Preparation method of tenofovir intermediate R-(+)-9-(2-hydroxypropyl) adenine
The problem of high isomer impurities is solved by using adenine and R-propylene oxide catalyzed with sodium hydroxide, and the preparation of tenofovir intermediates with high purity and high yield is achieved, reducing energy consumption and cost.
Patent Information
- Application Number
- CN202510611624.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-05-13
- Publication Date
- 2025-08-15
AI Technical Summary
Prior Art When synthesizing the tenofovir intermediate R-(+)-9-(2-hydroxypropyl) adenine, the isomer impurity content is high, which affects the purity and yield of the product.
Adenine and R-propylene oxide were used as raw materials, tetraethylammonium bromide was used as catalyst, and the ring-opening condensation reaction was carried out under the action of sodium hydroxide, and the non-aqueous polar solvent DMF was used as the medium to control the reaction conditions to generate the tenofovir intermediate R-(+)-9-(2-hydroxypropyl)adenine.
The isomer impurity content is significantly reduced to less than 2%, the molar yield of T3 is increased to 98%, and the reaction temperature and time are reduced, side reaction impurities are reduced, production energy consumption is reduced, raw materials are cheap and easy to operate.
Smart Images
Figure BDA0005399840050000021 
Figure BDA0005399840050000022 
Figure BDA0005399840050000031
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of chemical pharmacy and relates to a method for preparing a tenofovir intermediate R-(+)-9-(2-hydroxypropyl)adenine. Background Art
[0002] Tenofovir, chemically known as (R)-9-(2-methoxypropylphosphate)adenine, also known as tenofovir, is a key intermediate in the antiviral drug tenofovir disoproxil fumarate. Tenofovir disoproxil fumarate is a novel ring-opening nucleotide reverse transcriptase inhibitor that rapidly converts to active tenofovir after oral administration. Developed by Gilead Sciences, tenofovir disoproxil fumarate was first marketed in the United States in October 2001 as an anti-AIDS drug, with a dose of up to 300 mg / day. In August 2008, the FDA approved tenofovir disoproxil fumarate for use against hepatitis B. In 2011, tenofovir disoproxil fumarate was marketed in China as an anti-AIDS drug and in 2014 as a treatment for chronic hepatitis B.
[0003] Tenofovir disoproxilfumarate (Tenofovir bis(isopropyloxymethyl)fumarate), chemically known as (R)-[[2-(6-amino-9H-purin-9-yl]-1-methylethoxy]methyl]phosphonic acid bis(isopropyloxymethyl)fumarate, is an orally available ring-opening nucleotide monophosphonate prodrug that is rapidly converted to tenofovir (PMPA,2) after oral absorption. PMPA has been shown to exhibit broad-spectrum antiviral activity against human immunodeficiency virus (HIV) and other retroviruses and was approved by the US FDA in 2001 for the clinical treatment of AIDS. Tenofovir disoproxil fumarate is also undergoing clinical trials for the treatment of chronic hepatitis B virus (HBV) infection, with the hope of using it as a first-line anti-HBV treatment or in combination with other anti-HBV drugs.
[0004] R-(+)-9-(2-Hydroxypropyl)adenine (T3) is a key intermediate in tenofovir, and its quality and cost have a crucial impact on the quality of the product. The currently common domestic synthesis route for this key intermediate in tenofovir involves an alkylation reaction between adenine and R-propylene carbonate in the presence of a base to produce the target product, T3.
[0005] The structural formula of T3 is as follows:
[0006]
[0007] At present, there are several routes for synthesizing T3 at home and abroad:
[0008] (1) Using S-glycidol as raw material
[0009] Using S-glycidol as raw material, it is catalytically hydrogenated and reduced, and then undergoes an ester exchange reaction with diethyl carbonate to produce R-propylene carbonate, which is then condensed with adenine to produce T3.
[0010] The reaction steps are as follows:
[0011]
[0012] (2) R-methyl lactate as raw material
[0013] R-methyl lactate is reacted with benzyl bromide to form a benzyl ether to protect the hydroxyl group; the ester bond is then reduced to an alcohol using lithium aluminum tetrahydride, chlorinated, and catalytically hydrogenated to remove the benzyl ether to obtain R-1-chloro-2-propanol; R-1-chloro-2-propanol reacts with paraformaldehyde / HCl to obtain R-1-chloro-2-chloromethoxypropane, which reacts with triisopropyl phosphite to obtain R-2-[bis-(isopropyl)-phosphomethoxy]-propyl chloride, which then reacts with adenine and hydrolyzes to obtain T3. The specific synthetic route is as follows:
[0014]
[0015] (3) Using R-1,2-propylene glycol as raw material
[0016] Ouyang Nianping, Li Wei, Bao Lanlan and others invented a new process for preparing tenofovir. This process uses adenine as a raw material and R-propylene carbonate to synthesize T3. The specific synthesis steps are as follows:
[0017]
[0018] In actual production, when the third route was used to synthesize tenofovir, it was found that during the alkylation reaction, an isomer impurity was produced: (R)-(+)-3-(2-hydroxypropyl)adenine, with the following structural formula:
[0019]
[0020] The content of this impurity reaches 10%, which not only affects the purity of the product, but also affects the purity and yield of the next step of synthesis. Summary of the Invention
[0021] In view of the difference from the existing technology, the present invention provides a method for preparing a tenofovir intermediate R-(+)-9-(2-hydroxypropyl)adenine, which greatly reduces the content of isomer impurities and improves the yield of the finished product.
[0022] In order to solve the above technical problems, the purpose of the present invention is achieved through the following technical solutions:
[0023] The preparation method of tenofovir intermediate R-(+)-9-(2-hydroxypropyl)adenine comprises using adenine and R-propylene oxide as raw materials, tetraethylammonium bromide as a catalyst, and sodium hydroxide to carry out a ring-opening condensation reaction as shown in the following formula to produce tenofovir intermediate R-(+)-9-(2-hydroxypropyl)adenine;
[0024]
[0025] In the above-mentioned method for preparing the tenofovir intermediate R-(+)-9-(2-hydroxypropyl)adenine, the reaction is mediated by the non-aqueous polar solvent DMF; the amount of DMF added is determined to ensure smooth reaction.
[0026] In the above-mentioned method for preparing the tenofovir intermediate R-(+)-9-(2-hydroxypropyl)adenine, the molar ratio of R-propylene oxide to adenine is 1:1.1.
[0027] In the above-mentioned method for preparing the tenofovir intermediate R-(+)-9-(2-hydroxypropyl)adenine, the amount of sodium hydroxide added is 5%-20%, preferably 10%, of the R-propylene oxide, calculated on a substance basis.
[0028] In the above-mentioned method for preparing the tenofovir intermediate R-(+)-9-(2-hydroxypropyl)adenine, the amount of tetraethylammonium bromide added is 1%-2% of the total amount of reactants, calculated on a substance basis.
[0029] In the above-mentioned method for preparing the tenofovir intermediate R-(+)-9-(2-hydroxypropyl)adenine, the reaction temperature is 70-80°C.
[0030] The high content of the isomeric impurity (R)-(+)-3-(2-hydroxypropyl)adenine is due to alkylation at the 3-position of adenine instead of the required 9-position. Under the action of a base, the hydrogen on the nitrogen at the 9-position of adenine forms a negative ion. Since negative ions on a five-membered ring are thermodynamically less stable than those on a six-membered ring, under certain temperature conditions, this negative ion isomerizes to the 3-position of the adenine ring, where it then undergoes a substitution reaction, resulting in the formation of the impurity.
[0031] The invention achieves the goal of synthesizing T3 by cutting the NC bond at the 9-position of adenine and performing a nucleophilic substitution reaction with adenine and another substance (propylene oxide) capable of introducing an R-(+)-9-(2-hydroxypropyl) group.
[0032] Furthermore, the present invention also adopts a novel phase transfer technology to increase the reaction activity of the hydroxide ion of sodium hydroxide to improve the reaction speed.
[0033] Compared with the prior art, the present invention has the following beneficial effects:
[0034] The present invention provides a method for preparing a tenofovir intermediate, R-(+)-9-(2-hydroxypropyl)adenine. The method can significantly reduce the production of the isomeric impurity (R)-(+)-3-(2-hydroxypropyl)adenine in the T3 synthesis process. The T3 molar yield of the present invention is increased from less than 89% in the conventional method to approximately 98%, and the impurity content is reduced to less than 2%. The present invention can also reduce the reaction temperature and shorten the reaction time, thereby reducing production energy consumption. The present invention has low raw material prices, is easy to perform experimental operations, produces few side reaction impurities, is environmentally friendly, has broad industrialization prospects, and further enhances the market competitiveness of the product. DETAILED DESCRIPTION
[0035] The present invention will be further illustrated below through the description of specific implementation methods, but this is not intended to limit the present invention. Those skilled in the art can make various modifications or improvements based on the basic concept of the present invention, but as long as they do not deviate from the basic concept of the present invention, they are all within the scope of the present invention.
[0036] The raw materials used in this embodiment were all purchased from the market, and the specifications were all 99%.
[0037] Example 1
[0038] Synthesis of R-(+)-9-(2-Hydroxypropyl)adenine (T3, HPAD)
[0039] Add 1.1 mol of adenine and 0.1 mol of caustic soda to a reactor, pump in 1 mol of R-propylene oxide and 1000 ml of DMF, start stirring, and heat to 70-80°C for reaction. After the reaction is complete, cool the reaction mixture and allow it to react. After the reaction is complete, filter the mixture. Testing reveals that the purity of R-(+)-9-(2-hydroxypropyl)adenine is >98%, with an isomeric impurity content of <2%. Collect the filtrate and distill it through a distillation tower at atmospheric pressure to recover the DMF for reuse. The filter cake is used in the next reaction.
[0040] Example 2
[0041] The R-(+)-9-(2-hydroxypropyl)adenine prepared in Example 1 was used to further synthesize the finished tenofovir product, specifically comprising:
[0042] ①Synthesis of diethyl p-toluenesulfonyloxymethylphosphonate (TSDEP)
[0043] Diethyl phosphite was pumped into the reactor, paraformaldehyde and formaldehyde solution were added, stirring was started, the temperature was raised and kept for reaction, the temperature was lowered after the heat preservation was completed, p-toluenesulfonyl chloride was added, and liquid alkali was pumped in again. After the addition of the materials, the temperature was kept. After the reaction was completed, water and toluene were added, stirred, allowed to stand, separated, and the organic phase was concentrated under reduced pressure to obtain TSDEP, and the toluene was recovered and reused.
[0044] ②Synthesis of magnesium isopropoxide (A6)
[0045] DMF, methanol and magnesium were added to the reactor, the temperature was raised and kept for reaction, isopropanol was added, the temperature was raised and kept for reaction, and methanol, isopropanol and DMF were recovered by distillation in a distillation tower. After the distillation was completed, A6 was obtained.
[0046] ③Synthesis of Tenofovir Diethyl Ester
[0047] DMF and TSDEP were pumped into the reactor, followed by HPAD and A6. Stirring was initiated, and the temperature was raised and maintained for reaction. After the reaction was complete, the temperature was lowered and hydrochloric acid was added. After this addition, a mechanical vacuum pump was activated to distill the solvent under reduced pressure. The DMF and isopropyl alcohol in the recovered solution were then reused to obtain tenofovir diethyl ester and magnesium p-toluenesulfonate.
[0048] ④ Synthesis of tenofovir (T4)
[0049] After distillation, add hydrobromic acid solution to the reactor and heat it up to maintain the reaction. Due to the low boiling point of ethyl bromide, the co-produced ethyl bromide is condensed and recovered in a storage tank during the reaction. After the reaction, cool the reaction and filter the mixture. The resulting filter cake is the co-produced magnesium p-toluenesulfonate, and the filtrate is carried to the next step.
[0050] ⑤ Neutralization, crystallization filtration, refined drying
[0051] After the filtration step, the pH of the filtrate is adjusted with liquid alkali, cooled and kept warm, and then filtered to obtain crude tenofovir. Water is added to the refining kettle, and the crude tenofovir is placed in the refining kettle. The temperature is increased and kept warm. After the temperature is reduced and kept warm, the temperature is pressed and filtered. The filter cake is collected and dried to obtain the finished tenofovir.
[0052] The yield of tenofovir in Example 2 is increased by about 15-20% compared with the existing process. Through testing, the main technical indicators of tenofovir in Example 2 are as follows:
[0053]
Claims
1. A method for preparing a tenofovir intermediate R-(+)-9-(2-hydroxypropyl)adenine, characterized in that: Adenine and R-propylene oxide are used as raw materials, tetraethylammonium bromide is used as a catalyst, and in the presence of sodium hydroxide, a ring-opening condensation reaction as shown in the following formula is carried out to generate the tenofovir intermediate R-(+)-9-(2-hydroxypropyl)adenine; 2. The method for preparing the tenofovir intermediate R-(+)-9-(2-hydroxypropyl)adenine according to claim 1, wherein: The reaction is mediated by the non-aqueous polar solvent DMF.
3. The method for preparing the tenofovir intermediate R-(+)-9-(2-hydroxypropyl)adenine according to claim 1, wherein: The molar ratio of the R-propylene oxide to adenine is 1:1.
1.
4. The method for preparing the tenofovir intermediate R-(+)-9-(2-hydroxypropyl)adenine according to claim 1, wherein: The amount of tetraethylammonium bromide added is 1%-2% of the total amount of reactants, calculated on the basis of the amount of substance.
5. The method for preparing the tenofovir intermediate R-(+)-9-(2-hydroxypropyl)adenine according to claim 1, characterized in that: The reaction temperature is 70-80°C.