CN108178772B - Preparation method of tenofovir disoproxil fumarate intermediate - Google Patents
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- CN108178772B CN108178772B CN201710990974.2A CN201710990974A CN108178772B CN 108178772 B CN108178772 B CN 108178772B CN 201710990974 A CN201710990974 A CN 201710990974A CN 108178772 B CN108178772 B CN 108178772B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 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 title claims description 24
- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 title claims description 23
- 229960001355 tenofovir disoproxil Drugs 0.000 claims abstract description 30
- JFVZFKDSXNQEJW-CQSZACIVSA-N tenofovir disoproxil Chemical compound N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N JFVZFKDSXNQEJW-CQSZACIVSA-N 0.000 claims abstract description 30
- -1 phosphate ester Chemical class 0.000 claims abstract description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 29
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- 150000001875 compounds Chemical class 0.000 claims description 20
- 238000006460 hydrolysis reaction Methods 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 13
- 230000007062 hydrolysis Effects 0.000 claims description 12
- UOEFFQWLRUBDME-UHFFFAOYSA-N diethoxyphosphorylmethyl 4-methylbenzenesulfonate Chemical compound CCOP(=O)(OCC)COS(=O)(=O)C1=CC=C(C)C=C1 UOEFFQWLRUBDME-UHFFFAOYSA-N 0.000 claims description 10
- JHYNXXBAHWPABC-UHFFFAOYSA-N chloromethyl propan-2-yl carbonate Chemical compound CC(C)OC(=O)OCCl JHYNXXBAHWPABC-UHFFFAOYSA-N 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 7
- LVOASXNJWPROPP-UHFFFAOYSA-N (4-methylphenyl)sulfonyloxymethylphosphonic acid Chemical compound CC1=CC=C(S(=O)(=O)OCP(O)(O)=O)C=C1 LVOASXNJWPROPP-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- 238000006482 condensation reaction Methods 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 2
- VUQUOGPMUUJORT-UHFFFAOYSA-N methyl 4-methylbenzenesulfonate Chemical compound COS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 7
- 238000000746 purification Methods 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 3
- 229910019142 PO4 Inorganic materials 0.000 abstract 1
- 239000010452 phosphate Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 238000006243 chemical reaction Methods 0.000 description 22
- 239000010410 layer Substances 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 238000003756 stirring Methods 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000005886 esterification reaction Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
- 241000725303 Human immunodeficiency virus Species 0.000 description 3
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 150000005690 diesters Chemical class 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 150000002148 esters Chemical group 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000011112 process operation Methods 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- PINIEAOMWQJGBW-FYZOBXCZSA-N tenofovir hydrate Chemical compound O.N1=CN=C2N(C[C@@H](C)OCP(O)(O)=O)C=NC2=C1N PINIEAOMWQJGBW-FYZOBXCZSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 1
- 229940126656 GS-4224 Drugs 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- 101900297506 Human immunodeficiency virus type 1 group M subtype B Reverse transcriptase/ribonuclease H Proteins 0.000 description 1
- 229940123527 Nucleotide reverse transcriptase inhibitor Drugs 0.000 description 1
- 102000003929 Transaminases Human genes 0.000 description 1
- 108090000340 Transaminases Proteins 0.000 description 1
- 239000002259 anti human immunodeficiency virus agent Substances 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 238000002514 liquid chromatography mass spectrum Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 229960004556 tenofovir Drugs 0.000 description 1
- SGOIRFVFHAKUTI-ZCFIWIBFSA-N tenofovir (anhydrous) Chemical compound N1=CN=C2N(C[C@@H](C)OCP(O)(O)=O)C=NC2=C1N SGOIRFVFHAKUTI-ZCFIWIBFSA-N 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
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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 Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
Abstract
The invention discloses a preparation method of a tenofovir disoproxil intermediate. The tenofovir disoproxil intermediate disclosed by the invention opens up a new preparation path for preparing tenofovir disoproxil, purification of subsequent steps is not needed, related substances of the tenofovir disoproxil related to phosphate ester in pharmacopoeia can be effectively controlled, the yield is high, impurities are few, and the preparation of the tenofovir disoproxil with higher purity is facilitated.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a preparation method of a tenofovir disoproxil fumarate intermediate.
Background
Tenofovir Disoproxil Fumarate (TDF), chemically known as (R) - [ [2- (6-amino-9H-purin-9-yl) -1-methylethoxy ] methyl ] phosphonic acid diisopropoxycarbonyloxymethyl ester Fumarate, is a novel nucleotide reverse transcriptase inhibitor developed by Gilead Sciences, USA, which inhibits replication of HIV virus mainly by inhibiting activity of HIV-1 reverse transcriptase. The preparation is firstly marketed in the United states in 2001, is marketed in a plurality of countries and regions such as Canada, Europe and the like at present, and has good application prospect as a first-line medicament for treating HIV. Although the proportion of HIV infected people in the general population is low in China at present, the number of infected people is 2 in Asia and has a tendency of increasing year by year, so that the demand of anti-AIDS drugs is gradually increased. The tenofovir disoproxil fumarate is used as a first-line antiviral treatment medicine for free AIDS, and the demand is obviously increased. In addition, tenofovir disoproxil has the functions of inhibiting hepatitis B virus replication and stabilizing the state of illness, can reduce transaminase to a certain extent, has the effect of protecting the liver, and has a good effect on the treatment of the hepatitis B. Based on the good market demand of tenofovir disoproxil fumarate, the improvement and optimization of the synthesis process of tenofovir disoproxil fumarate are of great significance to the society and enterprises.
The existing production process of tenofovir disoproxil fumarate is to synthesize tenofovir disoproxil through esterification reaction between tenofovir monohydrate or anhydride serving as an intermediate and chloromethyl isopropyl carbonate, and then salify the tenofovir disoproxil fumarate with fumaric acid to obtain the tenofovir disoproxil fumarate, but the existing synthesis technology has low reaction conversion rate and is easy to generate impurities. The main reason is that tenofovir is subjected to mono-esterification firstly during esterification and then continuously reacted into diester, but the monoester is always existed in the reaction to influence the reaction yield because the steric hindrance is increased, the reaction activity is reduced and the diester difficulty is increased after mono-esterification. And because a large amount of monosubstituted products exist, the treatment after the reaction is difficult, and the product quality is difficult to ensure. Although the forward progress of the reaction is promoted by increasing the amount of raw materials, the production cost is greatly increased, and related impurities (such as the impurities shown in figure I) of tenofovir disoproxil begin to appear as the reaction progresses. In a word, the existing method for preparing tenofovir disoproxil has the defects of low yield, high cost, more impurities and the like.
In order to overcome the defects of using tenofovir monohydrate or anhydride as an intermediate, a new intermediate for efficiently preparing tenofovir disoproxil with higher purity needs to be developed.
Disclosure of Invention
The invention aims to provide a preparation method of a tenofovir disoproxil intermediate, which aims to solve the problems in the background technology.
In order to achieve the purpose, the invention provides the following technical scheme:
a tenofovir disoproxil fumarate intermediate having the structure of formula (ii):
the preparation method of the tenofovir disoproxil fumarate intermediate adopts a synthetic route shown as follows:
the method specifically comprises the following steps: 1) carrying out hydrolysis reaction on diethyl p-toluenesulfonyloxymethylphosphonate under the action of a hydrolysis reagent to obtain a compound p-toluenesulfonyloxymethylphosphonic acid shown as a formula (III); 2) condensing the compound p-toluenesulfonyloxymethylphosphonic acid obtained in the step 1) and represented by the formula (III) with chloromethyl isopropyl carbonate under the action of alkali to obtain a tenofovir disoproxil intermediate represented by the formula (II), wherein the tenofovir disoproxil intermediate represented by the formula (II) is named as ((bis ((isopropoxycarbonyl) oxy) methoxy) phosphoryl) methyl 4-methylbenzenesulfonate.
As a still further scheme of the invention: in the step 1), the hydrolysis reagent is one or a combination of two of trimethyl bromosilane and 48% hydrogen bromide water solution; in the step 2), the alkali is pyridine, 4-dimethylaminopyridine, N-diisopropylethylamine, 2, 6-dimethylpyridine, sodium carbonate, potassium carbonate, triethylamine or diethylamine.
As a still further scheme of the invention: in the step 1), the hydrolysis reagent is trimethyl bromosilane; in the step 2), the alkali is triethylamine.
As a still further scheme of the invention: in the step 1), the molar ratio of the diethyl p-toluenesulfonyloxymethylphosphonate to the hydrolysis reagent is 1: 3-10; in the step 2), the molar ratio of the compound shown in the formula (III), alkali and chloromethyl isopropyl carbonate is 1:3-5: 2.5-5.
As a still further scheme of the invention: in the step 1), the molar ratio of the diethyl p-toluenesulfonyloxymethylphosphonate to the hydrolysis reagent is 1: 8; in step 2), the molar ratio of the compound represented by the formula (III), the base and chloromethyl isopropyl carbonate is 1:3: 5.
As a still further scheme of the invention: in the step 1), the hydrolysis temperature is 10-80 ℃; in the step 2), the temperature of the condensation reaction is 30-80 ℃.
As a still further scheme of the invention: in the step 1), the hydrolysis temperature is 30 ℃; in step 2), the temperature of the condensation reaction is 60 ℃.
As a still further scheme of the invention: in the step 1), the solvent is N, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, acetonitrile or N-methylpyrrolidone; in the step 2), the solvent is acetonitrile, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide or N-methylpyrrolidone; in the step 1), the dosage of the solvent is 5-40 times of that of diethyl p-toluenesulfonyloxymethylphosphonate in terms of W/V; in the step 2), the dosage of the solvent is 5-10 times of that of the compound shown in the formula (III) according to W/V.
As a still further scheme of the invention: in the step 1), the solvent is acetonitrile; in the step 2), the solvent is N, N-dimethylformamide.
Compared with the prior art, the invention has the beneficial effects that:
1. the tenofovir disoproxil intermediate disclosed by the invention opens up a new preparation path for preparing tenofovir disoproxil, because a phosphonic acid bis (isopropionyloxymethyl) ester part is synthesized firstly, purification of subsequent steps is not needed, tenofovir disoproxil related substances related to a phosphate part in pharmacopoeia can be effectively controlled, the yield is high, impurities are few, and the preparation of high-purity tenofovir disoproxil is facilitated;
2. according to the preparation method of the tenofovir disoproxil intermediate, high-risk products such as n-butyl lithium, sodium hydride and the like are not adopted, so that the production process is safer, the process operation is simple, the reaction condition is mild, the method is suitable for industrial production, and a better synthesis mode of the tenofovir disoproxil intermediate is realized.
Drawings
FIG. 1 shows the NMR spectrum of a tenofovir disoproxil intermediate.
Figure 2 is an LCMS spectrum of a tenofovir disoproxil intermediate.
Detailed Description
The technical solution of the present invention will be described in further detail with reference to specific embodiments.
A tenofovir disoproxil fumarate intermediate having the structure of formula (ii):
the preparation method of the tenofovir disoproxil fumarate intermediate adopts a synthetic route shown as follows:
example 1
Preparation of p-toluenesulfonyloxymethylphosphonic acid, a compound of formula (III):
adding 15g (0.046mol) of diethyl p-toluenesulfonyloxymethylphosphonate and 450ml of acetonitrile into a 1L reaction bottle, stirring, slowly dropwise adding 56.4g (0.37mol) of trimethyl bromosilane under ice bath, after the dropwise adding is finished, heating to 30 ℃, keeping the temperature at 30 ℃, reacting for 24 hours, after the reaction is finished, removing the acetonitrile by reduced pressure concentration, adding 100ml of toluene into the concentrated solution, transferring into a 500ml three-neck bottle, cooling to 10-20 ℃ by ice bath, adding 100ml of precooling water, keeping the temperature at 10-20 ℃, stirring for 10 minutes, standing, layering and removing an organic layer. Washing the water layer with 100ml ethyl acetate for 3 times, keeping the temperature at 10-20 ℃, removing the water layer after washing, combining the ethyl acetate layers, then adding 100ml saturated saline water into the ethyl acetate layer, keeping the temperature at 10-20 ℃, stirring for 5-10 min, standing, layering, and removing the water layer. Adding anhydrous magnesium sulfate into the ethyl acetate layer, drying, keeping the temperature at 10-20 ℃, stirring for 10min, filtering, and concentrating the dry ethyl acetate in vacuum to obtain 12.3g of a colorless transparent oily liquid of the compound (III), wherein the yield is 98 percent, and the 1H-NMR (DMSO-d6, delta ppm): 2.40(s, 3H), 3.90(d,2H),7.46(d,2H), 7.77(d, 2H).
Example 2
Preparation of p-toluenesulfonyloxymethylphosphonic acid, a compound of formula (III):
adding 20g (0.06mol) of diethyl p-toluenesulfonyloxymethylphosphonate, 500ml of N, N-dimethylformamide and 21.7g (0.882mol) of sodium bromide into a 1L reaction bottle, stirring, slowly dropwise adding 32.6g (1.26mol) of trimethylchlorosilane into the reaction bottle in ice bath, heating to 60 ℃ to react for 16 hours after dropwise adding is finished, finishing the reaction, cooling the reaction solution to room temperature, filtering, distilling the filtrate in high vacuum to remove the solvent N, N-dimethylformamide, adding 100ml of toluene into the concentrated solution, transferring the mixture into a 500ml three-neck flask, cooling to 10-20 ℃ in ice bath, adding 100ml of precooling water, keeping the temperature at 10-20 ℃ and stirring for 10 minutes, standing, layering and removing an organic layer. Washing the water layer with 100ml ethyl acetate for 3 times, keeping the temperature at 10-20 ℃, removing the water layer after washing, combining the ethyl acetate layers, then adding 100ml saturated saline water into the ethyl acetate layer, keeping the temperature at 10-20 ℃, stirring for 5-10 min, standing, layering, and removing the water layer. And adding anhydrous magnesium sulfate into the ethyl acetate layer, drying, keeping the temperature at 10-20 ℃, stirring for 10min, filtering, and concentrating the dry ethyl acetate in vacuum to obtain 15.3g of compound (III) colorless transparent oily liquid with the yield of 91%.
Example 3
Preparation of a tenofovir disoproxil fumarate intermediate compound represented by formula (II):
a500 mL reaction flask was charged with 20g of Compound (III) (0.075mol), and then 200mL of N, N-dimethylformamide was added thereto, followed by stirring and mixing at room temperature. Then, 23.2g of triethylamine (0.228mol) is slowly dropped into the solution, and the solution is stirred for about 1 hour after the dropping is finished; then, 57.2g of chloromethyl isopropyl carbonate (0.38mol) was added to the reaction solution, and the reaction solution was heated to 60 ℃ and reacted for 5 hours while maintaining the temperature. And after the reaction is finished, cooling the reaction liquid to 10-20 ℃, adding 75ml of cyclohexane, stirring, standing, layering, removing a cyclohexane layer, and washing the N, N-dimethylformamide layer again according to the method. Then, 450ml of ethyl acetate was added to N, N-dimethylformamide, and the mixture was stirred for 0.5 hour, filtered, and the filtrate was washed three times with 150ml of water, once with 150ml of saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness to obtain 28g of compound (ii) as a pale yellow oily liquid with a yield of 75%, 1H-NMR (DMSO-d6, δ ppm): 1.22(m, 12H), 2.42(s, 3H), 4.49(d, 2H), 4.80(m, 2H), 5.57(d, 4H), 7.48(d, 2H), 7.80(d, 2H).
Example 4
Preparation of a tenofovir disoproxil fumarate intermediate compound represented by formula (II):
50g of Compound (III) (0.18mol) was charged into a 1L reaction flask, and 500ml of N-methylpyrrolidone was added thereto, followed by stirring and mixing at room temperature. Then, 29.4g N N-diisopropylethylamine (0.54mol) is slowly dripped, and the mixture is stirred for about 1 hour after dripping; then, 137.4g of chloromethyl isopropyl carbonate (0.90mol) was added to the reaction solution, and the reaction solution was heated to 60 ℃ and reacted for 5 hours while maintaining the temperature. And after the reaction is finished, cooling the reaction liquid to 10-20 ℃, adding 75ml of cyclohexane, stirring, standing, layering, removing a cyclohexane layer, and washing the N-methylpyrrolidone layer again according to the method. Then, 450ml of ethyl acetate was added to N-methylpyrrolidone, and the mixture was stirred for 0.5 hour, filtered, the filtrate was washed three times with 150ml of water, once with 150ml of saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness to obtain 64g of compound (ii) as a pale yellow oily liquid with a yield of 68%.
The tenofovir disoproxil intermediate disclosed by the invention opens up a new preparation path for preparing tenofovir disoproxil, because a phosphonic acid bis (isopropionyloxymethyl) ester part is synthesized firstly, purification of subsequent steps is not needed, tenofovir disoproxil related substances related to a phosphate part in pharmacopoeia can be effectively controlled, the yield is high, impurities are few, and the preparation of high-purity tenofovir disoproxil is facilitated; according to the preparation method of the tenofovir disoproxil intermediate, high-risk products such as n-butyl lithium, sodium hydride and the like are not adopted, so that the production process is safer, the process operation is simple, the reaction condition is mild, the method is suitable for industrial production, and a better synthesis mode of the tenofovir disoproxil intermediate is realized.
While the preferred embodiments of the present invention have been described in detail, the present invention is not limited to the above embodiments, and various changes can be made without departing from the spirit of the present invention within the knowledge of those skilled in the art.
Claims (7)
1. A preparation method of a tenofovir disoproxil fumarate intermediate is characterized by adopting a synthetic route shown as follows:
the method specifically comprises the following steps:
1) carrying out hydrolysis reaction on diethyl p-toluenesulfonyloxymethylphosphonate under the action of a hydrolysis reagent to obtain a compound p-toluenesulfonyloxymethylphosphonic acid shown as a formula (III);
2) condensing the compound p-toluenesulfonyloxymethylphosphonic acid obtained in the step 1) and represented by the formula (III) with chloromethyl isopropyl carbonate under the action of alkali to obtain a tenofovir disoproxil intermediate represented by the formula (II), wherein the tenofovir disoproxil intermediate represented by the formula (II) is named as ((bis ((isopropoxycarbonyl) oxy) methoxy) phosphoryl) methyl 4-methylbenzenesulfonate.
2. The method for preparing a tenofovir disoproxil fumarate intermediate according to claim 1, wherein in step 1), the molar ratio of the diethyl p-toluenesulfonyloxymethylphosphonate to the hydrolysis reagent is 1: 3-10; in the step 2), the molar ratio of the compound shown in the formula (III), alkali and chloromethyl isopropyl carbonate is 1:3-5: 2.5-5.
3. The method for preparing a tenofovir disoproxil fumarate intermediate as claimed in claim 2, wherein in step 1), the molar ratio of the diethyl p-toluenesulfonyloxymethylphosphonate to the hydrolysis reagent is 1: 8; in step 2), the molar ratio of the compound represented by the formula (III), the base and chloromethyl isopropyl carbonate is 1:3: 5.
4. The method for preparing a tenofovir disoproxil fumarate intermediate according to claim 1, wherein in step 1), the hydrolysis temperature is 10-80 ℃; in the step 2), the temperature of the condensation reaction is 30-80 ℃.
5. The method for preparing tenofovir disoproxil fumarate intermediate according to claim 4, wherein in step 1), the hydrolysis temperature is 30 ℃; in step 2), the temperature of the condensation reaction is 60 ℃.
6. The method for preparing a tenofovir disoproxil intermediate according to claim 1, wherein in step 1), the solvent used is N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, acetonitrile or N-methylpyrrolidone; in the step 2), the solvent is acetonitrile, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide or N-methylpyrrolidone; in the step 1), the dosage of the solvent is 5-40 times of that of diethyl p-toluenesulfonyloxymethylphosphonate in terms of W/V; in the step 2), the dosage of the solvent is 5-10 times of that of the compound shown in the formula (III) according to W/V.
7. The method for preparing a tenofovir disoproxil fumarate intermediate according to claim 6, wherein in step 1), the solvent used is acetonitrile; in the step 2), the solvent is N, N-dimethylformamide.
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| WO2015085256A1 (en) * | 2013-12-05 | 2015-06-11 | Chimerix, Inc. | Branched chain acyclic nucleoside phosphonate esters and methods of synthesis and uses thereof |
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| WO2015085256A1 (en) * | 2013-12-05 | 2015-06-11 | Chimerix, Inc. | Branched chain acyclic nucleoside phosphonate esters and methods of synthesis and uses thereof |
| CN106061982A (en) * | 2013-12-05 | 2016-10-26 | 奇默里克斯公司 | Branched chain acyclic nucleoside phosphonate esters and methods of synthesis and uses thereof |
| CN103641858A (en) * | 2013-12-31 | 2014-03-19 | 湖南千金湘江药业股份有限公司 | Tenofovir disoproxil fumarate and preparation method thereof |
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