CN114369120A - Preparation method of key intermediate of prophenoltenofovir - Google Patents
Preparation method of key intermediate of prophenoltenofovir Download PDFInfo
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- CN114369120A CN114369120A CN202210108472.3A CN202210108472A CN114369120A CN 114369120 A CN114369120 A CN 114369120A CN 202210108472 A CN202210108472 A CN 202210108472A CN 114369120 A CN114369120 A CN 114369120A
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- 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
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Abstract
The invention relates to the technical field of medical intermediates, and provides a preparation method of a key intermediate of prophenoltenofovir, which takes (R) -9- (2-phosphomethoxyl propyl) -adenine as a reactant to obtain 9- [ (R) -2- [ [ (phenoxy) -hydroxyphosphinyl ] methoxyl ] propyl ] adenine through an esterification reaction. Through the technical scheme, the problems of high raw material cost, low yield, long reaction time and low purity of an intermediate in the prior art are solved.
Description
Technical Field
The invention relates to the technical field of medical intermediates, in particular to a preparation method of a key intermediate of prophenoltenofovir.
Background
Propofovir Fumarate, the english name Tenofovir Alafenamide Fumarate (TAF), is chemically 9- { (R) -2- [ ((S) - { [ (S) -1- (isopropoxycarbonyl) ethyl ] amino } -phenoxyphosphinyl) methoxy ] propyl } adenine Fumarate (2:1), and is a nucleic acid reverse transcriptase inhibitor. Tenofovir fumarate, developed by Jilided scientific Inc. of USA, is sold under the trade name Vemlidy, is approved by FDA of USA in 2016 to be marketed, is used for treating chronic Hepatitis B Virus (HBV) infection of patients with adult compensatory liver diseases once a day, and is approved in 11 months in 2018 to be marketed in China. TAF and the most commonly used hepatitis B drug, namely Tenofovir Disoproxil Fumarate (TDF), are prodrugs of Tenofovir (TFV), TAF can generate an antiviral effect equivalent to TDF only by one tenth of dosage, exposure of tenofovir in blood circulation is reduced, renal toxicity and osteoporosis risks are greatly reduced, and the safety and tolerance are higher.
The molecular structure of 9- [ (R) -2- [ [ (phenoxy) -hydroxyphosphinyl ] methoxy ] propyl ] adenine which is a key intermediate of TAF is as follows:
various methods have been reported, and Jilide science corporation in patent US2005009043 discloses two methods for synthesizing 9- [ (R) -2- [ [ (phenoxy) -hydroxyphosphinyl ] methoxy ] propyl ] adenine.
The method comprises the following steps: the (R) -9- (2-phosphomethoxy propyl) -adenine (PMPA) and phenol are taken as raw materials, azomethidone (NMP) is taken as a solvent, and the raw materials are catalyzed and condensed by a condensing agent Dicyclohexylcarbodiimide (DCC) to synthesize the 9- [ (R) -2- [ [ (phenoxy) -hydroxyphosphinyl ] methoxy ] propyl ] adenine, wherein the synthetic route is as follows:
in the synthesis route, a relatively expensive condensing agent DCC (dicyclohexylcarbodiimide) is used in the esterification reaction, so that the reaction yield is low, the production cost is high, and the method is not suitable for industrial production.
The second method comprises the following steps: taking (R) -9- (2-phosphomethoxy propyl) -adenine (PMPA) as a raw material, taking sulfolane as a solvent, forming acyl chloride under the catalysis of a small amount of thionyl chloride and a small amount of N, N-dimethylformamide, and then adding benzyl trimethylsilane for condensation to generate 9- [ (R) -2- [ [ (phenoxy) -hydroxyphosphinyl ] methoxy ] propyl ] adenine. The synthetic route is as follows:
in the synthetic route, the yield is high, but the operation is complex, expensive benzyl trimethylsilane is used, and a large amount of waste water is generated due to the treatment of excessive active substances such as thionyl chloride, so that the production cost is high, and the synthetic route is not suitable for industrial production.
The third method comprises the following steps: gillidder science also discloses in US2013090473 a process for the preparation of the compound 9- [ (R) -2- [ [ (phenoxy) -hydroxyphosphinyl ] methoxy ] propyl ] adenine which comprises treating PMPA with triphenyl phosphite in the presence of a suitable base to prepare 9- [ (R) -2- [ [ (phenoxy) -hydroxyphosphinyl ] methoxy ] propyl ] adenine. Preferably by treating PMPA with triphenyl phosphite in acetonitrile in the presence of triethylamine and dimethylaminopyridine at about 80 ℃. The synthetic route is as follows:
compared with other routes, the synthesis route has the advantages that the esterification reaction obviously improves the yield, but acetonitrile and DMAP with higher price are largely used in the process, the reaction time is longer, and the economical efficiency is poorer.
The method four comprises the following steps: patent CN201710140550 reports a novel synthetic route, wherein (chloromethyl) diphenyl phosphonate is used as a raw material, and 9- [ (R) -2- [ [ (phenoxy) -hydroxyphosphinyl ] methoxy ] propyl ] adenine is obtained by three reactions including iodine substitution, hydrolysis, condensation substitution and the like, and the synthetic route is as follows:
in the synthetic route, the raw material cost is low, but the reaction yield of each step is low, and the purification by ion exchange resin is required, so that the synthetic route is not suitable for industrial production.
The method five comprises the following steps: philippine delphinium et al report that treatment of PMPA with triphenyl phosphite under the action of triethylamine yielded 9- [ (R) -2- [ [ (phenoxy) -hydroxyphosphinyl ] methoxy ] propyl ] adenine using toluene as solvent (Zhaomine, Kingji, Shuwei, et al. Tenofovir fumarate synthetic chemistry [ J ] synthetic chemistry, 2020,28(3):7.) followed by crystallization from acetone, filtration and drying to give the anhydrous product, the synthetic route is as follows:
the reaction has simple operation, low cost of raw materials and high yield, but the starting materials PMPA and the intermediate PMPA phosphoric anhydride are difficult to control according to the repeated process of a literature method, the content of the product is only about 65 percent, and the product has more unknown impurities and can not meet the requirements of intermediates for drug synthesis.
Therefore, it is very important to design a method for preparing the key intermediate 9- [ (R) -2- [ [ (phenoxy) -hydroxyphosphinyl ] methoxy ] propyl ] adenine of the prophenoltenofovir, which is simple and convenient to operate and more suitable for industrialization.
Disclosure of Invention
The invention provides a preparation method of a key intermediate of prophenoltenofovir, in particular relates to a preparation method of 9- [ (R) -2- [ [ (phenoxy) -hydroxyphosphinyl ] methoxy ] propyl ] adenine, and solves the problems of high raw material cost, low yield, long reaction time and low intermediate purity in the prior art.
The technical scheme of the invention is as follows:
a preparation method of a key intermediate of prophenoltenofovir is characterized in that the key intermediate of prophenoltenofovir is 9- [ (R) -2- [ [ (phenoxy) -hydroxyphosphinyl ] methoxy ] propyl ] adenine, and 9- [ (R) -2- [ [ (phenoxy) -hydroxyphosphinyl ] methoxy ] propyl ] adenine is obtained through an esterification reaction by taking (R) -9- (2-phosphomethoxypropyl) -adenine as a reactant.
Preferably, the solvent for the esterification reaction is one or more of toluene, o-xylene, and 7 to 11 saturated alkanes, and is preferably toluene.
Preferably, the esterification reagent for the esterification reaction comprises a catalyst, an organic base and phenol.
Preferably, the organic base is one or more of triethylamine, tributylamine and diisopropylethylamine, and triethylamine is preferred.
Preferably, the molar ratio of the organic base to the reactant is 1-3: 1, preferably 1.5-2.5: 1, and most preferably 2: 1.
Preferably, the catalyst is one or more of triphenyl phosphite and dicyclohexylcarbodiimide, and is preferably triphenyl phosphite.
Preferably, the molar ratio of the catalyst to the reactants is from 0.5 to 2:1, preferably from 0.8 to 1.3, optimally from 1.1: 1.
Preferably, the molar ratio of the phenol to the reactant is 0.5 to 5.0, preferably 1.0 to 3.0, and most preferably 2.0.
Preferably, the esterification reaction temperature is 50-150 ℃, preferably 105-115 ℃.
Preferably, the reaction time of the esterification reaction is 12 to 48 hours, and preferably 24 hours.
Preferably, the method further comprises the following post-treatment after the reaction is finished: and after reduced pressure distillation, washing with water and ethyl acetate, adjusting the pH value to 3.0, and washing and drying to obtain a finished product.
The invention has the beneficial effects that:
1. the invention aims to design a synthetic method which has cheap and easily obtained raw materials, simple and convenient operation and short reaction time and can obtain high-purity 9- [ (R) -2- [ [ (phenoxy) -hydroxyphosphinyl ] methoxy ] propyl ] adenine. The synthesis method of the invention takes (R) -9- (2-phosphomethoxyl propyl) -adenine (PMPA) as a reactant, and obtains 9- [ (R) -2- [ [ (phenoxy) -hydroxyphosphinyl ] methoxyl ] propyl ] adenine through esterification reaction, the cost of raw materials is reduced by 20%, the reaction time is shortened, the energy consumption is reduced, and the process is more environment-friendly. The product prepared by the preparation method has the advantages of high HPLC purity up to 99.6%, yield up to more than 80%, high product quality and suitability for industrial production.
Drawings
The present invention will be described in further detail with reference to the accompanying drawings and specific embodiments.
FIG. 1 is a high resolution mass spectrum of example 19- [ (R) -2- [ [ (phenoxy) -hydroxyphosphinyl ] methoxy ] propyl ] adenine;
FIG. 2 shows the hydrogen spectrum of example 19- [ (R) -2- [ [ (phenoxy) -hydroxyphosphinyl ] methoxy ] propyl ] adenine.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any inventive step, are intended to be within the scope of the present invention.
Example 1
Adding 100mL of toluene, 80g of PMPA, 53g of phenol, 56g of triethylamine and 95g of triphenyl phosphite into a 1L round-bottom flask, stirring and heating to 105 ℃, controlling the temperature to be 105-115 ℃, reacting for 24h, removing most of solvent by reduced pressure distillation, adding 160g of water, washing with ethyl acetate (200mL of 3), adding hydrochloric acid to adjust the pH to 3.0, filtering, washing a filter cake with 100mL of water with the pH of 2.0, and drying to obtain 84g of 9- [ (R) -2- [ [ (phenoxy) -hydroxyphosphinyl ] methoxy ] propyl ] adenine product (the HPLC purity is 99.6%, the maximum single impurity content is less than or equal to 0.1%, the content is 100.3%, and the yield is 83%).
And (3) analyzing structure confirmation data:
HRMS(m/e)：[M+H]+＝364.1174；
1H-NMR(400MHz，D28.227(s, 1H), 8.320(s, 1H), 7.228(t, 2H, J-7.3 Hz), 7.098(t, 1H, J-7.3 Hz), 6.733(D, 2H, J-7.9 Hz), 4.280-4.432 (m,2H), 4.084(m, 1H), 3.586-3.849 (m,2H), 1.302(D, 3H, J-6.1 Hz), active hydrogen of O-H and N-H is protected by D2O is exchanged in1No signal peak is shown on the H-NMR spectrum.
13C-NMR(150MHz，D2O)δ(ppm):18.72，51.79，67.14，79.12，120.65，123.14，127.02，132.46，147.48，148.32，151.46，152.66，154.07。
Example 2
Adding 125mL of toluene, 80g of PMPA, 60g of phenol, 56g of triethylamine and 90g of triphenyl phosphite into a 1L round-bottom flask, stirring and heating to 105 ℃, controlling the temperature to be 105-115 ℃, reacting for 24h, removing most of solvent by reduced pressure distillation, adding 200g of water, washing with ethyl acetate (200mL of 3), adding hydrochloric acid to adjust the pH to 3.0, filtering, washing a filter cake with 100mL of water with the pH of 2.0, and drying to obtain 81g of 9- [ (R) -2- [ [ (phenoxy) -hydroxyphosphinyl ] methoxy ] propyl ] adenine product (the HPLC purity is 99.5%, the maximum single impurity content is less than or equal to 0.10%, the content is 99.7%, and the yield is 80%).
Comparative example 1
100mL of toluene, 80g of PMPA, 56g of triethylamine and 95g of triphenyl phosphite are added into a 1L round-bottom flask, the mixture is stirred and heated to reflux reaction for 24 hours, most of solvent is removed by reduced pressure distillation, 1000mL of acetone is added, hydrochloric acid is added to adjust the pH value to 3.0, the filter cake is washed by 200mL of acetone after filtration, and 134g of 9- [ (R) -2- [ [ (phenoxy) -hydroxyphosphinyl ] methoxy ] propyl ] adenine product (the HPLC purity is 97.6%, the maximum single impurity is more than 0.3%, the content is 66.4%, and the purification yield is 88%) is obtained after drying.
Injection yield calculation formula: [ yield of monophenyl PMPA. multiplied by content). times. 287.22]/[ 363.31X 80 ]. times.100%
The present invention is not limited to the above preferred embodiments, and any modifications, equivalent substitutions, improvements, etc. within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A preparation method of a key intermediate of Propofovir is disclosed, wherein the key intermediate of Propofovir is 9- [ (R) -2- [ [ (phenoxy) -hydroxyphosphinyl ] methoxy ] propyl ] adenine, and is characterized in that (R) -9- (2-phosphomethoxypropyl) -adenine is used as a reactant, and 9- [ (R) -2- [ [ (phenoxy) -hydroxyphosphinyl ] methoxy ] propyl ] adenine is obtained through an esterification reaction.
2. The method for preparing the prophenoltenofovir key intermediate as claimed in claim 1, wherein the solvent for the esterification reaction is one or more of toluene, o-xylene and 7 to 11 saturated alkanes.
3. The method for preparing a prophenoltenofovir key intermediate as claimed in claim 1, wherein the esterification reagent comprises a catalyst, an organic base and phenol.
4. The method for preparing the key intermediate of the prophenoltenofovir according to claim 3, wherein the organic base is one or more of triethylamine, tributylamine and diisopropylethylamine.
5. The preparation method of a propanphenol tenofovir key intermediate according to claim 4, wherein the molar ratio of the organic base to the reactants is 1-3: 1.
6. The method for preparing the prophenoltenofovir key intermediate as claimed in claim 3, wherein the catalyst is one or more of triphenyl phosphite and dicyclohexylcarbodiimide.
7. The method for preparing a prophenoltenofovir key intermediate as claimed in claim 3, wherein the molar ratio of the catalyst to the reactants is 0.5-2: 1.
8. The preparation method of a propanol tenofovir key intermediate according to claim 3, wherein the molar ratio of the phenol to the reactants is 0.5-5.0.
9. The method for preparing a prophenoltenofovir key intermediate as claimed in claim 1, wherein the esterification reaction temperature is 50-150 ℃.
10. The method for preparing a prophenoltenofovir key intermediate as claimed in claim 1, wherein the reaction time of the esterification reaction is 12-48 h.
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Citations (5)
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| CN1706855A (en) * | 2000-07-21 | 2005-12-14 | 吉里德科学公司 | Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same |
| CN106478725A (en) * | 2016-10-14 | 2017-03-08 | 上海礼泰医药科技有限公司 | The preparation method and applications of high-purity phosphine the third tenofovir intermediate |
| CN108409790A (en) * | 2018-03-30 | 2018-08-17 | 南京哈柏医药科技有限公司 | A kind of tenofovir Chinese mugwort draws the easy synthesis technology of phenol amine hemifumarate |
| CN108467410A (en) * | 2018-04-09 | 2018-08-31 | 重庆三圣实业股份有限公司 | The preparation method and product of a kind of TAF intermediates and application |
| CN110372749A (en) * | 2019-07-06 | 2019-10-25 | 石家庄龙泽制药股份有限公司 | A kind of preparation method of third phenol tenofovir key intermediate, one phenyl PMPA |
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- 2022-01-28 CN CN202210108472.3A patent/CN114369120A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1706855A (en) * | 2000-07-21 | 2005-12-14 | 吉里德科学公司 | Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same |
| CN106478725A (en) * | 2016-10-14 | 2017-03-08 | 上海礼泰医药科技有限公司 | The preparation method and applications of high-purity phosphine the third tenofovir intermediate |
| CN108409790A (en) * | 2018-03-30 | 2018-08-17 | 南京哈柏医药科技有限公司 | A kind of tenofovir Chinese mugwort draws the easy synthesis technology of phenol amine hemifumarate |
| CN108467410A (en) * | 2018-04-09 | 2018-08-31 | 重庆三圣实业股份有限公司 | The preparation method and product of a kind of TAF intermediates and application |
| CN110372749A (en) * | 2019-07-06 | 2019-10-25 | 石家庄龙泽制药股份有限公司 | A kind of preparation method of third phenol tenofovir key intermediate, one phenyl PMPA |
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