CN117024374A - Synthesis method of 3-methyl-1, 2, 4-thiadiazole-5-carbohydrazide or salt thereof - Google Patents
Synthesis method of 3-methyl-1, 2, 4-thiadiazole-5-carbohydrazide or salt thereof Download PDFInfo
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- UJQISHJANPSPTN-UHFFFAOYSA-N 3-methyl-1,2,4-thiadiazole-5-carbohydrazide Chemical compound CC1=NSC(C(=O)NN)=N1 UJQISHJANPSPTN-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 150000003839 salts Chemical class 0.000 title claims abstract description 14
- 238000001308 synthesis method Methods 0.000 title abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 22
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims abstract description 18
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 17
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 12
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 12
- 229910052744 lithium Inorganic materials 0.000 claims abstract description 6
- 239000011777 magnesium Substances 0.000 claims abstract description 6
- 229910052749 magnesium Inorganic materials 0.000 claims abstract description 6
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims abstract description 5
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims abstract description 4
- 150000002148 esters Chemical class 0.000 claims abstract 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 21
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 15
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 14
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 10
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 claims description 8
- 230000002194 synthesizing effect Effects 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 5
- -1 halogenated alkyl magnesium Chemical compound 0.000 claims description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- GZDFHIJNHHMENY-UHFFFAOYSA-N Dimethyl dicarbonate Chemical compound COC(=O)OC(=O)OC GZDFHIJNHHMENY-UHFFFAOYSA-N 0.000 claims description 3
- FFYPMLJYZAEMQB-UHFFFAOYSA-N diethyl pyrocarbonate Chemical compound CCOC(=O)OC(=O)OCC FFYPMLJYZAEMQB-UHFFFAOYSA-N 0.000 claims description 3
- 239000004316 dimethyl dicarbonate Substances 0.000 claims description 3
- 235000010300 dimethyl dicarbonate Nutrition 0.000 claims description 3
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 claims description 2
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims description 2
- JMPVESVJOFYWTB-UHFFFAOYSA-N dipropan-2-yl carbonate Chemical compound CC(C)OC(=O)OC(C)C JMPVESVJOFYWTB-UHFFFAOYSA-N 0.000 claims description 2
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 claims description 2
- VXWPONVCMVLXBW-UHFFFAOYSA-M magnesium;carbanide;iodide Chemical compound [CH3-].[Mg+2].[I-] VXWPONVCMVLXBW-UHFFFAOYSA-M 0.000 claims description 2
- LVKCSZQWLOVUGB-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].C[CH-]C LVKCSZQWLOVUGB-UHFFFAOYSA-M 0.000 claims description 2
- XGITVAYMIKUXIN-UHFFFAOYSA-M magnesium;propane;iodide Chemical compound [Mg+2].[I-].C[CH-]C XGITVAYMIKUXIN-UHFFFAOYSA-M 0.000 claims description 2
- OQQTZLSEKBDXRS-UHFFFAOYSA-N propan-2-yl propan-2-yloxycarbonyl carbonate Chemical compound CC(C)OC(=O)OC(=O)OC(C)C OQQTZLSEKBDXRS-UHFFFAOYSA-N 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 3
- 239000003795 chemical substances by application Substances 0.000 claims 2
- 239000007818 Grignard reagent Substances 0.000 abstract description 3
- 150000004795 grignard reagents Chemical class 0.000 abstract description 3
- 239000006227 byproduct Substances 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- 238000009776 industrial production Methods 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- LRFYFSQFLKUMEP-UHFFFAOYSA-N 5-bromo-3-methyl-1,2,4-thiadiazole Chemical compound CC1=NSC(Br)=N1 LRFYFSQFLKUMEP-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 239000007810 chemical reaction solvent Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- SJXSCUKEIASMFO-UHFFFAOYSA-N C(=O)(S(=O)Cl)Cl Chemical compound C(=O)(S(=O)Cl)Cl SJXSCUKEIASMFO-UHFFFAOYSA-N 0.000 description 2
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L magnesium chloride Substances [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 229960001475 zolpidem Drugs 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- IBANRDPEOYZVGW-UHFFFAOYSA-N 3-methyl-1,2,4-thiadiazole Chemical compound CC=1N=CSN=1 IBANRDPEOYZVGW-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 102000002003 Neurokinin-3 Receptors Human genes 0.000 description 1
- 108010040716 Neurokinin-3 Receptors Proteins 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 238000007083 alkoxycarbonylation reaction Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000006315 carbonylation Effects 0.000 description 1
- 238000005810 carbonylation reaction Methods 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 230000002267 hypothalamic effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- CETVQRFGPOGIQJ-UHFFFAOYSA-N lithium;hexane Chemical compound [Li+].CCCCC[CH2-] CETVQRFGPOGIQJ-UHFFFAOYSA-N 0.000 description 1
- 230000009245 menopause Effects 0.000 description 1
- QABLOFMHHSOFRJ-UHFFFAOYSA-N methyl 2-chloroacetate Chemical compound COC(=O)CCl QABLOFMHHSOFRJ-UHFFFAOYSA-N 0.000 description 1
- OBWFJXLKRAFEDI-UHFFFAOYSA-N methyl cyanoformate Chemical compound COC(=O)C#N OBWFJXLKRAFEDI-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 230000001331 thermoregulatory effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- ZAFYATHCZYHLPB-UHFFFAOYSA-N zolpidem Chemical compound N1=C2C=CC(C)=CN2C(CC(=O)N(C)C)=C1C1=CC=C(C)C=C1 ZAFYATHCZYHLPB-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/08—1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Abstract
The invention relates to the technical field of intermediate synthesis, in particular to a synthesis method of 3-methyl-1, 2, 4-thiadiazole-5-carbohydrazide or a salt thereof, which comprises the following steps of: reacting 5-halo-3-methyl-1, 2, 4-thiadiazole with an alkyllithium reagent to form lithium intermediate IV-a, or exchanging with a grignard reagent or forming haloalkylmagnesium intermediate IV-b with magnesium, then reacting with an alkoxycarbonyl reagent to obtain 3-methyl-1, 2, 4-thiadiazole-5-carbonate, step 2: the 3-methyl-1, 2, 4-thiadiazole-5-carbonic ester reacts with hydrazine monohydrate to form 3-methyl-1, 2, 4-thiadiazole-5-carbohydrazide, the reaction yield is greatly improved by changing the feeding sequence in experimental operation, the generation of byproducts is avoided, and the method is novel; meanwhile, the used reagent has wide sources, low cost and easy obtainment; the comprehensive production cost is low, and the market competitiveness is achieved.
Description
Technical Field
The invention mainly relates to the technical field of intermediate synthesis, in particular to a method for synthesizing 3-methyl-1, 2, 4-thiadiazole-5-carbohydrazide or a salt thereof.
Background
Non-zolpidem is a An Si-derived, independently developed, oral selective neurokinin 3 receptor (NK 3) antagonist that modulates the neuronal activity of the hypothalamic thermoregulatory central nerve, primarily by blocking the binding of NKB to KNDY neurons, thereby treating VMS associated with menopause.
The synthesis of fezobactam described in patent WO2014/154895 and WO 2019/012333 both involve a key intermediate, 3-methyl-1, 2, 4-thiadiazole-5-carbohydrazide (compound I).
Patent WO2013/050424 discloses a preparation method of 3-methyl-1, 2, 4-thiadiazole-5-carbohydrazide (compound I), namely, corresponding 3-methyl-1, 2, 4-thiadiazole-5-methyl carbonate is prepared by taking acetamide, chlorocarbonyl sulfinyl chloride and methyl cyanoformate as raw materials, and then reacting with hydrazine monohydrate.
The high-risk reagents chlorocarbonyl sulfinyl chloride and methyl cyanobormate involved in the method are avoided in industrial production. Sulfur impurities are generated in this route and can have a major impact on the quality of the final product. Furthermore, the overall yield of the route is still below 30% through continuous optimization.
Patent CN113767094a discloses the synthesis of 3-methyl-1, 2, 4-thiadiazole-5-carbohydrazide and its methyl-d 3 deuterated form, and the 3-methyl-1, 2, 4-thiadiazole is prepared by using 5-halo-3-methyl-1, 2, 4-thiadiazole as a raw material, and then performing an alkoxycarbonyl reaction to prepare 3-methyl-1, 2, 4-thiadiazole-5-methyl carbonate or ethyl ester, and then reacting with hydrazine monohydrate to prepare compound I.
In the examples disclosed therein, the alkoxycarbonylations are carried out under two conditions, 1) in the presence of carbon monoxide, a palladium catalyst, an organophosphorus ligand, a base and an alcohol solvent, and 2) in the presence of n-hexyllithium and methyl chloroacetate, to prepare methyl 3-methyl-1, 2, 4-thiadiazole-5-carbonate.
Although the method avoids high-risk reagents, the method still cannot well meet industrial production due to the fact that carbon monoxide dangerous gas, expensive palladium catalyst and ligand are involved.
In conclusion, the preparation method of the 3-methyl-1, 2, 4-thiadiazole-5-carbohydrazide (compound I) which is concise in route, low in cost and suitable for industrial production is developed, and has great significance for synthesizing the fezobactam.
Disclosure of Invention
1. Technical problem to be solved by the invention
The invention provides a synthesis method of a non-zolpidem intermediate 3-methyl-1, 2, 4-thiadiazole-5-carbohydrazide, which has the advantages of high yield, simple route and mild reaction conditions and is suitable for industrial production, and the synthesis method is used for solving the technical problems in the background technology.
2. Technical proposal
The invention provides a preparation method of 3-methyl-1, 2, 4-thiadiazole-5-carbohydrazide (compound I), which comprises the following reaction routes:
the method of the invention comprises the following steps:
step 1: reacting 5-halo-3-methyl-1, 2, 4-thiadiazole (compound III) with an alkyllithium reagent to form lithium intermediate IV-a, or exchanging with a grignard reagent or forming haloalkylmagnesium intermediate IV-b with magnesium, then reacting with an alkoxycarbonyl reagent to obtain 3-methyl-1, 2, 4-thiadiazole-5-carbonate (compound II):
wherein X represents halogen, R represents alkyl or aralkyl;
step 2: reacting the compound II with hydrazine monohydrate to form a compound I;
further, in step 1, X represents bromine or iodine, and R represents an alkyl group or an aralkyl group;
further, X is preferably bromine, R is preferably tert-butyl, methyl, ethyl, and most preferably tert-butyl.
Further, the alkyllithium reagent in step 1 is selected from the group consisting of n-butyllithium, t-butyllithium, and most preferably n-butyllithium.
Further, the molar ratio of the alkyl lithium reagent to the compound III in step 1 is (1.0-3.0): 1, a step of; most preferably 1.2:1.
further, in the step 1, the reaction solvent is one or two of tetrahydrofuran, diethyl ether, methyltetrahydrofuran, dioxane and toluene; most preferred is tetrahydrofuran.
Further, the reaction temperature in the step 1 is-78-0 ℃; most preferably at-78 ℃.
Further, the grignard reagent in step 1 is selected from the group consisting of methyl magnesium bromide, methyl magnesium chloride, methyl magnesium iodide, isopropyl magnesium bromide, isopropyl magnesium chloride, isopropyl magnesium iodide; most preferred are isopropyl magnesium chloride and methyl magnesium chloride.
Further, the molar ratio of the formazan reagent to the compound III in step 1 is (1.0-3.0): 1, a step of; most preferably 1.3:1.
further, the reaction solvent for exchanging the compound III with the format reagent in the step 1 is one or two of tetrahydrofuran, methyltetrahydrofuran and diethyl ether; most preferred is tetrahydrofuran.
Further, the reaction temperature of the exchange of the compound III and the format reagent in the step 1 is-78-25 ℃; most preferably at-40 ℃.
Further, in the step 1, the alkoxycarbonyl reagent is di-tert-butyl dicarbonate, dimethyl dicarbonate, diethyl dicarbonate, diisopropyl dicarbonate, dimethyl carbonate, diethyl carbonate, diisopropyl carbonate; preferably di-tert-butyl dicarbonate, dimethyl dicarbonate, diethyl dicarbonate; most preferred is di-tert-butyl dicarbonate.
Further, the molar ratio of the alkoxycarbonylating reagent to the compound III in step 1 is (1.0-3.0): 1, a step of; most preferably 1.5:1.
further, the solvent for the alkoxycarbonyl reaction in the step 1 is one or two of tetrahydrofuran, methyltetrahydrofuran and diethyl ether; most preferred is tetrahydrofuran.
Further, in the step 1, lithium intermediate IV-a is subjected to the alkoxycarbonyl reaction at the temperature of minus 78 ℃ to minus 50 ℃ and is added dropwise, and the reaction is carried out at the temperature of 0 ℃ to 25 ℃; most preferably-78℃and 25 ℃.
Further, in the step 1, the magnesium halide intermediate IV-b is subjected to the alkoxycarbonyl reaction at the temperature of minus 78 ℃ to minus 10 ℃ and is added dropwise, and the reaction is carried out at the temperature of 0 ℃ to 25 ℃; most preferably-40℃and 25 ℃.
Further, the step 1 of reacting the intermediate (IV-a or IV-b) with the alkoxycarbonyl reaction is performed by slowly dropping a solution of the intermediate (IV-a or IV-b) into a solution of the alkoxycarbonyl reagent.
Further, the reaction solvent of the compound II and the hydrazine monohydrate in the step 2 is ethanol or isopropanol, and the reaction is carried out under the reflux condition.
3. Advantageous effects
Compared with the prior art, the technical scheme provided by the invention has the following beneficial effects:
1. the invention adopts the most commonly used carbonylation method, and has simple and convenient operation;
2. according to the invention, the reaction yield is greatly improved by changing the feeding sequence in experimental operation, the generation of byproducts is avoided, and the method is novel;
3. the reagent used by the invention has wide sources, low cost and easy obtainment; the comprehensive production cost is low, and the market competitiveness is achieved;
4. the reaction condition of the invention has no process risk and special equipment requirement, and is suitable for industrial production.
Drawings
FIG. 1 is a synthetic flow chart of the present invention;
Detailed Description
In order that the invention may be readily understood, a more particular description of the invention will be rendered by reference to specific embodiments thereof which are illustrated in the appended drawings, in which, however, the invention may be embodied in many different forms and are not limited to the embodiments described herein, but are instead provided for the purpose of providing a more thorough and complete disclosure of the invention.
Example 1
Synthesis of 3-methyl-1, 2, 4-thiadiazole-5-carbonic acid tert-butyl ester (Compound II) -method I
5-bromo-3-methyl-1, 2, 4-thiadiazole (compound III) (35.8 g) was dissolved in dry THF (500 ml), then cooled to-78deg.C, n-hexane solution of n-butyllithium (2.4M, 100 ml) was slowly added dropwise, and after dropping, the mixture was reacted at-78deg.C for 30min; di-tert-butyl dicarbonate (65.46 g) is dissolved in anhydrous THF (500 ml), cooled to-78 ℃, then the obtained 5-lithium-3-methyl-1, 2, 4-thiadiazole solution is slowly dripped into the solution, the reaction liquid is slowly warmed to room temperature for reaction for 2 hours, saturated ammonium chloride solution is added for quenching reaction, diethyl ether or ethyl acetate is added for extraction, anhydrous sodium sulfate is added for drying, filtration and reduced pressure concentration are carried out, thus obtaining pale yellow oily compound II (35 g), the product point is single, the product point can be directly used for the next reaction, and the yield is 88%.
Example 2
Synthesis of 3-methyl-1, 2, 4-thiadiazole-5-carbonic acid tert-butyl ester (Compound II) -method II
5-bromo-3-methyl-1, 2, 4-thiadiazole (compound III) (3.85 g) was dissolved in dry THF (50 ml), then cooled to-40℃and a THF solution (1.6M) (18.75 ml) of isopropyl magnesium chloride was slowly added dropwise thereto, and after that, the mixture was allowed to react at 0℃for 1 hour; di-tert-butyl dicarbonate (6.55 g) is dissolved in anhydrous THF (50 ml), cooled to 0 ℃, then the obtained 3-methyl-1, 2, 4-thiadiazole-5-magnesium chloride solution is slowly dripped into the solution, the reaction liquid is slowly warmed to room temperature for reaction for 2 hours, saturated ammonium chloride solution is added for quenching reaction, diethyl ether or ethyl acetate is added for extraction, anhydrous sodium sulfate is added for drying, filtration and reduced pressure concentration are carried out, light yellow oily compound II (3.2 g) is obtained, the product point is single, the product point can be directly used for the next reaction, and the yield is 80%.
Example 3
Synthesis of 3-methyl-1, 2, 4-thiadiazole-5-tert-butyl carbonate (Compound II) -method III
5-bromo-3-methyl-1, 2, 4-thiadiazole (Compound III) (3.85 g) was dissolved in dry THF (50 ml) and placed in a dropping funnel, magnesium (0.58 g) and a catalytic amount of iodine were added to a three-necked flask, 10ml of the above solution was dropped, the reaction was initiated by heating, the THF solution of Compound III was added dropwise, the reflux was maintained, the dropping was completed, and the reflux reaction was initiated by heating for 2 hours. Di-tert-butyl dicarbonate (6.55 g) is dissolved in anhydrous THF (50 ml), the temperature is reduced to 0 ℃, then the obtained 3-methyl-1, 2, 4-thiadiazole-5-magnesium chloride solution is slowly dripped into the solution, the reaction liquid is slowly warmed to room temperature for reaction for 2 hours, saturated ammonium chloride solution is added for quenching reaction, diethyl ether or ethyl acetate is added for extraction, anhydrous sodium sulfate is added for drying, filtration and reduced pressure concentration are carried out, light yellow oily compound II (3.1 g) is obtained, the product point is single, and the product point can be directly used for the next reaction yield of 78%.
1 H NMR(500MHz，Chloroform-d)δ2.76(s，3H)，1.64(s，9H)。
Example 4
Synthesis of 3-methyl-1, 2, 4-thiadiazole-5-carbohydrazide (Compound I)
3-methyl-1, 2, 4-thiadiazole-5-tert-butyl carbonate (40 g) is dissolved in ethanol or isopropanol (200 ml), hydrazine monohydrate (1.5 eq) is added, stirring is carried out at room temperature overnight or reflux reaction is carried out under heating for 2h, after cooling to room temperature or 0 ℃, a large amount of solid is separated out, filtration is carried out, and the obtained yellow solid (27.8 g) is the target product I after washing with cold alcohol solution. The yield thereof was found to be 88%. The filtrate was concentrated and the TLC detection was still relatively pure and recoverable.
1 H NMR(500MHz，CDCl 3 )δ8.44(s，1H)，4.14(s，2H)，2.70(s，3H)。
The foregoing examples merely illustrate certain embodiments of the invention and are described in more detail and are not to be construed as limiting the scope of the invention; it should be noted that it is possible for a person skilled in the art to make several variants and modifications without departing from the concept of the invention, all of which fall within the scope of protection of the invention; accordingly, the scope of protection of the present invention is to be determined by the appended claims.
Claims (10)
1. A method for synthesizing 3-methyl-1, 2, 4-thiadiazole-5-carbohydrazide or a salt thereof, which comprises the following steps:
step 1: reacting 5-halo-3-methyl-1, 2, 4-thiadiazole (compound III) with an alkyllithium reagent to form lithium intermediate IV-a, and then reacting with an alkoxycarbonyl reagent to obtain 3-methyl-1, 2, 4-thiadiazole-5-carbonate (compound II);
step 2: reacting the compound II with hydrazine monohydrate to form 3-methyl-1, 2, 4-thiadiazole-5-carbohydrazide (compound I);
wherein X represents halogen, and R represents alkyl or aralkyl.
2. A method for synthesizing 3-methyl-1, 2, 4-thiadiazole-5-carbohydrazide or a salt thereof, which comprises the following steps:
step 1: exchanging 5-halogeno-3-methyl-1, 2, 4-thiadiazole (compound III) with a format reagent to form a halogenated alkyl magnesium intermediate IV-b, and then reacting with an alkoxycarbonyl reagent to obtain 3-methyl-1, 2, 4-thiadiazole-5-carbonic ester (compound II);
step 2: reacting the compound II with hydrazine monohydrate to form 3-methyl-1, 2, 4-thiadiazole-5-carbohydrazide (compound I);
wherein X represents halogen, and R represents alkyl or aralkyl.
3. A method for synthesizing 3-methyl-1, 2, 4-thiadiazole-5-carbohydrazide or a salt thereof, which comprises the following steps:
step 1: 5-halo-3-methyl-1, 2, 4-thiadiazole (compound III) forms a haloalkylmagnesium intermediate IV-b with magnesium metal, and then reacts with an alkoxycarbonyl reagent to give 3-methyl-1, 2, 4-thiadiazole-5-carbonate (compound II);
step 2: reacting the compound II with hydrazine monohydrate to form 3-methyl-1, 2, 4-thiadiazole-5-carbohydrazide (compound I);
wherein X represents halogen, and R represents alkyl or aralkyl.
4. A process for the synthesis of 3-methyl-1, 2, 4-thiadiazole-5-carbohydrazide or salts thereof according to any one of claims 1-3, wherein: the alkoxycarbonyl reagent is at least one of di-tert-butyl dicarbonate, dimethyl dicarbonate, diethyl dicarbonate, diisopropyl dicarbonate, dimethyl carbonate, diethyl carbonate and diisopropyl carbonate.
5. A process for the synthesis of 3-methyl-1, 2, 4-thiadiazole-5-carbohydrazide or salts thereof according to any one of claims 1-3, wherein: the molar ratio of the alkoxycarbonyl reagent to the compound III is (1.0-3.0): 1.
6. a process for the synthesis of 3-methyl-1, 2, 4-thiadiazole-5-carbohydrazide or salts thereof according to any one of claims 1-3, wherein: the solvent for the alkoxycarbonyl reaction is one or two of tetrahydrofuran, methyltetrahydrofuran and diethyl ether.
7. A process for the synthesis of 3-methyl-1, 2, 4-thiadiazole-5-carbohydrazide or salts thereof according to any one of claims 1-3, wherein: the reaction of the intermediate (IV-a or IV-b) with the alkoxycarbonylating agent in step 1 is carried out by slowly dropping a solution of the intermediate (IV-a or IV-b) into a solution of the alkoxycarbonylating agent.
8. The method for synthesizing 3-methyl-1, 2, 4-thiadiazole-5-carbohydrazide or a salt thereof according to claim 2, wherein: the format reagent is at least one selected from methyl magnesium bromide, methyl magnesium chloride, methyl magnesium iodide, isopropyl magnesium bromide, isopropyl magnesium chloride and isopropyl magnesium iodide.
9. The method for synthesizing 3-methyl-1, 2, 4-thiadiazole-5-carbohydrazide or a salt thereof according to claim 1, wherein: the lithium intermediate IV-a is subjected to the alkoxycarbonyl reaction at the temperature of minus 78 ℃ to minus 50 ℃ and is added dropwise, and the temperature of 0 ℃ to 25 ℃ is reacted.
10. A method for synthesizing 3-methyl-1, 2, 4-thiadiazole-5-carbohydrazide or a salt thereof according to claim 2 or 3, wherein: the magnesium halide intermediate IV-b is subjected to alkoxycarbonyl reaction at the temperature of minus 78 ℃ to minus 10 ℃ and is added dropwise, and the reaction is carried out at the temperature of 0 ℃ to 25 ℃.
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