CN110272454B - Preparation method of (R) -9- [ (2-phenoxyl phosphomethoxy) propyl ] adenine - Google Patents
Preparation method of (R) -9- [ (2-phenoxyl phosphomethoxy) propyl ] adenine Download PDFInfo
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- CN110272454B CN110272454B CN201810221133.XA CN201810221133A CN110272454B CN 110272454 B CN110272454 B CN 110272454B CN 201810221133 A CN201810221133 A CN 201810221133A CN 110272454 B CN110272454 B CN 110272454B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
Abstract
The invention provides a process method for synthesizing tenofovir alafenamide intermediate (R) -9- [ (2-phenoxyl methoxyl phosphate) propyl ] adenine, which takes (R) -9- (2-phenoxyl methoxyl phosphate propyl) adenine as a starting material and reacts with diphenyl phosphite or diphenyl phosphite and phenol in the presence of a proper solvent M. The solvent M is selected from pyridine, 2, 6-lutidine, triethylamine and diisopropylethylamine; pyridine is preferred. The method has the beneficial effects that: diphenyl phosphite is adopted for esterification reaction in the preparation process of the compound shown in the formula I, so that the yield and the purity are greatly improved, the yield reaches over 90 percent and the purity reaches over 98 percent in a specific experiment, and the production cost is greatly reduced; the method is simple to operate, short in reaction time, high in production efficiency and easy to amplify; in addition, the method has simple post-treatment process and little environmental pollution, and is suitable for industrial production.
Description
Technical Field
The invention relates to a synthesis method of an important intermediate of tenofovir alafenamide fumarate, in particular to a process synthesis method of (R) -9- [ (2-phenoxyl methoxyl phosphate) propyl ] adenine, belonging to the technical field of medicines and intermediates thereof.
Background
Tenofovir alafenamide fumarate (compound of formula II, trade name: VEMLIDY) is a Hepatitis B Virus (HBV) nucleoside analogue reverse transcriptase inhibitor and is useful as a treatment for chronic hepatitis B virus infection in the adult with compensated liver disease. When the dosage of the medicament is less than one tenth of that of Viread (Viread, TDF) which is a medicament sold in the market of Jilidedi, the medicament has very high antiviral effect, and can improve renal function and bone parameters. In addition, two-in-one and three-in-one compound containing tenofovir alafenamide fumarate is also available on the market as a medicine for treating HIV infection.
The compound of formula I is a key intermediate for synthesizing tenofovir alafenamide fumarate. There are two main methods for the synthesis of the compounds of formula I reported so far:
firstly, directly preparing a compound of a formula I from tenofovir;
secondly, preparing the compound shown in the formula I by selective hydrolysis of tenofovir disoproxil or mixed ester.
Among them, method one reports a process for the preparation of compounds of formula I under 4 different conditions:
patent WO0208241 discloses the preparation of compounds of formula I using two methods:
taking tenofovir as a raw material and NMP (N-methylpyrrolidone) as a solvent, and reacting with phenol under the action of DCC (dicyclohexylcarbodiimide) and triethylamine to prepare the compound shown in the formula I, wherein the reaction formula is as follows:
the method has low yield of only 50 percent, and a coupling reagent DCC (dicyclohexylcarbodiimide) is used in the preparation process, and a large amount of byproducts which are difficult to remove are generated after the reaction of the reagent, so that the purification difficulty of the product is increased.
Reacting tenofovir serving as a raw material and sulfolane serving as a solvent with thionyl chloride under the catalysis of DMF to prepare acyl chloride, and then reacting with phenoxy trimethylsilane to prepare the compound, wherein the reaction formula is as follows:
the yield of the method can reach 80%, but the preparation process uses non-conventional reagents of sulfolane and phenoxytrimethylsilane, and the product cost is increased.
The third method can be seen in patent WO2013052094, which discloses a method for preparing a compound of formula I by reacting tenofovir as a raw material with triphenyl phosphite under the action of triethylamine and N, N-dimethylaminopyridine, using acetonitrile as a solvent, wherein the reaction formula is as follows:
the yield of the method is only 81%, the reaction time is at least 48 hours, the time consumption is long, the energy consumption is large during industrial amplification, and the yield is not high, so that the production cost is high and the efficiency is low on the whole; in addition, the post-treatment process of the method still needs extraction and washing, products need to be separated out in a water phase, the process is complicated, and the generated waste liquid and solid waste are more, so that the method is not beneficial to environmental protection.
The fourth method, Hangzhou and ze medicine company, in patent CN104628773A, discloses that tenofovir reacts directly with triphenyl phosphite in pyridine solvent to prepare the compound of formula I, the reaction formula is as follows:
it is disclosed in the patent that when pyridine is used as a solvent, the post-treatment operation is simple, but the yield is as high as 89.9%, the purity is as high as 95.9%, and the reaction time is long.
Method two can be seen in patent CN107021984, which is a method for preparing a compound of formula I by selective hydrolysis of a diphenyl tenofovir or a mixed phenyl ester, the reaction formula is as follows:
the method firstly prepares the tenofovir disoproxil diphenyl ester, then prepares the mixed phosphate ester by ester exchange, and finally prepares the compound shown in the formula I by hydrolyzing the tenofovir disoproxil diphenyl ester or the mixed phosphate ester (the compound shown in the formula III), the operation process is complex, and the control difficulty of selectively hydrolyzing an ester group is higher during hydrolysis.
Disclosure of Invention
In order to solve the technical problem, the invention provides a method for preparing a compound shown in the formula I by reacting tenofovir and diphenyl phosphite.
After extensive research in the literature, the inventors did not find any report on the phenylation reaction using diphenyl phosphite, and the inventors have surprisingly found that: diphenyl phosphite is adopted for esterification reaction in the preparation process of the compound shown in the formula I, so that the yield and the purity are greatly improved, the yield reaches over 90 percent and the purity reaches over 98 percent in a specific experiment, and the production cost is greatly reduced; the method is simple to operate, short in reaction time, high in production efficiency and easy to amplify; in addition, the method has simple post-treatment process and little environmental pollution, and is suitable for industrial production.
The invention firstly provides a first process for the preparation of a compound of the formula I,
which comprises reacting tenofovir and diphenyl phosphite in the presence of a suitable solvent M
To obtain a compound of formula I;
the suitable solvent M is an alkaline solvent selected from pyridine, 2, 6-lutidine, triethylamine, diisopropylethylamine; a preferred suitable solvent M is pyridine.
The preparation method of the invention adopts diphenyl phosphite which is never used in the prior art as a raw material, and the diphenyl phosphite reacts with tenofovir in the presence of an alkaline solvent M to prepare the compound shown in the formula I. The preparation method has the advantages of easily available raw materials, simple operation, short reaction time, easy amplification and suitability for industrial production, and the prepared target product has the yield of more than 90 percent and the purity of more than 98 percent, thereby greatly reducing the production cost and improving the production efficiency. Especially when the appropriate solvent M is pyridine, the reaction time is greatly shortened, the reaction efficiency is integrally improved, and the yield and the purity are also improved to a certain degree.
In a preferred embodiment of the preparation method, the feeding molar ratio of tenofovir and diphenyl phosphite is 1: 2-10, and most preferably 1: 3-6.
In the preparation method, in a preferred embodiment, the reaction temperature is 80-140 ℃, preferably 90-120 ℃, and most preferably 100-110 ℃. When the reaction temperature is 90-120 ℃, the reaction speed is increased, and the effect is good; when the reaction temperature is 100-110 ℃, the reaction speed and the effect are good, the reaction time is saved, and the efficiency is further improved.
In the preparation method of the present invention, preferably, after the reaction is completed, the reaction solution is subjected to post-treatment;
the post-treatment comprises treatment with a suitable solvent N;
the suitable solvent N is selected from alcohols, esters, ethers or ketones, including methanol, ethanol, isopropanol, ethyl acetate, methyl acetate, isopropyl acetate, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, isopropyl ether, acetone or butanone;
preferably, the suitable solvent N is selected from ethereal solvents including tetrahydrofuran, diethyl ether, methyl tert-butyl ether or isopropyl ether; most preferably the suitable solvent N is methyl tert-butyl ether.
In the invention, when the proper solvent N adopts an ether solvent, the impurity removal effect is better.
The term "treatment" as used in the work-up procedure of the present invention means to separate or extract the desired product from the reaction solution by conventional treatment methods in the art, such as beating, extraction, washing, drying, vacuum concentration, recrystallization, etc.
In the post-treatment procedure of the present invention, the treatment with the solvent N comprises: the reaction solution is filtered, and the resulting filter cake is washed or slurried with a suitable solvent N and then dried.
The preparation method has simple and easy post-treatment operation, less waste liquid and solid waste and less environmental pollution.
The preparation method of the invention comprises the following steps in a group of preferred embodiments:
(1) adding tenofovir and diphenyl phosphite into a proper solvent M at 0-120 ℃;
(2) heating to 80-140 ℃, stirring and reacting for 0-24 hours, and cooling to below 30 ℃ after the reaction is finished;
(3) filtering, washing or pulping the filter cake by using a proper solvent N, and then drying to prepare the (R) -9- [ (2-phenoxyl phosphomethoxyl) propyl ] adenine.
The preparation method of the invention, in a group of preferred embodiments, comprises: in the step (1):
the feeding temperature is 0-80 ℃;
the feeding molar ratio of the tenofovir to the diphenyl phosphite is 1: 2-10, and 1: 3-6 is more preferable;
said suitable solvent M is a basic solvent selected from pyridine, 2, 6-lutidine, triethylamine or diisopropylethylamine, most preferably pyridine;
in the step (2): the temperature of the stirring reaction is 90-120 ℃;
in the step (3): the suitable solvent N is selected from alcohols, esters, ethers or ketones, including methanol, ethanol, isopropanol, ethyl acetate, methyl acetate, isopropyl acetate, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, isopropyl ether, acetone or butanone,
more preferably, the suitable solvent N is selected from ethereal solvents including tetrahydrofuran, diethyl ether, methyl tert-butyl ether or isopropyl ether, most preferably the suitable solvent N is methyl tert-butyl ether.
In the invention, when the proper solvent N adopts an ether solvent, the impurity removal effect is better.
According to the preparation method disclosed by the invention, most preferably, the feeding temperature in the step (1) is 0-30 ℃; the temperature of the stirring reaction in the step (2) is 100-110 ℃.
In the preferred embodiment, the feeding temperature is selected at room temperature, the operation steps are simple, the working procedure and time are saved, and the overall reaction efficiency is improved.
The invention also provides a second process for the preparation of a compound of formula I,
which comprises reacting tenofovir and diphenyl phosphite with phenol in the presence of a suitable solvent M
To obtain a compound of formula I;
the suitable solvent M is an alkaline solvent selected from pyridine, 2, 6-lutidine, triethylamine, diisopropylethylamine; a preferred suitable solvent M is pyridine.
The preparation method of the invention adopts diphenyl phosphite which is never used in the prior art as a starting material, and reacts with tenofovir and phenol in the presence of an alkaline solvent M to prepare the compound shown in the formula I. The preparation method has the advantages of easily available raw materials, simple operation, short reaction time, easy amplification and suitability for industrial production, and the prepared target product has the yield of more than 90 percent and the purity of more than 98 percent, thereby greatly reducing the production cost and improving the production efficiency. Especially when the appropriate solvent M is pyridine, the reaction time is greatly shortened, the reaction efficiency is integrally improved, and the yield and the purity are also improved to a certain degree.
In a preferred embodiment of the preparation method of the present invention, the feeding molar ratio of tenofovir to diphenyl phosphite to phenol is 1:1:1 to 1:10:10, and most preferably 1:2:2 to 1:4: 8.
In the preparation method, in a preferred embodiment, the reaction temperature is 80-140 ℃, preferably 90-120 ℃, and most preferably 100-110 ℃. When the reaction temperature is 90-120 ℃, the reaction speed is increased, and the effect is good; when the reaction temperature is 100-110 ℃, the reaction speed and the effect are good, the reaction time is saved, and the efficiency is further improved.
In the preparation method of the present invention, preferably, after the reaction is completed, the reaction solution is subjected to post-treatment;
the post-treatment comprises treatment with a suitable solvent N;
the suitable solvent N is selected from alcohols, esters, ethers or ketones, including methanol, ethanol, isopropanol, ethyl acetate, methyl acetate, isopropyl acetate, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, isopropyl ether, acetone or butanone;
preferably, the suitable solvent N is selected from ethereal solvents including tetrahydrofuran, diethyl ether, methyl tert-butyl ether or isopropyl ether; the most preferred suitable solvent N is methyl tert-butyl ether.
In the invention, when the proper solvent N adopts an ether solvent, the impurity removal effect is better.
The term "treatment" as used in the post-treatment procedure of the present invention means to separate or extract the target product from the reaction solution by the conventional treatment methods in the art, such as beating, extraction, washing, drying, vacuum concentration, recrystallization, etc.
In the post-treatment procedure of the present invention, the treatment with the solvent N comprises: the reaction solution is filtered, and the resulting filter cake is washed or slurried with a suitable solvent N and then dried.
The preparation method has simple and easy post-treatment operation, less waste liquid and solid waste and less environmental pollution.
The preparation method of the invention comprises the following steps in a group of preferred embodiments:
(1) adding tenofovir, diphenyl phosphite and phenol into a proper solvent M at 0-120 ℃;
(2) heating to 80-140 ℃, stirring and reacting for 0-24 hours, and cooling to below 30 ℃ after the reaction is finished;
(3) filtering, washing or pulping the filter cake by using a proper solvent N, and then drying to prepare the (R) -9- [ (2-phenoxyl phosphomethoxyl) propyl ] adenine.
The preparation method of the invention, in a group of preferred embodiments, comprises: in the step (1):
the feeding temperature is 0-80 ℃;
the feeding molar ratio of tenofovir to diphenyl phosphite to phenol is 1:1: 1-1: 10:10, preferably 1:2: 2-1: 4: 8;
the suitable solvent M is a basic solvent selected from pyridine, 2, 6-lutidine, triethylamine, diisopropylethylamine, most preferably pyridine;
in the step (2): the temperature of the stirring reaction is 90-120 ℃;
in the step (3): the suitable solvent N is selected from alcohols, esters, ethers or ketones, including methanol, ethanol, isopropanol, ethyl acetate, methyl acetate, isopropyl acetate, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, isopropyl ether, acetone or butanone,
more preferably, the suitable solvent N is selected from ethereal solvents including tetrahydrofuran, diethyl ether, methyl tert-butyl ether or isopropyl ether, most preferably the suitable solvent N is methyl tert-butyl ether.
In the invention, when the proper solvent N adopts an ether solvent, the impurity removal effect is better.
According to the preparation method disclosed by the invention, most preferably, the feeding temperature in the step (1) is 0-30 ℃; the temperature of the stirring reaction in the step (2) is 100-110 ℃.
In the preferred embodiment, the feeding temperature is selected at room temperature, the operation steps are simple, the working procedure and time are saved, and the overall reaction efficiency is improved.
Detailed Description
The invention is further illustrated by the following examples. It should be understood that: the embodiments of the present invention are given for illustration only and not for limitation, and the simple modifications of the present invention in the light of the technical solutions of the present invention are within the scope of the present invention.
Example 1
Adding 16mL of pyridine into a reaction bottle at room temperature, adding 2.0g of tenofovir and 6.5g of diphenyl phosphite, heating the system to 110-120 ℃, reacting for 4 hours at the temperature, detecting by TLC (thin layer chromatography) until the tenofovir basically disappears, cooling the reaction system to room temperature, filtering, washing a filter cake with 20mL of methyl tert-butyl ether, and drying to obtain 2.31g of the compound shown in the formula I, wherein the yield is 91.7%, and the purity is 99.1%.
Comparative example 1
Adding 16mL of pyridine into a reaction bottle at room temperature, adding 2.0g of tenofovir and 8.6g of triphenyl phosphite, heating the system to 110-120 ℃, reacting for 8 hours at the temperature, detecting by TLC until the tenofovir basically disappears, cooling the reaction system to room temperature, filtering, washing a filter cake with 20mL of ethyl acetate, and drying to obtain 2.23g of the compound of the formula I, wherein the yield is 88.1% and the purity is 96.0%.
The following table shows the main parameter pairs for example 1 and comparative example 1:
as can be seen from the above table, the technical scheme of the invention adopts diphenyl phosphite as the starting material under the same conditions, so that the reaction time is short, the yield is high, and the purity is high.
Example 2
Adding 16mL of pyridine into a reaction bottle at room temperature, adding 2.0g of tenofovir and 16.3g of diphenyl phosphite, heating the system to 100-110 ℃, reacting for 6 hours at the temperature, detecting by TLC (thin layer chromatography) until the tenofovir serving as a raw material basically disappears, cooling the reaction system to room temperature, filtering, washing a filter cake with 20mL of ethyl acetate, and drying to obtain 2.30g of the compound shown in the formula I, wherein the yield is 90.9%, and the purity is 98.0%.
Example 3
Adding 16mL of pyridine into a reaction bottle at room temperature, adding 2.0g of tenofovir and 6.5g of diphenyl phosphite, heating the system to 100-110 ℃, reacting for 6 hours at the temperature, detecting by TLC (thin layer chromatography) until the tenofovir serving as a raw material basically disappears, cooling the reaction system to room temperature, filtering, washing a filter cake with 20mL of isopropyl ether slurry, and drying to obtain 2.29g of a compound shown in the formula I, wherein the yield is 90.6% and the purity is 99.0%.
Example 4
Adding 64mL of pyridine into a reaction bottle at room temperature, adding 8.0g of tenofovir, 13.0g of diphenyl phosphite and 5.2g of phenol, heating the system to 100-110 ℃, reacting for 6 hours, detecting by TLC (thin layer chromatography) until the tenofovir basically disappears, cooling the reaction system to room temperature, filtering, washing a filter cake with 40mL of ethyl acetate, and drying to obtain 9.10g of a compound shown in the formula I, wherein the yield is 89.9% and the purity is 98.5%.
Example 5
Adding 64L of pyridine into a 100L middle reaction kettle at room temperature, adding 8.0kg of tenofovir, 19.6kg of diphenyl phosphite and 13.1kg of phenol, heating the system to 100-110 ℃, reacting for 2 hours, detecting by TLC to show that the tenofovir basically disappears, cooling the reaction system to room temperature, filtering, washing a filter cake with 40L of methyl tert-butyl ether, filtering, and drying to obtain 9.11kg of a compound shown as a product formula I, wherein the yield is 90.0%, and the purity is 99.2%.
Example 6
Adding 64mL of pyridine into a reaction bottle at room temperature, adding 8.0g of tenofovir, 26.1g of diphenyl phosphite and 21.0g of phenol, heating the system to 100-110 ℃ for reaction for 2 hours, detecting by TLC (thin layer chromatography) until the tenofovir basically disappears, cooling the reaction system to room temperature, filtering, washing a filter cake with 40mL of methyl tert-butyl ether, and drying to obtain 9.61g of a compound shown in the formula I, wherein the yield is 95.0% and the purity is 98.8%.
Example 7
At room temperature, adding 64mL of 2, 6-lutidine into a reaction bottle, adding 8.0g of tenofovir, 19.6g of diphenyl phosphite and 13.1g of phenol, heating the system to 110-120 ℃, reacting for 24 hours, detecting by TLC (thin layer chromatography) until the tenofovir basically disappears, cooling the reaction system to room temperature, filtering, washing a filter cake with 40mL of methyl tert-butyl ether, and drying to obtain 8.92g of a compound shown as a formula I, wherein the yield is 88.1% and the purity is 95.8%.
Example 8
Adding 64mL of pyridine into a reaction bottle at room temperature, adding 8.0g of tenofovir, 19.6g of diphenyl phosphite and 13.1g of phenol, heating the system to 100-110 ℃, reacting for 2 hours, detecting by TLC (thin layer chromatography) until the tenofovir basically disappears, cooling the reaction system to room temperature, filtering, washing a filter cake with 40mL of methyl tert-butyl ether, and drying to obtain 9.61g of a compound shown in the formula I, wherein the yield is 95.0% and the purity is 99.1%.
Example 9
Adding 64mL of pyridine into a reaction bottle at room temperature, adding 8.0g of tenofovir, 19.6g of diphenyl phosphite and 13.1g of phenol, heating the system to 110-120 ℃, reacting for 2 hours, detecting by TLC (thin layer chromatography) until the tenofovir serving as a raw material basically disappears, cooling the reaction system to room temperature, filtering, washing a filter cake by 40mL of methanol slurry, and drying to obtain 9.52g of a compound shown in the formula I, wherein the yield is 94.1% and the purity is 98.1%.
Example 10
Adding 64mL of pyridine into a reaction bottle at room temperature, adding 8.0g of tenofovir, 19.6g of diphenyl phosphite and 13.1g of phenol, heating the system to 100-110 ℃, reacting for 2 hours, detecting by TLC (thin layer chromatography) until the tenofovir serving as a raw material basically disappears, cooling the reaction system to room temperature, filtering, washing a filter cake by using 40mL of isopropyl ether, and drying to obtain 9.22g of a compound shown as a product in a formula I, wherein the yield is 91.1% and the purity is 98.8%.
Claims (23)
1. A process for the preparation of a compound of formula I,
which comprises the reaction of tenofovir and diphenyl phosphite with pyridine as solvent
To obtain the compound of formula I.
2. The preparation method according to claim 1, wherein the charging molar ratio of tenofovir to diphenyl phosphite is 1: 2-10.
3. The preparation method according to claim 1, wherein the charging molar ratio of tenofovir to diphenyl phosphite is 1: 3-6.
4. A process for the preparation of a compound of formula I,
which comprises using pyridine as solvent, reacting tenofovir and diphenyl phosphite with phenol
To obtain the compound of formula I.
5. The preparation method according to claim 4, wherein the charging molar ratio of tenofovir to diphenyl phosphite to phenol is 1:1: 1-1: 10: 10.
6. The preparation method according to claim 4, wherein the feeding molar ratio of tenofovir to diphenyl phosphite to phenol is 1:2:2 to 1:4: 8.
7. The production method according to claim 1 or 4, wherein the reaction temperature is 80 to 140 ℃.
8. The production method according to claim 1 or 4, wherein the reaction temperature is 90 to 120 ℃.
9. The production method according to claim 1 or 4, wherein the reaction temperature is 100 to 110 ℃.
10. The production method according to claim 1 or 4, wherein after the completion of the reaction, a reaction solution is subjected to a post-treatment; the post-treatment comprises treatment with a suitable solvent N; the suitable solvent N is selected from alcohols, esters, ethers or ketones.
11. The method according to claim 10, wherein the solvent N is selected from methanol, ethanol, isopropanol, ethyl acetate, methyl acetate, isopropyl acetate, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, isopropyl ether, acetone and methyl ethyl ketone.
12. The process according to claim 10, wherein the suitable solvent N is selected from tetrahydrofuran, diethyl ether, methyl tert-butyl ether or isopropyl ether.
13. The method of claim 10, wherein the suitable solvent is N-methyl tert-butyl ether.
14. The method of manufacturing according to claim 1, comprising the steps of:
(1) adding tenofovir and diphenyl phosphite into pyridine at 0-120 ℃;
(2) heating to 80-140 ℃, stirring and reacting for 0-24 hours, and cooling to below 30 ℃ after the reaction is finished;
(3) filtering, washing or pulping the filter cake by using a proper solvent N, and then drying to prepare the (R) -9- [ (2-phenoxyl phosphomethoxyl) propyl ] adenine.
15. The method of claim 4, comprising the steps of:
(1) adding tenofovir, diphenyl phosphite and phenol into pyridine at 0-120 ℃;
(2) heating to 80-140 ℃, stirring and reacting for 0-24 hours, and cooling to below 30 ℃ after the reaction is finished;
(3) filtering, washing or pulping the filter cake by using a proper solvent N, and then drying to prepare the (R) -9- [ (2-phenoxyl phosphomethoxyl) propyl ] adenine.
16. The production method according to claim 14 or 15,
in the step (1): the feeding temperature is 0-80 ℃;
in the step (2): the temperature of the stirring reaction is 90-120 ℃;
in the step (3): the suitable solvent N is selected from alcohols, esters, ethers or ketones.
17. The process according to claim 16, wherein the suitable solvent N is selected from methanol, ethanol, isopropanol, ethyl acetate, methyl acetate, isopropyl acetate, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, isopropyl ether, acetone or butanone.
18. The production method according to claim 14, wherein in step (1): the feeding molar ratio of the tenofovir to the diphenyl phosphite is 1: 2-10.
19. The production method according to claim 14, wherein in step (1): the feeding molar ratio of the tenofovir to the diphenyl phosphite is 1: 3-6.
20. The production method according to claim 15, wherein in step (1): the feeding molar ratio of tenofovir to diphenyl phosphite to phenol is 1:1: 1-1: 10: 10.
21. The production method according to claim 15, wherein in step (1): the feeding molar ratio of tenofovir to diphenyl phosphite to phenol is 1:2: 2-1: 4: 8.
22. The production method according to claim 16, wherein,
in the step (1): the feeding temperature is 0-30 ℃;
in the step (2): the temperature of the stirring reaction is 100-110 ℃;
in the step (3): the suitable solvent N is selected from tetrahydrofuran, diethyl ether, methyl tert-butyl ether or isopropyl ether.
23. The production method according to claim 16, wherein in step (3): the suitable solvent N is methyl tert-butyl ether.
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