CN108003188A - A kind of new purification process of alkyl phosphoric acid esters compound - Google Patents
A kind of new purification process of alkyl phosphoric acid esters compound Download PDFInfo
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- CN108003188A CN108003188A CN201711414348.5A CN201711414348A CN108003188A CN 108003188 A CN108003188 A CN 108003188A CN 201711414348 A CN201711414348 A CN 201711414348A CN 108003188 A CN108003188 A CN 108003188A
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- purification process
- phosphoric acid
- compound
- acid esters
- alkyl phosphoric
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- -1 alkyl phosphoric acid esters compound Chemical class 0.000 title claims abstract description 26
- 238000000746 purification Methods 0.000 title claims abstract description 13
- 239000003480 eluent Substances 0.000 claims abstract description 9
- 230000007935 neutral effect Effects 0.000 claims abstract description 7
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000004440 column chromatography Methods 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 41
- 239000000047 product Substances 0.000 claims description 18
- 239000012043 crude product Substances 0.000 claims description 13
- 150000001875 compounds Chemical class 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 239000003463 adsorbent Substances 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 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 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 230000002152 alkylating effect Effects 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 238000010828 elution Methods 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 3
- 239000003444 phase transfer catalyst Substances 0.000 claims description 3
- 238000010189 synthetic method Methods 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims 1
- 229910052782 aluminium Inorganic materials 0.000 claims 1
- 239000004411 aluminium Substances 0.000 claims 1
- 239000002699 waste material Substances 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- LNJAJHJFSKUCIR-UHFFFAOYSA-N ditert-butyl chloromethyl phosphate Chemical compound CC(C)(C)OP(=O)(OCCl)OC(C)(C)C LNJAJHJFSKUCIR-UHFFFAOYSA-N 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 239000012286 potassium permanganate Substances 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- MBKMSNIPVJQGSH-UHFFFAOYSA-N C(OC(C)(C)C)(OC(C)(C)C)=O.P(=O)(O)(O)O Chemical compound C(OC(C)(C)C)(OC(C)(C)C)=O.P(=O)(O)(O)O MBKMSNIPVJQGSH-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- YEWZQCDRZRYAEB-UHFFFAOYSA-N ditert-butyl hydrogen phosphate Chemical compound CC(C)(C)OP(O)(=O)OC(C)(C)C YEWZQCDRZRYAEB-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 150000003014 phosphoric acid esters Chemical class 0.000 description 2
- 238000012805 post-processing Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- CZUSEYCGNRYJRD-UHFFFAOYSA-N C(OC(C)(C)C)(OC(C)(C)C)=O.P(O)(O)O Chemical compound C(OC(C)(C)C)(OC(C)(C)C)=O.P(O)(O)O CZUSEYCGNRYJRD-UHFFFAOYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical group C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- AJSHDAOMUKXVDC-UHFFFAOYSA-N butan-1-amine;sulfuric acid Chemical compound CCCC[NH3+].OS([O-])(=O)=O AJSHDAOMUKXVDC-UHFFFAOYSA-N 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- ODCCJTMPMUFERV-UHFFFAOYSA-N ditert-butyl carbonate Chemical compound CC(C)(C)OC(=O)OC(C)(C)C ODCCJTMPMUFERV-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 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
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- CSBZSNQGGCURDX-UHFFFAOYSA-N tetrabutyl-$l^{4}-sulfane Chemical compound CCCCS(CCCC)(CCCC)CCCC CSBZSNQGGCURDX-UHFFFAOYSA-N 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- 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
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/11—Esters of phosphoric acids with hydroxyalkyl compounds without further substituents on alkyl
Landscapes
- 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 belongs to chemosynthesis technical field, there is provided a kind of purification process of alkyl phosphoric acid esters compound.The purification process is：Negative pressure column chromatography purifies, and separating medium is neutral alumina.The purification process separating rate is fast, the purity of alkyl phosphoric acid esters compound that is efficient, obtaining can reach more than 99%.And eluent recoverable, it is cost-effective, reduce three waste discharge.
Description
Technical field
The invention belongs to chemosynthesis technical field, more particularly to a kind of purification process of alkyl phosphoric acid esters compound.
The present invention purified with negative pressure column chromatography to the alkyl phosphoric acid esters compound, obtained product purity can reach 99% with
On.
Background technology
Alkyl phosphoric acid esters compound is to prepare the important intermediate of phosphoric acid ester prodrug, and phosphoric acid ester prodrug, is had
Improve drug selectivity, masking agents foreign odor, improve the effect such as medicine stability, bioavilability.By phosphate prodrugs
The shortcomings that being further processed into phosphoric acid salt derivative, and its poorly water-soluble can be overcome.
According to the literature, the purification process of alkyl phosphoric acid esters compound：First, using the post processing that routinizes, that is, extract,
Liquid separation, be concentrated to give product；Second, silica gel column chromatography.
Patent US2012157411：In the solution containing phase transfer catalyst 4-butyl ammonium hydrogen sulfate and sodium acid carbonate,
React to obtain di-t-butyl chloromethyl phosphate with di-t-butyl phosphate and chloromethyl chlorosulfonic acid ester.Through extraction, liquid separation, organic
End-product is obtained after mutually concentrating.Product yield is low, is only 52.6%.
Patent CN102482305：Di-t-butyl chloromethyl phosphate is synthesized using above-mentioned similar synthetic method, is being obtained
Product crude product in add n,N-dimethylacetamide (DMAc), boil off the product for obtaining being mixed with DMAc after other solvents.Wherein
The purity (＞ 99%) of report is product in DMAc1HNMR purity.What the disadvantage of this method was is to be mixed with greatly
Measure the mixture of DMAc.
Patent WO2013019169：Chloromethyl two has been synthesized by di-t-butyl phosphate and the reaction of chloromethyl chlorosulfonic acid ester
T-butyl phosphate ester, product crude product are purified with silica gel column chromatography, and eluent is ethyl acetate/n-hexane (1:3), ultimate yield
72%.
Patent WO2008070149：Chloromethyl di-t-butyl phosphate is purified using silica gel column chromatography, eluent is acetic acid
Ethyl ester/n-hexane.Impurity phosphoric acid double (di-t-butyl methyl esters) in the patent report product is difficult to be removed, i.e.,：Use 100%
Ethyl acetate eluent, still have 10%~15% impurity residual.The purity of products obtained therefrom is less than 90%.
In conclusion the conventional post-processing approach for the alkyl phosphoric acid esters compound reported at present, obtained crude product without
Method reaches the requirement of high-purity.And silica gel column chromatography is used to crude product repurity, still suffer from being difficult to separated impurity in product
In the presence of.And phosphate compounds stability is poor, there is hydrolysis risk in acid silica gel.Can so finding one kind
Above-mentioned drawback, method that is workable, being adapted to industrialized production are solved, is of great significance.
The content of the invention
The present invention is intended to provide a kind of purification process of alkyl phosphoric acid esters compound, to solve the above problems.
A kind of synthetic method of the alkyl phosphoric acid esters compound with III structure of formula, comprises the following steps：
Wherein, R1For methyl, ethyl, the tert-butyl group；R2For hydrogen, methyl, ethyl, isopropyl.
(A) under the action of condensing agent, react to obtain chemical compounds I with phosphorous acid and alcohol；
(B) under conditions of alkali coexists, oxidized dose of oxidation of chemical compounds I obtains compound ii；
(C) in the solution containing phase transfer catalyst and alkali, compound ii and chlorine alkylating reagent reaction are made
The crude product of compound III.Crude product is purified to obtain high-purity alkyl phosphoric acid esters compound.
Alcohol described in step (A) is methanol, ethanol, the tert-butyl alcohol；Condensing agent is N, N'- dicyclohexylcarbodiimides (DCC)；
Solvent is ethyl acetate (EA).The amount ratio of the material of phosphorous acid, alcohol and condensing agent is 1 ﹕, 2.2 ﹕ 2.05.Reaction temperature is 30 DEG C；
Reaction time is 3h.
Oxidant described in step (B) is potassium permanganate；Alkali is NaHCO3；The amount of the material of chemical compounds I and potassium permanganate
Than for 1 ﹕ 0.7.
Chlorine alkylating reagent described in step (C) is chloromethyl chlorosulfonic acid ester, 1- chloroethyl chlorosulfonic acids ester, 1- chloropropyl chlorine
Sulphonic acid ester, 1- chloro-2-methyl propyl chloride sulphonic acid esters；Alkali is NaHCO3；Solvent is water and DCM.
(C) purification process of the compound III crude product described in quickly elutes for neutral alumina negative pressure column chromatography.
Selected adsorbent is 200~300 mesh neutral aluminas, and the addition of adsorbent is the 3~5 of product crude product weight
Times, preferably 4 times.
For petroleum ether, (PE) ︰ ethyl acetate (EA)=10~2 ︰ 1, is preferably 3 ︰ 1 to eluent.
Negative pressure elution vacuum is -0.05~-0.09MPa, preferably -0.06MPa.
The novelty of patent of the present invention is as follows：The present invention uses neutral alumina column chromatographic purifying product, this method separation
Speed is fast, efficient, product is stablized in adsorbent, and products obtained therefrom purity is high, can reach more than 99%.The recyclable profit of eluent
With, it is cost-effective, reduce three waste discharge.
Embodiment
The present invention is described further for the following examples, and following embodiments are only used for illustrating rather than limit
The system present invention.
Embodiment 1
1. chloromethyl di-t-butyl phosphate synthesis
(1) synthesis of phosphorous acid di tert butyl carbonate
Ethyl acetate (24L) is added into 100L reaction kettles, stir it is lower add phosphorous acid (2.400kg, 29.27mol) and
The tert-butyl alcohol (4.773kg, 64.40mol), the ethyl acetate of DCC (12.371kg, 60.00mol) is added dropwise into reaction bulb
(12.50L) solution, 1.0h are added dropwise.Controlling reaction temperature is 30 DEG C of reaction 3h.There are a large amount of solids to separate out.Solid is filtered out, is filtered
Liquid be concentrated under reduced pressure remove ethyl acetate after compound phosphorous acid di tert butyl carbonate (4.285kg, 22.07mol), molar yield
75.4%.
(2) synthesis of phosphoric acid di tert butyl carbonate
The addition 20.00L water into 100L there-necked flasks, the lower addition compound phosphorous acid di tert butyl carbonate of stirring (4.000kg,
20.60mol), 0 DEG C of ice salt bath temperature control, is slowly added to sodium acid carbonate (2.596kg, 30.90mol), there is a small amount of bubble formation, control
0 DEG C of temperature reaction 1h, points 5 batches add potassium permanganate (2.278kg, 14.42mol), and reaction solution gradually becomes black by pink, and 25
DEG C reaction 1h.It is warming up to 60 ± 3 DEG C of reaction 15min.Heat filtering, activated carbon (0.400kg) is added in filtrate in 60 DEG C of stirrings
30min, heat filtering, filtrate are cooled to 0~5 DEG C.It is 2 that 6mol/L hydrochloric acid (2.37L, 14.22mol), which is slowly added dropwise, and adjusts pH value,
Crystallization 2h is stood in 0~5 DEG C.Filtering, filter cake are eluted with 3 ± 2 DEG C of cold water (1.00L).White solid phosphoric acid is obtained after filtration cakes torrefaction
Di tert butyl carbonate (3.005kg, 14.30mol), TLC are detected as single point, molar yield 69.40%.
(3) chloromethyl di-t-butyl phosphate synthesis
Nitrogen protection under, into 100L reaction kettles add water (24.00L) and phosphoric acid di tert butyl carbonate (3.000kg,
14.27mol), temperature is controlled at 0 ± 2 DEG C, and point 5 batches of addition sodium acid carbonates (4.7954kg, 57.08mol) add tetrabutyl sulphur afterwards
Sour hydrogen ammonium (0.485kg, 1.427mol).Temperature is controlled at 0 ± 2 DEG C, dropwise addition chloromethyl chlorosulfonic acid ester (3.099kg,
Dichloromethane (dry) (6.20L) solution 17.12mol), about 3h are dripped off.30 DEG C of reaction 2h of temperature control, reaction terminate.Filtering, filter
Liquid phase liquid separation, lower floor's dichloromethane layer are dried with anhydrous sodium sulfate, filter out solid, filtrate decompression be concentrated to give crude product (3.554kg,
13.74mol), crude yield 96.27%.
2. chloromethyl di-t-butyl phosphate purifying crude
Neutral alumina (14.22kg) solid of 200~300 mesh loads chromatographic column, the quartz of upper strata tiling about 1cm thickness
Sand.Wet method sample introduction：Product crude product (3.554kg, 13.74mol) is slowly poured into chromatography after being diluted with (PE/EA=3/1,7.11L)
In column.Eluted with eluent (PE/EA=3/1) negative pressure, vacuum is -0.06MPa.TLC detections (phosphomolybdic acid colour developing) extremely elute
In liquid without product after, elution terminates.Gained eluent is concentrated under reduced pressure, the recycled solvent steamed, obtains two uncle of fine work chloromethyl
Butyl phosphoric acid ester (2.910kg, 11.25mol), column chromatography yield 81.89%.
The overall yield of reaction is：78.84%,1HNMR purity：>99%.The compound molecule formula：C9H20ClO3P；Molecule
Amount：242.08；Nuclear magnetic resonance is as follows：1HNMR(300MHz,CDCl3) δ ppm 5.63 (d, J=15Hz, 2H), 1.51 (s, 18H).
Claims (4)
1. a kind of synthetic method of the alkyl phosphoric acid esters compound with III structure of formula, comprises the following steps：
Wherein, R1For methyl, ethyl, the tert-butyl group；R2For hydrogen, methyl, ethyl, isopropyl；
(A) under the action of condensing agent, react to obtain chemical compounds I with phosphorous acid and alcohol；
(B) under conditions of alkali coexists, oxidized dose of oxidation of chemical compounds I obtains compound ii；
(C) in the solution containing phase transfer catalyst and alkali, compound ii and chlorine alkylating reagent is made to react to obtain compound
III crude product；Crude product is purified to obtain high-purity alkyl phosphoric acid esters compound；It is characterized in that the compound III described in (C) is thick
The purification process of product quickly elutes for neutral alumina negative pressure column chromatography.
2. according to the purification process described in (C) in claim 1, it is characterised in that adsorbent is 200~300 mesh neutral aluminas
Aluminium, the addition of adsorbent are 3~5 times, preferably 4 times of product crude product weight.
3. according to the purification process described in (C) in claim 1, it is characterised in that eluent is petroleum ether (PE) ︰ ethyl acetate
(EA)=10~2 ︰ 1, is preferably 3 ︰ 1.
4. purification process according to claim 1, it is characterised in that negative pressure elution vacuum is -0.05~-0.09MPa,
It is preferred that -0.06MPa.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024058085A1 (en) * | 2022-09-13 | 2024-03-21 | リファインホールディングス株式会社 | Method for producing tributyl phosphate, purified tributyl phosphate obtained thereby, and extractant using same |
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| CN101775033A (en) * | 2010-01-19 | 2010-07-14 | 青岛大学 | Preparation method of phosphite ester by using dividing wall tower reaction rectification technique |
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