CN108586280A - Synthesis N '-[（2S,3S）-2-（Benzyloxy）Amyl- 3- yls] formylhydrazine method - Google Patents
Synthesis N '-[（2S,3S）-2-（Benzyloxy）Amyl- 3- yls] formylhydrazine method Download PDFInfo
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- CN108586280A CN108586280A CN201711474200.0A CN201711474200A CN108586280A CN 108586280 A CN108586280 A CN 108586280A CN 201711474200 A CN201711474200 A CN 201711474200A CN 108586280 A CN108586280 A CN 108586280A
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- Prior art keywords
- formylhydrazine
- benzyloxy
- amyl
- yls
- stirred
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- XZBIXDPGRMLSTC-UHFFFAOYSA-N formohydrazide Chemical compound NNC=O XZBIXDPGRMLSTC-UHFFFAOYSA-N 0.000 title claims abstract description 46
- 238000000034 method Methods 0.000 title claims abstract description 21
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 17
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 30
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims abstract description 26
- NBBJYMSMWIIQGU-UHFFFAOYSA-N propionic aldehyde Natural products CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 claims abstract description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 15
- 238000012805 post-processing Methods 0.000 claims abstract description 14
- 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 abstract description 12
- 239000011734 sodium Substances 0.000 claims abstract description 12
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 12
- XWAVPOFYNPXXEL-QMMMGPOBSA-N (2s)-2-phenylmethoxypropanoic acid Chemical compound OC(=O)[C@H](C)OCC1=CC=CC=C1 XWAVPOFYNPXXEL-QMMMGPOBSA-N 0.000 claims abstract description 9
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000007818 Grignard reagent Substances 0.000 claims abstract description 9
- 150000004795 grignard reagents Chemical class 0.000 claims abstract description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 28
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- 239000000243 solution Substances 0.000 claims description 16
- 239000011541 reaction mixture Substances 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000000047 product Substances 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 7
- 238000001556 precipitation Methods 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 238000010792 warming Methods 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- 235000019441 ethanol Nutrition 0.000 claims description 6
- 239000012044 organic layer Substances 0.000 claims description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical class OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 4
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims description 4
- 150000003869 acetamides Chemical class 0.000 claims description 4
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 claims description 4
- 239000000284 extract Substances 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 239000011630 iodine Substances 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 239000003208 petroleum Substances 0.000 claims description 4
- 239000012266 salt solution Substances 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical class C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims 1
- 239000007795 chemical reaction product Substances 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 150000008085 4,5-dihydro-1H-imidazoles Chemical class 0.000 abstract description 3
- -1 Benzyloxyethyl Chemical group 0.000 abstract 4
- KSVAVOFBEXSSNM-UHFFFAOYSA-N N-(2-phenylmethoxypropylideneamino)formamide Chemical compound O=CNN=CC(C)OCC1=CC=CC=C1 KSVAVOFBEXSSNM-UHFFFAOYSA-N 0.000 abstract 1
- KSVAVOFBEXSSNM-JTQLQIEISA-N N-[[(2S)-2-phenylmethoxypropylidene]amino]formamide Chemical compound O=CNN=C[C@H](C)OCC1=CC=CC=C1 KSVAVOFBEXSSNM-JTQLQIEISA-N 0.000 abstract 1
- 229910052782 aluminium Inorganic materials 0.000 abstract 1
- 238000012545 processing Methods 0.000 abstract 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- RAGOYPUPXAKGKH-XAKZXMRKSA-N posaconazole Chemical compound O=C1N([C@H]([C@H](C)O)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@H]3C[C@@](CN4N=CN=C4)(OC3)C=3C(=CC(F)=CC=3)F)=CC=2)C=C1 RAGOYPUPXAKGKH-XAKZXMRKSA-N 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 229960001589 posaconazole Drugs 0.000 description 4
- 0 C[C@](*)C1=NCC[*-]1 Chemical compound C[C@](*)C1=NCC[*-]1 0.000 description 3
- 206010007134 Candida infections Diseases 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
- 238000002390 rotary evaporation Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 238000003747 Grignard reaction Methods 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 description 2
- SIPUZPBQZHNSDW-UHFFFAOYSA-N diisobutylaluminium hydride Substances CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 150000000178 1,2,4-triazoles Chemical class 0.000 description 1
- UEMGWPRHOOEKTA-UHFFFAOYSA-N 1,3-difluorobenzene Chemical compound FC1=CC=CC(F)=C1 UEMGWPRHOOEKTA-UHFFFAOYSA-N 0.000 description 1
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 description 1
- 201000002909 Aspergillosis Diseases 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- 208000036641 Aspergillus infections Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000032826 Ring chromosome 3 syndrome Diseases 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 125000005909 ethyl alcohol group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 1
- 229960004884 fluconazole Drugs 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 229940099075 noxafil Drugs 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 description 1
- 229960004740 voriconazole Drugs 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
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
- C07C45/562—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with nitrogen as the only hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D233/22—Radicals substituted by oxygen atoms
-
- 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
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention discloses a kind of synthesis N ' [(2S, 3S) 2 (benzyloxies), penta 3 base] formylhydrazine method, (S) 2 benzyloxypropionic acid and reacting ethylenediamine are obtained into (S) 2 (1 Benzyloxyethyl) 4,5 dihydro 1H imidazoles；(S) 2 (1 Benzyloxyethyl) 4,5 dihydro 1H imidazoles is added after metallic sodium is stirred to react processing and obtains (S) 2 benzyloxy propionic aldehyde under nitrogen protection；(S) 2 benzyloxy propionic aldehyde and formyl hydrazine reaction, post-processing obtain (S) N ' (2 benzyloxy propylidene) formylhydrazine；(S) N ' (2 benzyloxy propylidene) formylhydrazine is reacted with Grignard Reagent, and post-processing is carried out after the completion of reaction and obtains product N ' [(2S, 3S) 2 (benzyloxy) penta 3 base] formylhydrazine.With without using expensive and unsafe organo-aluminum compound, manufacturing cost is low, and post-processing is simple, advantage easy to operate.
Description
Technical field
The present invention relates to posaconazole intermediate synthesis technical fields, specially design a kind of synthesis N '-[(2S, 3S) -2-
(benzyloxy) amyl- 3- yls] formylhydrazine method.
Background technology
Posaconazole (chemical name：4- [4- [4- [4- [[(3R, 5R) -5- (2,4 difluorobenzene base) -5- (1,2,4- triazoles -
1- ylmethyls) penta ring -3- bases of oxa-] methoxyl group] phenyl] piperazine -1- bases] phenyl] -2- [the amyl- 3- of (2S, 3S) -2- hydroxyls
Base] -1,2,4- triazole -3- ketone, English name：Posaconazole), structural formula is shown below：
It is developed by Schering Plough company of the U.S., the U.S. FDA of in September, 2006 approval listing, is a kind of highly lipophilic wide spectrum three
Triazole antifungal agent.Trade name Noxafil (promise section flies), oral suspensions are mainly used for preventing 13 years old and the above patient
Intrusive Aspergillus and monilial infection, and treatment pars oralis pharyngis monilial infection and to Fluconazole and the drug resistant mouth of voriconazole
Pharyngeal monilial infection.
N '-[the amyl- 3- yls of (2S, 3S) -2- (benzyloxy)] formylhydrazine is the intermediate for synthesizing posaconazole, and structural formula is such as
Shown in following formula：
International PCT patent application WO 2013042138 is disclosed synthesizes N '-[(2S, 3S)-by (S) -2- benzyloxypropionic acids
The amyl- 3- yls of 2- (benzyloxy)] formylhydrazine method, be shown below：
This method preparation process length (up to five steps) can cause that side reaction is more, low yield, and more outstanding is that it was prepared
To use expensive and while post-processing in journey is easy to the diisobutyl aluminium hydride to catch fire, and reaction condition need it is anhydrous
Condition is very harsh, causes the production of N '-[the amyl- 3- yls of (2S, 3S) -2- (benzyloxy)] formylhydrazine dangerous big, of high cost, behaviour
It is big to make difficulty.
Invention content
The present invention in view of the above shortcomings of the prior art, provides a kind of without using expensive and unsafe organic calorize
Object is closed, manufacturing cost is low, and post-processing is simple, synthesizes N '-[the amyl- 3- yls of (2S, 3S) -2- (benzyloxy)] formyl easily to operate
The method of hydrazine.
In order to solve the above-mentioned technical problem, the technical solution adopted by the present invention is：A kind of synthesis N '-[(2S, 3S) -2-
(benzyloxy) amyl- 3- yls] formylhydrazine method, the synthesis path of the synthetic method is：
Specifically, the method for above-mentioned synthesis N '-[the amyl- 3- yls of (2S, 3S) -2- (the benzyloxy)] formylhydrazine of the present invention, the conjunction
Include at the step of method：
(1)) first by (S) -2- benzyloxypropionic acids and reacting ethylenediamine, (S) -2- (1- Benzyloxyethyls) -4,5- bis- is obtained
Hydrogen -1H- imidazoles；
(2) by (S) -2- (1- Benzyloxyethyls) -4,5- dihydro -1H- imidazoles is dissolved in absolute ethyl alcohol, then in nitrogen protection
Lower addition metallic sodium is stirred to react；Ethyl alcohol is removed after completion of the reaction, and residue is slowly added into saturated oxalic acid under nitrogen protection
In solution, rear back flow reaction is stirred evenly, extracts after completion of the reaction, is dry, filtering, (S) -2- benzyloxies are obtained after removing solvent
Propionic aldehyde；
(3) by (S) -2- benzyloxies propionic aldehyde and formyl hydrazine reaction, solvent is removed after the completion of reaction, then post-processing obtains
(S)-N '-(2- benzyloxies propylidene) formylhydrazine；
(4) (S)-N '-(2- benzyloxies propylidene) formylhydrazine is reacted with Grignard Reagent, is post-processed after the completion of reaction
Obtain product N '-[the amyl- 3- yls of (2S, 3S) -2- (benzyloxy)] formylhydrazine.
The molar ratio of (S) -2- benzyloxypropionic acids and ethylenediamine is 1 in step (1) of the present invention:0.8-1.5, preferably 1:1-
1.2；Using the material matching of said ratio structure, the yield and reaction completeness of intermediate product can be improved, while reducing pair
The generation of product.
The molar ratio of (S) -2- (1- Benzyloxyethyls) -4,5- dihydro -1H- imidazoles and metallic sodium in step (2) of the present invention
It is 1:1.5-3 further preferably 1:2-2.5.
The temperature range being stirred to react in step (2) of the present invention is -5 DEG C~5 DEG C, and it is 20~40 points to be stirred to react the time
Clock；Preferably, the temperature range being stirred to react is -1 DEG C~1 DEG C, and it is 25~35 minutes to be stirred to react the time.
Dichloromethane, benzene, toluene, chloroform, four chlorinations may be used in the extractant of extraction in step (2) of the present invention
One or more of carbon etc..
Metallic sodium may be used the addition form of metallic sodium silk and be reacted in step (2) of the present invention, using metallic sodium silk
Reaction more mitigates, and reacts more abundant.
The molar ratio of (S) -2- benzyloxies propionic aldehyde and formylhydrazine is 1 in step (3) of the present invention:0.8-1.5, further preferably
It is 1:1-1.2.
Post-processing in step (3) of the present invention is：It is added ethyl acetate into the reactant after removal solvent, 25-30 DEG C
Petroleum ether is added after removing ethyl acetate in lower stirring 0.5-2 hours, filtering, obtained filtrate, and stirring 0.5-2 is small at 25-30 DEG C
When after filter out precipitation, after precipitation drying product (S)-N '-(2- benzyloxies propylidene) formylhydrazine.
Step (4) Grignard Reagent of the present invention is prepared again before, i.e., current existing system, specific preparation process packet
It includes：Magnesium, iodine and methyl tertiary butyl ether(MTBE) are mixed, 35-45 DEG C is heated under nitrogen protection, bromoethane is then added dropwise, drip
Methyl tertiary butyl ether(MTBE) is added after；Reaction mixture is warming up to 50~55 DEG C, is stirred to react 1.5-2.5 hours；It has reacted
0~10 DEG C is cooled to after finishing, obtains the reaction mixture containing Grignard Reagent.
(S)-N '-(2- benzyloxies propylidene) formylhydrazine is first dissolved in methyl tertiary butyl ether(MTBE) in step (4) of the present invention, so
After add N, the bis- trimethyl silicane yl acetamides of O- are stirred to react 0.5-1.5 hours at 25~30 DEG C；Then reaction solution is added
Into the reaction mixture containing Grignard Reagent, it is stirred to react at 25~30 DEG C 6-10 hours.
Post-processing in step (4) of the present invention is：Solution after reaction is cooled to -5-5 DEG C, it is molten then to add acetic acid
Liquid is stirred and separates organic layer, and organic layer saturated salt solution, each washing of washing 1-3 times, then dry, filtering removes first
Base tertbutyl ether obtains product N '-[the amyl- 3- yls of (2S, 3S) -2- (benzyloxy)] formylhydrazine.
The advantages of the present invention：
1. the present invention uses (S) -2- benzyloxypropionic acids with ethylenediamine as raw material for the first time, (prior art wants five to point four steps
Step) prepare (S)-N '-(2- benzyloxies propylidene) formylhydrazine；Preparation process is few, side reaction is few, high income, and more attaches most importance to
What is wanted is that preparation process does not use expensive and while post-processing to be easy to the diisobutyl aluminium hydride to catch fire, using anti-
It answers relatively mild ethyl alcohol, ethylenediamine, formylhydrazine and is now used grignard reagent CH3CH2MgCl, to substantially increase behaviour
Make safety and reduces production cost；And preparation process is more mild, easily operated, is needed without traditional handicraft reaction
Anhydrous condition more easily operates, industrialized production easy to implement.
2. product prepared by the present invention, post-processing is simple, it is thus only necessary to it precipitates, filter, drying and can be obtained final product,
High income.
Specific implementation mode
The present invention is described in further detail below by embodiment, but the present invention is not limited solely to following embodiment.
Embodiment 1
1, in the 250ml round-bottomed flasks equipped with water knockout drum be added (S) -2- benzyloxypropionic acids (18.02 grams, 0.10mol),
Ethylenediamine (7.21 grams, 0.12mol) and 150ml toluene, are heated to reflux and divide water.When the water separated reaches 1.60ml
After (0.09mol), stop heating, rotary evaporation removes toluene, and gained reaction mixture is heated under 10 mmhg pressures
150 DEG C are reacted two hours, and (S) -2- (1- Benzyloxyethyls) -4,5- dihydro -1H- imidazoles 17.77 grams (0.087mol) is obtained, and are produced
Rate 87%；(S) nuclear magnetic data of -2- (1- Benzyloxyethyls) -4,5- dihydro -1H- imidazoles is：1H NMR (400MHz,
CDCl3)：δ=1.19 (d, 3H), 2.77 (t, 2H), 3.41 (t, 2H), 3.92 (q, 1H), 4.49 (s, 2H), 6.97 (s, 1H),
7.27~7.35 (br, 5H)；HRMS (ESI) calcd for C12H16N2O [M+H]+205.1336, found 205.1358；
It fully confirms to coincide with (the S) -2- (1- Benzyloxyethyls) to be obtained -4,5- dihydro -1H- glyoxaline structures of the invention.
2, by (S) -2- (1- Benzyloxyethyls) -4,5- dihydro -1H- imidazoles 20.43 grams (0.10mol) be dissolved in 100ml without
Metallic sodium silk 5.75 grams (0.25mol) is added under nitrogen protection, is stirred to react 30 minutes at 0 DEG C for water-ethanol.It removes after completion of the reaction
It goes ethyl alcohol, residue to be slowly added under nitrogen protection in 150 milliliters of saturated oxalic acid solution, stirs evenly rear back flow reaction 1
Hour.After completion of the reaction three times with dichloromethane extraction, each 50ml.Extract liquor washed once with 5% sodium bicarbonate solution, nothing
Aqueous sodium persulfate is dried.Filtering obtains 13.46 grams of product (S) -2- benzyloxies propionic aldehyde, yield 83% after removing solvent.
3, formylhydrazine 7.21 grams (0.12mol) is dissolved in 100ml methanol, is added dissolved with 16.42 grams after being cooled to 0 DEG C
The toluene solution 100ml of (0.1mol) (S) -2- benzyloxy propionic aldehyde, continues to stir at such a temperature after being slowly warming up to 25-30 DEG C
Reaction 3 hours, after completion of the reaction rotary evaporation remove solvent, 50ml ethyl acetate is added in residue, 1 is stirred at 25-30 DEG C
Hour, it filters off and precipitates, 50ml petroleum ethers are added in gained semi-solid product after mother liquor removing ethyl acetate, are stirred at 25-30 DEG C
Precipitation is filtered out after 1.5 hours, and product (S)-N '-(2- benzyloxies propylidene) 16.91 grams of formylhydrazine, yield 82% are obtained after drying.
4, by magnesium rod 18 grams (0.75mol), iodine 0.03 gram (0.12mmol), methyl tertiary butyl ether(MTBE) 150ml is added to 500ml
In three neck round bottom flask, bromoethane 81.8 grams (0.75mol) is slowly added dropwise in nitrogen protection, mixture after being heated to 40 DEG C.It is added dropwise
After add 60ml methyl tertiary butyl ether(MTBE)s, reaction mixture is then warming up to 53 DEG C, is stirred to react 2 hours.It has reacted
5 DEG C are cooled to after finishing.Separately N, the bis- trimethyl silicane yl acetamides of O- 60.9 grams (0.3mol) is taken to be slowly added into dissolved with (S)-N '-
In the 150ml methyl tertiary butyl ether(MTBE)s of (2- benzyloxies propylidene) 30 grams of formylhydrazine (0.15mol), 1 is stirred to react at 25~30 DEG C
The solution of gained is added at nitrogen protection, 5 DEG C in above-mentioned grignard reaction mixture after hour, adds rear reaction mixture liter
Temperature is to 25~30 DEG C and is stirred to react 8 hours.A concentration of 8% acetic acid is added at 0 DEG C into reaction mixture after completion of the reaction
Solution, stirring separate organic layer after 30 minutes, and saturated salt solution washed once, then wash primary, mistake after anhydrous sodium sulfate drying
Filter removes methyl tertiary butyl ether(MTBE) and obtains product N '-[the amyl- 3- yls of (2S, 3S) -2- (benzyloxy)] 21.3 grams of formylhydrazine
(0.09mol), yield 60%.
Embodiment 2
1, (S) -2- benzyloxypropionic acids (0.10mol), ethylenediamine are added in the 250ml round-bottomed flasks equipped with water knockout drum
(0.13mol) and 160ml toluene, is heated to reflux and divides water.After the water separated reaches 1.70ml, stop heating, rotary evaporation
Toluene is removed, gained reaction mixture is heated to 150 DEG C under 10 mmhg pressures and reacts two hours, obtains (S) -2- (1- benzyls
Oxygroup ethyl) -17.36 grams of 4,5- dihydro -1H- imidazoles, yield 85%；(S) -2- (1- Benzyloxyethyls) -4,5- dihydros -1H-
The nuclear magnetic data of imidazoles is：1H NMR (400MHz, CDCl3)：δ=1.19 (d, 3H), 2.77 (t, 2H), 3.41 (t, 2H),
3.92 (q, 1H), 4.49 (s, 2H), 6.97 (s, 1H), 7.27~7.35 (br, 5H)；HRMS(ESI)calcd for
C12H16N2O [M+H]+205.1336, found 205.1358；It fully confirms and (S) -2- (the 1- benzyloxies of the invention to be obtained
Ethyl) -4,5- dihydro -1H- glyoxaline structures coincide.
2, (S) -2- (1- Benzyloxyethyls) -4,5- dihydro -1H- imidazoles 0.10mol are dissolved in 100ml absolute ethyl alcohols, nitrogen
Metallic sodium silk, 0.30mol are added under gas shielded, is stirred to react 35 minutes at -1 DEG C.Ethyl alcohol is removed after completion of the reaction, and residue exists
It is slowly added under nitrogen protection in 150 milliliters of saturated oxalic acid solution, stirs evenly rear back flow reaction 1 hour.After completion of the reaction
Three times with toluene extraction, each 50ml.Extract liquor washed once with 5% sodium bicarbonate solution, anhydrous sodium sulfate drying.Filtering,
13.30 grams of product (S) -2- benzyloxies propionic aldehyde, yield 82% are obtained after removing solvent.
3, formylhydrazine 0.13mol is dissolved in 110ml methanol, is added dissolved with 0.1mol (S) -2- benzyloxies third after being cooled to -2 DEG C
The toluene solution 110ml of aldehyde continues to be stirred to react at such a temperature 3 hours after being slowly warming up to 25-30 DEG C, revolve after completion of the reaction
Turn evaporation of solvent, 55ml ethyl acetate is added in residue, is stirred 1.2 hours at 25-30 DEG C, filters off precipitation, mother liquor removes
It goes after ethyl acetate that 55ml petroleum ethers are added in gained semi-solid product, filters out precipitation after stir 1.6 hours at 25-30 DEG C, baking
Product (S)-N '-(2- benzyloxies propylidene) 16.70 grams of formylhydrazine, yield 81% are obtained after dry.
4, by magnesium rod 0.80mol), iodine 0.13mmol, methyl tertiary butyl ether(MTBE) 150ml is added to 500ml three neck round bottom flask
In, bromoethane 0.80mol is slowly added dropwise in nitrogen protection, mixture after being heated to 40 DEG C.65ml methyl is added after being added dropwise
Then reaction mixture is warming up to 55 DEG C by tertbutyl ether, be stirred to react 2.5 hours, cool to 2 DEG C after completion of the reaction；Separately take
The bis- trimethyl silicane yl acetamides of N, O- 60.9 grams (0.3mol) are slowly added into dissolved with (S)-N '-(2- benzyloxies propylidene) first
In the 150ml methyl tertiary butyl ether(MTBE)s of hydrazides 0.15mol, the solution of gained is protected in nitrogen after being stirred to react at 25~30 DEG C 1 hour
It protects, be added in above-mentioned grignard reaction mixture at 5 DEG C, add rear reaction mixture and be warming up to 25~30 DEG C and be stirred to react 8
Hour.A concentration of 8% acetum is added at 0 DEG C into reaction mixture after completion of the reaction, stirring has separated after 30 minutes
Machine layer, saturated salt solution washed once, then wash once, be filtered after anhydrous sodium sulfate drying, and removing methyl tertiary butyl ether(MTBE) must produce
Object N '-[the amyl- 3- yls of (2S, 3S) -2- (benzyloxy)] 20.95 grams of formylhydrazine, yield 59%.
It is easily operated from above-described embodiment it is found that the method post-reaction treatment of the present invention is simple, safe, it is easy to industrialize
Production.
Claims (10)
1. a kind of method of synthesis N '-[the amyl- 3- yls of (2S, 3S) -2- (benzyloxy)] formylhydrazine, it is characterised in that：It is specific to close
It is at path：
2. the method for synthesis N '-[the amyl- 3- yls of (2S, 3S) -2- (benzyloxy)] formylhydrazine according to claim 1, special
Sign is：The specific steps of the synthetic method include：
(1)) first by (S) -2- benzyloxypropionic acids and reacting ethylenediamine, (S) -2- (1- Benzyloxyethyls) -4,5- dihydros-are obtained
1H- imidazoles；
(2) by (S) -2- (1- Benzyloxyethyls) -4,5- dihydro -1H- imidazoles is dissolved in absolute ethyl alcohol, then adds under nitrogen protection
Enter metallic sodium to be stirred to react；Ethyl alcohol is removed after completion of the reaction, and residue is slowly added into saturated oxalic acid solution under nitrogen protection
In, rear back flow reaction is stirred evenly, extracts after completion of the reaction, is dry, filtering, (S) -2- benzyloxy propionic aldehyde is obtained after removing solvent；
(3) by (S) -2- benzyloxies propionic aldehyde and formyl hydrazine reaction, solvent is removed after the completion of reaction, then post-processing obtains (S) -
N '-(2- benzyloxies propylidene) formylhydrazine；
(4) (S)-N '-(2- benzyloxies propylidene) formylhydrazine is reacted with Grignard Reagent, post-processing acquisition is carried out after the completion of reaction
Product N '-[the amyl- 3- yls of (2S, 3S) -2- (benzyloxy)] formylhydrazine.
3. the method for synthesis N '-[the amyl- 3- yls of (2S, 3S) -2- (benzyloxy)] formylhydrazine according to claim 2, special
Sign is：The molar ratio of (S) -2- benzyloxypropionic acids and ethylenediamine is 1 in step (1):0.8-1.5, preferred molar ratio are 1:
1-1.2。
4. the method for synthesis N '-[the amyl- 3- yls of (2S, 3S) -2- (benzyloxy)] formylhydrazine according to claim 2, special
Sign is：The molar ratio of (S) -2- (1- Benzyloxyethyls) -4,5- dihydro -1H- imidazoles and metallic sodium is 1 in step (2):1.5-
3, preferably 1:2-2.5；The extractant of extraction is dichloromethane, benzene, toluene, chloroform, carbon tetrachloride etc. in step (2)
One or more of；Metallic sodium is reacted using the addition form of metallic sodium silk in step (2).
5. the method for synthesis N '-[the amyl- 3- yls of (2S, 3S) -2- (benzyloxy)] formylhydrazine according to claim 2, special
Sign is：The temperature range being stirred to react in step (2) is -5 DEG C~5 DEG C, and it is 20~40 minutes to be stirred to react the time；Preferably
The temperature range being stirred to react is -1 DEG C~1 DEG C, and it is 25~35 minutes to be stirred to react the time.
6. the method for synthesis N '-[the amyl- 3- yls of (2S, 3S) -2- (benzyloxy)] formylhydrazine according to claim 2, special
Sign is：The molar ratio of (S) -2- benzyloxies propionic aldehyde and formylhydrazine is 1 in step (3):0.8-1.5, preferably 1:1-1.2.
7. the method for synthesis N '-[the amyl- 3- yls of (2S, 3S) -2- (benzyloxy)] formylhydrazine according to claim 2, special
Sign is：Post-processing in step (3) is：Ethyl acetate is added into the reactant after removal solvent, is stirred at 25-30 DEG C
0.5-2 hours, petroleum ether was added after removing ethyl acetate in filtering, obtained filtrate, is filtered after being stirred 0.5-2 hours at 25-30 DEG C
Go out precipitation, product (S)-N '-(2- benzyloxies propylidene) formylhydrazine is obtained after precipitation drying.
8. the method for synthesis N '-[the amyl- 3- yls of (2S, 3S) -2- (benzyloxy)] formylhydrazine according to claim 2, special
Sign is：Step (4) Grignard Reagent is using preceding preparation, and specific preparation process includes：Magnesium, iodine and methyl tertiary butyl ether(MTBE) are mixed
It closes, is heated to 35-45 DEG C under nitrogen protection, bromoethane is then added dropwise, methyl tertiary butyl ether(MTBE) is added after being added dropwise to complete；It will be anti-
It answers mixture to be warming up to 50~55 DEG C, is stirred to react 1.5-2.5 hours；0~10 DEG C is cooled to after completion of the reaction, is obtained containing lattice
The reaction mixture of family name's reagent.
9. the method for synthesis N '-[the amyl- 3- yls of (2S, 3S) -2- (benzyloxy)] formylhydrazine according to claim 2, special
Sign is：(S)-N '-(2- benzyloxies propylidene) formylhydrazine is first dissolved in methyl tertiary butyl ether(MTBE), then adds in step (4)
The bis- trimethyl silicane yl acetamides of N, O-, are stirred to react 0.5-1.5 hours at 25~30 DEG C；Then by reaction solution be added to containing
In the reaction mixture of Grignard Reagent, it is stirred to react at 25~30 DEG C 6-10 hours.
10. the method for synthesis N '-[the amyl- 3- yls of (2S, 3S) -2- (benzyloxy)] formylhydrazine according to claim 2, special
Sign is：Post-processing in step (4) is：Solution after reaction is cooled to -5-5 DEG C, then adds acetum, stirring is mixed
Conjunction separates organic layer, and organic layer saturated salt solution, each washing of washing 1-3 times, then dry, filtering removes methyl tertbutyl
Ether obtains product N '-[the amyl- 3- yls of (2S, 3S) -2- (benzyloxy)] formylhydrazine.
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| CN109796368A (en) * | 2018-12-28 | 2019-05-24 | 浙江大学宁波理工学院 | A kind of synthetic method of N '-[(2S, 3S) -2-(benzyloxy) amyl- 3- yl] formylhydrazine |
| CN109796368B (en) * | 2018-12-28 | 2021-11-02 | 浙江大学宁波理工学院 | Synthesis method of N' - [ (2S,3S) -2- (benzyloxy) pentan-3-yl ] formylhydrazine |
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