

[0021] Example 1

[0022] A magnet was placed in a 100 ml three-necked flask, a three-way valve with a nitrogen balloon was connected in the middle, a thermometer was inserted into one end, and (R)-1-(6-amino-9H-purine-9-yl)propan-2-ol 1g, tert-butyl magnesium 2.647g, and N-methylpyrrolidone 25ml were added in sequence. After the other end of the three-necked flask was sealed, nitrogen was replaced 3 times, and the temperature was raised to 70°C. Then, a mixture of 3.466g of (bis(benzyloxy)phosphoryl)methyl 4-methylbenzenesulfonate and 10ml of N-methylpyrrolidone was added dropwise to the reaction solution through a 20ml syringe within 10 minutes. The mixture was heated at 70°C. The reaction was stopped after 10 hours of reaction. The solvent N-methylpyrrolidone was removed by reduced pressure distillation to obtain a brown-yellow oily viscous substance. 50 ml of ethyl acetate was added and stirred for 1 hour, and the solution was filtered. The filtrate was transferred to a separatory funnel and 50 ml of water was added for extraction and separation. The organic layer was collected, anhydrous sodium sulfate was added and filtered, and the filtrate was rotary evaporated to remove ethyl acetate to obtain 1.741 g of yellow oily liquid (R)-(((1-(6-amino-9H-purine-9-yl)propan-2-yl)oxy)methyl)phosphonic acid dibenzyl ester with a purity of 95.474% and a yield of 68.71%.

[0023] Add 1.662g of (R)-(((1-(6-amino-9H-purine-9-yl)propan-2-yl)oxy)methyl)phosphonic acid dibenzyl ester, 0.332g of Pd / C, and 40ml of anhydrous methanol in sequence to the polytetrafluoroethylene liner of the autoclave. Close the autoclave, replace the nitrogen three times, introduce hydrogen at a pressure of 1MPa, set the temperature to 30°C, and wait for 12h. After the reaction is completed, the hydrogen pressure is 0.9MPa, transfer the reaction solution to a flask, add 95ml of deionized water, add a magnetron, heat to 70°C, filter while hot to obtain a transparent solution, remove the filtrate by rotary evaporation to obtain 0.93g of white solid R-9-(2-phosphomethoxypropyl)adenine, with a purity of 97% and a yield of 95.56%.

[0024] The total yield of R-9-(2-methoxypropylphosphophosphate)adenine synthesized from (R)-1-(6-amino-9H-purin-9-yl)propan-2-ol was 65.66%.

[0025] (R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonic acid dibenzyl ester NMR data:

[0026] H NMR: (400 MHz, Methanol-d4) δ8.20 (s, 1H), 8.07 (s, 1H), 7.35-7.24 (m, 10H), 5.01-4.89 (m, 4H), 4.32 (dd, J = 14.6, 3.1 Hz, 1H), 4.18 (dd, J = 14.6, 7.7 Hz, 1H), 3.94 (dd, J = 14.0, 8.6 Hz, 2H), 3.74 (dd, J = 14.0, 9.5 Hz, 1H), 1.17 (d, J = 6.2 Hz, 3H).

[0027] C NMR spectrum: 13 C NMR (101MHz, Methanol-d4) δ155.87, 152.32, 149.49, 142.23, 135.96 (t, J = 5.8Hz), 128.27, 127.71, 118.28, 76.23 (d, J = 12.1Hz), 67.95 (dd, J = 6.6, 3.8Hz), 62.77, 61.11, 47.71, 15.31.

[0028] R-9-(2-methoxypropylphosphophosphate)adenine NMR data:

[0029] H NMR: (400 MHz, DMSO-d6) δ8.15 (s, 2H), 7.30 (s, 2H), 4.34-4.12 (m, 2H), 3.95-3.85 (m, 1H), 3.67-3.50 (m, 2H), 1.02 (d, J = 6.2 Hz, 3H).

[0030] C NMR spectrum: 13 C NMR (101MHz, DMSO-d6) δ156.26, 152.61, 150.22, 142.14, 118.68, 75.73 (d, J = 12.4Hz), 64.89 (d, J = 163.0Hz), 46.90, 17.46.

[0031] Example 2

[0032] A magnet was placed in a 100 ml three-necked flask, a three-way valve with a nitrogen balloon was connected in the middle, a thermometer was inserted into one end, and (R)-1-(6-amino-9H-purine-9-yl)propan-2-ol 1g, tert-butyl magnesium 2.647g, and N-methylpyrrolidone 25ml were added in sequence. After the other end of the three-necked flask was sealed, nitrogen was replaced 3 times, and the temperature was raised to 70°C. Then, a mixture of 6.932g of (bis(benzyloxy)phosphoryl)methyl 4-methylbenzenesulfonate and 10ml of N-methylpyrrolidone was added dropwise to the reaction solution through a 20ml syringe within 10 minutes. The mixture was stirred at 70°C. After reacting for 9 hours at ℃, the reaction was stopped. The solvent N-methylpyrrolidone was removed by reduced pressure distillation to obtain a brown-yellow oily viscous substance. 50 ml of ethyl acetate was added and stirred for 1 hour, and the solution was filtered. The filtrate was transferred to a separatory funnel and 50 ml of water was added for extraction and separation. The organic layer was collected, anhydrous sodium sulfate was added and filtered, and the filtrate was rotary evaporated to remove ethyl acetate to obtain a yellow oily liquid (R)-(((1-(6-amino-9H-purine-9-yl)propan-2-yl)oxy)methyl)phosphonic acid dibenzyl ester 1.791 g, purity 94.48%, yield 70.03%

[0033] Add 1.692g of (R)-(((1-(6-amino-9H-purine-9-yl)propan-2-yl)oxy)methyl)phosphonic acid dibenzyl ester, 0.338g of Pd / C, and 40ml of anhydrous methanol in sequence to the polytetrafluoroethylene liner of the autoclave. Close the autoclave, replace the nitrogen three times, introduce hydrogen at a pressure of 1MPa, set the temperature to 30°C, and wait for 14h. After the reaction is completed, the hydrogen pressure is 0.91MPa, transfer the reaction solution to a flask, add 95ml of deionized water, add a magnetron, heat to 70°C, filter while hot to obtain a transparent solution, remove the filtrate by rotary evaporation to obtain 0.99g of white solid R-9-(2-phosphomethoxypropyl)adenine, with a purity of 98% and a yield of 93.46%.

[0034] The total yield of R-9-(2-methoxypropylphosphophosphate)adenine synthesized from (R)-1-(6-amino-9H-purin-9-yl)propan-2-ol was 65.42%.

[0035] Example 3

[0036] A magnet was added to a 100ml three-necked flask, a three-way valve with a nitrogen balloon was connected in the middle, a thermometer was inserted into one port, and 1g of (R)-1-(6-amino-9H-purine-9-yl)propan-2-ol, 2.647g of magnesium tert-butylate, and 25ml of N,N-dimethylformamide were added in sequence. After the other end of the three-necked flask was sealed, nitrogen was replaced three times, and the temperature was raised to 80°C. Then, a mixture of 3.466g of (bis(benzyloxy)phosphoryl)methyl 4-methylbenzenesulfonate and 10ml of N,N-dimethylformamide was dripped into the reaction solution through a 20ml syringe within 10 minutes. After reacting at 80°C for 8 hours, the reaction was stopped. The solvent N-methylpyrrolidone was removed by reduced pressure distillation to obtain a brown-yellow oily viscous substance. 50 ml of ethyl acetate was added and stirred for 1 hour, and the solution was filtered. The filtrate was transferred to a separatory funnel and 50 ml of water was added for extraction and separation. The organic layer was collected, anhydrous sodium sulfate was added and filtered, and the filtrate was rotary evaporated to remove ethyl acetate to obtain 1.77 g of yellow oily liquid (R)-(((1-(6-amino-9H-purine-9-yl)propan-2-yl)oxy)methyl)phosphonic acid dibenzyl ester with a purity of 96.7% and a yield of 70.75%.

[0037] Add 1.711g of (R)-(((1-(6-amino-9H-purine-9-yl)propan-2-yl)oxy)methyl)phosphonic acid dibenzyl ester, 0.342g of Pd / C, and 40ml of anhydrous methanol in sequence to the polytetrafluoroethylene liner of the autoclave. Close the autoclave, replace the nitrogen three times, introduce hydrogen at a pressure of 1MPa, set the temperature to 40°C, and wait for 16h. After the reaction is completed, the hydrogen pressure is 0.89MPa, transfer the reaction solution to a flask, add 95ml of deionized water, add a magnetron, heat to 70°C, filter while hot to obtain a transparent solution, remove the filtrate by rotary evaporation to obtain 1.01g of white solid R-9-(2-phosphomethoxypropyl)adenine, with a purity of 98% and a yield of 94.26%.

[0038] The total yield of R-9-(2-methoxypropylphosphophosphate)adenine synthesized from (R)-1-(6-amino-9H-purin-9-yl)propan-2-ol was 66.69%.

[0039] Example 4

[0040] A magnet was placed in a 100 ml three-necked flask, a three-way valve with a nitrogen balloon was connected in the middle, a thermometer was inserted into one end, and (R)-1-(6-amino-9H-purine-9-yl)propan-2-ol 1g, tert-butyl magnesium 2.647g, and N-methylpyrrolidone 25ml were added in sequence. After the other end of the three-necked flask was sealed, nitrogen was replaced 3 times, and the temperature was raised to 70°C. Then, a mixture of (bis(benzyloxy)phosphoryl)methyl 4-methylbenzenesulfonate 3.466g and 10ml N-methylpyrrolidone was added dropwise to the reaction solution through a 20ml syringe within 10 minutes. After reacting for 9 hours at 0°C, the reaction was stopped. The solvent N-methylpyrrolidone was removed by reduced pressure distillation to obtain a brown-yellow oily viscous substance. 50 ml of ethyl acetate was added and stirred for 1 hour, and the solution was filtered. The obtained filtrate was transferred to a separatory funnel and 50 ml of water was added for extraction and separation. The organic layer was collected, anhydrous sodium sulfate was added and filtered, and the obtained filtrate was rotary evaporated to remove ethyl acetate to obtain a yellow oily liquid (R)-(((1-(6-amino-9H-purine-9-yl)propan-2-yl)oxy)methyl)phosphonic acid dibenzyl ester 1.841 g, purity 95.6%, yield 72.75%

[0041] Add 1.759 g of (R)-(((1-(6-amino-9H-purine-9-yl)propan-2-yl)oxy)methyl)phosphonic acid dibenzyl ester, 0.351 g of Pd / C, and 40 ml of anhydrous methanol in sequence to the polytetrafluoroethylene liner of the autoclave. Close the autoclave, replace the nitrogen three times, introduce hydrogen at a pressure of 1 MPa, set the temperature to 30°C, and wait for 14 hours. After the reaction is completed, the hydrogen pressure is 0.88 MPa, transfer the reaction solution to a flask, add 95 ml of deionized water, add a magnetron, heat to 70°C, filter while hot to obtain a transparent solution, remove the filtrate by rotary evaporation to obtain 1.05 g of white solid R-9-(2-phosphomethoxypropyl)adenine, with a purity of 98% and a yield of 95.36%.

[0042] The total yield of R-9-(2-methoxypropylphosphophosphate)adenine synthesized from (R)-1-(6-amino-9H-purin-9-yl)propan-2-ol was 69.37%.

Claims

1. A method for preparing R-9-(2-methoxypropyl phosphate) adenine, characterized in that: The method comprises the following steps: using (R)-1-(6-amino-9H-purine-9-yl)propan-2-ol and (bis(benzyloxy)phosphoryl)methyl 4-methylbenzenesulfonate as starting materials, adding a solvent and a base, replacing with nitrogen three times, stirring and reacting at 60-100° C. for 7-14 hours, and after the reaction is completed, removing the solvent by reduced pressure distillation to obtain a brown-yellow oily liquid, adding ethyl acetate, stirring, and filtering to obtain a yellow filtrate, adding water to the filtrate for extraction and separation, collecting the organic layer, adding anhydrous sodium sulfate, filtering, and rotary evaporation to remove ethyl acetate to obtain a yellow oily product (R)-(((1-(6-amino-9H-purine-9-yl)propan-2-yl)oxy)methyl)phosphonic acid dibenzyl ester, and finally hydrogenating in an autoclave to obtain R-9-(2-phosphorylmethoxypropyl)adenine. The reaction equation is as follows:

2. The method for preparing R-9-(2-methoxypropyl phosphate)adenine according to claim 1, characterized in that: The added solvent is dimethyl sulfoxide, N-methylpyrrolidone or N,N-dimethylformamide, and the base is magnesium tert-butoxide, sodium carbonate, potassium carbonate or cesium carbonate.

3. The method for preparing R-9-(2-methoxypropyl phosphate)adenine according to claim 1, characterized in that: The molar ratio of (R)-1-(6-amino-9H-purin-9-yl)propan-2-ol and (bis(benzyloxy)phosphoryl)methyl 4-methylbenzenesulfonate is 1:1-3.

4. The method for preparing R-9-(2-methoxypropyl phosphate)adenine according to claim 2, characterized in that: The molar ratio of (R)-1-(6-amino-9H-purin-9-yl)propan-2-ol to the base is 1:2-4.

5. The method for preparing R-9-(2-methoxypropyl phosphate)adenine according to claim 2, characterized in that: The mass ratio of the solvent to (R)-1-(6-amino-9H-purin-9-yl)propan-2-ol is 30-40:

1.

6. The method for preparing R-9-(2-methoxypropyl phosphate)adenine according to claim 1, characterized in that: Solvent and catalyst need to be added in the autoclave hydrogenation process, the solvent is water, ethanol, methanol, a mixed solution of methanol and water or a mixed solution of ethanol and water, the catalyst is Pd / C, the mass ratio of the solvent to (R)-(((1-(6-amino-9H-purine-9-yl)propan-2-yl)oxy)methyl)phosphonic acid dibenzyl ester and the solution is 18-30:1, the solution reaction temperature is 30-40°C, the reaction time is 12-16h, the hydrogen pressure is 1Mpa, and the amount of the catalyst Pd / C is 20% of the mass of (R)-(((1-(6-amino-9H-purine-9-yl)propan-2-yl)oxy)methyl)phosphonic acid dibenzyl ester.

7. The method for preparing R-9-(2-methoxypropyl phosphate) adenine according to claim 1, characterized in that: The molar ratio of (R)-1-(6-amino-9H-purin-9-yl)propan-2-ol and (bis(benzyloxy)phosphoryl)methyl 4-methylbenzenesulfonate is 1:1.5, the molar ratio of (R)-1-(6-amino-9H-purin-9-yl)propan-2-ol and base is 1:3, the reaction temperature is 70°C, and the reaction time is 9 hours.

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