CN102108086B - Method for preparing p-tosyloxymethyl diethyl phosphonate - Google Patents
Method for preparing p-tosyloxymethyl diethyl phosphonate Download PDFInfo
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- CN102108086B CN102108086B CN 200910244036 CN200910244036A CN102108086B CN 102108086 B CN102108086 B CN 102108086B CN 200910244036 CN200910244036 CN 200910244036 CN 200910244036 A CN200910244036 A CN 200910244036A CN 102108086 B CN102108086 B CN 102108086B
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Abstract
The invention discloses a method for preparing p-tosyloxymethyl diethyl phosphonate. The method obtains the p-tosyloxymethyl diethyl phosphonate through the following steps: reacting diethyl phosphite and triethylamine with paraformaldehyde at a temperature of 80-110 DEG C, adding an organic solvent after the reaction is completed, cooling to 0-5 DEG C, and adding p-tosylchloride to perform a reaction. The used organic solvent is any one of N,N-dimethyl formamide, tetrahydrofuran, or dioxane, or a mixture mixed by several above solvents with a random mixing ratio. The amount of the organic solvent is 400 g organic solvent per 1 mole p-tosylchloride. The molar ratio of diethyl phosphate, triethylamine, paraformaldehyde and p-tosylchloride is 437:1000:500:500. Paraformaldehyde is added for 2-4 times. The temperature for the reaction performed after p-tosylchloride is added is room temperature, and the reaction time is 10-20 hours. The operation of the method is safe; the product has a correct structure, a high purity, and a high yield; the pollution cost is low; and the method is applicable to industrial production.
Description
Technical field
The present invention relates to a kind of method of cidofovir intermediate, particularly a kind of method for preparing tolysulfonyl oxygen ylmethyl diethyl phosphoric acid.
Background technology
The chemistry of cidofovir (cidofovir) is called 1-[(S)-3-hydroxyl-2-(phosphono methoxyl group) propyl group] the cytosine(Cyt) dihydrate, its structural formula is a kind of acyclic nucleotide phosphoric acid ester broad-spectrum antiviral drug suc as formula shown in the I.This medicine is developed by Gilead (U.S.) company, Vistide is in May, 1996 FDA approval listing, France and Canada is approval use in succession also, commodity are called Vistide, injection for intravenous, the CMV retinitis that is used for the treatment of AIDS patient, particularly stronger to the poxvirus effect, the medicine that U.S. army is used for smallpox carries out strategic reserves.The antivirus action mechanism of this medicine is that cidofovir can suppress viral dna polymerase, under the effect of cell thymidine kinase, be converted into active metabolite phosplate, bisphosphate and with the affixture of phosphorylcholine.The cidofovir bisphosphate suppresses the DNA that deoxycytidine-5-triguaiacyl phosphate is integrated into virus competitively by suppressing archaeal dna polymerase, slows down the synthetic of DNA, and makes the viral DNA loss of stability, thereby suppress duplicating of virus, and play a role.
(formula I)
The cidofovir synthesis route of external report has several, and the synthetic route for WO92/02511 reported that wherein is fit to production requirement is as follows.
This method be with (the R)-Racemic glycidol of the tritylation shown in the formula II structural formula and the N4-benzoylation cytosine(Cyt) shown in the formula III structural formula in the presence of the sodium hydride of catalytic amount; 105 ℃ of ring-opening reactions of carrying out Racemic glycidol in the N.N-dimethyl formamide; obtain the nucleoside derivates shown in the formula IV structural formula, productive rate 82%.Tolysulfonyl oxygen ylmethyl diethyl phosphoric acid shown in nucleoside derivates and the 1.5 normal formula V structural formulas is at NaH ((80%; 3 equivalents) react in 0 ℃ in; obtain (the S)-nucleosides ester shown in the formula VI structural formula; (S)-the nucleosides ester feeds HCl gas in 0-5 ℃ in methylene dichloride carries out acid catalyzed reaction and obtains alcohol corresponding shown in the VII structural formula; the nitrogen protection in methylene dichloride of this alcohol adds bromotrimethylsilane under also stirring; the reactant room temperature stirred 24 hours; concentrate; obtain the amido protecting product shown in the formula VIII structural formula; this product reacts in strong aqua again, obtains cidofovir shown in the formula I structural formula.
In the above-mentioned reaction scheme, in the synthetic method of tolysulfonyl oxygen ylmethyl diethyl phosphoric acid, react very violent, the normal spray jar that takes place reacts; In addition, reaction has used pyridine to make solvent, difficulty in the separatory process, and large-tonnage product loss, and productive rate is low, and is seriously polluted, the cost height.Therefore still need and further improve technology.
Summary of the invention
The purpose of this invention is to provide a kind of method for preparing tolysulfonyl oxygen ylmethyl diethyl phosphoric acid.
The method for preparing tolysulfonyl oxygen ylmethyl diethyl phosphoric acid provided by the invention, be with diethyl phosphite and triethylamine, react in 80-110 ℃ with Paraformaldehyde 96, after finishing, reaction adds organic solvent again, be cooled to 0-5 ℃, react after adding Tosyl chloride, obtain described tolysulfonyl oxygen ylmethyl diethyl phosphoric acid.
In this method, used organic solvent is N, and any one or a few in dinethylformamide, tetrahydrofuran (THF) or the dioxane be with arbitrary proportion blended mixture, as tetrahydrofuran (THF) and dioxane with 1: 1 blended mixture; The consumption of organic solvent is that per 1 mole of Tosyl chloride adds 400 gram organic solvents.The preferred trioxymethylene of described Paraformaldehyde 96.Paraformaldehyde 96 is that branch adds for 2-4 time.Adding the temperature of reacting behind the Tosyl chloride is room temperature, and as 15-25 ℃ or 18-20 ℃, the reaction times is 10-20 hour, specifically can be 10-15 hour, 12-18 hour or 15-20 hour.The mol ratio of described diethyl phosphite, triethylamine, Paraformaldehyde 96 and Tosyl chloride is 437: 1000: 500: 500.
Shown in the following equation of the synthetic route of this method:
(formula V)
The method for preparing tolysulfonyl oxygen ylmethyl diethyl phosphoric acid provided by the invention, operational safety, the products therefrom structure is correct, the purity height, the productive rate height, pollution cost is low, is applicable to suitability for industrialized production.
Embodiment
The invention will be further described below in conjunction with specific embodiment, but the present invention is not limited to following examples.Used Paraformaldehyde 96 is trioxymethylene among the following embodiment.
Embodiment 1
In retort, add diethyl phosphite 60kg (437mol), Paraformaldehyde 96 15kg (500mol) and triethylamine 101kg (1000mol), above-mentioned reaction mixture under agitation is heated to 90 ℃, in 30 minutes, the white soup compound becomes settled solution, after 3 hours reaction mixture is cooled to room temperature; Add DMF200kg postcooling to 0 ℃, in 5 minutes, add Tosyl chloride 96g (500mol),, add ethyl acetate 200L reaction mixture stirring at room 16 hours, the elimination insolubles, filtrate uses saturated sodium bicarbonate, water and saturated sodium-chloride (200L) to wash respectively, and anhydrous magnesium sulfate drying filters, filtrate concentrates, debris add toluene (2 * 250ml) concentrating under reduced pressure, the tolysulfonyl oxygen ylmethyl diethyl phosphoric acid 106kg of clarified yellow oil shape, yield is 75%.
The nucleus magnetic hydrogen spectrum data of this product are as follows:
1H NMR (CDCl3):
δ7.817(d，2H)；7.384(d，2H)；4.196(s，2H)；4.172(m，4H)；1.339(t，6H)。By above-mentioned data as can be known, this compound structure is correct, is the tolysulfonyl oxygen ylmethyl diethyl phosphoric acid shown in the formula V.
Embodiment 2
In retort, add diethyl phosphite 60kg (437mol), Paraformaldehyde 96 5kg (166.7mol) and triethylamine 101kg (1000mol), above-mentioned reaction mixture under agitation is heated to 110 ℃, and in 30 minutes, white soup compound becomes settled solution, temperature is reduced to 80 ℃, add Paraformaldehyde 96 10kg (333mol) again, under agitation be heated to 110 ℃, in 10 minutes, the white soup compound becomes settled solution, after 3 hours reaction mixture is cooled to room temperature; Add DMF200kg postcooling to 0 ℃, in 5 minutes, add Tosyl chloride 96g (500mol),, add ethyl acetate 200L reaction mixture stirring at room 16 hours, the elimination insolubles, filtrate uses saturated sodium bicarbonate, water and saturated sodium-chloride (200L) to wash respectively, and anhydrous magnesium sulfate drying filters, filtrate concentrates, debris add toluene (2 * 250ml) concentrating under reduced pressure, the tolysulfonyl oxygen ylmethyl diethyl phosphoric acid 128kg of clarified yellow oil shape, yield is 90%.Detect through nucleus magnetic hydrogen spectrum, this product structure is correct.
Embodiment 3
In retort, add diethyl phosphite 60kg (437mol), Paraformaldehyde 96 15kg (500mol) and triethylamine 101kg (1000mol), above-mentioned reaction mixture under agitation is heated to 110 ℃, in 30 minutes, the white soup compound becomes settled solution, after 3 hours reaction mixture is cooled to room temperature; Add tetrahydrofuran (THF) 200kg postcooling to 0 ℃, in 5 minutes, add Tosyl chloride 96g (500mol),, add ethyl acetate 200L reaction mixture stirring at room 16 hours, the elimination insolubles, filtrate uses saturated sodium bicarbonate, water and saturated sodium-chloride (200L) to wash respectively, and anhydrous magnesium sulfate drying filters, filtrate concentrates, debris add toluene (2 * 250ml) concentrating under reduced pressure, the tolysulfonyl oxygen ylmethyl diethyl phosphoric acid 100kg of clarified yellow oil shape, yield is 71%.Detect through nucleus magnetic hydrogen spectrum, this product structure is correct.
Embodiment 4
In retort, add diethyl phosphite 60g (437mol), Paraformaldehyde 96 5kg (166.7mol) and triethylamine 101kg (1000mol), above-mentioned reaction mixture under agitation is heated to 110 ℃, and in 30 minutes, white soup compound becomes settled solution, temperature is reduced to 80 ℃, add Paraformaldehyde 96 10kg (333mol) again, under agitation be heated to 110 ℃, in 10 minutes, the white soup compound becomes settled solution, after 3 hours reaction mixture is cooled to room temperature; Add tetrahydrofuran (THF) 200kg postcooling to 0 ℃, in 5 minutes, add Tosyl chloride 96g (500mol),, add ethyl acetate 200L reaction mixture stirring at room 16 hours, the elimination insolubles, filtrate uses saturated sodium bicarbonate, water and saturated sodium-chloride (200L) to wash respectively, and anhydrous magnesium sulfate drying filters, filtrate concentrates, debris add toluene (2 * 250ml) concentrating under reduced pressure, the tolysulfonyl oxygen ylmethyl diethyl phosphoric acid 116kg of clarified yellow oil shape, yield is 82%.Detect through nucleus magnetic hydrogen spectrum, this product structure is correct.
Embodiment 5
In retort, add diethyl phosphite 60kg (437mol), Paraformaldehyde 96 15kg (500mol) and triethylamine 101kg (1000mol), above-mentioned reaction mixture under agitation is heated to 110 ℃, in 30 minutes, the white soup compound becomes settled solution, after 3 hours reaction mixture is cooled to room temperature; Add dioxane 200kg postcooling to 0 ℃, in 5 minutes, add Tosyl chloride 96g (500mol),, add ethyl acetate 200L reaction mixture stirring at room 16 hours, the elimination insolubles, filtrate uses saturated sodium bicarbonate, water and saturated sodium-chloride (200L) to wash respectively, and anhydrous magnesium sulfate drying filters, filtrate concentrates, debris add toluene (2 * 250ml) concentrating under reduced pressure, the tolysulfonyl oxygen ylmethyl diethyl phosphoric acid 102kg of clarified yellow oil shape, yield is 72%.Detect through nucleus magnetic hydrogen spectrum, this product structure is correct.
Embodiment 6
In retort, add diethyl phosphite 60g (437mol), Paraformaldehyde 96 5kg (166.7mol) and triethylamine 101kg (1000mol), above-mentioned reaction mixture under agitation is heated to 100 ℃, and in 30 minutes, white soup compound becomes settled solution, temperature is reduced to 80 ℃, add Paraformaldehyde 96 10kg (333mol) again, under agitation be heated to 110 ℃, in 10 minutes, the white soup compound becomes settled solution, after 3 hours reaction mixture is cooled to room temperature; Add dioxane 200kg postcooling to 0 ℃, in 5 minutes, add Tosyl chloride 96g (500mol),, add ethyl acetate 200L reaction mixture stirring at room 16 hours, the elimination insolubles, filtrate uses saturated sodium bicarbonate, water and saturated sodium-chloride (200L) to wash respectively, and anhydrous magnesium sulfate drying filters, filtrate concentrates, debris add toluene (2 * 250ml) concentrating under reduced pressure, the tolysulfonyl oxygen ylmethyl diethyl phosphoric acid 109kg of clarified yellow oil shape, yield is 77%.Detect through nucleus magnetic hydrogen spectrum, this product structure is correct.
Embodiment 7
In retort, add diethyl phosphite 60g (437mol), Paraformaldehyde 96 5kg (166.7mol) and triethylamine 101kg (1000mol), above-mentioned reaction mixture under agitation is heated to 110 ℃, and in 30 minutes, white soup compound becomes settled solution, temperature is reduced to 80 ℃, add Paraformaldehyde 96 10kg (333mol) again, under agitation be heated to 110 ℃, in 10 minutes, the white soup compound becomes settled solution, after 3 hours reaction mixture is cooled to room temperature; Add dioxane 100kg and tetrahydrofuran (THF) 100kg mixing solutions postcooling to 0 ℃, in 5 minutes, add Tosyl chloride 96g (500mol), with reaction mixture stirring at room 16 hours, add ethyl acetate 200L, the elimination insolubles, filtrate uses saturated sodium bicarbonate, water and saturated sodium-chloride (200L) to wash respectively, anhydrous magnesium sulfate drying, filter, filtrate concentrates, debris add toluene (2 * 250ml) concentrating under reduced pressure, the tolysulfonyl oxygen ylmethyl diethyl phosphoric acid 110kg of clarified yellow oil shape, yield is 77.8%.Detect through nucleus magnetic hydrogen spectrum, this product structure is correct.
Claims (1)
1. method for preparing tolysulfonyl oxygen ylmethyl diethyl phosphoric acid, it is characterized in that: in retort, add diethyl phosphite 60kg, Paraformaldehyde 96 5kg and triethylamine 101kg, above-mentioned reaction mixture under agitation is heated to 110 ℃, in 30 minutes, the white soup compound becomes settled solution, temperature is reduced to 80 ℃, add Paraformaldehyde 96 10kg again, under agitation be heated to 110 ℃, in 10 minutes, white soup compound becomes settled solution, after 3 hours reaction mixture is cooled to room temperature; Add DMF 200kg postcooling to 0 ℃, in 5 minutes, add Tosyl chloride 96g, with reaction mixture stirring at room 16 hours, add ethyl acetate 200L, the elimination insolubles, filtrate is used saturated sodium bicarbonate solution, water and saturated nacl aqueous solution (200L) washing respectively, anhydrous magnesium sulfate drying filters, and filtrate concentrates, debris adds 2x250ml toluene concentrating under reduced pressure, gets the tolysulfonyl oxygen ylmethyl diethyl phosphoric acid of clarified yellow oil shape.
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| CN103848866A (en) * | 2012-12-04 | 2014-06-11 | 上海医药工业研究院 | Method for preparing sulfonyl oxymethyl diethyl phosphate compounds |
| CN102993235B (en) * | 2012-12-17 | 2015-03-11 | 新发药业有限公司 | Method for cleaner production of vitamin A intermediate product |
| CN105541910A (en) * | 2015-12-21 | 2016-05-04 | 山东金城医药化工股份有限公司 | Diethyl p-toluenesulfonyloxy methylphosphonate synthesis method |
| CN109021011A (en) * | 2018-08-14 | 2018-12-18 | 山东沾化永浩医药科技有限公司 | A method of synthesis tolysulfonyl oxygen methylphosphonic acid diethylester |
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Non-Patent Citations (2)
| Title |
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| "阿德福韦酯的合成";蒋晔 等;《中国医药工业杂志》;20071231;第38卷(第1期);第4-6页 * |
| 蒋晔 等."阿德福韦酯的合成".《中国医药工业杂志》.2007,第38卷(第1期),第4-6页. |
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