CN112876379A - Method for synthesizing benserazide hydrochloride by using fixed bed hydrogenation equipment - Google Patents
Method for synthesizing benserazide hydrochloride by using fixed bed hydrogenation equipment Download PDFInfo
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- CN112876379A CN112876379A CN202110103770.9A CN202110103770A CN112876379A CN 112876379 A CN112876379 A CN 112876379A CN 202110103770 A CN202110103770 A CN 202110103770A CN 112876379 A CN112876379 A CN 112876379A
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- BNQDCRGUHNALGH-UHFFFAOYSA-N benserazide Chemical compound OCC(N)C(=O)NNCC1=CC=C(O)C(O)=C1O BNQDCRGUHNALGH-UHFFFAOYSA-N 0.000 title claims abstract description 29
- 229960001335 benserazide hydrochloride Drugs 0.000 title claims abstract description 25
- 238000000034 method Methods 0.000 title claims abstract description 25
- 238000005984 hydrogenation reaction Methods 0.000 title claims abstract description 22
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 97
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims abstract description 19
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims abstract description 19
- 229940125904 compound 1 Drugs 0.000 claims abstract description 18
- 239000003054 catalyst Substances 0.000 claims abstract description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 14
- 239000003223 protective agent Substances 0.000 claims abstract description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 114
- 150000001875 compounds Chemical class 0.000 claims description 41
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 34
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 24
- 239000002994 raw material Substances 0.000 claims description 17
- 239000012065 filter cake Substances 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 229940125898 compound 5 Drugs 0.000 claims description 14
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 14
- 229940126062 Compound A Drugs 0.000 claims description 10
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 10
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 10
- 229940125782 compound 2 Drugs 0.000 claims description 9
- 229940126214 compound 3 Drugs 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 238000002425 crystallisation Methods 0.000 claims description 8
- 230000008025 crystallization Effects 0.000 claims description 8
- MTCFGRXMJLQNBG-UHFFFAOYSA-N serine Chemical compound OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims description 8
- CRPNQSVBEWWHIJ-UHFFFAOYSA-N 2,3,4-trihydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C(O)=C1O CRPNQSVBEWWHIJ-UHFFFAOYSA-N 0.000 claims description 7
- 238000004537 pulping Methods 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- 230000002378 acidificating effect Effects 0.000 claims description 4
- 150000001298 alcohols Chemical class 0.000 claims description 4
- 238000006482 condensation reaction Methods 0.000 claims description 4
- 238000005886 esterification reaction Methods 0.000 claims description 4
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 3
- 239000007868 Raney catalyst Substances 0.000 claims description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 2
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 2
- MJSHDCCLFGOEIK-UHFFFAOYSA-N benzyl (2,5-dioxopyrrolidin-1-yl) carbonate Chemical compound O=C1CCC(=O)N1OC(=O)OCC1=CC=CC=C1 MJSHDCCLFGOEIK-UHFFFAOYSA-N 0.000 claims description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims description 2
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 claims description 2
- 239000003638 chemical reducing agent Substances 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 239000000706 filtrate Substances 0.000 claims description 2
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical group Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 claims description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical group C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 12
- 238000003786 synthesis reaction Methods 0.000 abstract description 12
- 238000000746 purification Methods 0.000 abstract description 6
- 239000012295 chemical reaction liquid Substances 0.000 abstract description 4
- 238000010924 continuous production Methods 0.000 abstract description 3
- 230000006866 deterioration Effects 0.000 abstract description 2
- 239000011949 solid catalyst Substances 0.000 abstract description 2
- 238000001308 synthesis method Methods 0.000 abstract description 2
- 239000007787 solid Substances 0.000 description 22
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 18
- 238000003756 stirring Methods 0.000 description 14
- 235000019441 ethanol Nutrition 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 11
- 238000001035 drying Methods 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 238000000967 suction filtration Methods 0.000 description 9
- 239000012043 crude product Substances 0.000 description 7
- 238000003760 magnetic stirring Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 229910004373 HOAc Inorganic materials 0.000 description 6
- 238000007792 addition Methods 0.000 description 6
- 238000004140 cleaning Methods 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 238000009736 wetting Methods 0.000 description 6
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 5
- -1 benzyl serine hydrazine Chemical compound 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 229960000911 benserazide Drugs 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000002386 leaching Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- STMOVTSFWYRCOB-DKWTVANSSA-N (2s)-2-amino-3-hydroxypropanoic acid;hydrochloride Chemical compound Cl.OC[C@H](N)C(O)=O STMOVTSFWYRCOB-DKWTVANSSA-N 0.000 description 3
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 3
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 229940125907 SJ995973 Drugs 0.000 description 3
- XZMHJYWMCRQSSI-UHFFFAOYSA-N n-[5-[2-(3-acetylanilino)-1,3-thiazol-4-yl]-4-methyl-1,3-thiazol-2-yl]benzamide Chemical compound CC(=O)C1=CC=CC(NC=2SC=C(N=2)C2=C(N=C(NC(=O)C=3C=CC=CC=3)S2)C)=C1 XZMHJYWMCRQSSI-UHFFFAOYSA-N 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- QBXVXKRWOVBUDB-GRKNLSHJSA-N ClC=1C(=CC(=C(CN2[C@H](C[C@H](C2)O)C(=O)O)C1)OCC1=CC(=CC=C1)C#N)OCC1=C(C(=CC=C1)C1=CC2=C(OCCO2)C=C1)C Chemical compound ClC=1C(=CC(=C(CN2[C@H](C[C@H](C2)O)C(=O)O)C1)OCC1=CC(=CC=C1)C#N)OCC1=C(C(=CC=C1)C1=CC2=C(OCCO2)C=C1)C QBXVXKRWOVBUDB-GRKNLSHJSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 2
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- ANSUDRATXSJBLY-VKHMYHEASA-N methyl (2s)-2-amino-3-hydroxypropanoate Chemical compound COC(=O)[C@@H](N)CO ANSUDRATXSJBLY-VKHMYHEASA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- YTHVXUGXVASXJZ-REOHCLBHSA-N (2s)-2-amino-3-hydroxypropanehydrazide Chemical compound NNC(=O)[C@@H](N)CO YTHVXUGXVASXJZ-REOHCLBHSA-N 0.000 description 1
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 1
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 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
- 125000003277 amino group Chemical group 0.000 description 1
- BIVUUOPIAYRCAP-UHFFFAOYSA-N aminoazanium;chloride Chemical compound Cl.NN BIVUUOPIAYRCAP-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 239000003954 decarboxylase inhibitor Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229960004502 levodopa Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C241/00—Preparation of compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
- C07C241/04—Preparation of hydrazides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for synthesizing benserazide hydrochloride by using fixed bed hydrogenation equipment, which is characterized in that a compound 1 reacts with an amino protective agent to carry out amino protection reaction, so that the subsequent purification is easy, and the consumption of hydrazine hydrate in the synthesis method is small; the method uses fixed bed hydrogenation equipment for synthesis, the fixed bed reactor is filled with a solid catalyst or a reactor for realizing a heterogeneous reaction process, the catalyst in the fixed bed reactor is relatively fixed, reaction liquid flows through a bed layer, and by adjusting the flow rate and the reaction pressure, the reaction liquid can flow out of the fixed bed to obtain a qualified product, so that continuous production can be realized, and the product deterioration caused by long-time contact of the product and the catalyst can be avoided.
Description
Technical Field
The invention relates to the field of chemical industry, and in particular relates to a method for synthesizing benserazide hydrochloride by using fixed bed hydrogenation equipment.
Background
Benserazide hydrochloride is a peripheral decarboxylase inhibitor, and is commonly combined with levodopa to prepare a composite preparation poly-barserazide for treating the Parkinson's disease in the medical market at present.
Benserazide hydrochloride is white or off-white crystalline powder, is easily soluble in water, slightly soluble in methanol and insoluble in ethanol or acetone. It is extremely unstable and sensitive to changes in solvent pH, light, temperature and humidity.
In the prior art, the benzyl serine hydrazine is generally synthesized by firstly synthesizing benzyl serine hydrazone, and then reducing the benzyl serine hydrazone into the benzyl serine hydrazine, so that the method has the following defects: (1) the serine methyl ester crude product is recrystallized by water and ethanol, the production period is longer, and the yield is not very high; (2) the amino group in the serine methyl ester is not protected, and the subsequent purification is not easy; (3) large excess hydrazine hydrate is added in the synthesis of the serine hydrazide, and the purification and the removal of the excess hydrazine hydrochloride are difficult; (4) the synthesis of the benzylserine hydrazone hydrochloride has longer purification period and lower purity. (5) The benzyl hydrazone hydrochloride needs to be separated and purified, is not stable to heat and humidity and is difficult to control; (6) benserazide hydrochloride is subjected to various purifications to remove residual DMF or MeOH. The whole process is complex and is not suitable for large-scale industrial production.
Moreover, benserazide has high pressure reaction in the production process, the high pressure reaction has serious potential safety hazard, the dosage of the catalyst in the production process of benserazide is large, and the catalyst is in contact with a product, so that the product is easy to deteriorate, and therefore, the key point of the invention is to solve the problem.
Disclosure of Invention
In order to overcome the technical problems, the invention aims to provide a method for synthesizing benserazide hydrochloride by using fixed bed hydrogenation equipment, which comprises the following steps: performing esterification reaction by using DL-serine and thionyl chloride as initial raw materials to generate a compound 1, performing amino protection reaction on the compound 1 and an amino protective agent at the reaction temperature of 20-30 ℃ to obtain a compound 2, performing amine ester exchange reaction on the compound 2 and hydrazine hydrate, adjusting the pH value of a reaction system by using hydrochloric acid after the reaction is finished, concentrating to remove excessive hydrazine hydrate, adjusting the reaction system to be acidic, adding alcohol for crystallization to obtain a compound 3, performing condensation reaction on the compound 3 and 2,3, 4-trihydroxybenzaldehyde in an ethanol water system to generate a compound A, performing post-treatment on the compound A to obtain a compound 4, performing hydrogenation reaction on the compound 4 by using a reaction device of a fixed bed, concentrating a solvent, adding alcohol and performing crystallization to generate a compound B, performing post-treatment on the compound B to obtain a compound 5, the compound 5 is subjected to salt forming reaction to obtain a compound 6, namely benserazide hydrochloride, and the problems that high-pressure reaction exists in the production process of the existing benserazide, serious potential safety hazards exist in the high-pressure reaction, the dosage of a catalyst is large in the production process of the benserazide, and the catalyst is in contact with a product, so that the product is easy to deteriorate are solved.
The purpose of the invention can be realized by the following technical scheme:
a method for synthesizing benserazide hydrochloride by using fixed bed hydrogenation equipment comprises the following steps:
the method comprises the following steps: taking DL-serine and thionyl chloride as initial raw materials, and carrying out esterification reaction at the reaction temperature of 70-80 ℃ to generate a compound 1;
step two: carrying out amino protection reaction on the compound 1 and an amino protective agent at the reaction temperature of 20-30 ℃ to obtain a compound 2;
step three: performing amine ester exchange reaction on the compound 2 and hydrazine hydrate at the reaction temperature of 20-30 ℃, adjusting the pH value of a reaction system by using hydrochloric acid after the reaction is finished, concentrating to remove excessive hydrazine hydrate, adjusting the reaction system to be acidic, adding alcohols, and crystallizing at the crystallization temperature of 0-15 ℃ to obtain a compound 3;
step four: carrying out condensation reaction on a compound 3 and 2,3, 4-trihydroxybenzaldehyde in an ethanol water system at the reaction temperature of 50-55 ℃ to generate a compound A, and carrying out post-treatment on the compound A to obtain a compound 4;
step five: carrying out hydrogenation reaction on the compound 4 by using a fixed bed reaction device at the reaction temperature of 25-30 ℃, concentrating a solvent, adding alcohols, crystallizing to generate a compound B, and carrying out post-treatment on the compound B to obtain a compound 5;
step six: and carrying out salt forming reaction on the compound 5 to obtain a compound 6, namely benserazide hydrochloride.
As a further scheme of the invention: the synthetic route of benserazide hydrochloride is as follows:
wherein R is H, Boc, Cbz or Bn.
As a further scheme of the invention: and the amino protective agent in the second step is one of (Boc)2O, CbzCl, CbzOsu, BnCl and BnBr.
As a further scheme of the invention: the hydrazine hydrate in the third step is 85 wt% of hydrazine hydrate; the alcohol is one of ethanol, isopropanol and n-butanol.
As a further scheme of the invention: the post-treatment step in the fourth step is as follows: after the compound A is generated in the reaction system, cooling the reaction system to room temperature, filtering the reaction solution, collecting a filter cake to obtain a crude compound, and then recrystallizing and crystallizing the crude compound in methanol to obtain the compound 4.
As a further scheme of the invention: the reducing agent in the hydrogenation reaction in the fifth step is hydrogen, and the catalyst is palladium carbon or Raney nickel; the solvent is a hydrogen chloride methanol solution.
As a further scheme of the invention: the post-treatment step of the fifth step is as follows: after the compound B is generated in the reaction system, filtering the reaction solution by using kieselguhr, washing a filter cake by using methanol, concentrating the filtrate under reduced pressure at the temperature of not higher than 40 ℃ to obtain a concentrated residue, and pulping the concentrated residue in ethanol or isopropanol at the temperature of 0-5 ℃ to obtain a compound 5.
The invention has the beneficial effects that:
the invention relates to a method for synthesizing benserazide hydrochloride by using fixed bed hydrogenation equipment, which comprises the steps of taking DL-serine and thionyl chloride as initial raw materials, carrying out esterification reaction at the reaction temperature of 70-80 ℃ to generate a compound 1, carrying out amino protection reaction on the compound 1 and an amino protective agent at the reaction temperature of 20-30 ℃ to obtain a compound 2, carrying out amine ester exchange reaction on the compound 2 and hydrazine hydrate at the reaction temperature of 20-30 ℃, adjusting the pH value of a reaction system by using hydrochloric acid after the reaction is finished, concentrating to remove excessive hydrazine hydrate, adjusting the hydrazine hydrate to be acidic, adding alcohol, crystallizing at the crystallization temperature of 0-15 ℃ to obtain a compound 3, carrying out condensation reaction on the compound 3 and 2,3, 4-trihydroxybenzaldehyde in an ethanol water system at the reaction temperature of 50-55 ℃ to generate a compound A, carrying out a post-treatment step on the compound A to obtain a compound 4, carrying out hydrogenation reaction on the compound 4 by using a fixed bed reaction device at the reaction temperature of 25-30 ℃, concentrating a solvent, adding alcohol, crystallizing to generate a compound B, carrying out a post-treatment step on the compound B to obtain a compound 5, and carrying out a salt-forming reaction on the compound 5 to obtain a compound 6, namely benserazide hydrochloride;
the compound 1 reacts with an amino protective agent to carry out amino protection reaction, so that the subsequent purification is easy, and the consumption of hydrazine hydrate in the synthesis method is low;
the method for synthesizing the benserazide hydrochloride utilizes fixed bed hydrogenation equipment, the fixed bed reactor is also called a packed bed reactor, and a reactor filled with a solid catalyst or a solid for realizing a heterogeneous reaction process, the catalyst in the fixed bed reactor is relatively fixed, reaction liquid flows through the bed layer, the reaction liquid can flow out of the fixed bed to obtain a qualified product by adjusting the flow rate and the reaction pressure, continuous production can be realized, the product deterioration caused by long-time contact of the product and the catalyst can be avoided, the product with the same amount can be produced due to continuous production, the volume of the reactor can be very small, the safety problem caused by high-pressure reaction is greatly reduced, the amount of the catalyst used in the reaction is less, and the production cost is reduced.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1:
the embodiment is a method for synthesizing benserazide hydrochloride by using fixed bed hydrogenation equipment, which comprises the following steps:
s11, synthesis of compound 1:
adding 100.0g of serine hydrochloride and 400mL of methanol into a 1L three-necked bottle, mechanically stirring, dropwise adding 135.8g of thionyl chloride into the system at the temperature of below 10 ℃, controlling the temperature of the system to be not higher than 20 ℃ in the dropwise adding process, stirring and reacting for 6h at the temperature of 80 ℃ after the dropwise adding is finished, detecting that the raw materials are completely reacted by using a TLC (MeOH: EA ═ 4: 1) color developing agent, stopping heating, reducing the temperature of the reaction system to 50 ℃, concentrating under reduced pressure to obtain a white solid crude product, pulping the white solid crude product with 500mL of n-heptane, performing suction filtration, leaching the filter cake with 50mL of n-heptane once, and drying to obtain a white solid compound 1, wherein the yield is 89.7%;
s12, synthesis of compound 2 b:
to a 100mL three-necked flask was added 1.50g of compound 15mL of DCM and 2.15g of TEA under magnetic stirring, N2Under the protection and the temperature of 0 ℃, slowly adding 2.31g of (Boc)2O into the reaction system, stirring the mixture at room temperature for reaction for 2 hours after the addition is finished, detecting the reaction completion of the raw materials by using a TLC (MeOH: EA ═ 4: 1) color development agent, adding 10mL of saturated saline solution into the reaction system for quenching, adjusting the pH value of the reaction system to 6 by using 1N diluted hydrochloric acid, extracting the mixture for 3 times by using 15mL of DCM, combining organic phases, washing the organic phase by using 5mL of saturated saline solution, drying the organic phase by using anhydrous magnesium sulfate, and concentrating to obtain 2.05g of compound 2b in light yellow oil, wherein the yield is 97.2%;
s13, synthesis of compound 3 b:
a50 mL three-necked flask was charged with 1.06g of Compound 2b and 10mL of methanol under magnetic stirring, N2Under protection and at a temperature of 0 ℃, slowly adding 1.29g of 85% wt hydrazine hydrate into the reaction system, stirring the mixture at room temperature for reaction for 2.5 hours after the addition is finished, detecting the completion of the reaction of the raw materials by using a TLC (MeOH: EA: 4: 1) color reagent, concentrating the reaction solution to remove the solvent, adding 5mL of saturated saline solution into the concentrated residue, extracting the mixture with 10mL of EA for 3 times, combining organic phases,then, drying the organic phase by using anhydrous magnesium sulfate, carrying out suction filtration and concentration to obtain 1.60g of semi-oil semi-solid, adding 0.8mL of ethanol and 8mL of EA into the semi-oil semi-solid, pulping for 1h, and carrying out suction filtration to obtain 1.00g of compound 3b in a white solid state, wherein the yield is 62.5%;
s14, synthesis of compound 4 b:
a50 mL three-necked flask was charged with 1.00g of Compound 3b, 10mL of isopropanol, and 0.70g of 2,3, 4-trihydroxybenzaldehyde under magnetic stirring2The reaction was stirred for 2h under protection and at 50 ℃ and complete reaction of the starting materials was detected with TLC (DCM: MeOH: 10: 1) developer, heating was stopped, the reaction system was cooled to 5 ℃ and stirred for 2h, suction filtered, the filter cake was washed with 3mL of isopropanol and then dried to give 1.46g of compound 4b as a white-like solid with a yield of 90.1%;
s15, synthesis of compound 5:
1.00g of Compound 4b was dissolved in 30mL of methanol for use, and 3.0g of Pd/Al was charged into the fixed-bed reactor2O3The catalyst is kept at the temperature of 30 ℃, a methanol cleaning valve wetting system is opened, the liquid flow rate is 1mL/min, a nitrogen valve is opened, the whole system is swept to be in the nitrogen atmosphere, the back pressure is adjusted to be 3-3.5MPa by using a back pressure valve, after the methanol wetting system is 30min, the nitrogen valve is closed, the hydrogen valve is opened, the back pressure is controlled to be 3-3.5MPa by using the back pressure valve, the methanol cleaning valve is closed, a material liquid valve is opened, the methanol solution of the compound 4b flows into the reaction system, the liquid flow rate is 0.5mL/min, the mixture is discharged through a discharge valve, and TLC (BuOH: HOAc: H) is used2O is 3: 1: 1) the color developing agent detects that the raw materials react completely, so that a methanol solution of a product is collected, and is concentrated under reduced pressure at the temperature of 40 ℃ to obtain 0.96g of concentrated remainder, namely the compound 5, and the yield is 100%;
s16, synthesis of compound 6:
to 0.96g of compound 5 was added 5mL of 4N HCl/EtOH, followed by crystallization with stirring for 1h, standing overnight at 0 ℃ and then by suction filtration, and the filter cake was dried to obtain 0.65g of compound 6 as a white solid with a yield of 82.3%.
Example 2:
the embodiment is a method for synthesizing benserazide hydrochloride by using fixed bed hydrogenation equipment, which comprises the following steps:
s21, synthesis of compound 1:
adding 100.0g of serine hydrochloride and 400mL of methanol into a 1L three-necked bottle, mechanically stirring, dropwise adding 135.8g of thionyl chloride into the system at the temperature of below 10 ℃, controlling the temperature of the system to be not higher than 20 ℃ in the dropwise adding process, stirring and reacting for 6h at the temperature of 80 ℃ after the dropwise adding is finished, detecting that the raw materials are completely reacted by using a TLC (MeOH: EA ═ 4: 1) color developing agent, stopping heating, reducing the temperature of the reaction system to 50 ℃, concentrating under reduced pressure to obtain a white solid crude product, pulping the white solid crude product with 500mL of n-heptane, performing suction filtration, leaching the filter cake with 50mL of n-heptane once, and drying to obtain a white solid compound 1, wherein the yield is 89.7%;
s22, synthesis of compound 2 c:
to a 250mL three-necked flask were added 10.00g of Compound 1, 50mL of THF, and 50mL of H2O, in magnetic stirring, N2Under the protection condition, after the solid is dissolved out, 22.21g of potassium carbonate is added into the reaction system, 12.06g of CbzCl is dropwise added into the reaction system at the temperature of 5 ℃, after the dropwise addition is finished, the reaction system is stirred at room temperature for 3 hours, and TLC (BuOH: HOAc: H) is used2O is 3: 1: 1) detecting that the raw materials completely react by using a color developing agent, adding 100mL of saturated saline solution into a reaction system for quenching, extracting for 3 times by using 150mL of EA, combining organic phases, drying the organic phases by using anhydrous sodium sulfate, and concentrating to obtain 16.28g of compound 2c similar to colorless oil, wherein the yield is 100%;
s23, synthesis of compound 3 c:
to a 250mL single-neck flask were added 16.28g of Compound 2c and 100mL of methanol under magnetic stirring, N2Under protection and at a temperature of 0 ℃, slowly adding 3.80g of 85% wt hydrazine hydrate into the reaction system, stirring the mixture at room temperature for reaction for 5 hours after the addition is finished, detecting the completion of the reaction of the raw materials by using a TLC (PE: EA ═ 1: 1) color developing agent, and adding 50mL of isopropanol into the reaction systemThen pulping for 1h at room temperature, filtering, washing the filter cake with 10mL of isopropanol for 2 times, and drying to obtain 13.41g of a white solid compound 3c with the yield of 82.4%;
s24, synthesis of compound 4 c:
a100 mL single-neck flask was charged with 5.00g of Compound 3c, 50mL of isopropanol, and 3.04g of 2,3, 4-trihydroxybenzaldehyde under magnetic stirring2The reaction was stirred for 5h under protection at room temperature, the starting material was detected to be completely reacted using TLC (DCM: MeOH ═ 10: 1) developer, filtered, the filter cake was washed with 10mL of isopropanol and dried to give 6.97g of compound 4c as a yellow solid in 90.7% yield;
s25, synthesis of compound 5:
5.00g of Compound 4c was dissolved in 150mL of methanol for use, and 3.0g of Pd/Al was charged into the fixed-bed reactor2O3The catalyst is kept at the temperature of 30 ℃, a methanol cleaning valve wetting system is opened, the liquid flow rate is 1mL/min, a nitrogen valve is opened, the whole system is swept to be in the nitrogen atmosphere, the back pressure is adjusted to be 3-3.5MPa by using a back pressure valve, after the methanol wetting system is 30min, the nitrogen valve is closed, the hydrogen valve is opened, the back pressure is controlled to be 3-3.5MPa by using the back pressure valve, the methanol cleaning valve is closed, a material liquid valve is opened, the methanol solution of a compound 4c flows into the reaction system, the liquid flow rate is 0.5mL/min, the mixture is discharged through a discharge valve, and TLC (BuOH: HOAc: H) is used2O is 3: 1: 1) the color developing agent detects that the raw materials react completely, so that a methanol solution of a product is collected, and is concentrated under reduced pressure at the temperature of 40 ℃ to obtain 3.30g of concentrated residues, namely the compound 5, and the yield is 100%;
s26, synthesis of compound 6:
to 3.30g of compound 5 was added 10mL of 4N HCl/EtOH, followed by crystallization with stirring for 1h, standing overnight at 0 ℃ and then by suction filtration, and the filter cake was dried to obtain 5.40g of compound 6 as a pale yellow solid with a yield of 46.1%.
Example 3:
the embodiment is a method for synthesizing benserazide hydrochloride by using fixed bed hydrogenation equipment, which comprises the following steps:
s31, synthesis of compound 1:
adding 100.0g of serine hydrochloride and 400mL of methanol into a 1L three-necked bottle, mechanically stirring, dropwise adding 135.8g of thionyl chloride into the system at the temperature of below 10 ℃, controlling the temperature of the system to be not higher than 20 ℃ in the dropwise adding process, stirring and reacting for 6h at the temperature of 80 ℃ after the dropwise adding is finished, detecting that the raw materials are completely reacted by using a TLC (MeOH: EA ═ 4: 1) color developing agent, stopping heating, reducing the temperature of the reaction system to 50 ℃, concentrating under reduced pressure to obtain a white solid crude product, pulping the white solid crude product with 500mL of n-heptane for 20min, performing suction filtration, leaching the filter cake once with 50mL of n-heptane, and drying to obtain a white solid compound 1 with the yield of 89.7%;
s32, synthesis of compound 3 a:
to a 250mL single-neck flask were added 10.00g of Compound 1 and 30mL of methanol under magnetic stirring, N2Under the protection and at the temperature of 0 ℃, 5.69g of 85% wt hydrazine hydrate is slowly added into the reaction system, after the addition is finished, the reaction is stirred at room temperature for 4 hours, and TLC (BuOH: HOAc: H) is used2O is 3: 1: 1) detecting that the raw materials completely react by using a color developing agent, adding a saturated sodium carbonate solution into a reaction system, adjusting the pH value of the system to be 8, concentrating the reaction solution to remove a solvent, adding 10mL of concentrated hydrochloric acid into concentrated residues for acidification, concentrating to obtain an oily substance, adding 50mL of isopropanol into the oily substance, stirring for 1h, performing suction filtration, washing a filter cake by using 5mL of isopropanol, and drying to obtain 8.92g of a white solid compound 3a with the yield of 89.2%
S33, synthesis of compound 4 a:
adding 5.00g of Compound 3a to 25mL of purified water to completely dissolve Compound 3a to obtain a purified aqueous solution of Compound 3a, adding 4.95g of 2,3, 4-trihydroxybenzaldehyde and 35mL of methanol to a 100mL single-neck flask, magnetically stirring, slowly adding the purified aqueous solution of Compound 3a to the reaction system, stirring at room temperature for 2H, and reacting by TLC (BuOH: HOAc: H)2O is 3: 1: 1) the color developing agent detects that the raw materials react completely, the raw materials are filtered, and the filter cake is washed by 10mL of ethanol with the volume fraction of 95 percentThen, the cake was dried to obtain 8.74g of compound 4a as a white-like solid with a yield of 93.2%;
s34, synthesis of compound 6:
5.00g of Compound 4a was dissolved in 150mL of methanol for use, and 3.0g of Pd/Al was charged into the fixed-bed reactor2O3The catalyst is kept at the temperature of 30 ℃, a methanol cleaning valve wetting system is opened, the liquid flow rate is 1mL/min, a nitrogen valve is opened, the whole system is swept to be in the nitrogen atmosphere, the back pressure is adjusted to be 3-3.5MPa by using a back pressure valve, after the methanol wetting system is 30min, the nitrogen valve is closed, the hydrogen valve is opened, the back pressure is controlled to be 3-3.5MPa by using the back pressure valve, the methanol cleaning valve is closed, a material liquid valve is opened, the methanol solution of the compound 4a flows into the reaction system, the liquid flow rate is 0.5mL/min, the material is discharged through a discharge valve, and TLC (BuOH: HOAc: H) is used2O is 3: 1: 1) and (3) detecting that the raw materials completely react by using a color developing agent, collecting a methanol solution of the product, concentrating under reduced pressure at 40 ℃ to obtain a concentrated residue, adding 70mL of absolute ethyl alcohol into the concentrated residue for crystallization, standing overnight, performing suction filtration, leaching a filter cake by using 10mL of absolute ethyl alcohol, and drying at 40 ℃ to constant weight to obtain 2.17g of off-white solid compound 6 with the yield of 43.1%.
Wherein a, b and c represent different R groups in a compound 2, a compound 3 and a compound 4, and then the formed product.
In the description herein, references to the description of "one embodiment," "an example," "a specific example" or the like are intended to mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.
The foregoing is illustrative and explanatory only and is not intended to be exhaustive or to limit the invention to the precise embodiments described, and various modifications, additions, and substitutions may be made by those skilled in the art without departing from the scope of the invention or exceeding the scope of the claims.
Claims (6)
1. A method for synthesizing benserazide hydrochloride by using fixed bed hydrogenation equipment is characterized by comprising the following steps:
the method comprises the following steps: taking DL-serine and thionyl chloride as initial raw materials, and carrying out esterification reaction at the reaction temperature of 70-80 ℃ to generate a compound 1;
step two: carrying out amino protection reaction on the compound 1 and an amino protective agent at the reaction temperature of 20-30 ℃ to obtain a compound 2;
step three: performing amine ester exchange reaction on the compound 2 and hydrazine hydrate at the reaction temperature of 20-30 ℃, adjusting the pH value of a reaction system by using hydrochloric acid after the reaction is finished, concentrating to remove excessive hydrazine hydrate, adjusting the reaction system to be acidic, adding alcohols, and crystallizing at the crystallization temperature of 0-15 ℃ to obtain a compound 3;
step four: carrying out condensation reaction on a compound 3 and 2,3, 4-trihydroxybenzaldehyde in an ethanol water system at the reaction temperature of 50-55 ℃ to generate a compound A, and carrying out post-treatment on the compound A to obtain a compound 4;
step five: carrying out hydrogenation reaction on the compound 4 by using a fixed bed reaction device at the reaction temperature of 25-30 ℃, concentrating a solvent, adding alcohols, crystallizing to generate a compound B, and carrying out post-treatment on the compound B to obtain a compound 5;
step six: and carrying out salt forming reaction on the compound 5 to obtain a compound 6, namely benserazide hydrochloride.
2. The method for synthesizing benserazide hydrochloride according to claim 1, wherein the amino protecting agent in the second step is one of (Boc)2O, CbzCl, CbzOsu, BnCl and BnBr.
3. The method for synthesizing benserazide hydrochloride according to claim 1, wherein the hydrazine hydrate in the third step is 85 wt% hydrazine hydrate; the alcohol is one of ethanol, isopropanol and n-butanol.
4. The method for synthesizing benserazide hydrochloride by using a fixed bed hydrogenation unit as claimed in claim 1, wherein the post-treatment step of the fourth step is: after the compound A is generated in the reaction system, cooling the reaction system to room temperature, filtering the reaction solution, collecting a filter cake to obtain a crude compound, and then recrystallizing and crystallizing the crude compound in methanol to obtain the compound 4.
5. The method for synthesizing benserazide hydrochloride by using a fixed bed hydrogenation device according to claim 1, wherein the reducing agent in the hydrogenation reaction in the step five is hydrogen, and the catalyst is palladium carbon or raney nickel; the solvent is a hydrogen chloride methanol solution.
6. The method for synthesizing benserazide hydrochloride by using a fixed bed hydrogenation device according to claim 1, wherein the five post-treatment steps comprise: after the compound B is generated in the reaction system, filtering the reaction solution by using kieselguhr, washing a filter cake by using methanol, concentrating the filtrate under reduced pressure at the temperature of not higher than 40 ℃ to obtain a concentrated residue, and pulping the concentrated residue in ethanol or isopropanol at the temperature of 0-5 ℃ to obtain a compound 5.
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| CN104788338A (en) * | 2014-10-17 | 2015-07-22 | 上海益生源药业有限公司 | Preparation method of benserazide hydrochloride |
| WO2015197909A1 (en) * | 2014-06-27 | 2015-12-30 | Fermion Oy | Process for the preparation of a crystalline polymorph of 2-amino-3-hydroxy-n'-(2,3,4-trihydroxybenzyl)propanehydrazide (benserazide) hydrochloride |
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| WO2015197909A1 (en) * | 2014-06-27 | 2015-12-30 | Fermion Oy | Process for the preparation of a crystalline polymorph of 2-amino-3-hydroxy-n'-(2,3,4-trihydroxybenzyl)propanehydrazide (benserazide) hydrochloride |
| CN104788338A (en) * | 2014-10-17 | 2015-07-22 | 上海益生源药业有限公司 | Preparation method of benserazide hydrochloride |
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