CN114380859A - Preparation method of dibenzyl phosphate and tetrabenzyl pyrophosphate - Google Patents
Preparation method of dibenzyl phosphate and tetrabenzyl pyrophosphate Download PDFInfo
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- CN114380859A CN114380859A CN202011138934.3A CN202011138934A CN114380859A CN 114380859 A CN114380859 A CN 114380859A CN 202011138934 A CN202011138934 A CN 202011138934A CN 114380859 A CN114380859 A CN 114380859A
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- permanganate
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- dibenzyl
- dibenzyl phosphate
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- HDFFVHSMHLDSLO-UHFFFAOYSA-M dibenzyl phosphate Chemical compound C=1C=CC=CC=1COP(=O)([O-])OCC1=CC=CC=C1 HDFFVHSMHLDSLO-UHFFFAOYSA-M 0.000 title claims abstract description 85
- NSBNXCZCLRBQTA-UHFFFAOYSA-N dibenzyl bis(phenylmethoxy)phosphoryl phosphate Chemical compound C=1C=CC=CC=1COP(OP(=O)(OCC=1C=CC=CC=1)OCC=1C=CC=CC=1)(=O)OCC1=CC=CC=C1 NSBNXCZCLRBQTA-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- RQKYHDHLEMEVDR-UHFFFAOYSA-N oxo-bis(phenylmethoxy)phosphanium Chemical compound C=1C=CC=CC=1CO[P+](=O)OCC1=CC=CC=C1 RQKYHDHLEMEVDR-UHFFFAOYSA-N 0.000 claims abstract description 34
- 239000012670 alkaline solution Substances 0.000 claims abstract description 15
- 239000012286 potassium permanganate Substances 0.000 claims abstract description 11
- 238000005805 hydroxylation reaction Methods 0.000 claims abstract description 10
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 84
- 238000000034 method Methods 0.000 claims description 32
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 28
- 239000002904 solvent Substances 0.000 claims description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 21
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 15
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims description 15
- 239000007787 solid Substances 0.000 claims description 15
- 239000012074 organic phase Substances 0.000 claims description 14
- 239000012024 dehydrating agents Substances 0.000 claims description 11
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 11
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 150000001412 amines Chemical class 0.000 claims description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 7
- 238000006482 condensation reaction Methods 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 7
- 238000005886 esterification reaction Methods 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 6
- 229940011051 isopropyl acetate Drugs 0.000 claims description 6
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical group CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 6
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 6
- 239000011736 potassium bicarbonate Substances 0.000 claims description 6
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical group [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 6
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 150000001340 alkali metals Chemical group 0.000 claims description 4
- 150000001350 alkyl halides Chemical class 0.000 claims description 4
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 239000004973 liquid crystal related substance Substances 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- 239000012071 phase Substances 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 238000010791 quenching Methods 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- JYLNVJYYQQXNEK-UHFFFAOYSA-N 3-amino-2-(4-chlorophenyl)-1-propanesulfonic acid Chemical compound OS(=O)(=O)CC(CN)C1=CC=C(Cl)C=C1 JYLNVJYYQQXNEK-UHFFFAOYSA-N 0.000 claims description 2
- 150000001718 carbodiimides Chemical group 0.000 claims description 2
- 230000001376 precipitating effect Effects 0.000 claims 1
- 238000007086 side reaction Methods 0.000 abstract description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 17
- 239000000047 product Substances 0.000 description 17
- 238000003756 stirring Methods 0.000 description 13
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 230000008034 disappearance Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000005265 energy consumption Methods 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000012450 pharmaceutical intermediate Substances 0.000 description 2
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- QUFBGLCLSVONQA-UHFFFAOYSA-M sodium;dibenzyl phosphate Chemical compound [Na+].C=1C=CC=CC=1COP(=O)([O-])OCC1=CC=CC=C1 QUFBGLCLSVONQA-UHFFFAOYSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 150000004685 tetrahydrates Chemical class 0.000 description 2
- -1 1-ethyl- (3-dimethylaminopropyl) carbodiimides hydrochloride Chemical class 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- ATALOFNDEOCMKK-OITMNORJSA-N aprepitant Chemical compound O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NNC(=O)N1 ATALOFNDEOCMKK-OITMNORJSA-N 0.000 description 1
- 229960001372 aprepitant Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- BARDROPHSZEBKC-OITMNORJSA-N fosaprepitant Chemical compound O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NC(=O)N(P(O)(O)=O)N1 BARDROPHSZEBKC-OITMNORJSA-N 0.000 description 1
- 229960002891 fosaprepitant Drugs 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000005406 washing 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 System
- 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
- C07F9/094—Esters of phosphoric acids with arylalkanols
-
- 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 System
- 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
- C07F9/098—Esters of polyphosphoric acids or anhydrides
Abstract
The invention discloses a preparation method of dibenzyl phosphate and tetrabenzyl pyrophosphate, wherein the preparation method of dibenzyl phosphate comprises the following steps: the dibenzyl phosphite and the permanganate generate hydroxylation reaction in an alkaline solution to generate dibenzyl phosphate. According to the preparation method of dibenzyl phosphate, the potassium permanganate and the alkaline solution are cooperatively matched, so that the dibenzyl phosphate is ensured to be generated by the reaction of dibenzyl phosphite, and the problem of low product yield caused by excessive side reactions can be effectively avoided, so that the dibenzyl phosphate can be obtained with a high yield of more than 60%.
Description
Technical Field
The invention belongs to the field of preparation of pharmaceutical intermediates, and particularly relates to a preparation method of dibenzyl phosphate and tetrabenzyl pyrophosphate.
Background
Tetrabenzyl pyrophosphate, english name: tetrabenzyl pyrophosphate, CAS No.: 990-91-0 is an important pharmaceutical intermediate, and plays a significant role in the preparation of fosaprepitant (prodrug of aprepitant oral preparation) and other bulk drugs.
Currently, one of the main methods for preparing tetrabenzyl pyrophosphate is: two molecules of dibenzyl phosphate are condensed by removing one molecule of water (see: CN 102675369A, the method disclosed in example 6). It follows that the key to the preparation of tetrabenzyl pyrophosphate is dibenzyl phosphate.
Dibenzyl phosphate can be prepared by known methods, one of which is as follows: (1) benzyl alcohol, phosphorus trichloride and triethylamine react in toluene to generate dibenzyl phosphite (purity is 69%); (2) dibenzyl phosphite and sodium hydroxide aqueous solution react in carbon tetrachloride to generate a tetrahydrate (purity 95%) of sodium dibenzyl phosphate, and the yield of the two steps is 46.8%; (3) reacting tetrahydrate of sodium dibenzyl phosphate with hydrochloric acid to generate dibenzyl phosphate (purity is 97%), yield is 85.6%; (4) refining with ethyl acetate/petroleum ether (purity 99.5%) at 88.1% (see: preparation of dibenzyl phosphate, Liudenaceae, Liumei, Huangchangjiang, Wang Pingyu chemical reagent, 2005, 27 (11): 697-.
The method has the disadvantages that dibenzyl phosphite needs to react with sodium hydroxide to generate sodium salt firstly, and then reacts with hydrochloric acid to generate dibenzyl phosphate, the steps and the operation are complicated, the total yield of a target product (dibenzyl phosphate) is low, the total yield of the first three steps (unrefined) is 40% (46.8% × 85.6%), the total yield of the fourth steps (refined) is 35.3% (46.8% × 85.6% × 88.1%), and 20-30 g of products are finally obtained, and the production efficiency is not high.
In order to increase the overall yield of dibenzyl phosphate, the prior art provides an improved process: the solvents in the steps (1) and (2) of the method are all changed into carbon tetrachloride, carbon tetrachloride is added in the step (1) at one time, triethylamine hydrochloride is separated after the reaction in the step (1) is finished, sodium hydroxide solution is added to directly carry out the reaction in the step (2) to generate sodium salt, and then the sodium salt is acidified to generate dibenzyl phosphate, wherein the total yield can reach 67.4 percent to the maximum (see: the improvement of the process for preparing dibenzyl phosphate, Bengqing, Dongyu, Zhongshan. synthetic chemistry, No. 18, No. 1, 116-.
In addition, the improved method also particularly indicates that carbon tetrachloride is an essential solvent for the reactions in the steps (2) and (3), and the yield of dibenzyl phosphate is zero in the absence of carbon tetrachloride. This means that the improved method and process route for preparing dibenzyl phosphate will be limited by carbon tetrachloride, and have certain limitations.
In view of the above, the present invention is especially proposed to provide more alternative process routes for the preparation of dibenzyl phosphate and/or tetrabenzyl pyrophosphate.
Disclosure of Invention
Aiming at the problems and/or defects in the prior art, the invention aims to provide a preparation method of dibenzyl phosphate and tetrabenzyl pyrophosphate. The method takes potassium permanganate and alkaline solution as process conditions, and successfully introduces hydroxyl into the molecule of dibenzyl phosphite, thereby obtaining dibenzyl phosphate, providing a completely different technical thought for the preparation of dibenzyl phosphate and/or tetrabenzyl pyrophosphate, and effectively avoiding and solving the problem of low product yield caused by excessive side reactions while ensuring the generation of dibenzyl phosphate by the reaction of dibenzyl phosphate.
The invention provides a preparation method of dibenzyl phosphate, which comprises the following steps: the dibenzyl phosphite and the permanganate generate hydroxylation reaction in an alkaline solution to generate dibenzyl phosphate.
Hydroxylation refers to the reaction of introducing hydroxyl groups into organic molecules. For example, dibenzyl phosphite of the present invention introduces a hydroxyl group to produce dibenzyl phosphate.
Further, in the above-mentioned case,
in the preparation method of dibenzyl phosphate, the permanganate is XMnO4X is selected from alkali metal (including but not limited to Li, Na, K, etc.) or NH4(ii) a Preferably, the permanganate is potassium permanganate or sodium permanganate;
and/or, the alkaline solution refers to a solution that is alkaline or weakly alkaline, such as: an aqueous solution of a carbonate or bicarbonate, etc.; superior foodOptionally, the solute of the alkaline solution is bicarbonate or carbonate, and/or the solvent of the alkaline solution is water; more preferably, the bicarbonate is YHCO3Y is selected from alkali metal or NH4(ii) a More preferably, the bicarbonate is potassium bicarbonate or sodium bicarbonate.
Further, in the above-mentioned case,
in the above method for producing dibenzyl phosphate, the molar ratio of permanganate to bicarbonate is 1:0.5 to 5 (e.g., 1:0.55, 1:0.8, 1:0.95, 1:1, 1:1.1, 1:1.2, 1:1.5, 1:1.6, 1:1.63, 1:1.7, or 1: 4.5); preferably, the molar ratio of the permanganate to the bicarbonate is 1: 0.5-2; more preferably, the molar ratio of the permanganate to the bicarbonate is 1: 0.5-1.2;
and/or the molar ratio of permanganate to carbonate is 1:0.3 to 5 (e.g., 1:0.3, 1:0.55, 1:0.8, 1:0.95, 1:1, 1:1.1, 1:1.2, 1:1.5, 1:1.6, 1:1.63, 1:1.7, or 1:4.5, etc.); preferably, the molar ratio of the permanganate to the carbonate is 1: 0.3-2; more preferably, the molar ratio of the permanganate to the carbonate is 1: 0.3-1.2;
and/or, the amount of the solvent of the alkaline solution may be selected conventionally, and it is sufficient to satisfy the requirement of the hydroxylation reaction, for example, the amount of the solvent is 0.5 to 5kg (e.g., 0.6kg, 1kg, 2kg, 2.5kg, 2.9kg, 3kg, 3.5kg, or 4kg, etc.) per mole of the bicarbonate;
and/or the molar ratio of dibenzylphosphite to permanganate is 1: 0.05-1 (e.g., 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, or 1:0.8, etc.); preferably, the molar ratio of dibenzylphosphite to permanganate is 1: 0.15-1; more preferably, the molar ratio of dibenzylphosphite to permanganate is 1: 0.15-0.75;
and/or the temperature of the hydroxylation reaction can be adjusted according to actual needs (considering the reaction rate, the occurrence of side reactions, energy consumption and the like), such as: -10 to 40 ℃, preferably-5 to 5 ℃ (e.g., 1 ℃, 2 ℃, or 3 ℃);
and/or the end point of the hydroxylation reaction can be controlled and determined by the reaction time and/or the amount of the starting material (dibenzylphosphite) remaining in the reaction solution (monitored by TLC or the like), for example, the substantial disappearance of dibenzylphosphite (remaining amount in the reaction solution. ltoreq.2 wt%) is used as the end point of the reaction.
Further, in the above-mentioned case,
in the preparation method of dibenzyl phosphate, the method further comprises the following post-treatment steps: after the hydroxylation reaction is finished, removing the solid in the solution, adding an ester solvent (such as ethyl acetate and the like), separating the solution, taking a water phase, adding a halogenated alkane solvent (such as dichloromethane and the like) and hydrochloric acid, separating the solution, taking an organic phase, removing water (such as adding anhydrous sodium sulfate), concentrating, adding methyl tert-butyl ether, heating, cooling, separating out the solid, separating and drying to obtain the dibenzyl phosphate.
Further, in the above-mentioned case,
in the above preparation method of dibenzyl phosphate, the method further comprises the step of preparing dibenzyl phosphite: benzyl alcohol and phosphorus trichloride are subjected to esterification reaction in the presence of organic amine and a halogenated alkane solvent to generate dibenzyl phosphite;
preferably, the organic amine is triethylamine, and/or the haloalkane solvent is dichloromethane.
Further, in the above-mentioned case,
in the step of preparing dibenzyl phosphite, the proportion between benzyl alcohol and phosphorus trichloride and the dosage of organic amine and haloalkane solvents can be determined or adjusted according to the proportion or dosage of the prior art;
preferably, the first and second liquid crystal materials are,
the molar ratio of the benzyl alcohol to the phosphorus trichloride is 1: 0.25-1 (for example, 1:0.4, 1:0.5, 1:0.52, 1:0.55, 1:0.6, 1:0.75 or 1:0.8, etc.), and more preferably, the molar ratio of the benzyl alcohol to the phosphorus trichloride is 1: 0.5-0.75;
and/or the molar ratio of the benzyl alcohol to the organic amine is 1: 1-2 (e.g., 1:1, 1:1.1, 1:1.2, 1:1.5, etc.), more preferably the molar ratio of the benzyl alcohol to the organic amine is 1: 1-1.2;
and/or the amount of the haloalkane solvent used per mole of benzyl alcohol is 0.5-5 kg (e.g., 0.6kg, 1kg, 2kg, 2.5kg, 3kg, 3.5kg, or 4 kg);
and/or the molar ratio of the benzyl alcohol to the permanganate is 1: 0.05-1 (namely, the relative dosage of the potassium permanganate is calculated by taking the benzyl alcohol as an initial raw material); preferably, the molar ratio of the benzyl alcohol to the permanganate is 1: 0.15-1; more preferably, the molar ratio of benzyl alcohol to permanganate is 1:0.15 to 0.5 (e.g., 1:0.2, 1:0.25, 1:0.3, or 1:0.4, etc.);
and/or, the temperature of the esterification reaction can be adjusted according to actual needs, preferably 10 to 40 ℃ (for example, 15 ℃, 20 ℃ or 25 ℃);
and/or the end point of the esterification reaction can be controlled and determined by the reaction time and/or the remaining amount of the raw material (benzyl alcohol) in the reaction solution (monitored by TLC or the like), for example, the substantial disappearance of benzyl alcohol (remaining amount in the reaction solution. ltoreq.2 wt%) is taken as the end point of the reaction.
Further, in the above-mentioned case,
in the step of preparing dibenzyl phosphite, the method further comprises the following post-treatment steps: and after the esterification reaction is finished, adding water to quench the reaction, separating liquid, taking an organic phase, concentrating, and optionally purifying (specifically, adding methyl tert-butyl ether/water as a purification solvent, separating liquid, taking the organic phase, washing the organic phase with a sodium bicarbonate aqueous solution and a sodium chloride aqueous solution respectively, adding anhydrous sodium sulfate to remove water, and concentrating), thereby obtaining the dibenzyl phosphite.
The invention also provides a preparation method of tetrabenzyl pyrophosphate, which comprises the following steps:
preparing dibenzyl phosphate according to any one of the preparation methods, wherein two molecules of dibenzyl phosphate are subjected to condensation reaction in the presence of a dehydrating agent and an ester solvent to generate tetrabenzyl pyrophosphate;
preferably, the first and second liquid crystal materials are,
the dehydrating agent is a carbodiimide dehydrating agent, and includes but is not limited to: n, N-Dicyclohexylcarbodiimide (DCC), N' -Diisopropylcarbodiimide (DIC), 1-ethyl- (3-dimethylaminopropyl) carbodiimides hydrochloride (EDC), etc., more preferably N, N-dicyclohexylcarbodiimide;
and/or the ester solvent is
R is C2～C3Hydrocarbyl (hydrocarbyl includes alkyl, alkenyl, alkynyl, etc.); more preferably, R is C3Alkyl (including n-propyl, isopropyl); more preferably, R is isopropyl.
Further, in the above-mentioned case,
in the preparation method of tetrabenzyl pyrophosphate, the dosage of the dehydrating agent and the ester solvent can be determined or adjusted according to the proportion or dosage of the prior art;
preferably, the first and second liquid crystal materials are,
the molar ratio of dibenzyl phosphate to dehydrating agent is 1: 0.5-1 (e.g., 1:0.5, 1:0.6, 1:0.7, or 1: 0.8); more preferably, the molar ratio of the dibenzyl phosphate to the dehydrating agent is 1: 0.5-0.75;
and/or the mass ratio of dibenzyl phosphate to the ester solvent is 1: 5-20 (e.g., 1:6, 1:9, 1:10, 1:12, or 1: 18); more preferably, the mass ratio of the dibenzyl phosphate to the ester solvent is 1: 5-15;
and/or, the temperature of the condensation reaction can be adjusted according to actual needs, preferably-5 to 20 ℃ (for example, 2 ℃, 5 ℃ or 10 ℃ and the like);
and/or the end point of the condensation reaction can be controlled and determined by the reaction time and/or the remaining amount of the starting material (dibenzyl phosphate) in the reaction solution (monitored by HPLC or the like), for example, the substantial disappearance of dibenzyl phosphate (remaining amount in the reaction solution. ltoreq.2 wt%) is used as the end point of the reaction.
Further, in the above-mentioned case,
the preparation method of the tetrabenzyl pyrophosphate further comprises the following post-treatment steps: after the condensation reaction is finished, filtering, concentrating, adding n-heptane to precipitate a solid, optionally recrystallizing (specifically, dissolving the precipitated solid in an ester solvent, adding n-heptane to precipitate a solid), separating, and drying to obtain tetrabenzyl pyrophosphate; preferably, the recrystallization solvent is an ester solvent (e.g., isopropyl acetate) and n-heptane.
The positive progress effects of the invention are as follows:
(1) according to the method, potassium permanganate and alkaline solution are used as process conditions, hydroxyl is successfully introduced into the molecule of dibenzyl phosphite, so that dibenzyl phosphate is prepared, and a completely different improvement idea is provided for the preparation of dibenzyl phosphate and downstream products (tetrabenzyl pyrophosphate);
(2) according to the method, by means of the synergistic cooperation of potassium permanganate and alkaline solution, the dibenzyl phosphate is ensured to be generated by the reaction of dibenzyl phosphite, and the problem of low product yield caused by excessive side reactions can be effectively avoided, so that the method can obtain high yield of more than 60% of dibenzyl phosphate;
(3) according to the method, methyl tert-butyl ether is used as a purification solvent, various impurities generated due to side reactions and the like can be effectively removed, so that the impurity content level in the dibenzyl phosphate product is controlled within 1%, and the product quality of dibenzyl phosphate and/or tetrabenzyl pyrophosphate and the safety of dibenzyl phosphate and/or tetrabenzyl pyrophosphate used in medical synthesis are better guaranteed;
(4) the method has the advantages of mild reaction conditions, convenient operation and control, high yield, low energy consumption and low cost, and is suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. In the present invention, those who do not specify the conditions are performed according to the conventional conditions or the conditions recommended by the manufacturer, and the reagents or apparatuses used are not specified by the manufacturer, and can be obtained by purchasing commercially available products or prepared by known methods.
With respect to definitions of terms used herein, the initial definitions provided for the terms herein apply to the terms throughout, unless otherwise specified; terms not specifically defined herein should be given their meanings to those skilled in the art in light of the disclosure and/or the context.
Ca～CbHydrocarbyl represents any hydrocarbon radical containing a to b carbon atomsFor example: c2～C3Hydrocarbyl means hydrocarbyl containing 2 or 3 carbon atoms, for example: ethyl, n-propyl, isopropyl, allyl, and the like; hydrocarbyl includes alkyl, alkenyl (alkenyl), alkynyl, and the like.
In the present invention, the classification and/or explanation of the solvent can be made with reference to the "solvent handbook" by Chenglin (4 th edition, Beijing: chemical industry Press).
Some of the schemes and examples below may omit some details of common reactions, isolation techniques and analytical procedures, and some may omit secondary products from chemical reactions. In addition, in some cases, the reaction intermediate may be used in subsequent steps without isolation and/or purification.
In general, the chemical transformations described in the specification may be carried out using substantially stoichiometric amounts of the reactants, although certain reactions may benefit from the use of an excess of one or more of the reactants. Any description herein of stoichiometry, temperature, etc., whether or not the term "range" is used explicitly, is intended to include the endpoints as recited.
Example 1
1. Preparation of dibenzyl phosphate
The method comprises the following steps:
adding 41kg (about 379mol) of benzyl alcohol, 41kg (about 405mol) of triethylamine and 27.0kg (about 197mol) of phosphorus trichloride into 300kg of dichloromethane, after the addition is finished, carrying out heat preservation reaction at 20-25 ℃ for 30min, carrying out TLC (thin layer chromatography) detection to obtain a reaction solution containing dibenzyl phosphite, cooling to-3 ℃, adding 150kg of purified water to carry out quenching reaction, stirring for 10min, standing, separating liquid, taking an organic phase, extracting an upper aqueous phase for 3 times by using dichloromethane (30kg multiplied by 3), combining the organic phases, and then carrying out reduced pressure distillation (the vacuum degree is less than or equal to-0.09 MPa, the temperature is 30-35 ℃) until no fraction is obtained basically;
and (3) further purification:
stirring the dibenzyl phosphite, 130kg of methyl tert-butyl ether and 30kg of purified water for 15min, standing, separating, taking an organic phase, adding 50kg of a 20 wt% sodium bicarbonate aqueous solution, stirring for 10min, standing, separating, taking an organic phase, extracting a lower-layer aqueous phase for 1 time by using methyl tert-butyl ether (20kg), combining the organic phases, adding 34kg of a 20 wt% sodium chloride aqueous solution, stirring for 20min, standing, separating, taking an organic phase, adding 15kg of anhydrous sodium sulfate, stirring, filtering, and distilling a filtrate under reduced pressure (the vacuum degree is less than or equal to-0.09 MPa, the temperature is 40-50 ℃) until no fraction is obtained;
② the purified dibenzyl phosphite of the step I reacts with 15kg (about 95mol) of potassium permanganate, 9kg (about 90mol) of potassium bicarbonate and 260kg of purified water under stirring at the temperature of-3 to 3 ℃ for 5.5h, after the TLC (thin layer chromatography) detection reaction is almost completely carried out (the residual amount of dibenzyl phosphite is less than or equal to 2.0 wt%), the solid in the dibenzyl phosphite is removed by centrifugation or filtration, 120kg of ethyl acetate is added, the mixture is stirred for 15min, the mixture is stood for liquid separation, the water phase is taken, 110kg of dichloromethane and 60kg of hydrochloric acid with the concentration of 4mol/L are added, the mixture is stood for liquid separation, the organic phase is taken, the water phase is extracted for 2 times by dichloromethane (50kg multiplied by 2), the organic phase is combined, 15kg of anhydrous sodium sulfate is added, the mixture is stirred and filtered, the filtrate is distilled under reduced pressure (the vacuum degree is less than or equal to 0.09MPa, the temperature is 40 to 50 ℃) until no fraction is produced basically, 10kg of methyl tert-butyl ether is added, the distillation is carried out continuously carried out under the reduced pressure until no fraction, adding 15kg of methyl tert-butyl ether, stirring for 20min at 40-50 ℃, then cooling to about 0 ℃, stirring for 1h, and centrifuging to obtain a wet dibenzyl phosphate product (the impurity content is about 2.5%);
and (3) further purification:
adding the wet dibenzyl phosphate into 20.0kg of methyl tert-butyl ether, stirring for 20min, centrifuging, and drying by air blowing (40-50 ℃) to obtain dibenzyl phosphate, white powdery solid, wherein the HPLC purity is 99.2%, and the total yield is 74.5% (calculated by benzyl alcohol).
Under the HPLC purity detection term, the retention time of the main peak of the test sample (dibenzyl phosphate product) is basically consistent with that of the main peak of the standard sample.
2. Preparation of tetrabenzyl pyrophosphate
The method comprises the following steps:
i. under the protection of inert gas (nitrogen), adding 16kg (about 57.5mol) of dibenzyl phosphate into 80kg of isopropyl acetate, then adding a solution of dicyclohexylcarbodiimide (DCC, 6.5kg, about 31.5mol) of isopropyl acetate (64kg), controlling the temperature of a reaction system at 2-10 ℃, stirring and reacting for 30min after the addition is finished, and obtaining a reaction solution after HPLC (high performance liquid chromatography) detects that the reaction is basically complete (the residual amount of dibenzyl phosphate is less than or equal to 2 wt%);
ii. Filtering the reaction liquid obtained in the step i, distilling the filtrate under reduced pressure (the vacuum degree is less than or equal to-0.09 MPa, and the temperature is 40-50 ℃) until the distillate is slowly or basically not produced, cooling to 10 +/-2 ℃, adding 30kg of n-heptane, cooling to 0 +/-2 ℃, stirring for 1-2 h, and filtering to obtain a wet product of tetrabenzyl pyrophosphate;
and (3) further purification:
and (3) recrystallization: adding wet tetrabenzyl pyrophosphate into 30kg of isopropyl acetate, heating, stirring and refluxing for 20-30 min, then adding 30kg of n-heptane, then cooling to 0 +/-2 ℃, stirring for 1-2 h, filtering, and vacuum drying (the vacuum degree is less than or equal to-0.09 MPa and the temperature is 30-35 ℃) to obtain tetrabenzyl pyrophosphate, wherein the purity of HPLC (high performance liquid chromatography) is 99.5%, and the yield is 88.9%.
The infrared absorption spectrum of the test sample (tetrabenzyl pyrophosphate product) is basically consistent with that of the standard sample; the retention time of the main peak of the sample (tetrabenzyl pyrophosphate product) under the HPLC purity detection item is basically consistent with that of the standard product.
Example 2
The same contents as in example 1 are not repeated, except that in the step (i) of preparing dibenzyl phosphate, the amount of triethylamine is adjusted to 38.5kg (about 380mol), that is: benzyl alcohol and triethylamine were in a molar ratio of 1:1 to prepare dibenzyl phosphate as a white powdery solid with an HPLC purity of 99.1% and a total yield of 68.8% (based on benzyl alcohol).
Example 3
The same contents as in example 1 are not repeated, except that in the step (i) of preparing dibenzyl phosphate, the amount of phosphorus trichloride is adjusted to 26.1kg (about 190mol), that is: benzyl alcohol and phosphorus trichloride in the molar ratio of 1:0.5, to prepare dibenzyl phosphate as white powdery solid with HPLC purity of 99.4% and total yield of 72.5% (based on benzyl alcohol).
Example 4
The same contents as in example 1 were not repeated, except that dibenzyl phosphate was prepared by adjusting the reaction temperature to 15 ℃ in the procedure of preparation of dibenzyl phosphate (first), and dibenzyl phosphate was prepared as a white powdery solid with an HPLC purity of 99.0% and an overall yield of 71.6% (in terms of benzyl alcohol).
Examples 5 and 6
The same contents as in example 1 are not repeated, except that in the step of preparing dibenzyl phosphate, the amounts of potassium permanganate to be used are adjusted to 11.8kg (about 74.7mol) and 3.16kg (about 20mol), respectively, that is: the molar ratio of potassium permanganate to potassium bicarbonate is 1:1.2 and 1:4.5 respectively, and dibenzyl phosphate is prepared, and the HPLC purity and the total yield are shown in Table 1.
TABLE 1 HPLC purity and Total yield of dibenzyl phosphate product
Examples 7 and 8
The same contents as in example 1 are not repeated, except that in the step of preparing dibenzyl phosphate, the amounts of potassium hydrogencarbonate used were adjusted to 5.2kg (about 52mol) and 15.5kg (about 155mol), respectively, that is: the molar ratio of potassium permanganate to potassium bicarbonate is 1:0.55 and 1:1.63 respectively, and dibenzyl phosphate is prepared, and the HPLC purity and the total yield are shown in Table 2.
TABLE 2 HPLC purities and Total yields of dibenzyl phosphate product
Example 9
The same contents as in example 1 were not repeated, except that in step i of preparing tetrabenzyl pyrophosphate, the amount of dicyclohexylcarbodiimide used was adjusted to 8kg (about 38.8mol) to prepare tetrabenzyl pyrophosphate as a white powdery solid with an HPLC purity of 98.2% and a yield of 89.1%.
Example 10
The same contents as in example 1 were not repeated except that in step i of preparing tetrabenzyl pyrophosphate, the amount of isopropyl acetate of dicyclohexylcarbodiimide was adjusted to 80kg to prepare tetrabenzyl pyrophosphate as a white powdery solid with an HPLC purity of 98.4% and a yield of 87.5%.
Claims (10)
1. A preparation method of dibenzyl phosphate is characterized by comprising the following steps: the dibenzyl phosphite and the permanganate generate hydroxylation reaction in an alkaline solution to generate dibenzyl phosphate.
2. The method for producing dibenzyl phosphate according to claim 1,
the permanganate is XMnO4X is selected from alkali metal or NH4(ii) a Preferably, the permanganate is potassium permanganate or sodium permanganate;
and/or, the alkaline solution is alkaline or weakly alkaline solution; preferably, the solute of the alkaline solution is bicarbonate or carbonate, and/or the solvent of the alkaline solution is water; more preferably, the bicarbonate is YHCO3Y is selected from alkali metal or NH4(ii) a More preferably, the bicarbonate is potassium bicarbonate or sodium bicarbonate.
3. The method for producing dibenzyl phosphate according to claim 2,
the molar ratio of the permanganate to the bicarbonate is 1: 0.5-5; preferably, the molar ratio of the permanganate to the bicarbonate is 1: 0.5-2; more preferably, the molar ratio of the permanganate to the bicarbonate is 1: 0.5-1.2;
and/or the molar ratio of the permanganate to the carbonate is 1: 0.3-5; preferably, the molar ratio of the permanganate to the carbonate is 1: 0.3-2; more preferably, the molar ratio of the permanganate to the carbonate is 1: 0.3-1.2;
and/or the dosage of the solvent corresponding to each mole of bicarbonate or carbonate is 0.5-5 kg;
and/or the molar ratio of dibenzyl phosphite to permanganate is 1: 0.05-1; preferably, the molar ratio of dibenzylphosphite to permanganate is 1: 0.15-1; more preferably, the molar ratio of dibenzylphosphite to permanganate is 1: 0.15-0.75;
and/or the reaction temperature of the hydroxylation reaction is-10-40 ℃, and preferably-5 ℃.
4. The method for preparing dibenzyl phosphate according to any one of claims 1 to 3, further comprising a post-treatment step of: after the hydroxylation reaction is finished, removing solids in the solution, adding an ester solvent, separating the solution, taking a water phase, adding a halogenated alkane solvent and hydrochloric acid, separating the solution, taking an organic phase, removing water, concentrating, adding methyl tert-butyl ether, heating, cooling, separating out solids, separating and drying to obtain the dibenzyl phosphate.
5. The method for preparing dibenzyl phosphate according to any one of claims 1 to 3, further comprising a step of preparing dibenzyl phosphite: benzyl alcohol and phosphorus trichloride are subjected to esterification reaction in the presence of organic amine and a halogenated alkane solvent to generate dibenzyl phosphite;
preferably, the organic amine is triethylamine, and/or the haloalkane solvent is dichloromethane.
6. The method for preparing dibenzyl phosphate according to claim 5, wherein, in the step of preparing dibenzyl phosphite:
the molar ratio of the benzyl alcohol to the phosphorus trichloride is 1: 0.25-1; preferably, the molar ratio of the benzyl alcohol to the phosphorus trichloride is 1: 0.5-0.75;
and/or the molar ratio of the benzyl alcohol to the organic amine is 1: 1-2; preferably, the molar ratio of the benzyl alcohol to the organic amine is 1: 1-1.2;
and/or the dosage of the halogenated alkane solvent corresponding to each mole of the benzyl alcohol is 0.5-5 kg;
and/or the molar ratio of the benzyl alcohol to the permanganate is 1: 0.05-1; preferably, the molar ratio of the benzyl alcohol to the permanganate is 1: 0.15-1; more preferably, the molar ratio of the benzyl alcohol to the permanganate is 1: 0.15-0.5;
and/or the reaction temperature of the esterification reaction is 10-40 ℃.
7. The method for preparing dibenzyl phosphate according to claim 5 or 6, further comprising a post-treatment step in the step of preparing dibenzyl phosphite: and after the esterification reaction is finished, adding water to quench the reaction, separating liquid, taking an organic phase, concentrating, and optionally purifying to obtain the dibenzyl phosphite.
8. A preparation method of tetrabenzyl pyrophosphate is characterized by comprising the following steps: preparing dibenzyl phosphate according to the preparation method of any one of claims 1 to 7, wherein two molecules of dibenzyl phosphate undergo a condensation reaction in the presence of a dehydrating agent and an ester solvent to generate tetrabenzyl pyrophosphate;
preferably, the first and second liquid crystal materials are,
the dehydrating agent is a carbodiimide dehydrating agent, and more preferably N, N-dicyclohexylcarbodiimide;
and/or the ester solvent is
R is C2～C3A hydrocarbyl group; more preferably, R is C3An alkyl group; more preferably, R is isopropyl.
9. The method of producing tetrabenzyl pyrophosphate according to claim 8, wherein,
the molar ratio of the dibenzyl phosphate to the dehydrating agent is 1: 0.5-1; preferably, the molar ratio of the dibenzyl phosphate to the dehydrating agent is 1: 0.5-0.75;
and/or the mass ratio of dibenzyl phosphate to the ester solvent is 1: 5-20; preferably, the mass ratio of the dibenzyl phosphate to the ester solvent is 1: 5-15;
and/or the reaction temperature of the condensation reaction is-5-20 ℃.
10. The method for preparing tetrabenzyl pyrophosphate according to claim 8 or 9, characterized by further comprising a post-treatment step of: after the condensation reaction is finished, filtering, concentrating, adding n-heptane, precipitating solid, and then optionally recrystallizing, separating and drying to obtain tetrabenzyl pyrophosphate; preferably, the recrystallization solvent is an ester solvent and n-heptane; more preferably, the ester solvent is isopropyl acetate.
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| US5985856A (en) * | 1997-12-31 | 1999-11-16 | University Of Kansas | Water soluble prodrugs of secondary and tertiary amine containing drugs and methods of making thereof |
| CN101678120A (en) * | 2006-12-05 | 2010-03-24 | 纽罗吉斯克斯公司 | Prodrugs and methods of making and using the same |
| CN111484519A (en) * | 2019-01-29 | 2020-08-04 | 正大天晴药业集团股份有限公司 | Preparation method of dibenzyl phosphate and derivatives thereof |
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| US5985856A (en) * | 1997-12-31 | 1999-11-16 | University Of Kansas | Water soluble prodrugs of secondary and tertiary amine containing drugs and methods of making thereof |
| CN101678120A (en) * | 2006-12-05 | 2010-03-24 | 纽罗吉斯克斯公司 | Prodrugs and methods of making and using the same |
| CN111484519A (en) * | 2019-01-29 | 2020-08-04 | 正大天晴药业集团股份有限公司 | Preparation method of dibenzyl phosphate and derivatives thereof |
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