CN115028603A - Preparation method of N-methyl-D3-piperazine hydrochloride - Google Patents
Preparation method of N-methyl-D3-piperazine hydrochloride Download PDFInfo
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- CN115028603A CN115028603A CN202210721612.4A CN202210721612A CN115028603A CN 115028603 A CN115028603 A CN 115028603A CN 202210721612 A CN202210721612 A CN 202210721612A CN 115028603 A CN115028603 A CN 115028603A
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- methyl
- piperazine
- toluenesulfonate
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- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims abstract description 37
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 29
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical class [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 claims abstract description 20
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims description 33
- 239000002904 solvent Substances 0.000 claims description 27
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- 239000000243 solution Substances 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- 239000012074 organic phase Substances 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 150000007529 inorganic bases Chemical class 0.000 claims description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 238000000967 suction filtration Methods 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- VUQUOGPMUUJORT-BMSJAHLVSA-N trideuteriomethyl 4-methylbenzenesulfonate Chemical compound [2H]C([2H])([2H])OS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-BMSJAHLVSA-N 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 7
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 239000012141 concentrate Substances 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- -1 saturated brine saturated sodium bicarbonate Chemical class 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 239000012670 alkaline solution Substances 0.000 claims description 3
- 239000012535 impurity Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- 239000008346 aqueous phase Substances 0.000 claims 1
- 238000001816 cooling Methods 0.000 claims 1
- 238000001914 filtration Methods 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 2
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 229910052805 deuterium Inorganic materials 0.000 description 13
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 11
- 150000001875 compounds Chemical class 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 239000007789 gas Substances 0.000 description 9
- 238000001514 detection method Methods 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000002360 explosive Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- INQOMBQAUSQDDS-BJUDXGSMSA-N iodomethane Chemical class I[11CH3] INQOMBQAUSQDDS-BJUDXGSMSA-N 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 238000004611 spectroscopical analysis Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000005695 dehalogenation reaction Methods 0.000 description 1
- 239000011903 deuterated solvents Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000007769 metal material Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N p-toluenesulfonic acid Substances CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- DBGVGMSCBYYSLD-RCUQKECRSA-N tributyl(deuterio)stannane Chemical compound CCCC[Sn]([2H])(CCCC)CCCC DBGVGMSCBYYSLD-RCUQKECRSA-N 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/023—Preparation; Separation; Stabilisation; Use of additives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/001—Acyclic or carbocyclic compounds
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/002—Heterocyclic compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
- C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
- C07D295/205—Radicals derived from carbonic acid
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Abstract
The invention provides a preparation method of a medical intermediate N-methyl-D3-piperazine hydrochloride, which comprises the steps of taking p-toluenesulfonyl chloride and deuterated methanol-D4 as raw materials, reacting under an alkaline condition to generate D3-methyl p-toluenesulfonate, reacting with 1-BOC-piperazine to generate N-BOC-4-methyl-D3-piperazine, and finally hydrolyzing with hydrochloric acid to generate N-methyl-D3-piperazine hydrochloride; the preparation method has the advantages of simple operation, mild conditions and high yield, and is suitable for large-scale industrial production.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of a pharmaceutical intermediate N-methyl-D3-piperazine hydrochloride.
Background
Deuterium (D) -labeled compounds have been widely used in many scientific fields such as organic chemistry, metal organic chemistry, spectroscopy, and medicine. Such as the application of isotopic labeling in the field of organic chemistry to study the mechanism of the reaction; preparing a novel metal material by using a deuterium-labeled compound in the field of metal organic; deuterium labeled compounds can be used as internal standard substances in spectroscopy; in the aspect of pharmacy, deuterium can be used for modifying the medicine so as to change the in vivo metabolic process of the medicine and further obtain the medicine with better curative effect.
Currently, deuterated compounds are mainly prepared by methods such as organic compound deoxidation, dehalogenation, hydrogen-deuterium exchange, unsaturated bond reduction and the like, and most of the processes involve expensive deuterium sources (such as deuterium gas and deuterated amine), toxic deuterium sources (such as tributyl tin deuteride), flammable and explosive deuterium sources (such as sodium boron deuteride and lithium aluminum deuteride) and the like; in which the preparation of deuterated compounds by hydrogen-deuterium exchange requires severe reaction conditions (high pressure, high temperature) or costly, structurally complex transition metal catalysts (palladium, platinum, ruthenium, etc.), the applicability and substrate suitability of these processes is greatly restricted.
N-Methyl-D3-Piperazine hydrochloride (N-Methyl-D3-Piperazine dihydrate) is a new medicine intermediate. The following two schemes are typical: one is that deuterated iodomethane and 1-BOC-piperazine (CAS:143238-38-4) react under alkaline condition to generate N-BOC-4-methyl-D3-piperazine, and then acidolysis is carried out to obtain the product, but deuterated iodomethane is expensive; referring to Chinese patent CN102190587B, deuterated methanol-D4 and 1-BOC-piperazine are reacted in tetrahydrofuran solvent in the presence of DEAD and triphenylphosphine to generate N-BOC-4-methyl-D3-piperazine, and then the N-BOC-4-methyl-D3-piperazine is subjected to acid hydrolysis to obtain a product, but the reaction has more impurities, complicated post-treatment and low yield, and is not beneficial to large-scale industrial production.
Disclosure of Invention
In view of the above drawbacks or needs for improvement in the prior art, the present invention is directed to a method for synthesizing a deuterated compound, wherein the reaction process of the key deuterated reduction reaction, the types and ratios of the raw materials used, and the corresponding reaction conditions are studied and improved, so that the problems of severe reaction conditions, expensive deuterium source, toxicity, flammability, and explosiveness in the preparation process of the deuterated compound can be effectively solved. The method has the advantages of mild reaction conditions, simple operation, low preparation cost, good substrate applicability, high yield and deuteration rate; in addition, by adopting a relatively cheap deuterated solvent as a deuterium source, the use of an expensive, toxic or flammable and explosive deuterium source in the preparation process of the deuterated compound is effectively avoided, and the preparation cost of the deuterated compound can be further reduced.
Specifically, the method is realized through the following technical routes:
a preparation method of N-methyl-D3-piperazine hydrochloride comprises the following steps;
2) mixing deuterated methanol-D4 with a solvent I to obtain a deuterated methanol-D4 solution for later use;
mixing tosyl chloride with a solvent I to obtain a tosyl chloride solution for later use;
mixing water with inorganic base I to obtain an alkaline solution, and dropwise adding the deuterated methanol-D4 solution; after the dripping is finished, the temperature is reduced to minus 5 ℃ to minus 10 ℃, and a tosyl chloride solution is dripped; after the reaction is finished, carrying out suction filtration, washing an organic phase, and drying to obtain D3-methyl p-toluenesulfonate;
the solvent I comprises at least one of tetrahydrofuran, methyltetrahydrofuran, acetonitrile, ethyl acetate, methyl tert-butyl ether and toluene;
the inorganic base I comprises at least one of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate;
the molar ratio of the deuterated methanol-D4 to the p-toluenesulfonyl chloride is 1.1-1.5: 1, preferably 1.3: 1;
the molar ratio of the inorganic base I to the p-toluenesulfonyl chloride is 1.6-2.0: 1, preferably 1.8: 1;
in the step, the solvent I plays a role in diluting the deuterated methanol-D4 or the benzenesulfonyl chloride, does not participate in the reaction, dilutes the reactant to ensure that the reaction is smooth, and the addition amount of the solvent I can be selected according to specific reaction conditions. In specific implementation, the deuterated methanol-D4 and the tosyl chloride can be selected from the same solvent I and mixed, or can be selected from different solvents I and preferably use the same solvent I.
2) Mixing D3-methyl p-toluenesulfonate obtained in the step 1) with a solvent II to obtain a D3-methyl p-toluenesulfonate solution for later use;
dissolving 1-BOC-piperazine in a solvent II, adding an inorganic base II, and then dropwise adding a D3-methyl p-toluenesulfonate solution, wherein the temperature is controlled to be 30 +/-2 ℃ in the reaction process; after the reaction is finished, carrying out suction filtration on the reactant, taking the filtrate and drying to obtain a residue; adding DCM and water into the residue, stirring and layering, and washing an organic phase to obtain an N-BOC-4-methyl-D3-piperazine solution;
the solvent II comprises at least one of tetrahydrofuran, methyltetrahydrofuran, acetonitrile, ethyl acetate, methyl tert-butyl ether and toluene;
the inorganic base II comprises at least one of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and sodium hydride; the molar ratio of the added inorganic base II to D3-methyl p-toluenesulfonate is 1.4-1.8: 1;
the molar ratio of the added 1-BOC-piperazine to D3-methyl p-toluenesulfonate is 1.0-1.3: 1
In the step, the solvent II plays a role in diluting 1-BOC-piperazine or D3-methyl p-toluenesulfonate, does not participate in the reaction, dilutes reactants to smooth the reaction, and the addition amount can be selected according to specific reaction conditions. In a specific embodiment, the 1-BOC-piperazine and the D3-p-toluenesulfonic acid can be mixed by selecting the same solvent II or different solvents II, and the same solvent II is preferably used.
3) Adding concentrated hydrochloric acid with the mass fraction of 36-38% into the N-BOC-4-methyl-D3-piperazine solution obtained in the step 2) for hydrolysis reaction, standing and layering the solution after the reaction is finished, taking an upper water phase, and carrying out reduced pressure distillation at 60-70 ℃ to obtain a concentrate; adding a solvent III into the concentrate for crystallization, and then carrying out suction filtration and washing to obtain N-methyl-D3-piperazine hydrochloride;
the solvent III comprises at least one of tetrahydrofuran, methyltetrahydrofuran, acetonitrile, methanol, ethanol and isopropanol;
the molar ratio of concentrated hydrochloric acid to N-BOC-4-methyl-D3-piperazine is 5-9: 1;
the mass ratio of the added solvent III to the concentrate is 2-6: 1.
further, the organic phase in the step 1) is washed and then dried, that is, the upper organic phase is washed with saturated brine saturated sodium bicarbonate, and then concentrated and dried at 45 ℃ under reduced pressure.
Further, adding DCM and water into the residue in the step 2), stirring and layering, and then taking an organic phase for washing, wherein the step is to take the residue, add DCM with the mass of 3.5 times that of D3-methyl p-toluenesulfonate and water with the mass of 2 times that of D3-methyl p-toluenesulfonate, stir and stratify; and (3) washing the upper organic phase with 2 times of water of D3-methyl p-toluenesulfonate, and then adding 0.1mol/L hydrochloric acid for washing until the mass percent of the residual 1-BOC-piperazine in the organic phase is less than 0.4%.
The above reaction involves the following chemical equation:
compared with the existing preparation method of related deuterated compounds, the preparation method provided by the application has the following beneficial effects:
1) the reaction route takes p-toluenesulfonyl chloride and deuterated methanol-D4 as raw materials, and the raw materials react under alkaline conditions to generate D3-methyl p-toluenesulfonate. Deuterated methanol-D4 is in excess, allowing p-toluenesulfonyl chloride to react to completion, since deuterated methanol-D4 is in excess and is easy to work up. The similar reaction reported in CN102190587B, namely p-toluenesulfonyl chloride is excessive, so that the problem of post-treatment is caused;
2) d3-methyl p-toluenesulfonate reacts with 1-BOC-piperazine under the alkaline condition to generate N-BOC-4-methyl-D3-piperazine. In a similar reaction reported in CN102190587B, deuterated methanol-D4 and 1-BOC-piperazine react in tetrahydrofuran solvent in the presence of DEAD and triphenylphosphine to generate N-BOC-4-methyl-D3-piperazine, and post-treatment is carried out by column purification, which brings great limitation to industrial scale-up production;
3) in the third step of the synthesis route, the intermediate product is hydrolyzed by concentrated hydrochloric acid to generate N-methyl-D3-piperazine hydrochloride. Compared with the similar route reported by the prior art (such as Chinese patent CN102190587B), the method uses 6N hydrochloric acid for hydrolysis, and is shorter in time consumption and easier in controlling the reaction process.
Drawings
FIG. 1 is a high performance liquid chromatogram of intermediate III prepared in example 1;
FIG. 2 is a high performance liquid chromatogram of intermediate V prepared in example 2;
FIG. 3 is a high performance liquid chromatogram of the target product VI prepared in example 3;
FIG. 4 shows the preparation of intermediate VI as the target product in example 3 1 H-NMR chart.
Detailed Description
The starting materials and reagents used in the following examples are commercially available unless otherwise specified.
The raw material deuterated methanol-D4 (II) is purchased from Shanghai' an Ji-tolerant chemical company, Ltd;
p-toluenesulfonyl chloride (I) and 1-BOC-piperazine (IV) were both available from Shanghai Michelin Biotech, Inc.
Example 1
The preparation method comprises the following specific steps:
step 1: 226.9g of water and 92.8g (2.32mol) of sodium hydroxide are put into a 2L three-necked flask, stirred to be dissolved clearly, cooled to 0 ℃, and a solution of 60g (1.67mol) of deuterated methanol-D4 (II) dissolved in 87g of tetrahydrofuran is added dropwise, and the dropping is finished after about 1 hour. After the dripping is finished, the temperature of the system is reduced to minus 5 ℃ to minus 10 ℃, a solution of 244.4g (1.28mol) of solid paratoluensulfonyl chloride (I) dissolved in 309g of tetrahydrofuran is dripped, and the internal temperature is kept between minus 5 ℃ and minus 10 ℃ in the dripping process for about 1 hour.
Step 2: when the reaction system is naturally heated to room temperature, a small amount of solid appears in the system. After about 3 hours of reaction, sampling gas phase detection (chromatographic column purchased from AT. SE-54,30m 320um 1um, front sample inlet temperature 240 ℃, column box temperature 40 ℃, detector temperature 250 ℃, chromatographic flow 3ml/min, split ratio 50:1, temperature programming: holding the initial temperature at 40 ℃ for 2min, then raising the temperature at 20 ℃/min to 230 ℃ for 16min, the same below).
And step 3: and (4) carrying out suction filtration, and separating an upper organic layer.
And 4, step 4: the organic layer was washed twice with 300g and 150g of saturated brine (saturated brine) and once with 300g of saturated sodium bicarbonate. The organic layer was concentrated to dryness at 45 ℃ under reduced pressure to give 241.5g of a residue, which was dissolved with 2.5 times the amount of the residue of DCM (dichloromethane) and 0.5 times the amount of the residue of water with stirring to separate the organic layer, which was dried over 64g of anhydrous sodium sulfate for 2 hours. Carrying out suction filtration again, and concentrating the filtrate at 45 ℃ under reduced pressure until the filtrate is dried to obtain 232.6g of colorless transparent liquid D3-methyl p-toluenesulfonate (III) for later use; the yield is 95.8%, and the purity is about 99% by gas phase detection (the detection conditions are the same as above). The gas chromatogram thereof is shown in FIG. 1.
Example 2
240.3g (1.29mol) of 1-BOC-piperazine (IV) and 1321.6g of acetonitrile were put into a 3L three-necked flask, and sufficiently dissolved by stirring for 15 min. 271.7g (1.96mol) of potassium carbonate solid were added and stirred for half an hour. 232.6g (1.23mol) of methyl D3-p-toluenesulfonate (III) obtained in example 1 dissolved in 360.4g of acetonitrile were added dropwise under controlled temperature with circulating water, and the reaction was allowed to release heat so that the internal temperature was maintained at about 30 ℃ (30. + -. 2 ℃). After about half an hour of dripping (in the specific implementation, the dripping is preferably controlled within 0.5-1 hour), the internal temperature is continuously controlled to be about 30 ℃ and 30 +/-2 ℃ for reaction for 2 hours, and the gas phase detection reaction is carried out (the chromatographic parameters are the same as those of example 1, N-BOC-4-methyl-D3-piperazine (V) account for about 70-75%, and the 1-BOC-piperazine remains about 20-25%). The reaction was filtered off with suction, the filtrate was taken and concentrated to dryness at 45 ℃ and the residue weighed 302.2 g. The residue was stirred with 3.5 times the mass of D3-methyl p-toluenesulfonate (III) in DCM and 2 times the mass of D3-methyl p-toluenesulfonate (III) in water and the upper organic phase was washed once more with 2 times the mass of D3-methyl p-toluenesulfonate (III) in water. Finally, the organic phase is washed with 1452g/726g/726g/500g/160g of 0.1mol/L hydrochloric acid for half an hour respectively until about 0.4% of 1-BOC-piperazine (IV) remains and the purity of the product (V) is about 98% (the detection conditions are the same as above). The gas chromatogram of product (V) is shown in FIG. 2. A small amount of the organic layer was concentrated under reduced pressure, and 123.6g of N-BOC-4-methyl-D3-piperazine (V) was contained in the organic layer as calculated by a ratio. The organic phase was suction filtered, essentially free of mechanical impurities, with a yield of 49.4%.
In this example, the organic phase was washed with a gradient of 0.1mol/L hydrochloric acid of different masses, the purpose of which was to wash out the unreacted 1-BOC-piperazine sufficiently and at the same time to reduce the loss of the product N-BOC-4-methyl-D3-piperazine, in order to increase the yield.
Example 3
After circulating water bath to control the temperature, 455.2g (4.49mol) of concentrated hydrochloric acid (generally 36 to 38 mass percent, 38 mass percent of the concentrated hydrochloric acid prepared in this example) was added dropwise to a 2L reaction flask containing 123.6g (0.608mol) of the N-BOC-4-methyl-D3-piperazine (V) obtained in example 2 and containing DCM organic phase, and the internal temperature was controlled to about 30 ℃. After about half an hour of the addition of hydrochloric acid, stirring was continued at room temperature for about 2 hours and a sample was taken for gas phase detection (chromatographic parameters as in example 1) until the hydrolysis of N-BOC-4-methyl-D3-piperazine (V) was complete. Standing for layering, keeping an upper water phase, transferring the water phase into a 1L three-necked bottle, connecting a distillation device, gradually heating to 60-70 ℃ within 1 hour, heating for 1 hour, and removing part of hydrogen chloride gas at normal pressure. Then, the mixture was distilled under reduced pressure, and the water bath was once raised to 78 ℃ to leave 128g of a bright yellow liquid. After the temperature is reduced to room temperature, 128g of isopropanol is added dropwise, and the mixture is stirred for 1 hour, fully stirred and dispersed, and the system is turbid. Then, 384g of isopropyl alcohol was added thereto, and the mixture was stirred for 4 hours to precipitate a white solid. And (4) carrying out suction filtration, and leaching a filter cake with isopropanol to obtain a wet product 123 g. Drying at 60-65 ℃ for 5 hours under reduced pressure to obtain 98g of N-methyl-D3-piperazine hydrochloride (VI) dry product with purity of about 99% (detection conditions are the same as above) and yield of 91.5%, wherein the gas chromatogram of the obtained N-methyl-D3-piperazine hydrochloride (VI) is shown in figure 3. 1 The H-NMR chart is shown in FIG. 4, and the nuclear magnetic spectrum confirms that the target product is N-methyl-D3-piperazine hydrochloride (VI).
By integrating the examples 1-3, 60g of deuterated methanol-D4 is added in total, 98g of dry N-methyl-D3-piperazine hydrochloride (VI) can be obtained, the total yield in three steps is 43.3%, and the yield is greatly improved compared with the prior art.
The above-mentioned embodiments, objects, technical solutions and advantages of the present invention are further described in detail, it should be understood that the above-mentioned embodiments are only illustrative of the present invention and are not intended to limit the present invention, and any modifications, equivalents, improvements and the like made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (5)
1. A preparation method of N-methyl-D3-piperazine hydrochloride is characterized by comprising the following steps;
1) mixing deuterated methanol-D4 with a solvent I to obtain a deuterated methanol-D4 solution for later use;
mixing tosyl chloride with a solvent I to obtain a tosyl chloride solution for later use;
mixing water with an inorganic base I to obtain an alkaline solution; dropwise adding the deuterated methanol-D4 solution into an alkaline solution; after dripping, cooling to minus 5 ℃ to minus 10 ℃, and then dripping the tosyl chloride solution; after the reaction is finished, carrying out suction filtration, washing an organic phase, and drying to obtain D3-methyl p-toluenesulfonate;
the solvent I comprises at least one of tetrahydrofuran, methyltetrahydrofuran, acetonitrile, ethyl acetate, methyl tert-butyl ether and toluene;
the inorganic base I comprises at least one of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate;
the molar ratio of the deuterated methanol-D4 to the p-toluenesulfonyl chloride is 1.1-1.5: 1;
the molar ratio of the inorganic base I to the p-toluenesulfonyl chloride is 1.6-2.0: 1;
2) mixing D3-methyl p-toluenesulfonate obtained in the step 1) with a solvent II to obtain a D3-methyl p-toluenesulfonate solution for later use;
mixing 1-BOC-piperazine with a solvent II, adding an inorganic base II, and then dropwise adding the D3-methyl p-toluenesulfonate solution, wherein the temperature is controlled to be 30 +/-2 ℃ in the reaction process; after the reaction is finished, carrying out suction filtration, taking filtrate and drying to obtain a residue; adding DCM and water into the residue, stirring and layering, and washing an organic phase to obtain N-BOC-4-methyl-D3-piperazine;
the solvent II comprises at least one of tetrahydrofuran, methyltetrahydrofuran, acetonitrile, ethyl acetate, methyl tert-butyl ether and toluene;
the inorganic base II comprises at least one of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and sodium hydride;
the molar ratio of the added inorganic base II to D3-methyl p-toluenesulfonate is 1.4-1.8: 1;
the molar ratio of the added 1-BOC-piperazine to D3-methyl p-toluenesulfonate is 1.0-1.3: 1
3) Adding a hydrochloric acid solution with the mass fraction of 36-38% into the N-BOC-4-methyl-D3-piperazine obtained in the step 2), standing and layering the solution after the reaction is finished, and distilling the upper aqueous phase under reduced pressure to obtain a concentrate; then adding a solvent III into the concentrate, crystallizing, filtering, and washing to obtain N-methyl-D3-piperazine hydrochloride;
the solvent III comprises at least one of tetrahydrofuran, methyltetrahydrofuran, acetonitrile, methanol, ethanol and isopropanol;
the molar ratio of the hydrochloric acid to the N-BOC-4-methyl-D3-piperazine is 5-9: 1;
the mass ratio of the added solvent III to the concentrate is 2-6: 1.
2. the method for preparing N-methyl-D3-piperazine hydrochloride according to claim 1, wherein the molar ratio of deuterated methanol-D4 to p-toluenesulfonyl chloride in step 1) is 1.3: 1.
3. The method for preparing N-methyl-D3-piperazine hydrochloride according to claim 1, wherein the molar ratio of the inorganic base I to p-toluenesulfonyl chloride in step 1) is 1.8: 1.
4. The process for preparing N-methyl-D3-piperazine hydrochloride according to claim 1, wherein the organic phase obtained in step 1) is washed and then dried, and the organic phase obtained in the upper layer is sequentially washed with saturated brine saturated sodium bicarbonate and then concentrated and dried at 45 ℃ under reduced pressure.
5. The process for preparing N-methyl-D3-piperazine hydrochloride according to claim 1, wherein in the step 2), DCM and water are added into the residue, and the mixture is stirred for layering and then washed with the organic phase, i.e. DCM with the mass of 3.5 times that of methyl D3-p-toluenesulfonate and water with the mass of 2 times that of methyl D3-p-toluenesulfonate are added into the residue, and then the mixture is stirred for layering; the organic phase is washed with water 2 times the mass of D3-methyl p-toluenesulfonate, and then washed with 0.1mol/L hydrochloric acid until the impurities meet the limit.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115353443A (en) * | 2022-09-19 | 2022-11-18 | 上海安谱实验科技股份有限公司 | Synthesis method of deuterium-labeled diethylstilbestrol |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103319476A (en) * | 2013-06-13 | 2013-09-25 | 济南德爱医药技术有限公司 | Kinase inhibitor |
| CN109593102A (en) * | 2018-01-04 | 2019-04-09 | 深圳市塔吉瑞生物医药有限公司 | A kind of preparation method and its crystal form of deuterated diphenylamino pyrimidines |
| WO2019184966A1 (en) * | 2018-03-28 | 2019-10-03 | 深圳市塔吉瑞生物医药有限公司 | Substituted diamino heterocyclic carboxamide compound and a composition containing the compound and use thereof |
| CN113493414A (en) * | 2020-03-19 | 2021-10-12 | 江苏苏中药业集团股份有限公司 | Deuterated substituted butene amide and preparation method and application thereof |
| WO2022037643A1 (en) * | 2020-08-20 | 2022-02-24 | 江苏正大丰海制药有限公司 | Heteroaromatic ring compound as ret kinase inhibitor, and preparation and use thereof |
-
2022
- 2022-06-17 CN CN202210721612.4A patent/CN115028603A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103319476A (en) * | 2013-06-13 | 2013-09-25 | 济南德爱医药技术有限公司 | Kinase inhibitor |
| CN109593102A (en) * | 2018-01-04 | 2019-04-09 | 深圳市塔吉瑞生物医药有限公司 | A kind of preparation method and its crystal form of deuterated diphenylamino pyrimidines |
| WO2019184966A1 (en) * | 2018-03-28 | 2019-10-03 | 深圳市塔吉瑞生物医药有限公司 | Substituted diamino heterocyclic carboxamide compound and a composition containing the compound and use thereof |
| CN113493414A (en) * | 2020-03-19 | 2021-10-12 | 江苏苏中药业集团股份有限公司 | Deuterated substituted butene amide and preparation method and application thereof |
| WO2022037643A1 (en) * | 2020-08-20 | 2022-02-24 | 江苏正大丰海制药有限公司 | Heteroaromatic ring compound as ret kinase inhibitor, and preparation and use thereof |
Non-Patent Citations (1)
| Title |
|---|
| CHIAKI YAMAMOTO 等: ""Copper-Catalyzed Intramolecular Benzylic C-H Amination for the Synthesis of Isoindolinones"", JOURNAL OF ORGANIC CHEMISTRY, vol. 81, no. 17, pages 7675 - 7684, XP055714814, DOI: 10.1021/acs.joc.6b01393 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115353443A (en) * | 2022-09-19 | 2022-11-18 | 上海安谱实验科技股份有限公司 | Synthesis method of deuterium-labeled diethylstilbestrol |
| CN115353443B (en) * | 2022-09-19 | 2023-09-15 | 上海安谱实验科技股份有限公司 | Synthetic method of deuterium-labeled diethylstilbestrol |
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