CN109942632A - Tenofovir Chinese mugwort draws the preparation method of phenol amine intermediate - Google Patents
Tenofovir Chinese mugwort draws the preparation method of phenol amine intermediate Download PDFInfo
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- CN109942632A CN109942632A CN201711383057.4A CN201711383057A CN109942632A CN 109942632 A CN109942632 A CN 109942632A CN 201711383057 A CN201711383057 A CN 201711383057A CN 109942632 A CN109942632 A CN 109942632A
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- propyl
- adenine
- phenol
- preparation
- phosphinylidyne
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- -1 phenol amine Chemical class 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims abstract description 45
- 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 abstract description 36
- 229960004556 tenofovir Drugs 0.000 title abstract description 12
- 235000010894 Artemisia argyi Nutrition 0.000 title description 8
- 244000030166 artemisia Species 0.000 title description 8
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 78
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims abstract description 75
- 229930024421 Adenine Natural products 0.000 claims abstract description 75
- 229960000643 adenine Drugs 0.000 claims abstract description 75
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims abstract description 47
- 239000002585 base Substances 0.000 claims abstract description 34
- 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 22
- 238000006482 condensation reaction Methods 0.000 claims abstract description 16
- 239000002904 solvent Substances 0.000 claims abstract description 16
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical group CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- 239000003513 alkali Substances 0.000 claims abstract description 9
- 239000003960 organic solvent Substances 0.000 claims abstract description 8
- 230000035484 reaction time Effects 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 26
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical group CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 9
- 150000007530 organic bases Chemical class 0.000 claims description 4
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 abstract description 15
- 238000012805 post-processing Methods 0.000 abstract description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- 238000000034 method Methods 0.000 description 16
- 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 compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 10
- 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
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 9
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 8
- 238000000605 extraction Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 7
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 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 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- WBOHXLDSPBIPTP-UHFFFAOYSA-N N,N-dimethyl-1,8-naphthyridin-4-amine Chemical compound CN(C1=CC=NC2=NC=CC=C12)C WBOHXLDSPBIPTP-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 210000004907 gland Anatomy 0.000 description 4
- 238000009413 insulation Methods 0.000 description 4
- 235000011121 sodium hydroxide Nutrition 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 208000031886 HIV Infections Diseases 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
- RRTCFFFUTAGOSG-UHFFFAOYSA-N benzene;phenol Chemical compound C1=CC=CC=C1.OC1=CC=CC=C1 RRTCFFFUTAGOSG-UHFFFAOYSA-N 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 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
- 238000012544 monitoring process Methods 0.000 description 2
- 230000005311 nuclear magnetism Effects 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
- 238000011160 research Methods 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
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 1
- 101100373011 Drosophila melanogaster wapl gene Proteins 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- 229940126656 GS-4224 Drugs 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 230000004308 accommodation Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 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
- 150000002576 ketones Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 210000004483 pasc Anatomy 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 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 1
- FYGHSUNMUKGBRK-UHFFFAOYSA-N trimethylbenzene Natural products CC1=CC=CC(C)=C1C FYGHSUNMUKGBRK-UHFFFAOYSA-N 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Landscapes
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
It ends the invention discloses a kind of tenofovir and draws the preparation method of phenol amine intermediate.The present invention provides the preparation methods of one kind (R) -9- [2- (phosphinylidyne phenol ylmethoxy) propyl] adenine; it is the following steps are included: in organic solvent; under the conditions of alkali and catalyst are existing, (R) -9- [2- (phosphoryl methoxy base) propyl] adenine and triphenyl phosphite are subjected to condensation reaction and obtain described (R) -9- [2- (the phosphinylidyne phenol ylmethoxy) propyl] adenine；The organic solvent is N-Methyl pyrrolidone.Preparation method solvent usage of the invention is few, the reaction time is short, and post-processing is simple, catalyst amount is few, high income, product purity obtained are high, production cost is low, equipment requirement is low, is suitable for industrialized production.
Description
Technical field
It ends the present invention relates to tenofovir and draws the preparation method of phenol amine intermediate.
Background technique
Gilid Science Co. (Gilead Sciences) develops a series of drug for the treatment of people's infected by HIV diseases,
Middle GS7340 is sent to great expectations, and announces on November 1st, 2012, and evaluation tenofovir Chinese mugwort draws phenol amine hemifumarate
One II clinical trial phase of (tenofoviralafenaminefumarate, TAF, GS-7340) has reached the main of research
Target, which is a kind of experimental novel precursors drug of tenofovir, for treating people's infected by HIV disease.Tenofovir Chinese mugwort
Draw the structural formula of phenol amine hemifumarate are as follows:
Gilid Science Co. has been started up the II phase clinical research that GS7340 treats adult infected by HIV
(NCT01497899).Result of study shows that tenofovir Chinese mugwort draws phenol amine hemifumarate (TAF, i.e. GS7340) 10 multiple doses of ratio
TDF have a stronger anti-virus ability and better safety, it is potential to become a new generation's PMPA prodrug.And it ends in tenofovir
In the synthesis process for drawing phenol amine hemifumarate (TAF, i.e. GS7340), (R) -9- [2- (phosphinylidyne phenol ylmethoxy) propyl] gland
Purine is key intermediate.
Currently, the method for the synthesis intermediate announced both at home and abroad mainly has:
Method one, WO2013052094 disclose the synthesis of (R) -9- [2- (phosphinylidyne phenol ylmethoxy) propyl] adenine
Method: with acetonitrile solvent, (R) -9- [2- (phosphoryl methoxy base) propyl] adenine (PMPA), triphenyl phosphite, three second
Amine and 4-dimethylaminopyridine (DMAP) are more than 48 hours in 80 DEG C of back flow reactions, pass through the monitoring reaction of nuclear-magnetism phosphorus, yield 81%.
This method reaction time is long, and more than 48 hours, energy consumption is high, and the production cycle is long；Using acetonitrile as solvent, and dosage is larger
(8vol, i.e. 8 times of volumes), high production cost；Reaction does middle control with nuclear-magnetism phosphorus, and equipment requirement is high, poor in timeliness；4- dimethylamino
Pyridine (DMAP) dosage is big；Post-processing needs to be evaporated off solvent acetonitrile, cumbersome；It is not suitable for industrialized production.
Method two, WO0208241 are disclosed with (R) -9- [2- (phosphoryl methoxy base) propyl] adenine (PMPA) and benzene
Phenol is raw material, and dicyclohexylcarbodiimide (DCC) is condensing agent, and N- ylmethylpyrrolidine ketone is solvent, small in 100 DEG C of reactions 22
When, the method for synthesis (R) -9- [2- (phosphinylidyne phenol ylmethoxy) propyl] adenine.
This method is condensing agent using dicyclohexylcarbodiimide (DCC), can generate a large amount of waste residue N, N- dicyclohexylurea
(DCU)；Post-processing sodium hydroxide and hydrochloric acid carry out acid-base accommodation, generate a large amount of inorganic salts, and it is difficult in the product to be easy residual
With removal；And reaction yield is low, is not suitable for industrialized production.
Method three, WO2002008041 are disclosed is with (R) -9- [2- (phosphoryl methoxy base) propyl] adenine (PMPA)
Raw material, sulfolane are solvent, the phosphate of PMPA are first transformed into acyl chlorides, then close in 100 DEG C and trimethylbenzene oxygroup pasc reaction
At the method for (R) -9- [2- (phosphinylidyne phenol ylmethoxy) propyl] adenine.
This method is reacted in two steps, cumbersome, and yield is low；Synthesis acyl chlorides uses thionyl chloride, needs waterless operation, right
Equipment requirement is high and pollution is big, is not suitable for industrialized production.
Therefore, searching reaction step is short, high income, reaction condition is mild, easy to operate, equipment requirement is low, production cost
It is that current urgent need is wanted that tenofovir Chinese mugwort that is low, being suitable for industrialized production, which draws the preparation method of phenol amine intermediate (TAF intermediate),
The technical issues of solution.
Summary of the invention
The technical problem to be solved by the present invention is to the preparation sides in order to overcome tenofovir Chinese mugwort drawing phenol amine in the prior art
Method severe reaction conditions, the time is long, catalyst amount is big, equipment requirement is high, post-processing operation complex steps, yield are low, atom
Less economical, high production cost, the defects of being not suitable for industrialized production, and propose a kind of tenofovir Chinese mugwort and draw among phenol amine
The preparation method of body.Preparation method solvent usage of the invention is few, the reaction time is short, high income, post-processes simple, catalyst use
Amount is less, production cost is low, equipment requirement is low, is suitable for industrialized production.
The present invention provides the preparation method of one kind (R) -9- [2- (phosphinylidyne phenol ylmethoxy) propyl] adenine, packets
Include following steps: in organic solvent, under the conditions of alkali and catalyst are existing, by (R) -9- [2- (phosphoryl methoxy base) propyl] gland
Purine (PMPA) and triphenyl phosphite carry out condensation reaction and obtain (R) -9- [2- (phosphinylidyne phenol ylmethoxy) third
Base] adenine；The organic solvent is N-Methyl pyrrolidone；
In the preparation method of described (R) -9- [2- (the phosphinylidyne phenol ylmethoxy) propyl] adenine, described is organic
The preferred 1mL/g of volume mass ratio of solvent and described (R) -9- [2- (phosphoryl methoxy base) propyl] adenine (PMPA)~
5mL/g, further preferred 1mL/g~2mL/g, such as 2mL/g.
In the preparation method of described (R) -9- [2- (the phosphinylidyne phenol ylmethoxy) propyl] adenine, the alkali is excellent
Select organic base；The preferred N of the organic base, N- diisopropylethylamine (DIPEA) or triethylamine (TEA).
In the preparation method of described (R) -9- [2- (the phosphinylidyne phenol ylmethoxy) propyl] adenine, the alkali with
The molar ratio preferably 1~3 of described (R) -9- [2- (phosphoryl methoxy base) propyl] adenine (PMPA), further preferably
1.5~2.5, such as 2.0.
In the preparation method of described (R) -9- [2- (the phosphinylidyne phenol ylmethoxy) propyl] adenine, the catalysis
The preferred 4-dimethylaminopyridine of agent (DMAP).
In the preparation method of described (R) -9- [2- (the phosphinylidyne phenol ylmethoxy) propyl] adenine, the catalysis
The molar ratio preferably 0.1~0.6 of agent and described (R) -9- [2- (phosphoryl methoxy base) propyl] adenine (PMPA), into one
Step preferably 0.1~0.5, such as 0.1 or 0.5.
In the preparation method of described (R) -9- [2- (the phosphinylidyne phenol ylmethoxy) propyl] adenine, the phosphorous
The molar ratio preferably 0.9~2 of triphenyl phosphate ester and described (R) -9- [2- (phosphoryl methoxy base) propyl] adenine (PMPA),
Further preferred 1.1~1.5, such as 1.1 or 1.5.
In the preparation method of described (R) -9- [2- (the phosphinylidyne phenol ylmethoxy) propyl] adenine, the condensation
Preferably 95 DEG C~140 DEG C of the temperature of reaction.When preferably 95 DEG C~110 DEG C of the reaction temperature of the condensation reaction (such as 95
DEG C~100 DEG C or 105 DEG C~110 DEG C), the time of the condensation reaction preferably 20 hours~25 hours, for example, 20 hours or
25 hours；When preferably 130 DEG C~140 DEG C of the temperature of the condensation reaction (such as 135 DEG C~140 DEG C), the condensation
The time of reaction preferably 2 hours~4 hours, such as 3 hours.
The preparation method of described (R) -9- [2- (the phosphinylidyne phenol ylmethoxy) propyl] adenine can use this field
In routine monitoring method (such as TLC, HPLC or NMR) detected, generally with (R) -9- [2- (phosphoryl methoxy
Base) propyl] adenine (PMPA) content lower than 0.1% be reaction terminal, when the condensation reaction temperature for 95 DEG C~
At 110 DEG C (such as 95 DEG C~100 DEG C or 105 DEG C~110 DEG C), the time of the condensation reaction preferably 16 hours~30 is small
When, further preferred 20 hours~25 hours, such as 20 hours or 25 hours；When the setting-up point be 130 DEG C~
At 140 DEG C (such as 135 DEG C~140 DEG C), the time of the condensation reaction preferably 1 hour~6 hours, further preferred 2 is small
When~4 hours, such as 3 hours.
The preparation method of described (R) -9- [2- (the phosphinylidyne phenol ylmethoxy) propyl] adenine preferably uses following anti-
It answers step: alkali, catalyst, (R) -9- [2- (phosphoryl methoxy base) propyl] adenine (PMPA) and triphenyl phosphite is added
Into organic solvent, progress condensation reaction obtains described (the R) -9- [2- (phosphinylidyne phenol ylmethoxy) propyl], and adenine is i.e.
It can；The organic solvent is N-Methyl pyrrolidone (NMP).
The preparation method of described (R) -9- [2- (the phosphinylidyne phenol ylmethoxy) propyl] adenine preferably use it is following after
Processing step: after reaction, cooling, extraction adjusts pH=2~4, obtains (R) -9- [2- (phosphinylidyne phenylol methoxy
Base) propyl] adenine.
Cooling, extraction and the adjusting pH can be using the conventional method of the generic operation in this field.The cooling
Preferably 0 DEG C~30 DEG C of temperature (such as 15 DEG C~25 DEG C).The preferred halogenated hydrocarbon solvent of solvent that the extraction uses；It is described
The preferred chlorinated hydrocarbon solvent of halogenated hydrocarbon solvent；The preferred methylene chloride of the chlorinated hydrocarbon solvent.Time of the extraction
Number preferably 1 time~3 times, such as 3 times.The adjusting pH preferably uses inorganic acid；The preferred hydrochloric acid of the inorganic acid.Described
Hydrochloric acid can be conventional commercial hydrochloric acid reagent；Preferred 10mol/L~the 12mol/L of the concentration of the hydrochloric acid；The concentration is
Refer to the mole of hydrogen chloride and the ratio of hydrochloric acid solution volume.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can any combination to get the present invention it is each preferably
Example.
The reagents and materials used in the present invention are commercially available.
In the present invention, the room temperature refers to that environment temperature is 10 DEG C~35 DEG C.
The positive effect of the present invention is that: preparation method solvent usage of the invention is few, catalyst amount is few, reaction
Time is short, high income, post-processes that product purity simple, obtained is high, production cost is low, equipment requirement is low, is suitable for industrializing
Production.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality
It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient
The selection of product specification.
Embodiment 1
By (R) -9- [2- (phosphoryl methoxy base) propyl] adenine (PMPA, 10.0g, 34.82mmol, 1.0eq), 4- bis-
Methylamino 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) is added in N-Methyl pyrrolidone (NMP) (20ml), is opened
Stirring is opened, is warming up to 135~140 DEG C of insulation reactions 3 hours, it is fast that HPLC monitors (R) -9- [2- (phosphoryl methoxy base) propyl] gland
Purine (PMPA) content is lower than 0.1%, stops reaction.It is cooled to room temperature (15~25 DEG C), is added water (40ml), methylene chloride
(40ml × 3) extraction, water phase adjust PH to 2~3 that solid is precipitated with concentrated hydrochloric acid (12M, 3.2ml), are cooled to 0~10 DEG C, filtering is dried
It is dry to obtain (R) -9- [2- (phosphinylidyne phenol ylmethoxy) propyl] adenine 11.3g, yield 89.3%, HPLC purity 99.91%.
Embodiment 2
By (R) -9- [2- (phosphoryl methoxy base) propyl] adenine (PMPA, 100.0g, 348.2mmol, 1.0eq), 4-
Dimethylamino naphthyridine (DMAP, 21.0g, 171.9mmol, 0.5eq), triphenyl phosphite (162.0g, 522.1mmol,
1.5eq), triethylamine (70.0g, 691.8mmol, 2.0eq) is added in N-Methyl pyrrolidone (NMP, 200ml), and unlatching is stirred
It mixes, is warming up to 105~110 DEG C of insulation reactions 20 hours, HPLC monitors (R) -9- [2- (phosphoryl methoxy base) propyl] adenine
(PMPA) content is lower than 0.1%, stops reaction.It is cooled to room temperature (15~25 DEG C), is added water (400ml), methylene chloride
(400ml × 3) extraction, water phase adjust PH to 2~3 that solid is precipitated with concentrated hydrochloric acid (12M, 32ml), are cooled to 0~10 DEG C, filtering is dried
It is dry to obtain (R) -9- [2- (phosphinylidyne phenol ylmethoxy) propyl] adenine 111.0g, yield 88.09%, HPLC purity
99.38%.
Embodiment 3
By (R) -9- [2- (phosphoryl methoxy base) propyl] adenine (PMPA, 100.0g, 348.2mmol, 1.0eq), 4-
Dimethylamino naphthyridine (DMAP, 21.0g, 171.9mmol, 0.5eq), triphenyl phosphite (162.0g, 522.1mmol,
1.5eq), triethylamine (70.0g, 691.8mmol, 2.0eq) is added in N-Methyl pyrrolidone (NMP, 200ml), and unlatching is stirred
It mixes, is warming up to 95~100 DEG C of insulation reactions 25 hours, HPLC monitors (R) -9- [2- (phosphoryl methoxy base) propyl] adenine
(PMPA) content is lower than 0.1%, stops reaction.It is cooled to room temperature (15~25 DEG C), is added water (400ml), methylene chloride
(400ml × 3) extraction, water phase adjust PH to 2~3 that solid is precipitated with concentrated hydrochloric acid (12M, 32ml), are cooled to 0~10 DEG C, filtering is dried
It is dry to obtain (R) -9- [2- (phosphinylidyne phenol ylmethoxy) propyl] adenine 111.9g, yield 88.80%, HPLC purity
99.35%.
Comparative example 1
By (R) -9- [2- (phosphoryl methoxy base) propyl] adenine (PMPA, 100.0g, 348.2mmol, 1.0eq), 4-
Dimethylamino naphthyridine (DMAP, 213g, 1.744mol, 5eq), triphenyl phosphite (129.6g, 417.7mmol, 1.2eq), three
Ethamine (176.3g, 1.744mol, 5eq), n,N-Dimethylformamide (DMF, 1L) are added into reaction flask, are heated to interior temperature
135 DEG C are reacted 5 hours, and LC-MS display is generated without (R) -9- [2- (phosphinylidyne phenol ylmethoxy) propyl] adenine.
Comparative example 2
By (R) -9- [2- (phosphoryl methoxy base) propyl] adenine (PMPA) (5.0g, 17.4mmol, 1.0eq), 4- bis-
Methylamino pyridine (DMAP, 2.1g, 17.4mmol, 1.0eq), triphenyl phosphite (8.1g, 26.1mmol, 1.5eq), triethylamine
(3.5g, 34.8mmol, 2.0eq) is added in dimethyl sulfoxide (DMSO) (20ml), is opened stirring, is warming up to 100~110 DEG C of guarantors
Temperature reaction 12 hours, LC-MS show that no product generates；Extend reaction to 25 hours, LC-MS shows that no product generates.
Comparative example 3 (CN201280048965 patent specification embodiment 5 of page 12)
By (R) -9- [2- (phosphoryl methoxy base) propyl] adenine (PMAP, 200.0g, 696.35mmol, 1.0eq), 4-
Dimethylamino naphthyridine (DMAP, 85.0g, 695.75mmol, 1.0eq), triphenyl phosphite (324.1g, 1044.51mmol,
1.5eq), triethylamine (140.8g, 1391.44mmol, 2.0eq) is added in acetonitrile (1.6L, 8mL/g), opens stirring, heating
To reflux (82 DEG C of interior temperature) insulation reaction 67 hours.HPLC shows that HPLC monitors (R) -9- [2- (phosphoryl methoxy base) propyl] gland
Purine (PMPA) content is lower than 0.1%, stops reaction.40~50 DEG C are concentrated to dryness, and are cooled to 20~30 DEG C, and water is added
(800ml) and ethyl acetate (800ml) are stirred 10 minutes and are layered, aqueous layer with ethyl acetate (600ml × 3) extraction.Water phase is with dense
Hydrochloric acid (about 66ml) adjusts PH to 2~3, and stirring and crystallizing is cooled to 0~10 DEG C and stirs 1~2 hour, filtering.With cold (0~10 DEG C)
1% dilute hydrochloric acid (150ml × 2) elution, 50 DEG C of drying obtain white solid 191g, yield 75.5%, purity 99.06%.
Comparative example 4 (embodiment for repeating WO0208241)
By (R) -9- [2- (phosphoryl methoxy base) propyl] adenine (PMAP 146.0g, 508.0mmol, 1.0eq), benzene
Phenol (96.0g, 1020.0mmol, 2.0eq) is added to N-Methyl pyrrolidone (300ml, 2.0vol), and triethylamine is added
(63.0g, 623.0mmol, 1.2eq).85 DEG C are heated to, 85~100 DEG C of dropwise addition dicyclohexylcarbodiimide (DCC of temperature control；
171.0g, 829.0mmol, 1.6eq) N-Methyl pyrrolidone (100ml, 0.7vol) solution, drip off within 2 hours.After dripping off, protect
100 DEG C of temperature are stirred 16 hours.15~25 DEG C are cooled to, water (290ml) is added and stirs 30 minutes, filtering, water (150ml) elution filter
Cake, 60 DEG C of merging filtrate are concentrated into constant weight, are added water (250ml), with mass concentration be 25% sodium hydrate aqueous solution tune PH extremely
11 (mass concentration refers to that the quality of sodium hydroxide accounts for the percentage of sodium hydrate aqueous solution gross mass), Celite pad mistake
Filter, water (40ml) elute filter cake, and merging filtrate is extracted with ethyl acetate (280ml), and water phase concentrated hydrochloric acid tune PH to 3, stirring is simultaneously
It is cooled to 0~10 DEG C, filtering, methanol (50ml × 2) elution dries and obtains 106.0g product, HPLC purity 98.12%, yield
57.4%.
Claims (10)
- The preparation method of one kind (R) -9- 1. [2- (phosphinylidyne phenol ylmethoxy) propyl] adenine, it is characterised in that including following Step: in organic solvent, under the conditions of alkali and catalyst are existing, will (R) -9- [2- (phosphoryl methoxy base) propyl] adenine with Triphenyl phosphite carries out condensation reaction and obtains described (R) -9- [2- (the phosphinylidyne phenol ylmethoxy) propyl] adenine； The organic solvent is N-Methyl pyrrolidone；
- 2. the preparation method of (R) -9- [2- (phosphinylidyne phenol ylmethoxy) propyl] adenine as described in claim 1, special Sign is: in the preparation method of described (R) -9- [2- (the phosphinylidyne phenol ylmethoxy) propyl] adenine, described is organic The volume mass ratio of solvent and described (R) -9- [2- (phosphoryl methoxy base) propyl] adenine (PMPA) be 1mL/g~ 5mL/g。
- 3. the preparation method of (R) -9- [2- (phosphinylidyne phenol ylmethoxy) propyl] adenine as claimed in claim 2, special Sign is: in the preparation method of described (R) -9- [2- (the phosphinylidyne phenol ylmethoxy) propyl] adenine, described is organic The volume mass ratio of solvent and described (R) -9- [2- (phosphoryl methoxy base) propyl] adenine (PMPA) be 1mL/g~ 2mL/g。
- 4. the preparation method of (R) -9- [2- (phosphinylidyne phenol ylmethoxy) propyl] adenine as described in claim 1, special Sign is: in the preparation method of described (R) -9- [2- (the phosphinylidyne phenol ylmethoxy) propyl] adenine, the alkali is Organic base.
- 5. the preparation method of (R) -9- [2- (phosphinylidyne phenol ylmethoxy) propyl] adenine as claimed in claim 4, special Sign is:In the preparation method of described (R) -9- [2- (the phosphinylidyne phenol ylmethoxy) propyl] adenine, the organic base is N, N- diisopropylethylamine or triethylamine.
- 6. the preparation method of (R) -9- [2- (phosphinylidyne phenol ylmethoxy) propyl] adenine as described in claim 1, special Sign is:In the preparation method of described (R) -9- [2- (the phosphinylidyne phenol ylmethoxy) propyl] adenine, the catalyst is 4-dimethylaminopyridine.
- 7. the preparation method of (R) -9- [2- (phosphinylidyne phenol ylmethoxy) propyl] adenine as described in claim 1, special Sign is:In the preparation method of described (R) -9- [2- (the phosphinylidyne phenol ylmethoxy) propyl] adenine, the alkali with it is described (R) -9- [2- (phosphoryl methoxy base) propyl] adenine molar ratio be 1~3；And/orIn the preparation method of described (R) -9- [2- (the phosphinylidyne phenol ylmethoxy) propyl] adenine, the catalyst with The molar ratio of described (R) -9- [2- (phosphoryl methoxy base) propyl] adenine is 0.1~0.6；And/orIn the preparation method of described (R) -9- [2- (the phosphinylidyne phenol ylmethoxy) propyl] adenine, the phosphorous acid three The molar ratio of phenyl ester and described (R) -9- [2- (phosphoryl methoxy base) propyl] adenine is 0.9~2.
- 8. the preparation method of (R) -9- [2- (phosphinylidyne phenol ylmethoxy) propyl] adenine as claimed in claim 7, special Sign is:In the preparation method of described (R) -9- [2- (the phosphinylidyne phenol ylmethoxy) propyl] adenine, the alkali with it is described (R) -9- [2- (phosphoryl methoxy base) propyl] adenine molar ratio be 1.5~2.5；And/orIn the preparation method of described (R) -9- [2- (the phosphinylidyne phenol ylmethoxy) propyl] adenine, the catalyst with The molar ratio of described (R) -9- [2- (phosphoryl methoxy base) propyl] adenine is 0.1~0.5；And/orIn the preparation method of described (R) -9- [2- (the phosphinylidyne phenol ylmethoxy) propyl] adenine, the phosphorous acid three The molar ratio of phenyl ester and described (R) -9- [2- (phosphoryl methoxy base) propyl] adenine is 1.1~1.5.
- 9. the preparation method of (R) -9- [2- (phosphinylidyne phenol ylmethoxy) propyl] adenine as described in claim 1, special Sign is:In the preparation method of described (R) -9- [2- (the phosphinylidyne phenol ylmethoxy) propyl] adenine, the condensation reaction Temperature be 95 DEG C~140 DEG C；And/orIn the preparation method of described (R) -9- [2- (the phosphinylidyne phenol ylmethoxy) propyl] adenine, the condensation reaction Time be 1 hour~30 hours.
- 10. the preparation method of (R) -9- [2- (phosphinylidyne phenol ylmethoxy) propyl] adenine as claimed in claim 9, special Sign is:When the reaction temperature of the condensation reaction is 95 DEG C~110 DEG C, time of the condensation reaction is 20 hours~ 25 hours；And/orWhen the temperature of the condensation reaction is 130 DEG C~140 DEG C, the time of the condensation reaction is 2 hours~4 small When.
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| CN1706855A (en) * | 2000-07-21 | 2005-12-14 | 吉里德科学公司 | Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same |
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