CN109942633B - Preparation method of tenofovir alafenamide intermediate - Google Patents
Preparation method of tenofovir alafenamide intermediate Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- LDEKQSIMHVQZJK-CAQYMETFSA-N tenofovir alafenamide Chemical compound O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1 LDEKQSIMHVQZJK-CAQYMETFSA-N 0.000 title abstract description 11
- 229960004946 tenofovir alafenamide Drugs 0.000 title abstract description 8
- 229930024421 Adenine Natural products 0.000 claims abstract description 43
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims abstract description 43
- 229960000643 adenine Drugs 0.000 claims abstract description 43
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 43
- HVLLSGMXQDNUAL-UHFFFAOYSA-N triphenyl phosphite Chemical compound C=1C=CC=CC=1OP(OC=1C=CC=CC=1)OC1=CC=CC=C1 HVLLSGMXQDNUAL-UHFFFAOYSA-N 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 24
- 238000006482 condensation reaction Methods 0.000 claims abstract description 19
- 239000003054 catalyst Substances 0.000 claims abstract description 13
- 239000003960 organic solvent Substances 0.000 claims abstract description 11
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical group CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims abstract description 10
- 230000035484 reaction time Effects 0.000 claims abstract description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical group CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 38
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 36
- DKTNEYRLXVJBHZ-ZCFIWIBFSA-N 9-[(2R)-2-[(oxo-lambda5-phosphanylidyne)methoxy]propyl]purin-6-amine Chemical compound P(=O)#CO[C@@H](CN1C2=NC=NC(=C2N=C1)N)C DKTNEYRLXVJBHZ-ZCFIWIBFSA-N 0.000 claims description 28
- 238000006243 chemical reaction Methods 0.000 claims description 23
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 5
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 4
- 150000007530 organic bases Chemical group 0.000 claims description 4
- 239000002904 solvent Substances 0.000 abstract description 13
- 238000009776 industrial production Methods 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 8
- -1 phosphoryl methoxy Chemical group 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- 238000001816 cooling Methods 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000003756 stirring Methods 0.000 description 11
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- SVUJNSGGPUCLQZ-FQQAACOVSA-N tenofovir alafenamide fumarate Chemical compound OC(=O)\C=C\C(O)=O.O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1.O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1 SVUJNSGGPUCLQZ-FQQAACOVSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 7
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 238000012544 monitoring process Methods 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000002386 leaching Methods 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 230000001376 precipitating effect Effects 0.000 description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 150000008280 chlorinated hydrocarbons Chemical group 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- SCCCIUGOOQLDGW-UHFFFAOYSA-N 1,1-dicyclohexylurea Chemical compound C1CCCCC1N(C(=O)N)C1CCCCC1 SCCCIUGOOQLDGW-UHFFFAOYSA-N 0.000 description 1
- 229940126656 GS-4224 Drugs 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 238000009521 phase II clinical trial Methods 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229960004556 tenofovir Drugs 0.000 description 1
- OJAJJFGMKAZGRZ-UHFFFAOYSA-N trimethyl(phenoxy)silane Chemical compound C[Si](C)(C)OC1=CC=CC=C1 OJAJJFGMKAZGRZ-UHFFFAOYSA-N 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The inventionDiscloses a preparation method of a tenofovir alafenamide intermediate. The invention provides (R) -9- [2- (phosphoryl phenol methoxyl) propyl]A method for preparing adenine comprising the steps of: in an organic solvent, in the presence of a base and a catalyst, (R) -9- [2- (phosphoryl methoxy) propyl]The (R) -9- [2- (phosphoryl phenol methoxyl) propyl is obtained by condensation reaction of adenine and triphenyl phosphite]Adenine; the organic solvent is N, N-dimethylacetamide. The preparation method has the advantages of less solvent consumption, short reaction time, simple post-treatment, less catalyst consumption, high yield, high purity of the prepared product, low production cost and low equipment requirement, and is suitable for industrial production.
Description
Technical Field
The invention relates to a preparation method of a tenofovir alafenamide intermediate.
Background
The gillidd science corporation (Gilead Sciences) developed a series of drugs for treating HIV-infected diseases in humans, of which GS7340 was promulgated and announced at 11/1/2012, and evaluated a phase II clinical trial of tenofovir alafenamide hemifumarate (TAF, GS-7340), which is an experimental novel prodrug of tenofovir, for the treatment of HIV-infected diseases in humans, to reach the main goal of the study. The structural formula of tenofovir alafenamide hemifumarate is as follows:
gillidd science has initiated a phase II clinical study of GS7340 to treat adult infection with HIV (NCT 01497899). The research result shows that tenofovir alafenamide hemifumarate (TAF, namely GS7340) has stronger antiviral capability and better safety than 10 times dosage of TDF, and has the potential to become a new generation of PMPA prodrug. In the synthesis process of tenofovir alafenamide hemifumarate (TAF), the (R) -9- [2- (phosphoryl phenol methoxyl) propyl ] adenine is a key intermediate.
At present, the method for synthesizing the intermediate, which is published at home and abroad, mainly comprises the following steps:
method one, WO2013052094 discloses a synthesis method of (R) -9- [2- (phosphoryl phenol methoxy) propyl ] adenine: acetonitrile is used as a solvent, and (R) -9- [2- (phosphoryl methoxy) propyl ] adenine (PMPA), triphenyl phosphite, triethylamine and 4-dimethylamino pyridine (DMAP) are refluxed for more than 48 hours at 80 ℃, and the reaction is monitored by nuclear magnetic phosphorus, and the yield is 81%.
The method has long reaction time which is more than 48 hours, large energy consumption and long production period; acetonitrile is used as a solvent, the using amount is large (8vol, namely 8 times of volume), and the production cost is high; nuclear magnetic phosphorus is used for reaction as central control, the equipment requirement is high, and the timeliness is poor; 4-Dimethylaminopyridine (DMAP) is used in a large amount; the post-treatment needs to evaporate the solvent acetonitrile, and the operation is complicated; is not suitable for industrial production.
Method II, WO0208241 discloses a method for synthesizing (R) -9- [2- (phosphoryl phenol methoxyl) propyl ] adenine by using (R) -9- [2- (phosphoryl methoxyl) propyl ] adenine (PMPA) and phenol as raw materials, dicyclohexyl carbodiimide (DCC) as a condensing agent and N-methyl pyrrolidone as a solvent and reacting for 22 hours at 100 ℃.
The method uses Dicyclohexylcarbodiimide (DCC) as a condensing agent, so that a large amount of waste residue N, N-Dicyclohexylurea (DCU) is generated; the post-treatment is acid-base regulated by sodium hydroxide and hydrochloric acid to generate a large amount of inorganic salt which is easy to remain in the product and difficult to remove, and the reaction yield is low; is not suitable for industrial production.
Method III, WO2002008041 discloses a method for synthesizing (R) -9- [2- (phosphoryl phenol methoxyl) propyl ] adenine by using (R) -9- [2- (phosphoryl methoxyl) propyl ] adenine (PMPA) as a raw material and sulfolane as a solvent, firstly converting phosphate groups of PMPA into acyl chloride, and then reacting with trimethyl phenoxy silicon at 100 ℃.
The method has two steps of reaction, and has the advantages of complex operation and low yield; the thionyl chloride used for synthesizing acyl chloride needs anhydrous operation, has high requirements on equipment and large pollution, and is not suitable for industrial production.
Therefore, the search for a preparation method of a tenofovir alafenamide intermediate (TAF intermediate) which has the advantages of short reaction steps, high yield, mild reaction conditions, simple operation, low equipment requirement, low production cost and suitability for industrial production is a technical problem which needs to be solved urgently at present.
Disclosure of Invention
The invention aims to solve the technical problem of overcoming the defects of harsh reaction conditions, long time, large catalyst consumption, high equipment requirement, complicated post-treatment operation steps, low yield, poor atom economy, high production cost, unsuitability for industrial production and the like of a preparation method of tenofovir alafenamide in the prior art, and provides a preparation method of a tenofovir alafenamide intermediate. The preparation method has the advantages of small solvent consumption, short reaction time, simple post-treatment, small catalyst consumption, high yield, low production cost and low equipment requirement, and is suitable for industrial production.
The invention provides a preparation method of (R) -9- [2- (phosphoryl phenol methoxyl) propyl ] adenine, which comprises the following steps: in an organic solvent, in the presence of alkali and a catalyst, (R) -9- [2- (phosphoryl methoxyl) propyl ] adenine (PMPA) and triphenyl phosphite are subjected to condensation reaction to obtain the (R) -9- [2- (phosphoryl phenol methoxyl) propyl ] adenine; the organic solvent is N, N-dimethylacetamide;
in the preparation method of (R) -9- [2- (phosphoryl phenol methoxy) propyl ] adenine, the volume-to-mass ratio of the organic solvent to the (R) -9- [2- (phosphoryl phenol methoxy) propyl ] adenine (PMPA) is preferably 1mL/g to 5mL/g, more preferably 1mL/g to 2mL/g, for example 2 mL/g.
In the process for producing (R) -9- [2- (phosphorylphenolmethoxy) propyl ] adenine, the base is preferably an organic base; the organic base is preferably N, N-Diisopropylethylamine (DIPEA) or Triethylamine (TEA).
In the method for producing (R) -9- [2- (phosphoryl-phenol-methoxy) propyl ] adenine, the molar ratio of the base to the (R) -9- [2- (phosphoryl-methoxy) propyl ] adenine (PMPA) is preferably 1 to 3, more preferably 1.5 to 2.5, for example 2.0.
In the preparation method of (R) -9- [2- (phosphoryl phenol methoxyl) propyl ] adenine, the catalyst is preferably 4-dimethylamino pyridine (DMAP).
In the method for preparing (R) -9- [2- (phosphoryl phenol methoxy) propyl ] adenine, the molar ratio of the catalyst to the (R) -9- [2- (phosphoryl phenol methoxy) propyl ] adenine (PMPA) is preferably 0.1 to 0.6, more preferably 0.1 to 0.5, for example 0.1 or 0.5.
In the preparation method of (R) -9- [2- (phosphoryl phenol methoxy) propyl ] adenine, the molar ratio of triphenyl phosphite to (R) -9- [2- (phosphoryl methoxy) propyl ] adenine (PMPA) is preferably 0.9-2, more preferably 1.1-1.5, such as 1.1, 1.2 or 1.5.
In the method for preparing (R) -9- [2- (phosphoryl phenol methoxyl) propyl ] adenine, the temperature of the condensation reaction is preferably 95-140 ℃. When the reaction temperature of the condensation reaction is preferably 95 to 110 ℃ (e.g., 95 to 100 ℃ or 105 to 110 ℃), the time of the condensation reaction is preferably 20 to 26 hours, e.g., 20 or 26 hours; when the temperature of the condensation reaction is preferably 130 to 140 ℃ (e.g., 130 to 135 ℃), the time of the condensation reaction is preferably 2 to 4 hours, e.g., 3 hours.
The preparation method of the (R) -9- [2- (phosphoryl phenol methoxy) propyl ] adenine can be detected by a conventional monitoring method in the field (such as TLC, HPLC or NMR), and generally, the end point of the reaction is that the content of the (R) -9- [2- (phosphoryl methoxy) propyl ] adenine (PMPA) is less than 0.1%, and when the temperature of the condensation reaction is 95-110 ℃ (such as 95-100 ℃ or 105-110 ℃), the time of the condensation reaction is preferably 16-30 hours, more preferably 20-26 hours, such as 20-26 hours; when the condensation reaction temperature is 130 ℃ to 140 ℃ (for example, 130 ℃ to 135 ℃), the time of the condensation reaction is preferably 1 hour to 6 hours, more preferably 2 hours to 4 hours, for example, 3 hours.
The preparation method of the (R) -9- [2- (phosphoryl phenol methoxyl) propyl ] adenine preferably adopts the following reaction steps: adding alkali, a catalyst, (R) -9- [2- (phosphoryl methoxyl) propyl ] adenine (PMPA) and triphenyl phosphite into an organic solvent, and carrying out condensation reaction to obtain the (R) -9- [2- (phosphoryl phenol methoxyl) propyl ] adenine; the organic solvent is N, N-Dimethylacetamide (DMA).
The preparation method of the (R) -9- [2- (phosphoryl phenol methoxyl) propyl ] adenine preferably adopts the following post-treatment steps: and after the reaction is finished, cooling, extracting, and adjusting the pH to 2-4 to obtain the (R) -9- [2- (phosphoryl phenol methoxyl) propyl ] adenine.
The cooling, extraction and pH adjustment may be carried out by methods conventional in the art for such procedures. The cooling temperature is preferably 0 ℃ to 30 ℃ (for example, 15 ℃ to 25 ℃). The solvent used for extraction is preferably halogenated hydrocarbon solvent; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane. The number of times of extraction is preferably 1 to 3 times. The pH is preferably adjusted by using inorganic acid; the inorganic acid is preferably hydrochloric acid. The hydrochloric acid can be a conventional and commercially available hydrochloric acid reagent; the concentration of the hydrochloric acid is preferably 10-12 mol/L; the concentration refers to the ratio of the molar amount of the hydrogen chloride to the volume of the hydrochloric acid solution.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
In the invention, the room temperature refers to the environment temperature of 10-35 ℃.
The positive progress effects of the invention are as follows: the preparation method has the advantages of less solvent consumption, less catalyst consumption, short reaction time, simple post-treatment, high yield, high purity of the prepared product, low production cost and low equipment requirement, and is suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1
Adding (R) -9- [2- (phosphoryl methoxy) propyl ] adenine (PMPA, 100.0g, 348.2mmol, 1.0eq), 4-dimethylamino pyridine (DMAP, 21.3g, 174.4mmol, 0.5eq), triphenyl phosphite (129.6g, 417.7mmol, 1.2eq), triethylamine (TEA, 70.5g, 696.7mmol, 2.0eq) into N, N-dimethylacetamide (DMA, 200ml), starting stirring, heating to 95-100 ℃, keeping the temperature for reaction for 26 hours, and stopping the reaction by monitoring the content of (R) -9- [2- (phosphoryl methoxy) propyl ] adenine (PMPA) by HPLC to be lower than 0.1%. Cooling to room temperature (15-25 ℃), adding water (400ml), extracting with dichloromethane (400ml × 3), adjusting the pH of the water phase to 2-3 with concentrated hydrochloric acid (12M, 32ml), precipitating a solid, cooling to 0-10 ℃, filtering and drying to obtain (R) -9- [2- (phosphoryl phenol methoxy) propyl ] adenine (110.6 g), the yield is 87.22%, and the HPLC purity is 99.22%.
Example 2
Adding (R) -9- [2- (phosphoryl methoxy) propyl ] adenine (PMPA, 100.0g, 348.2mmol, 1.0eq), 4-dimethylamino pyridine (DMAP, 21.3g, 174.4mmol, 0.5eq), triphenyl phosphite (129.6g, 417.7mmol, 1.2eq), triethylamine (TEA, 70.5g, 696.7mmol, 2.0eq) into N, N-dimethylacetamide (DMA, 200ml), starting stirring, heating to 105-110 ℃, keeping the temperature for reaction for 20 hours, and stopping the reaction by monitoring the content of (R) -9- [2- (phosphoryl methoxy) propyl ] adenine (PMPA) by HPLC to be lower than 0.1%. Cooling to room temperature (15-25 ℃), adding water (400ml), extracting with dichloromethane (400ml × 3), adjusting the pH of the water phase to 2-3 with concentrated hydrochloric acid (12M, 32ml), precipitating solid, cooling to 0-10 ℃, filtering and drying to obtain (R) -9- [2- (phosphoryl phenol methoxyl) propyl ] adenine 112.9g, the yield is 89.03%, and the HPLC purity is 99.24%.
Example 3
Adding (R) -9- [2- (phosphoryl methoxy) propyl ] adenine (PMPA, 10.0g, 34.82mmol, 1.0eq), 4-dimethylamino pyridine (DMAP, 0.4g, 3.27mmol, 0.1eq), triphenyl phosphite (11.9g, 38.35mmol, 1.1eq), N, N-diisopropylethylamine (DIPEA, 9.0g, 69.63mmol, 2.0eq) into N, N-dimethylacetamide (20ml), starting stirring, heating to 130-135 ℃ for reaction at a constant temperature for 3 hours, and stopping the reaction by monitoring the content of (R) -9- [2- (phosphoryl methoxy) propyl ] adenine (PMPA) by HPLC (detection). Cooling to room temperature (15-25 ℃), adding water (40ml), extracting with dichloromethane (40ml × 3), adjusting the pH of the water phase to 2-3 with concentrated hydrochloric acid (12M, 3.2ml), precipitating a solid, cooling to 0-10 ℃, filtering, and drying to obtain 11.2g of (R) -9- [2- (phosphoryl phenol methoxyl) propyl ] adenine, wherein the yield is 88.54%, and the HPLC purity is 99.13%.
Comparative example 1
(R) -9- [2- (phosphorylmethoxy) propyl ] adenine (PMPA, 100.0g, 348.2mmol, 1.0eq), 4-dimethylaminopyridine (DMAP, 213g, 1.744mol, 5eq), triphenyl phosphite (129.6g, 417.7mmol, 1.2eq), triethylamine (176.3g, 1.744mol, 5eq), N, N-dimethylformamide (DMF, 1L) were added to a reaction flask, heated to an internal temperature of 135 ℃ for reaction for 5 hours, and LC-MS showed no (R) -9- [2- (phosphorylphenoxymethoxy) propyl ] adenine.
Comparative example 2
Adding (R) -9- [2- (phosphoryl methoxy) propyl ] adenine (PMPA) (5.0g, 17.4mmol, 1.0eq), 4-dimethylamino pyridine (DMAP, 2.1g, 17.4mmol, 1.0eq), triphenyl phosphite (8.1g, 26.1mmol, 1.5eq) and triethylamine (3.5g, 34.8mmol, 2.0eq) into dimethyl sulfoxide (DMSO) (20ml), starting stirring, heating to 100-110 ℃, and carrying out heat preservation reaction for 12 hours, wherein LC-MS shows no product generation; the reaction was extended to 25 hours and LC-MS showed no product formation.
Comparative example 3(CN201280048965 patent Specification page 12 example 5)
(R) -9- [2- (phosphorylmethoxy) propyl ] adenine (PMAP, 200.0g, 696.35mmol, 1.0eq), 4-dimethylaminopyridine (DMAP, 85.0g, 695.75mmol, 1.0eq), triphenyl phosphite (324.1g, 1044.51mmol, 1.5eq), and triethylamine (140.8g, 1391.44mmol, 2.0eq) were added to acetonitrile (1.6L, 8mL/g), stirring was started, and the mixture was warmed to reflux (internal temperature 82 ℃ C.) and allowed to react for 67 hours. HPLC showed that the reaction was stopped with HPLC monitoring (R) -9- [2- (phosphorylmethoxy) propyl ] adenine (PMPA) content below 0.1%. Concentrating at 40-50 deg.C to dry, cooling to 20-30 deg.C, adding water (800ml) and ethyl acetate (800ml), stirring for 10 min, and extracting the water layer with ethyl acetate (600ml × 3). Adjusting the pH of the water phase to 2-3 by using concentrated hydrochloric acid (about 66ml), stirring for crystallization, cooling to 0-10 ℃, stirring for 1-2 hours, and filtering. The mixture is leached by cold (0-10 ℃) 1% diluted hydrochloric acid (150ml multiplied by 2) and dried at 50 ℃ to obtain 191g of white solid, the yield is 75.5%, and the purity is 99.06%.
Comparative example 4 (example of repetition WO 0208241)
(R) -9- [2- (phosphorylmethoxy) propyl ] adenine (PMAP 146.0g, 508.0mmol, 1.0eq), phenol (96.0g, 1020.0mmol, 2.0eq) were added to N-methylpyrrolidone (300ml, 2.0vol) and triethylamine (63.0g, 623.0mmol, 1.2eq) was added. Heating to 85 ℃, controlling the temperature to 85-100 ℃, dropwise adding N-methylpyrrolidone (100ml, 0.7vol) solution of dicyclohexylcarbodiimide (DCC; 171.0g, 829.0mmol, 1.6eq) for 2 hours. After the dripping is finished, stirring is carried out for 16 hours at the temperature of 100 ℃. Cooling to 15-25 ℃, adding water (290ml), stirring for 30 minutes, filtering, leaching filter cakes by water (150ml), combining filtrates, concentrating to constant weight at 60 ℃, adding water (250ml), adjusting the pH to 11 by using 25% sodium hydroxide aqueous solution (the mass concentration refers to the mass percentage of sodium hydroxide in the total mass of the sodium hydroxide aqueous solution), filtering by using a diatomite pad, leaching the filter cakes by using water (40ml), extracting the combined filtrates by using ethyl acetate (280ml), adjusting the pH of the aqueous phase to 3 by using concentrated hydrochloric acid, stirring, cooling to 0-10 ℃, filtering, leaching by using methanol (50ml multiplied by 2), drying to obtain 106.0g of product, wherein the HPLC purity is 98.12%, and the yield is 57.4%.
Claims (7)
1. A method for preparing (R) -9- [2- (phosphoryl phenol methoxyl) propyl ] adenine is characterized by comprising the following steps: in an organic solvent, in the presence of alkali and a catalyst, carrying out condensation reaction on (R) -9- [2- (phosphoryl methoxyl) propyl ] adenine and triphenyl phosphite to obtain the (R) -9- [2- (phosphoryl phenol methoxyl) propyl ] adenine; the organic solvent is N, N-dimethylacetamide; the base is organic base, and the organic base is N, N-diisopropylethylamine or triethylamine; the catalyst is 4-dimethylamino pyridine; the molar ratio of the alkali to the (R) -9- [2- (phosphoryl methoxy) propyl ] adenine is 1-3; the molar ratio of the catalyst to the (R) -9- [2- (phosphoryl methoxy) propyl ] adenine is 0.1-0.6;
2. the process for producing (R) -9- [2- (phosphorylphenolmethoxy) propyl ] adenine according to claim 1, wherein: in the preparation method of the (R) -9- [2- (phosphoryl phenol methoxyl) propyl ] adenine, the volume-to-mass ratio of the organic solvent to the (R) -9- [2- (phosphoryl methoxyl) propyl ] adenine (PMPA) is 1 mL/g-5 mL/g.
3. The process for producing (R) -9- [2- (phosphorylphenolmethoxy) propyl ] adenine according to claim 2, wherein: in the preparation method of the (R) -9- [2- (phosphoryl phenol methoxyl) propyl ] adenine, the volume-to-mass ratio of the organic solvent to the (R) -9- [2- (phosphoryl methoxyl) propyl ] adenine (PMPA) is 1 mL/g-2 mL/g.
4. The process for producing (R) -9- [2- (phosphorylphenolmethoxy) propyl ] adenine according to claim 1, wherein:
in the preparation method of the (R) -9- [2- (phosphoryl phenol methoxyl) propyl ] adenine, the molar ratio of the triphenyl phosphite to the (R) -9- [2- (phosphoryl methoxyl) propyl ] adenine is 0.9-2.
5. The process for producing (R) -9- [2- (phosphorylphenolmethoxy) propyl ] adenine according to claim 1, wherein:
in the preparation method of the (R) -9- [2- (phosphoryl phenol methoxyl) propyl ] adenine, the molar ratio of the alkali to the (R) -9- [2- (phosphoryl methoxyl) propyl ] adenine is 1.5-2.5;
and/or the presence of a gas in the gas,
in the preparation method of the (R) -9- [2- (phosphoryl phenol methoxyl) propyl ] adenine, the molar ratio of the catalyst to the (R) -9- [2- (phosphoryl methoxyl) propyl ] adenine is 0.1-0.5;
and/or the presence of a gas in the gas,
in the preparation method of the (R) -9- [2- (phosphoryl phenol methoxyl) propyl ] adenine, the molar ratio of the triphenyl phosphite to the (R) -9- [2- (phosphoryl methoxyl) propyl ] adenine is 1.1-1.5.
6. The process for producing (R) -9- [2- (phosphorylphenolmethoxy) propyl ] adenine according to claim 1, wherein:
in the preparation method of the (R) -9- [2- (phosphoryl phenol methoxyl) propyl ] adenine, the temperature of the condensation reaction is 95 to 140 ℃;
and/or the presence of a gas in the gas,
in the preparation method of (R) -9- [2- (phosphoryl phenol methoxyl) propyl ] adenine, the condensation reaction time is 1-30 hours.
7. The process for producing (R) -9- [2- (phosphorylphenolmethoxy) propyl ] adenine according to claim 6, wherein:
when the reaction temperature of the condensation reaction is 95-110 ℃, the time of the condensation reaction is 20-26 hours;
and/or the presence of a gas in the gas,
when the temperature of the condensation reaction is 130-140 ℃, the time of the condensation reaction is 2-4 hours.
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