CN106632340A

CN106632340A - A kind of method of synthesizing tenofovir intermediate

Info

Publication number: CN106632340A
Application number: CN201611185616.6A
Authority: CN
Inventors: 吕燕华
Original assignee: Qingdao Chenda Biotechnology Co Ltd
Current assignee: Shenzhen Wanwusheng Pharmaceutical Research And Development Co ltd
Priority date: 2016-12-20
Filing date: 2016-12-20
Publication date: 2017-05-10
Anticipated expiration: 2036-12-20
Also published as: CN106632340B

Abstract

The invention discloses a method for synthesizing a tenofovir intermediate. The method comprises the following step: performing oxidation reaction by adopting a compound 9-propenyl adenine shown in a formula 2 as a raw material and tetramethyl piperidine nitrogen oxide under the induction of (S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-dinaphthalene to obtain the tenofovir intermediate (R)-9-(2-hydroxypropyl)adenine shown in a formula 1. reaction conditions of the method for preparing the tenofovir intermediate (R)-9-(2-hydroxypropyl)adenine are milder, and the method is favorable for industrial application and popularization; a target product is high in yield and selectivity; use of a large amount of a chiral compound is avoided, and oxidation can be induced by only a small amount of a chiral auxiliary, so that the cost is lower.

Description

A kind of method of synthesis tenofovir intermediate

Technical field

The invention belongs to technical field of medicine synthesis, is related to a kind of synthesis tenofovir intermediate (R) -9- (2- hydroxyls third Base) adenine method.

Background technology

Tenofovir disoproxil fumaric acid (Tenofovir Disoproxil Fumarate), is that a kind of novel nucleoside acids turns Transcriptase inhibitors, the medicine is researched and developed by the lucky Deco in the U.S. (Gilead Sciences) company, main by suppressing HIV-1 Reverse transcriptase activity and suppress inhibition of HIV duplication.Calendar year 2001 lists first in the U.S., at present in Canada, Europe etc. The listing of multiple countries and regions, its as treatment HIV first-line drug, with good application prospect.Tenofovir disoproxil richness horse The chemical name of acid is (R)-[[2- (6- amino -9H- purine -9- bases) -1- methyl ethoxies] methyl] phosphonic acids diisopropyl oxygen carbonyl Epoxide methyl ester fumarate, tenofovir is its prodrug.Tenofovir disoproxil fumaric acid and the following institute of tenofovir concrete structure Show：

The preparation method of existing tenofovir with chiral alcoholic compound is mainly initiation material system by adenine It is standby.Such as CN101648974A discloses a kind of new process for synthesizing tenofovir disoproxil fumarate, and the method is spread out by adenine with chiral alcohol Prepared by biology, but the method process route, step are longer, and multistep has used the sodium hydride of excess, and condition requires harshness, It is unfavorable for industrial operation, yield is also than relatively low.Chiral alcohol is used in addition, it is expensive so that the method cost is also very high.Tool Body technology route is as follows：

CN103374038B discloses a kind of preparation method of tenofovir disoproxil fumarate, specifically, the preparation Method with adenine as initiation material quaternary ammonium catalysis under with (R)-propylene oxide reaction, it is crystallized to obtain (R) -9- (2- hydroxyls Propyl group) adenine, then obtain tenofovir through steps such as phosphorylated, hydrolysis, acidifyings.The method discloses one kind can be fast The method that speed introduces chiral alcohol in adenine 9- positions, but, the method needs to use expensive chiral cyclopropane in a large number, makes Obtain production cost higher, and the reaction yield is relatively low.Concrete route is as follows：

Therefore, in view of the problem in the preparation process of existing tenofovir and its intermediate, needs exploitation new Better method.

The content of the invention

Present invention aim to overcome that the preparation of existing tenofovir intermediate (R) -9- (2- hydroxypropyls) adenine There are severe reaction conditions in method, using chiral reagent high cost, yield, there is provided a kind of new tenofovir The preparation method of intermediate (R) -9- (2- hydroxypropyls) adenine.

To achieve these goals, the present invention provides a kind of synthesis tenofovir intermediate (R) -9- (2- hydroxypropyls) gland The method of purine, the method includes：It is double in (S)-(-) -2,2'- with the compound 9- acrylic adenines shown in formula 2 as raw material (diphenyl phosphine) -1,1'- dinaphthalenes induction under, with tetramethyl piperidine nitrogen oxides occur oxidation reaction obtain shown in formula 1 for promise Good fortune Wei intermediate (R) -9- (2- hydroxypropyls) adenine；

In the present invention, inventor is induced using chiral auxiliary and the oxidation of tetramethyl piperidine nitrous oxides selectivity is obtained (R) -9- (2- hydroxypropyls) adenine, it is preferable that 9- acrylic adenine and tetramethyl piperidine nitrogen oxides, (S)-(-) -2, The consumption mol ratio of double (the diphenyl phosphine) -1,1'- dinaphthalenes of 2'- is 1：1.2～1.5：0.1～0.3, the solvent of oxidation reaction is two Chloromethanes, ethyl acetate, 1,4- dioxane, tetrahydrofuran, N,N-dimethylformamide or N, N- diethyl acetamide.

In the present invention, find in process of the test, temperature is too high unfavorable for the selectivity of oxidation reaction, preferably relatively low At a temperature of carry out oxidation reaction, it is contemplated that the selectivity of reaction and reaction efficiency, for example, the temperature of oxidation reaction is 10～30 ℃。

The present invention also provides the synthetic method of the compound 9- acrylic adenines shown in a kind of formula 2, the institute of formula 2 of the present invention The compound 9- acrylic adenines that show are synthesized by what following route was carried out, specifically include the chemical combination shown in formula 3 9- acrylic adenines obtained and Wittg reactions with ethyl triphenyl phosphonium salt in the basic conditions in thing 9- formoxyls adenine there is；

Specifically, the process of Wittg of the invention reaction can include：By 9- formoxyls adenine and ethyl triphenyl phosphine Salt is added in anhydrous tetrahydro furan, then instills aqueous slkali, and in 20～30 DEG C of stirring reactions, the aqueous slkali is lithium ethoxide Ethanol solution.The concentration of the ethanol solution of the lithium ethoxide for example can be 1～2mol/L.The 9- formoxyls adenine and second Base triphenylphosphine salt, the consumption mol ratio of alkali are 1：1.1～1.5：1.2～1.5.

In the present invention, it is preferred to Wittg reagents be brand-new reagent, the preparation of the reagent do not have special feature, according to Phosphorus ylide customary preparation methods, for example, bromoethane and triphenylphosphine are stirred 8～12 hours in reflux in toluene, from So cooling, will separate out solid suction filtration, toluene washing, vacuum drying.

For 9- formoxyl adenines, present invention provides a kind of synthetic schemes of the compound, such as shown in formula 3 Compound 9- formoxyls adenine is obtained by the compound shown in formula 5 with Ethyl formate back flow reaction and then basic hydrolysis, is had Body route is as follows：

In the present invention, in 9- formoxyls adenine building-up process, by add a small amount of formic acid can accelerate reaction and The yield of reaction is improved, under preferable case, the consumption of formic acid is 0.01～0.02 with the mol ratio of the compound shown in formula 5：1. Basic hydrolysis removes the reaction temperature of Acetyl Protecting Groups preferably between 55～70 DEG C, this is because when temperature is too high, for example More than 80 DEG C, 9- formoxyls also can part come off.

The method that the present invention is provided has obtained (R) -9- (2- hydroxypropyls) adenine with high selectivity in high yield, as The key intermediate of tenofovir, then obtains tenofovir by steps such as phosphorylated, hydrolysis and acidifyings.

By the present invention provide method prepare tenofovir intermediate (R) -9- (2- hydroxypropyls) adenine, with Lower advantage：1st, the method reaction condition that the present invention is provided is gentleer, promotes beneficial to industrial applications；2nd, target of the invention is produced Thing high income, selectivity are good；3rd, the method for the present invention induces oxygen without using a large amount of chipal compounds using a small amount of chiral auxiliary Change.

Specific embodiment

With reference to specific embodiment, the present invention is described in detail.Following examples will be helpful to the technology of this area Personnel further understand the present invention, but the invention is not limited in any way.It should be pointed out that the ordinary skill to this area For personnel, without departing from the inventive concept of the premise, some deformations and improvement can also be made.These belong to the present invention Protection domain.

Preparation example

In 1500ml reaction flasks, 54g (0.5mol) bromoethanes and 210g (0.8mol) triphenylphosphine are added, and added 1000ml toluene, intensification is stirred at reflux 10 hours, and reactant liquor is cooled to 50 DEG C, and a large amount of solids are separated out, and suction filtration, filter cake uses toluene Washing (50ml*3 time), solid 50 DEG C of dryings in vacuum drying chamber obtain Ethyltriphenylphosphonium brimide 170.4g, yield 91.8%, m.p.：206.5 DEG C～208.5 DEG C.

Embodiment 1

The synthesis of 9- formoxyls-adenine (compound shown in formula 3)

8.9g (50mmol) 6- acetylamino purine (compound shown in formula 5) is added in 10ml Ethyl formates and is dripped Enter 0.05g formic acid, temperature rising reflux reacts 7 hours, is cooled to room temperature, and reactant liquor is poured in water, and dichloromethane is extracted three times, merges Organic phase, reduced pressure concentration, then concentrate be added in 15ml 4mol/L sodium hydrate aqueous solutions 60 DEG C and stir 2 hours, dichloro Methane is extracted, and anhydrous sodium sulfate drying, reduced pressure concentration, petroleum ether is recrystallized to give 9- formoxyls-adenine 7.5g, yield 92.4%, HPLC purity 99.07%.¹HNMR(400MHz,CDCl₃)：δ8.35(s,1H),8.11(s,1H),7.82(s,1H), 5.74(brs,2H)。

Embodiment 2

The synthesis of 9- formoxyls-adenine (compound shown in formula 3)

17.7g (100mmol) 6- acetylamino purine (compound shown in formula 5) is added in 25ml Ethyl formates simultaneously 0.1g formic acid is instilled, temperature rising reflux reacts 6 hours, is cooled to room temperature, and reactant liquor is poured in water, and dichloromethane is extracted three times, closes And organic phase, reduced pressure concentration, then concentrate be added in 20ml 4mol/L sodium hydrate aqueous solutions 70 DEG C and stir 2 hours, two Chloromethanes is extracted, and anhydrous sodium sulfate drying, reduced pressure concentration, petroleum ether is recrystallized to give 9- formoxyls-adenine 15.4g, yield 94.4%, HPLC purity 98.97%.

Embodiment 3

9- formoxyls adenine 3.3g (20mmol) and Ethyltriphenylphosphonium brimide 8.2g (22mmol) are added to anhydrous In tetrahydrofuran, the ethanol solution of the lithium ethoxide of 30ml 1mol/L is then instilled, in 20 DEG C of stirring reactions 0.5 hour, add ice Water quenching is gone out, and now a large amount of solids are generated, and then suction filtration washs filter cake with 50% ethanol, petroleum ether recrystallization, is vacuum dried 9- acrylic adenine 3.2g, yield 91.2%, HPLC purity 99.27%.¹HNMR(400MHz,CDCl₃)：δ8.35(s,1H), 7.82 (s, 1H), 5.70 (s, 2H), 5.41 (d, J=13.0,1H), 5.24 (d, J=13.0Hz, 1H), 2.01 (s, 3H).

Embodiment 4

9- formoxyls adenine 8.2g (50mmol) and Ethyltriphenylphosphonium brimide 22.3g (60mmol) are added to into 60ml In anhydrous tetrahydro furan, the ethanol solution of the lithium ethoxide of 70ml 1mol/L is then instilled, in 30 DEG C of stirring reactions 1 hour, added Frozen water is quenched, and now a large amount of solids are generated, and then suction filtration washs filter cake with 50% ethanol, petroleum ether recrystallization, vacuum drying Obtain 9- acrylic adenine 7.9g, yield 90.4%, HPLC purity 99.14%.

Embodiment 5

The synthesis of tenofovir intermediate (R) -9- (2- hydroxypropyls) adenine

By double (the diphenyl phosphine) -1,1'- dinaphthalene 3.1g of 9- acrylic adenine 8.7g (50mmol) and (S)-(-) -2,2'- (5mmol) in being added to the reaction flask equipped with dichloromethane, keeping temperature is 15 DEG C, opens stirring, and tetramethyl is then added dropwise The dichloromethane solution (9.4g of nitrogen oxides containing tetramethyl piperidine) of piperidines nitrogen oxides, drop finishes, and continues keeping temperature reaction 5 little When, reactant liquor washing, saturated sodium bicarbonate are washed three times, separation organic phase, anhydrous sodium sulfate drying, reduced pressure concentration, and n-hexane/ Dichloromethane (volume ratio 10:1) tenofovir intermediate (R) -9- (2- hydroxypropyls) adenine 9.1g, yield are recrystallized to give 94.7%, ee value 99.35%.MS(ESI)：m/z[M+H]⁺194.11。

¹HNMR(400MHz,d⁶-DMSO)：δ8.34(s,1H),7.79(s,1H),5.68(s,2H),4.72(s,1H), 4.27-4.21(m,2H),3.82(m,1H),1.27(d,3H)。

Embodiment 6

The synthesis of tenofovir intermediate (R) -9- (2- hydroxypropyls) adenine

By double (the diphenyl phosphine) -1,1'- dinaphthalene 6.2g of 9- acrylic adenine 8.7g (50mmol) and (S)-(-) -2,2'- (10mmol) in being added to the reaction flask equipped with dichloromethane, keeping temperature is 25 DEG C, opens stirring, and tetramethyl is then added dropwise The dichloromethane solution (10.2g of nitrogen oxides containing tetramethyl piperidine) of piperidines nitrogen oxides, drop finishes, and continues keeping temperature reaction 4 Hour, reactant liquor washing, saturated sodium bicarbonate wash three times, separate organic phase, anhydrous sodium sulfate drying, reduced pressure concentration, just oneself Alkane/dichloromethane (volume ratio 10:1) tenofovir intermediate (R) -9- (2- hydroxypropyls) adenine 9.0g is recrystallized to give, Yield 93.6%, ee values 99.12%.

Embodiment 7

The synthesis of tenofovir intermediate (R) -9- (2- hydroxypropyls) adenine

By double (the diphenyl phosphine) -1,1'- dinaphthalene 3.7g of 9- acrylic adenine 3.5g (20mmol) and (S)-(-) -2,2'- (6mmol) in being added to the reaction flask equipped with dichloromethane, keeping temperature is 30 DEG C, opens stirring, and tetramethyl is then added dropwise The dichloromethane solution (3.8g of nitrogen oxides containing tetramethyl piperidine) of piperidines nitrogen oxides, drop finishes, and continues keeping temperature reaction 5 little When, reactant liquor washing, saturated sodium bicarbonate are washed three times, separation organic phase, anhydrous sodium sulfate drying, reduced pressure concentration, and n-hexane/ Dichloromethane (volume ratio 10:1) tenofovir intermediate (R) -9- (2- hydroxypropyls) adenine 3.6g, yield are recrystallized to give 94.4%, ee value 99.04%.

Comparative example 1

By double (the diphenyl phosphine) -1,1'- dinaphthalene 6.2g of 9- acrylic adenine 8.7g (50mmol) and (R)-(+) -2,2'- (10mmol) in being added to the reaction flask equipped with dichloromethane, keeping temperature is 25 DEG C, opens stirring, and tetramethyl is then added dropwise The dichloromethane solution (10.2g of nitrogen oxides containing tetramethyl piperidine) of piperidines nitrogen oxides, drop finishes, and continues keeping temperature reaction 5 Hour, reactant liquor washing, saturated sodium bicarbonate are washed three times, separate organic phase, anhydrous sodium sulfate drying, reduced pressure concentration, post layer Analysis obtains tenofovir intermediate 4.2g, yield 43.8%, ((S) -9- (2- hydroxypropyls) the adenine mistake of ee values 84.63% Amount).

Comparative example 2

9- acrylic adenine 8.7g (50mmol) is added in the reaction flask equipped with dichloromethane, keeping temperature is 25 DEG C, stirring is opened, the dichloromethane solution (nitrogen oxides containing tetramethyl piperidine of tetramethyl piperidine nitrogen oxides is then added dropwise 10.2g), drip and finish, continue keeping temperature and react 5 hours, reactant liquor washing, saturated sodium bicarbonate are washed three times, separate organic phase, Anhydrous sodium sulfate drying, reduced pressure concentration, rapid column chromatography obtains tenofovir intermediate (R) -9- (2- hydroxypropyls) adenine 1.7g, yield 17.6%, ee values 12.21%.

Claims

1. a method for synthesizing tenofovir intermediates, the method comprises: taking compound 9-propenyl adenine shown in formula 2 as raw material, in (S)-(-)-2,2'-bis( Under the induction of diphenylphosphino)-1,1'-binaphthyl, an oxidation reaction occurs with tetramethylpiperidine nitroxide to obtain the tenofovir intermediate (R)-9-(2-hydroxyl Propyl) adenine;

2. The method according to claim 1, characterized in that, 9-propenyl adenine and tetramethylpiperidine nitrogen oxide, (S)-(-)-2,2'-bis(diphenylphosphino) )-1,1'-binaphthyl molar ratio is 1:1.2～1.5:0.1～0.3, the solvent for oxidation reaction is dichloromethane, ethyl acetate, 1,4-dioxane, tetrahydrofuran, N, N-dimethylformamide or N,N-diethylacetamide.

3. The method according to claim 1, characterized in that the temperature of the oxidation reaction is 10-30°C.

4. according to the described method of claim 1-3, it is characterized in that, the compound 9-propenyl adenine shown in formula 2 is carried out by following route, specifically comprises the compound 9-formyl adenine shown in formula 3 In the presence of a base, a Wittg reaction occurs with ethyl triphenylphosphine salt to obtain 9-propenyl adenine;

5. method according to claim 4, it is characterized in that, the specific process of Wittg reaction comprises: 9-formyl adenine and ethyl triphenylphosphine salt are joined in anhydrous tetrahydrofuran, drop into alkali solution then, Stir and react at 20-30°C, the alkaline solution is an ethanol solution of lithium ethoxide, and the molar ratio of the 9-formyl adenine, ethyl triphenylphosphine salt, and alkali is 1:1.1-1.5:1.2- 1.5.

6. according to the described method of claim 4 or 5, it is characterized in that, the compound 9-formyl adenine shown in formula 3 is obtained by alkaline hydrolysis then by the compound shown in formula 5 and ethyl formate reflux reaction;

7. The method according to claim 6, characterized in that, in the compound shown in formula 5 and ethyl formate reflux reaction, formic acid is added as a catalyst, and the molar ratio of the amount of formic acid to the compound shown in formula 5 is 0.01～0.02 :1.