CN105131037B - Preparation method for high-purity tedizolid phosphate - Google Patents
Preparation method for high-purity tedizolid phosphate Download PDFInfo
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- CN105131037B CN105131037B CN201510448852.1A CN201510448852A CN105131037B CN 105131037 B CN105131037 B CN 105131037B CN 201510448852 A CN201510448852 A CN 201510448852A CN 105131037 B CN105131037 B CN 105131037B
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- azoles amine
- safe ground
- phosphorus oxychloride
- ground azoles
- phosphate
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- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- QCGUSIANLFXSGE-GFCCVEGCSA-N tedizolid phosphate Chemical compound CN1N=NC(C=2N=CC(=CC=2)C=2C(=CC(=CC=2)N2C(O[C@@H](COP(O)(O)=O)C2)=O)F)=N1 QCGUSIANLFXSGE-GFCCVEGCSA-N 0.000 title abstract 5
- 229960003947 tedizolid phosphate Drugs 0.000 title abstract 5
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims abstract description 33
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000006243 chemical reaction Methods 0.000 claims abstract description 16
- 235000019445 benzyl alcohol Nutrition 0.000 claims abstract description 10
- 238000006264 debenzylation reaction Methods 0.000 claims abstract description 8
- 239000003054 catalyst Substances 0.000 claims abstract description 4
- -1 azoles amine phosphate ester Chemical class 0.000 claims description 84
- 229910019142 PO4 Inorganic materials 0.000 claims description 31
- 239000010452 phosphate Substances 0.000 claims description 31
- 239000000543 intermediate Substances 0.000 claims description 23
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 20
- HDFFVHSMHLDSLO-UHFFFAOYSA-N Dibenzyl phosphate Chemical group C=1C=CC=CC=1COP(=O)(O)OCC1=CC=CC=C1 HDFFVHSMHLDSLO-UHFFFAOYSA-N 0.000 claims description 19
- BZCGWAXQDLXLQM-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O.ClP(Cl)(Cl)=O BZCGWAXQDLXLQM-UHFFFAOYSA-N 0.000 claims description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 238000001514 detection method Methods 0.000 claims description 12
- 239000012065 filter cake Substances 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 239000002994 raw material Substances 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 229960004217 benzyl alcohol Drugs 0.000 claims description 7
- 239000007787 solid Substances 0.000 claims description 7
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- 230000000977 initiatory effect Effects 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 3
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 6
- 238000000034 method Methods 0.000 abstract description 4
- 229960003879 tedizolid Drugs 0.000 abstract 5
- XFALPSLJIHVRKE-GFCCVEGCSA-N tedizolid Chemical compound CN1N=NC(C=2N=CC(=CC=2)C=2C(=CC(=CC=2)N2C(O[C@@H](CO)C2)=O)F)=N1 XFALPSLJIHVRKE-GFCCVEGCSA-N 0.000 abstract 5
- HDFFVHSMHLDSLO-UHFFFAOYSA-M dibenzyl phosphate Chemical compound C=1C=CC=CC=1COP(=O)([O-])OCC1=CC=CC=C1 HDFFVHSMHLDSLO-UHFFFAOYSA-M 0.000 abstract 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract 1
- 238000000746 purification Methods 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- 239000000047 product Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 7
- 238000005516 engineering process Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 241000194017 Streptococcus Species 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000007086 side reaction Methods 0.000 description 3
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 241000194008 Streptococcus anginosus Species 0.000 description 2
- 150000003938 benzyl alcohols Chemical class 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 229960003085 meticillin Drugs 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- VRESBNUEIKZECD-UHFFFAOYSA-N 2-methyltetrazole Chemical compound CN1N=CN=N1 VRESBNUEIKZECD-UHFFFAOYSA-N 0.000 description 1
- 241000194033 Enterococcus Species 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241000193985 Streptococcus agalactiae Species 0.000 description 1
- 108010059993 Vancomycin Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-N diphosphoric acid Chemical compound OP(O)(=O)OP(O)(O)=O XPPKVPWEQAFLFU-UHFFFAOYSA-N 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229960003907 linezolid Drugs 0.000 description 1
- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229940005657 pyrophosphoric acid Drugs 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 1
- 229940048102 triphosphoric acid Drugs 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention discloses a preparation method for high-purity tedizolid phosphate. The method is characterized by comprising the following steps: subjecting starting materials tedizolid and phosphorus oxychloride to a reaction so as to produce a tedizolid phosphorus oxychloride intermediate; then reacting the tedizolid phosphorus oxychloride intermediate with benzyl alcohol so as to produce a tedizolid dibenzyl phosphate intermediate; and carrying out debenzylation under the action of a catalyst so as to obtain tedizolid phosphate. Meanwhile, all the parameters of procedures are systematically adjusted. The introduced dibenzyl phosphate intermediate has good stability; benzyl protection removal reaction conditions are mild; compared with conventional preparation methods for tedizolid, by-reactions and generation of impurities are greatly reduced in the invention; the purity of the prepared tedizolid phosphate can reach more than 99.9%; and the preparation method omits the step of product purification, has more simplified steps and improves preparation efficiency of the tedizolid phosphate.
Description
Technical field
The present invention relates to pharmaceutical compound preparing technical field, and in particular to a kind of system of high-purity safe ground azoles amine phosphate ester
Preparation Method.
Background technology
Safe ground azoles amine phosphate ester, chemical name for ((R) -3- (the fluoro- 4- of 3- (6- (2- methyl -2H- tetrazole -5-) pyridine -
3-) phenyl) -2- oxazoline ketone -5-) methyldiphosphonic acid ester, molecular formula is C17H16FN6O6P, structural formula is as follows：
。
Safe ground azoles amine phosphate ester is Cubist Pharmaceuticals, Inc.（CubistPharms）The injection lyophilized powder of research and development and piece
Agent medicine, is that resisting gram-positive antibacterial includes staphylococcus aureuses, methicillin-resistant and methicillin sensitive strain, pyogenesis
Streptococcus, streptococcus agalactiae, streptococcus anginosuses（Include streptococcus anginosuses, middle type streptococcus and group of stars streptococcus）And excrement
The medicine of the infection that enterococcus cause.Indication is acute bacterial skin and skin structure infection of the adult caused by sensitive organism
（ABSSSI）.Compare with first generation product Linezolid, drug effect and side effect substantially make moderate progress, safety is to a certain extent
Also increase.The safe ground azoles amine phosphate ester mechanism of action also different from vancomycin, for Gram-positive borne pathogens have
The effect that the order of magnitude increases.Therefore, azoles amine phosphate ester in safe ground has increases drug effect and shortens treatment persistent period double dominant, and
And can also reduce the appearance of fastbacteria.
Existing technology of preparing（Scheme 1）By the safe ground azoles amine of initiation material 1 and phosphorus oxychloride reaction, in generating phosphoryl chloride phosphorus oxychloride
Mesosome 2,2 continues hydrolysis and obtains safe ground azoles amine phosphate ester I.Easily produce during by initiation material 1 and phosphorus oxychloride reaction
Dimer impurity, gained phosphinylidyne chloromethylated intermediate stability is poor, obtains easily being degraded during phosphate ester in phosphoryl chloride phosphorus oxychloride hydrolysis, gathers
Close, easily produce the impurity such as pyrophosphoric acid, triphosphoric acid, purge process is loaded down with trivial details, and operation is more, low production efficiency, and is difficult to obtain height
The safe ground azoles amine phosphate ester of purity, causes to have a strong impact on to the application effect and production efficiency of safe ground azoles amine phosphate ester.Scheme
1 technology path is as follows：
。
The impurity for easily producing：
。
The content of the invention
In order to solve above the problems of the prior art, a kind of with the proposing high-purity Thailand azoles amine phosphorus of the invention
Gently, side reaction is few, greatly reduces the generation of impurity, system for the preparation method of acid esters, the preparation method reaction and operating condition
Up to more than 99.9%, high income eliminates purifying products step to the purity of standby safe ground azoles amine phosphate ester, and step more simplifies,
Substantially increase the preparation efficiency of safe ground azoles amine phosphate ester.
The present invention is adopted the technical scheme that：
A kind of preparation method of high-purity safe ground azoles amine phosphate ester, initiation material safe ground azoles amine and phosphorus oxychloride reaction are given birth to
Into phosphoryl chloride phosphorus oxychloride safe ground azoles amine intermediate, its feature is that phosphoryl chloride phosphorus oxychloride safe ground azoles amine intermediate generates phosphoric acid dibenzyl with benzylalcohol reaction again
Ester safe ground azoles amine intermediate, debenzylation obtains safe ground azoles amine phosphate ester under catalyst action, in the middle of the phosphate dibenzyl ester of introducing
Stably well, debenzylation protection group reaction condition is gentle, and side reaction is few for body, and the safe ground azoles amine phosphate ester purity of preparation is high.
Technology path is as follows：
。
Preparation process is as follows：
（1）Safe ground azoles amine, solvents tetrahydrofurane, alkaline agent DIPEA are proportionally added in there-necked flask, ice bath is to interior temperature
0+2 DEG C, stirring is slowly added dropwise phosphorus oxychloride, and control temperature is less than 10 DEG C, after completion of dropping, warms naturally to 20+2 DEG C, continue
Stirring 4h, TLC detection raw material disappears, and obtains the solution of phosphoryl chloride phosphorus oxychloride safe ground azoles amine intermediate, the safe ground azoles amine of addition, alkaline agent
DIPEA, the mass ratio of phosphorus oxychloride are safe ground azoles amine:Alkaline agent DIPEA:Phosphorus oxychloride is 2～4:1:1～1.5.
（2）DIPEA is added in the solution of phosphoryl chloride phosphorus oxychloride safe ground azoles amine intermediate, is cooled to 0+2 DEG C or so, stirring, slow drop
Plus benzylalcohol, control temperature and be less than 10 DEG C, after completion of dropping, warm naturally to 20+2 DEG C, continue to stir 8h, TLC detection raw materials disappear
Lose, filter, filter cake adds re-crystallizing in ethyl acetate, filter, filter cake is in 40+2 DEG C are vacuum dried 10 hours, obtain phosphate dibenzyl ester safe
Ground azoles amine intermediate, benzylalcohol addition and step（1）The mass ratio of the safe ground azoles amine of middle addition is 1.3～2:1, the safe ground of phosphoryl chloride phosphorus oxychloride
DIPEA amounts are added in the solution of azoles amine intermediate and adds benzylalcohol mass ratio to be 1～2:1.
（3）Under nitrogen protection, phosphate dibenzyl ester safe ground azoles amine intermediate, tetrahydrofuran, palladium carbon are proportionally added into
In there-necked flask, lead to hydrogen, 4h is stirred at room temperature, TLC detection reactions are finished, filtered, and filtrate concentration obtains solid, and solid is added
Stirring at normal temperature 1h in methanol, filters, and filter cake is in 40+2 DEG C are vacuum dried 10 hours, obtain high-purity safe ground azoles amine phosphate ester.
Catalyst in above-described debenzylation is palladium carbon, catalysis plus palladium carbon addition and phosphate dibenzyl ester safe ground azoles amine
The mass ratio of intermediate is 100～120:1.
Beneficial effects of the present invention are：It is creative after phosphoryl chloride phosphorus oxychloride safe ground azoles amine intermediate in the preparation method of the present invention
Add benzylalcohol to introduce phosphate dibenzyl ester intermediate, target product safe ground azoles amine is obtained by phosphate dibenzyl ester intermediate debenzylation
Phosphate ester, preferably, reaction and operating condition are more gentle for phosphate dibenzyl ester intermediate stability, and follow-up debenzylation does not have secondary anti-
Should occur, compare the existing preparation technology of safe ground azoles amine phosphate ester, greatly reduce the generation of side reaction, reduce the product of impurity
Raw, up to more than 99.9%, maximum single contaminant content is less than 0.05% to the safe ground azoles amine phosphate ester purity for preparing, total recovery
More than 85%, product purity is substantially increased, improve the quality of product.Also, the preparation method postprocessing working procedures phase of the present invention
To less, the preparation efficiency of safe ground azoles amine phosphate ester is improve, the popularization and application of industrialized production are easily facilitated, with higher
Market popularization value.
Figure of description
Fig. 1 is the chromatograph phenogram of the safe ground azoles amine phosphate ester product 1 that embodiment 1 is obtained.
Fig. 2 is the chromatograph phenogram of the safe ground azoles amine phosphate ester product 2 that embodiment 2 is obtained.
Specific embodiment
Clearly to illustrate the technical characterstic of the present invention program, with reference to specific embodiment, and with reference to its accompanying drawing, to this
Invention is illustrated.
Embodiment 1
37.0g safe ground azoles amine, 400ml tetrahydrofurans, 12.9gDIPEA are added in there-necked flask, ice bath is to interior temperature 0
DEG C or so, stirring is slowly added dropwise 15.3g phosphorus oxychloride, controls 10 DEG C of temperature ＜, after completion of dropping, warms naturally to 20 DEG C, after
Continuous stirring 4h, TLC detection raw material disappears, and obtains the solution of phosphoryl chloride phosphorus oxychloride safe ground azoles amine intermediate.
Upwards 25.9gDIPEA is added in solution, be cooled to 0 DEG C or so, stirring is slowly added dropwise 21.6g benzylalcohols, controls temperature
10 DEG C of ＜, after completion of dropping, warms naturally to 20 DEG C, continues to stir 8h, and TLC detection raw materials disappear, filter, and filter cake adds 200ml
Re-crystallizing in ethyl acetate, filters, and filter cake is vacuum dried 10 hours in 40 DEG C, obtains phosphate dibenzyl ester safe ground azoles amine intermediate and is total to
52.3g, yield 83%.The nuclear magnetic resonance data of the phosphate dibenzyl ester safe ground azoles amine intermediate for obtaining is as follows： 1H NMR（DMSO-
D6,300MHz）δ3.98（Dd, 1H, J=6.1Hz, 9.1Hz）, 4.02（M, 2H）, 4.18（M, 1H）, 4.55（S, 3H）, 4.99（D,
1H, J=3.3Hz）, 5.62（S, 4H）, 7.42（Dd, 1H, J=2.5Hz, 8.4Hz）, 7.83（M, 2H）, 8.02（M, 2H）, 8.86
（S, 1H）.
Under nitrogen protection, by above-mentioned phosphate dibenzyl ester safe ground azoles amine intermediate, 500ml tetrahydrofurans, 0.44g palladium carbons are added
To in there-necked flask, lead to hydrogen, be stirred at room temperature 4h, TLC detection reactions are finished, and are filtered, filtrate concentration obtains solid, by solid plus
Enter stirring at normal temperature 1h in 100ml methanol, filter, filter cake is vacuum dried 10 hours in 40 DEG C, obtain the safe ground of product 1 azoles amine phosphate ester
35.1g, yield 94%, purity 99.90%.The nuclear magnetic data of the safe ground of product 1 azoles amine phosphate ester is as follows：1H NMR（DMSO-d,
300MHz）δ3.945（Dd, 1H, J=6.3Hz, 9.3Hz）, 4.111（M, 2H）, 4.200（M, 1H）, 4.498（S, 3H）, 4.990
（D, 1H, J=3.3Hz）, 7.519（Dd, 1H, J=2.7Hz, 8.7Hz）, 7.726（M, 2H）, 8.213（M, 2H）, 8.941（S,
1H）.
Embodiment 2：
74.1g safe ground azoles amine, 800ml tetrahydrofurans, 25.9gDIPEA are added in there-necked flask, ice bath is to interior temperature 0
DEG C or so, stirring is slowly added dropwise 30.7g phosphorus oxychloride, controls 10 DEG C of temperature ＜, after completion of dropping, warms naturally to 20 DEG C, after
Continuous stirring 4h, TLC detection raw material disappears, and obtains the solution of phosphoryl chloride phosphorus oxychloride safe ground azoles amine intermediate.
Upwards 51.7gDIPEA is added in solution, be cooled to 0 DEG C or so, stirring is slowly added dropwise 43.3g benzylalcohols, controls temperature
10 DEG C of ＜, after completion of dropping, warms naturally to 20 DEG C, continues to stir 8h, and TLC detection raw materials disappear, filter, and filter cake adds 400ml
Re-crystallizing in ethyl acetate, filters, and filter cake is vacuum dried 10 hours in 40 DEG C, obtains phosphate dibenzyl ester safe ground azoles amine intermediate and is total to
105.9g, yield 84%.The nuclear magnetic resonance data of the phosphate dibenzyl ester safe ground azoles amine intermediate for obtaining is as follows：1H NMR（DMSO-
D, 300MHz）δ 3.98（Dd, 1H, J=6.1Hz, 9.1Hz）, 4.02（M, 2H）, 4.18（M, 1H）, 4.55（S, 3H）, 4.99（D,
1H, J=3.3Hz）, 5.62（S, 4H）, 7.42（Dd, 1H, J=2.5Hz, 8.4Hz）, 7.83（M, 2H）, 8.02（M, 2H）, 8.86
（S, 1H）.
Under nitrogen protection, by above-mentioned phosphate dibenzyl ester safe ground azoles amine intermediate, 1000ml tetrahydrofurans, 0.89g palladium carbons add
Enter in there-necked flask, lead to hydrogen, 4h is stirred at room temperature, TLC detection reactions are finished, filtered, and filtrate concentration obtains solid, by solid
Stirring at normal temperature 1h in 200ml methanol is added to, is filtered, filter cake is vacuum dried 10 hours in 40 DEG C, obtain the safe ground of product 2 azoles amine phosphoric acid
Ester 71.8g, yield 95%, purity 99.93%.The nuclear magnetic data of the safe ground of product 2 azoles amine phosphate ester is as follows：1H NMR（DMSO-d,
300MHz）δ 3.94（Dd, 1H, J=6.3Hz, 9.3Hz）, 4.11（M, 2H）, 4.22（M, 1H）, 4.49（S, 3H）, 4.99（D,
1H, J=3.3Hz）, 7.51（Dd, 1H, J=2.7Hz, 8.7Hz）, 7.72（M, 2H）, 8.21（M, 2H）, 8.94（S, 1H）.
Claims (4)
1. a kind of preparation method of high-purity safe ground azoles amine phosphate ester, initiation material safe ground azoles amine and phosphorus oxychloride reaction are generated
Phosphoryl chloride phosphorus oxychloride safe ground azoles amine intermediate, it is characterised in that：Phosphoryl chloride phosphorus oxychloride safe ground azoles amine intermediate generates phosphoric acid dibenzyl with benzylalcohol reaction again
Ester safe ground azoles amine intermediate, debenzylation obtains safe ground azoles amine phosphate ester under catalyst action；Described phosphoryl chloride phosphorus oxychloride safe ground azoles amine
The preparation process of intermediate is as follows：Safe ground azoles amine, solvents tetrahydrofurane, alkaline agent DIPEA are proportionally added in there-necked flask,
Ice bath is to interior temperature 0+2 DEG C, stirring is slowly added dropwise phosphorus oxychloride, and control temperature is less than 10 DEG C, after completion of dropping, warms naturally to
20+2 DEG C, continue to stir 4h, TLC detection raw materials disappear, and obtain the solution of phosphoryl chloride phosphorus oxychloride safe ground azoles amine intermediate；
The preparation method of the phosphate dibenzyl ester safe ground azoles amine intermediate is：Add in the solution of phosphoryl chloride phosphorus oxychloride safe ground azoles amine intermediate
Enter DIPEA, be cooled to 0+2 DEG C or so, stirring is slowly added dropwise benzylalcohol, and control temperature is less than 10 DEG C, after completion of dropping, heats up naturally
To 20+2 DEG C, continue to stir 8h, TLC detection raw materials disappear, filter, and filter cake adds re-crystallizing in ethyl acetate, filters, and filter cake is in 40+2 DEG C are vacuum dried 10 hours, obtain phosphate dibenzyl ester safe ground azoles amine intermediate；
Described debenzylation step is as follows：Under nitrogen protection, by phosphate dibenzyl ester safe ground azoles amine intermediate, tetrahydrofuran, palladium
Carbon is proportionally added in there-necked flask, leads to hydrogen, and 4h is stirred at room temperature, and TLC detection reactions are finished, filtered, and filtrate concentration must consolidate
Body, by solid stirring at normal temperature 1h in methanol is added to, and is filtered, and filter cake is in 40+2 DEG C are vacuum dried 10 hours, obtain high-purity safe
Ground azoles amine phosphate ester.
2. the preparation method of a kind of high-purity safe ground as claimed in claim 1 azoles amine phosphate ester, it is characterised in that：Described
Safe ground azoles amine that the safe ground azoles amine intermediate of phosphoryl chloride phosphorus oxychloride is added in preparing, alkaline agent DIPEA, the mass ratio of phosphorus oxychloride are safe ground azoles
Amine:Alkaline agent DIPEA:Phosphorus oxychloride is 2～4:1:1～1.5.
3. the preparation method of a kind of high-purity safe ground as claimed in claim 1 azoles amine phosphate ester, it is characterised in that：Described benzyl
Alcohol addition is 1.3～2 with the mass ratio of the raw material safe ground azoles amine for preparing phosphoryl chloride phosphorus oxychloride safe ground azoles amine intermediate:1, phosphoryl chloride phosphorus oxychloride is safe
DIPEA amounts are added in the solution of ground azoles amine intermediate and adds benzylalcohol mass ratio to be 1～2:1.
4. the preparation method of a kind of high-purity safe ground as claimed in claim 1 azoles amine phosphate ester, it is characterised in that：The catalysis
Agent palladium carbon addition is 100～120 with the mass ratio of phosphate dibenzyl ester safe ground azoles amine intermediate:1.
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