CN115215774B - Deuteration method of methyl sulfide compound - Google Patents
Deuteration method of methyl sulfide compound Download PDFInfo
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- CN115215774B CN115215774B CN202110406555.6A CN202110406555A CN115215774B CN 115215774 B CN115215774 B CN 115215774B CN 202110406555 A CN202110406555 A CN 202110406555A CN 115215774 B CN115215774 B CN 115215774B
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- -1 methyl sulfide compound Chemical class 0.000 title claims abstract description 64
- 238000000034 method Methods 0.000 title claims abstract description 52
- 238000006243 chemical reaction Methods 0.000 claims abstract description 99
- 229910052805 deuterium Inorganic materials 0.000 claims abstract description 37
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims abstract description 36
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical class CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 claims abstract description 34
- 239000003054 catalyst Substances 0.000 claims abstract description 24
- 150000001875 compounds Chemical class 0.000 claims abstract description 22
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 14
- 125000003118 aryl group Chemical group 0.000 claims abstract description 13
- 239000002904 solvent Substances 0.000 claims abstract description 13
- 239000000376 reactant Substances 0.000 claims abstract description 11
- 125000001183 hydrocarbyl group Chemical group 0.000 claims abstract description 9
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 5
- 125000004103 aminoalkyl group Chemical group 0.000 claims abstract description 5
- 239000007788 liquid Substances 0.000 claims abstract description 5
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims abstract description 5
- 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 5
- 125000001931 aliphatic group Chemical group 0.000 claims abstract 2
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 claims description 30
- 229910052799 carbon Inorganic materials 0.000 claims description 17
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 12
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 7
- 238000007789 sealing Methods 0.000 claims description 5
- 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 claims description 3
- 150000001721 carbon Chemical group 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 2
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 claims 6
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 2
- 229910052744 lithium Inorganic materials 0.000 claims 2
- 229910052700 potassium Inorganic materials 0.000 claims 2
- 239000011591 potassium Substances 0.000 claims 2
- 239000011775 sodium fluoride Substances 0.000 claims 1
- 125000000524 functional group Chemical group 0.000 abstract description 8
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 7
- 239000000758 substrate Substances 0.000 abstract description 7
- 150000003463 sulfur Chemical class 0.000 abstract description 3
- 238000012360 testing method Methods 0.000 description 28
- 239000007789 gas Substances 0.000 description 27
- UHOVQNZJYSORNB-MZWXYZOWSA-N benzene-d6 Chemical compound [2H]C1=C([2H])C([2H])=C([2H])C([2H])=C1[2H] UHOVQNZJYSORNB-MZWXYZOWSA-N 0.000 description 26
- 230000005311 nuclear magnetism Effects 0.000 description 23
- 238000001228 spectrum Methods 0.000 description 21
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 11
- 239000001257 hydrogen Substances 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 11
- FOJGPFUFFHWGFQ-UHFFFAOYSA-N 1-(Methylthio)pentane Chemical class CCCCCSC FOJGPFUFFHWGFQ-UHFFFAOYSA-N 0.000 description 10
- IGKRCEMLHDKLEE-UHFFFAOYSA-N 1-methylsulfanyl-4-propan-2-ylbenzene Chemical class CSC1=CC=C(C(C)C)C=C1 IGKRCEMLHDKLEE-UHFFFAOYSA-N 0.000 description 6
- ROSSIHMZZJOVOU-UHFFFAOYSA-N 2-(methylthio)propane Chemical class CSC(C)C ROSSIHMZZJOVOU-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000012216 screening Methods 0.000 description 6
- CVZBYEKCIDMLRV-UHFFFAOYSA-N 1,4-bis(methylsulfanyl)benzene Chemical class CSC1=CC=C(SC)C=C1 CVZBYEKCIDMLRV-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- BMVUVEYWVYKKNB-UHFFFAOYSA-N n,n-dimethyl-2-methylsulfanylaniline Chemical class CSC1=CC=CC=C1N(C)C BMVUVEYWVYKKNB-UHFFFAOYSA-N 0.000 description 5
- BMEQLFPMTJNSMA-UHFFFAOYSA-N 1-methoxy-3-methylsulfanylpropane Chemical class COCCCSC BMEQLFPMTJNSMA-UHFFFAOYSA-N 0.000 description 4
- LIECPNKJSYVHBC-UHFFFAOYSA-N CSCCC[Si](C)(C)C Chemical class CSCCC[Si](C)(C)C LIECPNKJSYVHBC-UHFFFAOYSA-N 0.000 description 4
- QQBIOCGHCKNYGP-UHFFFAOYSA-N Methylsulfanylcyclohexane Chemical class CSC1CCCCC1 QQBIOCGHCKNYGP-UHFFFAOYSA-N 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- IQJZWNDBEOWAIY-UHFFFAOYSA-N n,n-dimethyl-3-methylsulfanylpropan-1-amine Chemical class CSCCCN(C)C IQJZWNDBEOWAIY-UHFFFAOYSA-N 0.000 description 4
- 231100000956 nontoxicity Toxicity 0.000 description 4
- 150000001338 aliphatic hydrocarbons Chemical group 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 3
- 229910000105 potassium hydride Inorganic materials 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 150000003568 thioethers Chemical class 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- 239000003341 Bronsted base Substances 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 238000010504 bond cleavage reaction Methods 0.000 description 1
- HOVYSSCJTQTKMV-UHFFFAOYSA-N cesium azanide Chemical compound [NH2-].[Cs+] HOVYSSCJTQTKMV-UHFFFAOYSA-N 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 150000001975 deuterium Chemical group 0.000 description 1
- 125000004431 deuterium atom Chemical group 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000036267 drug metabolism Effects 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical class IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 125000001741 organic sulfur group Chemical group 0.000 description 1
- 125000004817 pentamethylene group Chemical class [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 150000003464 sulfur compounds Chemical class 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
- C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
-
- 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
-
- 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
- C07B59/004—Acyclic, carbocyclic or heterocyclic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen, sulfur, selenium or tellurium
-
- 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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/0825—Preparations of compounds not comprising Si-Si or Si-cyano linkages
- C07F7/083—Syntheses without formation of a Si-C bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
Abstract
The invention provides a deuteration method of a methyl sulfide compound, and belongs to the technical field of organic synthesis. The method comprises the following steps: under inert atmosphere, taking alkali metal salt as a catalyst, taking methyl sulfide compounds which are in liquid state at the reaction temperature as reactants, filling deuterium into a reaction container, and performing airtight reaction for a certain time at the reaction temperature to obtain methyl sulfide deuterated compounds, or taking the methyl sulfide compounds as reactants, and then adding a solvent to obtain the methyl sulfide deuterated compounds, wherein the reaction general formula is shown in the formula 1:wherein R is 1 、R 2 Independently of one another, selected from any one of H, hydrocarbyl, aryl, substituted aryl, silyl, alkoxy or aminoalkyl groups or R 1 、R 2 Bonding to an aliphatic hydrocarbon ring or an aromatic ring. The deuterated method provided by the invention has the advantages of less catalyst consumption, mild reaction conditions, excellent compatibility of substrate functional groups and high deuteration rate, so that a new way for preparing deuterated sulfur-containing compounds and deuterated medicaments is opened up, and the method has higher application value.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a deuteration method of a methyl sulfide compound.
Background
Deuterated compounds are used as a class of high-added-value compounds and have wide application in the fields of organic synthesis, mechanism research, drug metabolism, drug modification and the like. The development of novel mild, efficient, and ubiquitous deuteration methods has been receiving considerable attention from chemists in recent years.
Organic sulfur-containing compounds are widely found in biologically active compounds, natural products and synthetic drug molecules. Of the 200 most popular drugs in 2019, about 19% contain sulfur atoms, and so deuteration of sulfur-containing compounds is particularly important. At present, a synthetic method of deuterated thioether compounds has been reported in literature, which comprises the following steps: reacting thiophenol with deuterated methyl iodide to synthesize deuterated phenyl methyl sulfide containing a plurality of deuterium atoms; the thioether compound is deprotonated under the condition of strong alkali, and the deuterium is quenched by water to synthesize the deuterated compound containing one deuterium atom. Currently, such methods generally require large amounts of deuterated reagents or reactive metal reagents to effect deuteration at low temperatures, and the functional groups of the reaction are limited in tolerance, requiring high conditions, and the synthesis of relatively complex deuterated products requires multiple steps.
However, sulfur-containing compounds generally have poisoning effects on transition metals, or cleavage of C-S bonds occurs in the presence of transition metals, which are costly and have low deuteration rates.
Disclosure of Invention
The present invention has been made to solve the above problems, and an object of the present invention is to provide a deuteration method of a methyl sulfide compound.
The invention provides a deuteration method of a methyl sulfide compound, which has the characteristics that the method comprises the following steps: under inert atmosphere, taking alkali metal salt as a catalyst, taking methyl sulfide compounds in liquid state at a reaction temperature as reactants, charging deuterium into a reaction container, performing airtight reaction for a certain time at the reaction temperature to obtain methyl sulfide deuterated compounds, or under inert atmosphere, taking alkali metal salt as a catalyst, taking methyl sulfide compounds as reactants, adding a solvent into the reaction container, charging deuterium, performing airtight reaction for a certain time at the reaction temperature to obtain methyl sulfide deuterated compounds,
the general reaction formula is shown in formula 1:
wherein R is 1 、R 2 Independently of one another, selected from any one of H, hydrocarbyl, aryl, substituted aryl, silyl, alkoxy or aminoalkyl groups or R 1 、R 2 Bonding to an aliphatic hydrocarbon ring or an aromatic ring.
The deuteration method of the methyl sulfide compound provided by the invention has the following characteristics: wherein the methyl thioether compound is phenyl methyl thioether compound, and the reaction general formula is shown in formula 2:
in formula 2, R 3 -R 7 Independently of one another, from H, C 1 -C 10 C is a hydrocarbon group of (C) 6 -C 20 Aryl, halogen, C 1 -C 10 Hydrocarbyloxy group, C 1 -C 10 Any one of the alkylthio group or N, N-dimethyl group, X is a carbon atom or a nitrogen atom.
The deuteration method of the methyl sulfide compound provided by the invention has the following characteristics: wherein the methyl thioether compound is a 1, 4-bis (methylthio) benzene compound, and the reaction formula is shown in formula 3:
the deuteration method of the methyl sulfide compound provided by the invention has the following characteristics: wherein the methyl thioether compound is an alkyl methyl thioether compound, and the reaction general formula is shown in formula 4:
the deuteration method of the methyl sulfide compound provided by the invention has the following characteristics: wherein the methyl thioether compound is a cyclic hydrocarbon methyl thioether compound, and the reaction general formula is shown in formula 5:
wherein n is 1-5.
The deuteration method of the methyl sulfide compound provided by the invention has the following characteristics: wherein the methyl thioether compound is methyl thioether compound, and the reaction general formula is shown in formula 6:
the deuteration method of the methyl sulfide compound provided by the invention has the following characteristics: wherein the catalyst is any one or a combination of a plurality of potassium bis (trimethylsilyl) amide, lithium bis (trimethylsilyl) amide, cesium fluoride, cesium amide, potassium hydride, yttrium amide, lithium diisopropylamide, potassium tert-butoxide and sodium bis (trimethylsilyl) amide.
The deuteration method of the methyl sulfide compound provided by the invention has the following characteristics: wherein the catalyst is any one of bis (trimethylsilyl) amidopotassium, a mixture of bis (trimethylsilyl) amidolithium and cesium fluoride, amidocesium, a mixture of potassium hydride and bis (trimethylsilyl) amidopotassium, a mixture of potassium hydride and amidoyttrium, a mixture of diisopropylamidolithium and potassium tert-butoxide, a mixture of sodium bis (trimethylsilyl) amidosodium and cesium fluoride, and a mixture of bis (trimethylsilyl) amidopotassium and cesium fluoride. Preferably, the catalyst is potassium bis (trimethylsilyl) amide or cesium fluoride to lithium bis (trimethylsilyl) amide in a molar ratio of 1: 1.
The deuteration method of the methyl sulfide compound provided by the invention has the following characteristics: wherein the dosage of the catalyst is 1-50% of the molar quantity of the methyl sulfide compound.
The deuteration method of the methyl sulfide compound provided by the invention has the following characteristics: wherein the solvent is any one of aromatic hydrocarbon solvent, alkane solvent or ether solvent, preferably any one of deuterated benzene, tetrahydrofuran, diethyl ether, methyl tertiary butyl ether, n-hexane or cyclohexane.
The deuteration method of the methyl sulfide compound provided by the invention has the following characteristics: wherein the reaction temperature is 60-120 ℃, and the reaction time is 12-96 hours, preferably 80 ℃, and preferably 24 hours.
The deuteration method of the methyl sulfide compound provided by the invention has the following characteristics: wherein deuterium gas is filled into the reaction vessel such that the pressure of deuterium gas in the reaction vessel is between 1bar and 50bar, preferably 4bar.
The deuteration method of the methyl sulfide compound provided by the invention has the following characteristics: wherein high deuteration rates of the reactants can be achieved through such a process two or more times by substituting the gas in the reaction vessel with new deuterium and then performing the reaction.
The deuteration method of the methyl sulfide compound provided by the invention has the following characteristics: the Bronsted base prepared from alkali metal is a cheaper metalizing reagent, uses alkali metal salt as a catalyst, is applied to deuteration reaction of thioether compounds, opens up a new low-cost, green and efficient way for preparing deuterated sulfur-containing compounds and deuterated medicaments, and has higher application value.
Effects and effects of the invention
The deuteration method of the methyl sulfide compound comprises the following steps: under inert atmosphere, taking alkali metal salt as a catalyst, taking methyl sulfide compounds in liquid state at the reaction temperature as reactants, filling deuterium into a reaction container, performing airtight reaction for a certain time at the reaction temperature to obtain methyl sulfide deuterated compounds, or taking methyl sulfide compounds as reactants, adding solvent into the reaction container, filling deuterium, performing airtight reaction for a certain time at the reaction temperature to obtain methyl sulfide deuterated compounds,
the general reaction formula is shown in formula 1:
wherein R is 1 、R 2 Independently of one another, selected from any one of H, hydrocarbyl, aryl, substituted aryl, silyl, alkoxy or aminoalkyl groups or R 1 、R 2 Bonding to an aliphatic hydrocarbon ring or an aromatic ring. The deuterated method provided by the invention has the advantages of low catalyst consumption, low cost, easy obtainment, no toxicity, simple and convenient operation, mild reaction conditions, excellent compatibility of substrate functional groups, high deuteration rate and capability of preparing deuterated products in one step, so that a novel low-cost, green and efficient way for preparing deuterated sulfur-containing compounds and deuterated medicaments is opened up, and the method has higher application value.
Furthermore, according to the deuteration method of the methyl sulfide compound, the methyl sulfide compound is used as the starting material, the tolerance of the functional group of the reaction is not limited, the reaction condition is mild, and the complex synthesis step can be omitted for synthesizing the deuterated methyl sulfide compound in one step. Therefore, the substrate provided by the invention has the advantages of wide application range, simple synthesis steps and better functional group compatibility.
Furthermore, according to the deuteration method of the methyl sulfide compound, the alkali metal salt is used as the catalyst, so that the alkali metal salt catalyst has the advantages of small dosage, low cost, easy obtainment, no toxicity, simple operation and mild reaction conditions, and therefore, the application range of the alkali metal salt catalyzed substrate is wide and the catalytic efficiency is high.
Furthermore, according to the deuteration method of the methyl sulfide compound, the methyl sulfide deuterated compound with high deuteration rate can be synthesized in the atmosphere of the autoclave deuterated gas.
Drawings
FIG. 1 is a hydrogen spectrum of deuterated phenyl methyl sulfide in example III of the present invention;
FIG. 2 is a carbon spectrum of deuterated phenyl methyl sulfide in example III of the present invention;
FIG. 3 is a hydrogen spectrum of deuterated 4-isopropyl-phenyl methyl sulfide in example four of the present invention;
FIG. 4 is a carbon spectrum of deuterated 4-isopropyl-phenyl methyl sulfide in example four of the present invention;
FIG. 5 is a hydrogen spectrum of deuterated 4-phenyl methyl sulfide according to example five of the present invention;
FIG. 6 is a carbon spectrum of deuterated 4-phenyl methyl sulfide according to example five of the present invention;
FIG. 7 is a hydrogen spectrum of deuterated 1, 4-bis (methylthio) benzene in example six of the present invention;
FIG. 8 is a carbon spectrum of deuterated 1, 4-bis (methylthio) benzene in example six of the present invention;
FIG. 9 is a hydrogen spectrum of deuterated o- (N, N-dimethylamino) phenyl methyl sulfide according to example seven of the present invention;
FIG. 10 is a carbon spectrum of deuterated o- (N, N-dimethylamino) phenyl methyl sulfide according to example seven of the present invention;
FIG. 11 is a hydrogen profile of deuterated amyl methyl sulfide in example eight of the present invention;
FIG. 12 is a carbon spectrum of deuterated amyl methyl sulfide in example eight of the present invention;
FIG. 13 is a hydrogen spectrum of deuterated isopropyl methyl sulfide in example nine of the present invention;
FIG. 14 is a carbon spectrum of deuterated isopropyl methyl sulfide in example nine of the present invention;
FIG. 15 is a hydrogen spectrum of deuterated methyl-cyclohexyl sulfide in example ten of the present invention;
FIG. 16 is a carbon spectrum of deuterated methyl-cyclohexyl sulfide in example ten of the present invention;
FIG. 17 is a hydrogen spectrum of deuterated 1-methoxy-3-methylthiopropane according to example eleven of the present invention;
FIG. 18 is a carbon spectrum of deuterated 1-methoxy-3-methylthiopropane according to example eleven of the present invention;
FIG. 19 is a hydrogen spectrum of deuterated 3-trimethylsilyl propyl methyl sulfide according to example twelve of the present invention;
FIG. 20 is a carbon spectrum of deuterated 3-trimethylsilyl propyl methyl sulfide according to example twelve of the present invention;
FIG. 21 is a hydrogen spectrum of deuterated N, N-dimethyl-3- (methylthio) -1-propanamine in example twelve of the present invention; and
FIG. 22 is a carbon spectrum of deuterated N, N-dimethyl-3- (methylthio) -1-propanamine in example twelve of the present invention.
Detailed Description
In order to make the technical means, the creation features, the achievement of the purpose and the effect of the present invention easy to understand, the present invention is specifically described below with reference to the embodiments and the drawings.
In the following examples, nuclear magnetism 1 The test frequency of H NMR was 400MHz and the deuterated reagent was C 6 D 6 。
In the embodiments described in the following description of the embodiments, 13 the C NMR test frequency was 400MHz and the deuterated reagent was C 6 D 6 。
Example 1
Deuterated reaction formula of phenyl methyl sulfide is as follows:
the screening method of the deuterated phenyl methyl sulfide reaction conditions is as follows:
under an inert atmosphere, phenyl methyl sulfide (CAS: 100-68-5) (0.0372 g,0.3 mmol) was added sequentially to a 25mL autoclave, deuterated benzene0.5mL of catalyst (0.015 mmol or 0.03 mmol), sealing the autoclave, filling deuterium gas to make the pressure of the deuterium gas in the autoclave be 4bar, heating at 40 ℃ or 60 ℃ for 12h or 24h, and directly performing nuclear magnetism on the reaction solution after the reaction is finished 1 HNMR test by 1 The H NMR data calculated the deuteration rate.
The specific screening conditions and deuteration rate are shown in Table 1.
TABLE 1 conditional screening of deuteration reactions of phenyl methyl sulfide and deuteration Rate
< example two >
The deuteration reaction of amyl methyl sulfide has the following reaction formula:
the screening method of the deuterated amyl methyl sulfide reaction conditions is as follows:
in an inert atmosphere, amyl methyl sulfide (CAS: 1741-83-9) (0.0354 g,0.3 mmol), deuterated benzene 0.5mL and catalyst (0.06 mmol or 0.03 mmol) are added in sequence into a 25mL autoclave, the autoclave is sealed, deuterium gas is filled into the autoclave to lead the pressure of the deuterium gas in the autoclave to be 4bar, the autoclave is heated at 80 ℃ for 48h or 24h, and after the reaction is finished, the reaction liquid is directly subjected to nuclear magnetism 1 HNMR test by 1 HNMR data calculated deuteration rate.
The specific screening conditions and deuteration rate are shown in Table 2.
TABLE 2 screening conditions for deuteration of amyl methyl sulfide and deuteration rate
. a Carbon-sulfur bond cleavage products and pentenes.
Example III
The preparation method of the deuterated phenyl methyl sulfide comprises the following steps:
phenyl methyl sulfide (CAS: 100-68-5) (0.0372 g,0.3 mmol), 0.5mL of deuterated benzene, and potassium bis (trimethylsilyl) amide (0.0060 g,0.03 mmol) were sequentially added to a 25mL autoclave under an inert atmosphere, the autoclave was sealed, and deuterium gas was charged so that the pressure of deuterium gas in the autoclave became 4bar, and the autoclave was heated at 60℃for 24 hours. After the reaction, the reaction solution directly carries out nuclear magnetism 1 H NMR、 13 C NMR test, deuteration rate was 94%.
Nuclear magnetism 1 The test results of H NMR are shown in FIG. 1. 13 The results of the C NMR test are shown in FIG. 2.
Example IV
The preparation method of the deuterated 4-isopropyl-phenyl methyl sulfide comprises the following steps:
4-isopropylphenyl methyl sulfide (CAS: 70026-35-6) (0.0498 g,0.3 mmol), deuterated benzene 0.5mL, bis (trimethylsilyl) amidopotassium (0.0060 g,0.03 mmol) were added sequentially under an inert atmosphere in a 25mL autoclave. The autoclave was sealed and filled with deuterium gas to a pressure of 4bar and heated at 60℃for 24 hours. After the reaction, the reaction solution directly carries out nuclear magnetism 1 H NMR、 13 C NMR test, deuteration rate was 74%.
Nuclear magnetism 1 The test results of H NMR are shown in FIG. 3. 13 The results of C NMR are shown in FIG. 4.
< example five >
The preparation method of the deuterated 4-phenyl methyl sulfide comprises the following steps:
4-isopropylphenyl methyl sulfide (CAS: 19813-76-4) (0.0601 g,0.3 mmol), deuterated benzene 0.5mL, potassium bis (trimethylsilyl) amide (0.0060 g,0.03 mmol) were added sequentially under an inert atmosphere in a 25mL autoclave. The autoclave was sealed and filled with deuterium gas to a pressure of 4bar and heated at 80℃for 24 hours. After the reaction, the reaction solution directly carries out nuclear magnetism 1 H NMR、 13 C NMR test, deuteration rate was 98%.
Nuclear magnetism 1 The test results of H NMR are shown in FIG. 5. 13 The results of the C NMR test are shown in FIG. 6.
< example six >
The preparation method of deuterated 1, 4-bis (methylthio) benzene comprises the following steps:
1, 4-bis (methylthio) benzene (CAS: 699-20-7) (0.0510 g,0.3 mmol), deuterated benzene 0.5mL, and potassium bis (trimethylsilyl) amide (0.0060 g,0.03 mmol) were sequentially added to a 25mL autoclave under an inert atmosphere. The autoclave was sealed and filled with deuterium gas to a pressure of 4bar and heated at 60℃for 24 hours. After the reaction, the reaction solution directly carries out nuclear magnetism 1 H NMR、 13 C NMR test, deuteration rate was 74%.
Nuclear magnetism 1 The test results of H NMR are shown in FIG. 7. 13 The results of C NMR are shown in FIG. 8.
< example seven >
The preparation method of deuterated o- (N, N-dimethylamino) phenyl methyl sulfide comprises the following steps:
o- (N, N-dimethylamino) phenyl methyl sulfide (CAS: 2388-50-3) (0.0501 g,0.3 mmol), deuterated benzene 0.5mL, potassium bis (trimethylsilyl) amide (0.0060 g,0.03 mmol) were added sequentially under an inert atmosphere in a 25mL autoclave. The autoclave was sealed and filled with deuterium gas to a pressure of 4bar and heated at 80℃for 24 hours. After the reaction, the reaction solution directly carries out nuclear magnetism 1 H NMR、 13 C NMR test shows that the deuteration rate is 96%.
Nuclear magnetism 1 The test results of H NMR are shown in FIG. 9. 13 The results of C NMR are shown in FIG. 10.
< example eight >
The preparation method of the deuterated amyl methyl sulfide comprises the following steps:
to a 25mL autoclave was then added, under an inert atmosphere, pentylmethyl sulfide (CAS: 1741-83-9) (0.0354 g,0.3 mmol), deuterated benzene 0.5mL, cesium fluoride (0.0092 g,0.06 mmol), lithium bis (trimethylsilyl) amide (0.01 g,0.06 mmol) in sequence. The autoclave was sealed and filled with deuterium gas to a pressure of 4bar and heated at 80℃for 48 hours. After the reaction, the reaction solution directly carries out nuclear magnetism 1 H NMR、 13 C NMR test, deuteration rate was 92%.
Nuclear magnetism 1 The test results of H NMR are shown in FIG. 11. 13 The results of C NMR are shown in FIG. 12.
< example nine >
The preparation method of the deuterated isopropyl methyl sulfide comprises the following steps:
under an inert atmosphere, isopropyl methyl sulfide (CAS: 1551-21-9) (0.0270 g,0.3 mmol), deuterated benzene 0.5mL, cesium fluoride (0.0092 g,0.06 mmol), bis (trimethylsilyl) were added sequentially to a 25mL autoclaveLithium amide (0.01 g,0.06 mmol). The autoclave was sealed and filled with deuterium gas to a pressure of 4bar and heated at 80℃for 48 hours. After the reaction, the reaction solution directly carries out nuclear magnetism 1 H NMR、 13 C NMR test, deuteration rate was 88%.
Nuclear magnetism 1 The test results of H NMR are shown in FIG. 13. 13 The results of C NMR are shown in FIG. 14.
< example ten >
The preparation method of deuterated methyl thio-cyclohexyl ester comprises the following steps:
methyl cyclohexyl sulfide (CAS: 7133-37-1) (0.0391 g,0.3 mmol), deuterated benzene 0.5mL, cesium fluoride (0.0092 g,0.06 mmol), lithium bis (trimethylsilyl) amide (0.01 g,0.06 mmol) were added sequentially under an inert atmosphere in a 25mL autoclave. The autoclave was sealed, filled with deuterium gas to a pressure of 4bar in the autoclave, heated at 80℃for 48 hours, and refilled with deuterium gas to a pressure of 4bar in the autoclave, followed by a further 48 hours of reaction. After the reaction, the reaction solution directly carries out nuclear magnetism 1 H NMR、 13 C NMR test, deuteration rate was 93%.
Nuclear magnetism 1 The test results of H NMR are shown in FIG. 15. 13 The results of C NMR are shown in FIG. 16.
< example eleven >
The preparation method of deuterated 1-methoxy-3-methylthiopropane comprises the following steps:
1-methoxy-3-methylthiopropane (CAS: 67360-33-2) (0.0391 g,0.3 mmol), deuterated benzene 0.5mL, cesium fluoride (0.0092 g,0.06 mmol), lithium bis (trimethylsilyl) amide (0.01 g,0.06 mmol) were added sequentially under an inert atmosphere in a 25mL autoclave. Sealing the autoclave, and charging deuterium gas to make deuterium in the autoclaveThe pressure of the gas was 4bar, and after heating at 80℃for 48 hours, deuterium gas was refilled to give a pressure of 4bar in the autoclave, and the reaction was continued for 48 hours. After the reaction, the reaction solution directly carries out nuclear magnetism 1 H NMR、 13 C NMR test, deuteration rate was 93%.
Nuclear magnetism 1 The test results of H NMR are shown in FIG. 17. 13 The results of C NMR are shown in FIG. 18.
< example twelve >
The preparation method of the deuterated 3-trimethylsilyl propyl methyl sulfide comprises the following steps:
3-trimethylsilyl propyl methyl sulfide (CAS: 28247-28-1) (0.0487 g,0.3 mmol), deuterated benzene 0.5mL, cesium fluoride (0.0092 g,0.06 mmol), lithium bis (trimethylsilyl) amide (0.01 g,0.06 mmol) were added sequentially under an inert atmosphere in a 25mL autoclave. Sealing the autoclave, filling deuterium gas to make the pressure of deuterium gas in the autoclave be 4bar, heating at 80 deg.C for 48 hr, re-filling deuterium gas to make the pressure of deuterium gas in the autoclave be 4bar, continuously reacting for 48 hr, after the reaction is completed, directly making the reaction liquor undergo the process of nuclear magnetic reaction 1 H NMR、 13 C NMR test, deuteration rate was 93%.
Nuclear magnetism 1 The test results of H NMR are shown in FIG. 19. 13 The results of C NMR are shown in FIG. 20.
< example thirteen >
The preparation method of deuterated N, N-dimethyl-3- (methylthio) -1-propylamine comprises the following steps:
n, N-dimethyl-3- (methylthio) -1-propylamine (CAS: 16220-69-2) (0.0399 g,0.3 mmol), deuterated benzene 0.5mL, cesium fluoride (0.0092 g,0.06 mmol), lithium bis (trimethylsilyl) amide (0.01 g,0.06 mmol). Sealing the autoclave, filling deuterium gas to make the pressure of deuterium gas in the autoclave be 4bar, heating at 80 deg.C for 48 hr, after the reaction is completed, directly making the reaction liquor undergo the process of nuclear magnetic reaction 1 H NMR、 13 C NMR test, deuteration rate was 93%.
Nuclear magnetism 1 The test results of H NMR are shown in FIG. 21. 13 The results of C NMR are shown in FIG. 22.
Effects and effects of the examples
The deuteration method of the methyl sulfide compound according to the embodiment comprises the following steps: under inert atmosphere, taking alkali metal salt as a catalyst, taking methyl sulfide compounds in liquid state at the reaction temperature as reactants, filling deuterium into a reaction container, performing airtight reaction for a certain time at the reaction temperature to obtain methyl sulfide deuterated compounds, or taking methyl sulfide compounds as reactants, adding solvent into the reaction container, filling deuterium, performing airtight reaction for a certain time at the reaction temperature to obtain methyl sulfide deuterated compounds,
the general reaction formula is shown in formula 1:
wherein R is 1 、R 2 Independently of one another, selected from any one of H, hydrocarbyl, aryl, substituted aryl, silyl, alkoxy or aminoalkyl groups or R 1 、R 2 Bonding to an aliphatic hydrocarbon ring or an aromatic ring. The deuterated method provided by the embodiment has the advantages of small catalyst dosage, low cost, easy obtainment, no toxicity, simple and convenient operation, mild reaction conditions, excellent compatibility of substrate functional groups, high deuteration rate and capability of preparing deuterated products in one step, so that a novel low-cost, green and efficient way for preparing deuterated sulfur compounds and deuterated medicaments is opened up, and the method has higher application value.
Furthermore, according to the deuteration method of the methyl sulfide compound provided by the embodiment, the methyl sulfide compound is used as the starting material, the tolerance of the functional group of the reaction is not limited, the reaction condition is mild, and the complex synthesis step can be omitted for synthesizing the deuterated methyl sulfide compound in one step. Therefore, the substrate provided by the embodiment has wide application range, simple synthesis steps and better functional group compatibility.
Furthermore, according to the deuteration method of the methyl sulfide compound provided by the embodiment, the alkali metal salt is used as the catalyst, so that the alkali metal salt catalyst has the advantages of small dosage, low cost, easy obtainment, no toxicity, simple operation, mild reaction conditions, wide application range of the catalytic substrate and high catalytic efficiency.
Further, according to the deuteration method of the methyl sulfide compound provided in the present embodiment, since the methyl sulfide deuterated compound with high deuteration rate can be synthesized in the autoclave deuterated atmosphere.
The above embodiments are preferred examples of the present invention, and are not intended to limit the scope of the present invention.
Claims (10)
1. A deuteration method of a methyl sulfide compound, which is characterized by comprising the following steps:
under inert atmosphere, using alkali metal salt as catalyst, using methyl sulfide compound in liquid state at reaction temperature as reactant, charging deuterium gas into reaction container, sealing reaction for a certain time at reaction temperature to obtain methyl sulfide deuterated compound,
or (b)
Under inert atmosphere, alkali metal salt is used as a catalyst, methyl thioether compounds are used as reactants, a solvent is added into a reaction vessel, deuterium gas is filled into the reaction vessel, the reaction is closed for a certain time at the reaction temperature, thus obtaining methyl thioether deuterated compounds,
the general reaction formula is shown in formula 1:
wherein R is 1 、R 2 Independently of one another, selected from any one of H, hydrocarbyl, substituted aryl, silyl, alkoxy or aminoalkyl groups or R 1 、R 2 Bonding to an aliphatic hydrocarbon ring or an aromatic ring;
wherein the catalyst is any one of bis (trimethylsilyl) amidocyanogen potassium, bis (trimethylsilyl) amidocyanogen lithium and bis (trimethylsilyl) amidocyanogen sodium or the combination of any one of bis (trimethylsilyl) amidocyanogen potassium, bis (trimethylsilyl) amidocyanogen lithium and bis (trimethylsilyl) amidocyanogen sodium and cesium fluoride.
2. The deuteration method of the methyl sulfide compound according to claim 1, wherein:
wherein the methyl thioether compound is phenyl methyl thioether compound,
the general reaction formula is shown in formula 2:
in formula 2, R 3 -R 7 Independently of one another, from H, C 1 -C 10 C is a hydrocarbon group of (C) 6 -C 20 Aryl, halogen, C 1 -C 10 Hydrocarbyloxy group, C 1 -C 10 X is a carbon atom.
3. The deuteration method of the methyl sulfide compound according to claim 1, wherein:
wherein the methyl thioether compound is a 1, 4-bis (methylthio) benzene compound,
the reaction formula is shown in formula 3:
in formula 3, R 3 -R 4 、R 6 -R 7 Independently of each otherSelected from H, C 1 -C 10 C is a hydrocarbon group of (C) 6 -C 20 Aryl, halogen, C 1 -C 10 Hydrocarbyloxy group, C 1 -C 10 X is a carbon atom.
4. The deuteration method of the methyl sulfide compound according to claim 1, wherein:
wherein the methyl thioether compound is an alkyl methyl thioether compound,
the general reaction formula is shown in formula 4:
5. the deuteration method of the methyl sulfide compound according to claim 1, wherein:
wherein the methyl thioether compound is a cyclic hydrocarbon methyl thioether compound,
the general reaction formula is shown in formula 5:
wherein n is 1-5.
6. The deuteration method of the methyl sulfide compound according to claim 1, wherein:
wherein the methyl thioether compound is an alkyl methyl thioether compound,
the general reaction formula is shown in formula 6:
7. the deuteration method of the methyl sulfide compound according to claim 1, wherein:
wherein the catalyst is any one of potassium bis (trimethylsilyl) amide, a mixture of lithium bis (trimethylsilyl) amide and cesium fluoride, a mixture of sodium bis (trimethylsilyl) amide and cesium fluoride, and a mixture of potassium bis (trimethylsilyl) amide and cesium fluoride.
8. The deuteration method of the methyl sulfide compound according to claim 1, wherein:
wherein the dosage of the catalyst is 1-50% of the molar quantity of the methyl sulfide compound.
9. The deuteration method of the methyl sulfide compound according to claim 1, wherein:
wherein the solvent is any one of aromatic hydrocarbon solvent, alkane solvent or ether solvent.
10. The deuteration method of the methyl sulfide compound according to claim 1, wherein:
wherein the hydrocarbyl group is selected from aryl groups.
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| PCT/CN2022/085660 WO2022214045A1 (en) | 2021-04-09 | 2022-04-07 | Method for preparing deuterated chemical by means of deuteration reaction of carbon-hydrogen bond with deuterium gas under catalysis of alkali |
| EP22784111.1A EP4321499A1 (en) | 2021-04-09 | 2022-04-07 | Method for preparing deuterated chemical by means of deuteration reaction of carbon-hydrogen bond with deuterium gas under catalysis of alkali |
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| Aldol condensation of acetone over CsOH/SiO2: A mechanistic insight using isotopic labelling;A.S. Canning,等;Applied Catalysis A: General;第289卷;59-65 * |
| Alkali metal species in the reversible activation of H2;XU maotong，等;Angew. Chem.Int. Ed.;第57卷;11060-11054 * |
| Cesium Amide-Catalyzed Selective Deuteration of Benzylic C-H Bonds with D2 and Application for Tritiation of Pharmaceuticals;Du, hui-zhen,等;Angew. Chem.Int. Ed.;第62卷(第8期);e2022144 * |
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