CN109796368A - A kind of synthetic method of N '-[(2S, 3S) -2-(benzyloxy) amyl- 3- yl] formylhydrazine - Google Patents
A kind of synthetic method of N '-[(2S, 3S) -2-(benzyloxy) amyl- 3- yl] formylhydrazine Download PDFInfo
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- CN109796368A CN109796368A CN201811619219.4A CN201811619219A CN109796368A CN 109796368 A CN109796368 A CN 109796368A CN 201811619219 A CN201811619219 A CN 201811619219A CN 109796368 A CN109796368 A CN 109796368A
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- benzyloxy
- formylhydrazine
- reaction
- amyl
- synthetic method
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- XZBIXDPGRMLSTC-UHFFFAOYSA-N formohydrazide Chemical compound NNC=O XZBIXDPGRMLSTC-UHFFFAOYSA-N 0.000 title claims abstract description 51
- 238000010189 synthetic method Methods 0.000 title claims abstract description 20
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 60
- 238000006243 chemical reaction Methods 0.000 claims abstract description 54
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 claims abstract description 38
- 239000003054 catalyst Substances 0.000 claims abstract description 35
- 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 32
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 30
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 29
- 239000001257 hydrogen Substances 0.000 claims abstract description 29
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 24
- NBBJYMSMWIIQGU-UHFFFAOYSA-N propionic aldehyde Natural products CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 claims abstract description 24
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical group CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 16
- 239000007818 Grignard reagent Substances 0.000 claims abstract description 14
- 150000004795 grignard reagents Chemical class 0.000 claims abstract description 14
- 239000002904 solvent Substances 0.000 claims abstract description 14
- 239000012298 atmosphere Substances 0.000 claims abstract description 13
- 239000003153 chemical reaction reagent Substances 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 11
- 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 claims abstract description 9
- XMTKNMQAPNHLJP-QMMMGPOBSA-N (2s)-2-phenylmethoxypropanoyl chloride Chemical compound ClC(=O)[C@H](C)OCC1=CC=CC=C1 XMTKNMQAPNHLJP-QMMMGPOBSA-N 0.000 claims abstract description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 48
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 24
- 239000011541 reaction mixture Substances 0.000 claims description 23
- 239000000047 product Substances 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- 239000000243 solution Substances 0.000 claims description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 238000012805 post-processing Methods 0.000 claims description 12
- 238000010992 reflux Methods 0.000 claims description 11
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 9
- 230000001376 precipitating effect Effects 0.000 claims description 9
- 238000010792 warming Methods 0.000 claims description 9
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 238000003786 synthesis reaction Methods 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 239000012044 organic layer Substances 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- 239000003208 petroleum Substances 0.000 claims description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-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
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 239000011630 iodine Substances 0.000 claims description 4
- -1 methyl tertbutyl Chemical group 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 4
- 239000012266 salt solution Substances 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 239000000376 reactant Substances 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 238000006722 reduction reaction Methods 0.000 claims description 2
- XJGNRXDOYOEFKR-UHFFFAOYSA-N 3-phenylmethoxypropanoyl chloride Chemical compound ClC(=O)CCOCC1=CC=CC=C1 XJGNRXDOYOEFKR-UHFFFAOYSA-N 0.000 claims 1
- 239000013049 sediment Substances 0.000 claims 1
- 230000007613 environmental effect Effects 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000002390 rotary evaporation Methods 0.000 description 9
- 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 8
- 229960001589 posaconazole Drugs 0.000 description 7
- 230000007423 decrease Effects 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 206010007134 Candida infections Diseases 0.000 description 3
- SIPUZPBQZHNSDW-UHFFFAOYSA-N diisobutylaluminium hydride Substances CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- 238000004064 recycling Methods 0.000 description 3
- 239000012265 solid product Substances 0.000 description 3
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 2
- 238000003747 Grignard reaction Methods 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 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
- 230000001535 kindling effect Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- UEMGWPRHOOEKTA-UHFFFAOYSA-N 1,3-difluorobenzene Chemical compound FC1=CC=CC(F)=C1 UEMGWPRHOOEKTA-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
- 208000032826 Ring chromosome 3 syndrome Diseases 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 238000005452 bending Methods 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- VPCAAUUIFCAFRZ-UHFFFAOYSA-N butylalumane Chemical compound CCCC[AlH2] VPCAAUUIFCAFRZ-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229960004884 fluconazole Drugs 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
- 239000013067 intermediate product Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 229940099075 noxafil Drugs 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- OSFBJERFMQCEQY-UHFFFAOYSA-N propylidene Chemical group [CH]CC OSFBJERFMQCEQY-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007086 side reaction Methods 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
- 230000002194 synthesizing effect Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 229960004740 voriconazole Drugs 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
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
Abstract
A kind of synthetic method of N '-[the amyl- 3- yl of (2S, 3S) -2- (benzyloxy)] formylhydrazine, comprising: (S) -2- benzyloxypropionic acid is reacted into (S) -2- benzyloxy propionyl chloride with acylating reagent；Palladium barium sulphate catalyst is added in ortho-xylene, atmosphere of hydrogen is reacted 15-30 minutes；Add (S) -2- benzyloxy propionyl chloride atmosphere of hydrogen back flow reaction to not inhaling hydrogen；Catalyst is filtered off after completion of the reaction except ortho-xylene obtains (S) -2- benzyloxy propionic aldehyde；By (S) -2- benzyloxy propionic aldehyde and formyl hydrazine reaction, solvent is removed after the completion, post-processes (S)-N '-(2- benzyloxy propylidene) formylhydrazine；(S)-N '-(2- benzyloxy propylidene) formylhydrazine is reacted with Grignard Reagent, post-processes to obtain N '-[the amyl- 3- yl of (2S, 3S) -2- (benzyloxy)] formylhydrazine.The present invention using the cheap and reaction more acylating reagent of safety and environmental protection and can recycle repeatedly using palladium barium sulphate catalyst as reaction raw materials, reaction process is more in line with Atom economy principle, and reaction is milder.
Description
Technical field
The present invention relates to posaconazole intermediate synthesis technical fields, specifically design a kind of N '-[(2S, 3S) -2- (benzyloxy
Base) amyl- 3- yl] formylhydrazine synthetic method.
Background technique
Posaconazole (chemical name: 4- [4- [4- [4- [[(3R, 5R) -5- (2,4 difluorobenzene base) -5- (1,2,4- triazole -
1- ylmethyl) penta ring -3- base of oxa-] methoxyl group] phenyl] piperazine -1- base] phenyl] -2- [the amyl- 3- of (2S, 3S) -2- hydroxyl
Base] -1,2,4- triazole -3- ketone, English name: Posaconazole), structural formula is shown below:
It is developed by Schering Plough company, 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- yl 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, which is disclosed, synthesizes N '-[(2S, 3S)-by (S) -2- benzyloxypropionic acid
The amyl- 3- yl of 2- (benzyloxy)] formylhydrazine method, be shown below:
This method preparation step long (up to five steps) will cause that side reaction is more, low yield, and more outstanding is that it was prepared
To use the diisobutyl aluminium hydride that expensive and while post-processing is easy to kindling in journey, and reaction condition need it is anhydrous
Condition is very harsh, causes the production risk of N '-[the amyl- 3- yl of (2S, 3S) -2- (benzyloxy)] formylhydrazine big, at high cost, behaviour
It is big to make difficulty.
(the 2- benzyloxy Asia third (S)-N '-as follows is disclosed application No. is 201711474200.0 Chinese patent
Base) formylhydrazine synthetic method, this method avoid the uses of diisobutyl aluminium hydride, but entire reaction route Atom economy
Not high, using and post-processing for ethylenediamine will cause certain environmental pressure:
Therefore, it is necessary to a kind of methods of new synthesis N '-[the amyl- 3- yl of (2S, 3S) -2- (benzyloxy)] formylhydrazine, with suitable
The demand of important intermediate N '-[the amyl- 3- yl of (2S, 3S) -2- (benzyloxy)] formylhydrazine needed for answering posaconazole synthesis.
Summary of the invention
The present invention in view of the above shortcomings of the prior art, provides easily ignitable two different when one kind is not needed using post-processing
Butyl aluminum hydride as reaction raw materials, do not use the ethylenediamine for causing certain environment pressure yet；But it uses cheap and anti-
Should more the acylating reagent of safety and environmental protection and can recycle repeatedly using palladium barium sulphate catalyst as reaction raw materials, reacted
Journey is more in line with Atom economy principle, and reaction step is short, and reacts milder N '-[(2S, 3S) -2- (benzyloxy)
Amyl- 3- yl] formylhydrazine synthetic method.
In order to solve the above-mentioned technical problem, a kind of the technical solution adopted by the present invention are as follows: N '-[(2S, 3S) -2- (benzyloxy
Base) amyl- 3- yl] formylhydrazine synthetic method, the specific synthesis path of this method are as follows:
。
The synthetic method of above-mentioned N '-[the amyl- 3- yl of (2S, 3S) -2- (benzyloxy)] formylhydrazine of the invention, the synthetic method
Specific steps include:
(1) (S) -2- benzyloxypropionic acid (CAS accession number: 100836-85-9) is reacted first with acylating reagent, is obtained
(S) -2- benzyloxy propionyl chloride；
(2) then palladium barium sulphate catalyst (Luo Senmeng get catalyst) is added in ortho-xylene, then in nitrogen atmosphere
It encloses lower reduction reaction 15-30 minutes；It adds (S) -2- benzyloxy propionyl chloride, continues under an atmosphere of hydrogen that heating reflux reaction is extremely
Reaction mixture does not inhale hydrogen；Catalyst is filtered off after completion of the reaction, obtains (S) -2- benzyloxy propionic aldehyde after removing ortho-xylene；
(3) by (S) -2- benzyloxy propionic aldehyde and formyl hydrazine reaction, solvent is removed after the reaction was completed, and then post-processing obtains
(S)-N '-(2- benzyloxy propylidene) formylhydrazine；
(4) (S)-N '-(2- benzyloxy propylidene) formylhydrazine is reacted with Grignard Reagent, is post-processed after the reaction was completed
Obtain product N '-[the amyl- 3- yl of (2S, 3S) -2- (benzyloxy)] formylhydrazine.
The molar ratio of (S) -2- benzyloxypropionic acid and acylating reagent is 1:1.0-1.5 in step (1) of the present invention, preferably
1:1-1.2；Using the material matching of said ratio structure, the yield and reaction completeness of intermediate product can be improved, drop simultaneously
The generation of low by-product.
Acylating reagent described in step (1) of the present invention can be one of thionyl chloride, oxalyl chloride and phosphorus trichloride.
Step (1) of the present invention is using toluene as solvent, and the reaction time therein is 4-8 hours, and reaction temperature uses back
Stream temperature (boiling point of toluene) is reacted.
Step (2) atmosphere of hydrogen of the present invention is that the pressure inside holding reaction system is 0.05-0.15MPa.
Step (2) heating reflux reaction of the present invention does not inhale the Hydrogen Vapor Pressure in hydrogen i.e. reaction system to reaction mixture not
Become.
Palladium barium sulphate catalyst in step (2) of the present invention, wherein the mass percentage content of palladium in the catalyst is 8-
12%.
The molar ratio of palladium and (S) -2- benzyloxy propionyl chloride is 1 in palladium barium sulphate catalyst in step (2) of the present invention:
8-12, further preferably 1:9-10.
The molar ratio of (S) -2- benzyloxy propionic aldehyde and formylhydrazine is 1:0.8-1.5 in step (3) of the present invention, further preferably
For 1:1-1.2.
Post-processing in step (3) of the present invention are as follows: ethyl acetate is added 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 precipitating, after precipitating drying product (S)-N '-(2- benzyloxy propylidene) formylhydrazine.
Step (4) Grignard Reagent of the present invention is prepared again using preceding, i.e., current existing system, specific preparation process packet
It includes: magnesium, iodine and methyl tertiary butyl ether(MTBE) being 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- benzyloxy 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 are as follows: the 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- yl of (2S, 3S) -2- (benzyloxy)] formylhydrazine.
The advantages of the present invention:
1. the present invention is used as original as catalyst, (S) -2- benzyloxypropionic acid and acylating reagent using palladium barium sulfate for the first time
Material, can prepare (S) -2- benzyloxy propionic aldehyde in two steps, then by with formyl hydrazine reaction, reacted with Grignard Reagent and prepare mesh
Mark product；Since the palladium barium sulphate catalyst that uses of the present invention can recycle and reuse, and utilization efficiency and directly adopt
The effect of catalyst is suitable, therefore, can effectively reduce synthesis cost；And do not used in preparation process it is expensive and
It is easy to the diisobutyl aluminium hydride of kindling when post-processing, is produced into not only substantially increase operational safety and reduce
This, and preparation process is more mild, easily operated, it is easy to accomplish industrialized production.
2. method Atom economy of the invention is high, post-processing is simple, it is thus only necessary to filter, remove solvent and can be obtained
(S) -2- benzyloxy propionic aldehyde；Then with formyl hydrazine reaction by washing filtering, then react with Grignard Reagent through extraction,
Target product is dried and is obtained by filtration in washing；The step of column etc. is not easy industrial operation is not recrystallized or crossed, there is yield
Advantage high, easily operated, easy to industrialized production.
3. the present invention provides a kind of method of completely new preparation N '-[the amyl- 3- yl of (2S, 3S) -2- (benzyloxy)] formylhydrazine,
This method provides good solution to obtain above-mentioned product, while can also ensure that the intermediate N '-of synthesis posaconazole
[the amyl- 3- yl of (2S, 3S) -2- (benzyloxy)] formylhydrazine is obtained in a kind of more preferably method；The present invention is also first to lead to for the first time
Cross acylating reagent, again by palladium barium sulphate catalyst, then by formylhydrazine, finally by Grignard Reagent reactive mode and
Complete approach obtains N '-[the amyl- 3- yl of (2S, 3S) -2- (benzyloxy)] formylhydrazine, is the important intermediate N '-of posaconazole
The acquisition of [the amyl- 3- yl of (2S, 3S) -2- (benzyloxy)] formylhydrazine provides the method for more economical environmental protection.
Specific embodiment
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, (S) -2- benzyloxypropionic acid (18.02 grams, 0.10mol), thionyl chloride are added in 250ml round-bottomed flask
(14.16 grams, 0.12mol) and 150ml toluene, are heated to reflux, tail gas is absorbed with sodium hydroxide solution.Reaction stops after 6 hours
Heating, rotary evaporation remove toluene and excessive thionyl chloride, obtain 18.87 grams of propionyl chloride of (S) -2- benzyloxy (0.095mol),
Yield 95%.
2, it is 10.00 grams of palladium barium sulphate catalyst (being converted to Metal Palladium 0.01mol) of 10% for palladium content to be added to
In 100ml ortho-xylene, room temperature is down in (0.1MPa pressure) reflux after twenty minutes under atmosphere of hydrogen；Then step (1) system is added
Standby 19.86 grams of propionyl chloride of (S) -2- benzyloxy (0.10mol) then continues to add hydrogen and is back under 0.1MPa atmosphere of hydrogen
Until reaction mixture does not inhale hydrogen (Hydrogen Vapor Pressure does not decline in reaction system).Mixture is cooled to room temperature after completion of the reaction, filtering
Catalyst is removed, rotary evaporation obtains 14.76 grams of propionic aldehyde of (S) -2- benzyloxy after removing solvent ortho-xylene, yield 90%；
3, it is dissolved in 130ml methanol for 9.01 grams of formylhydrazine (0.15mol), is added after being cooled to 0 DEG C dissolved with 24.63 grams
The toluene solution 130ml of (0.15mol) (S) -2- benzyloxy propionic aldehyde, continues to stir at such a temperature after being slowly warming up to 25-30 DEG C
Mix reaction 3 hours；Rotary evaporation removes solvent after completion of the reaction, and 60ml ethyl acetate is added in residue, stirs at 25-30 DEG C
It mixes 1.5 hours, filters off precipitating, addition 60ml petroleum ether in gained semi-solid product after mother liquor removing ethyl acetate, 25-30 DEG C
Lower stirring filtered out precipitating after 1.5 hours, obtained 26.28 grams of formylhydrazine of (S)-N '-(2- benzyloxy propylidene) after drying
(0.128mol), yield 85%；
4, by 20 grams of magnesium rod (0.83mol), 0.0325 gram of iodine (0.13mmol), methyl tertiary butyl ether(MTBE) 150ml is added to
In 500ml three neck round bottom flask, nitrogen protection, mixture is slowly added dropwise 90.53 grams of bromoethane after being heated to 40 DEG C
(0.83mol).60ml methyl tertiary butyl ether(MTBE) is added after being added dropwise, and reaction mixture is then warming up to 55 DEG C, stirring is anti-
It answers 2 hours；5 DEG C are cooled to after completion of the reaction, obtain the reaction mixture containing Grignard Reagent；
N separately is taken, 81.2 grams of bis- trimethyl silicane yl acetamides of O- (0.4mol) are slowly added into dissolved with (S)-N '-(2- benzyloxy
Base propylidene) in 40 grams of formylhydrazine (0.2mol) of 150ml methyl tertiary butyl ether(MTBE), institute after being stirred to react at 25~30 DEG C 1 hour
Solution be added at nitrogen protection, 5 DEG C in above-mentioned grignard reaction mixture, add rear reaction mixture be warming up to 25~
It 30 DEG C and is stirred to react 8 hours.The acetum that concentration is 8%, stirring is added at 0 DEG C into reaction mixture after completion of the reaction
Organic layer is separated after 30 minutes, saturated salt solution washed once, then wash once, filters after anhydrous sodium sulfate is dry, removes first
Base tertbutyl ether obtains 31.17 grams of formylhydrazine (0.132mol) of product N '-[the amyl- 3- yl of (2S, 3S) -2- (benzyloxy)], yield
66%.
Comparison: repeat the above steps (2), and catalyst is changed to the palladium barium sulphate catalyst of step (2) recycling, obtains product
(S) 14.76 grams of -2- benzyloxy propionic aldehyde, yield 90%.Show that catalyst activity does not decline, can be used repeatedly, to drop
Low production cost.
(S) -2- benzyloxy propionic aldehyde MS (m/z): 164 (M+), 135,107,91,77.
(S) infrared analysis of -2- benzyloxy propionic aldehyde: there are phenyl ring skeletal vibration peak at 1454cm-1,698cm-1,
There are phenyl ring-CH out-of-plane bending vibration peaks at 738cm-1 two；In 1094cm-1, there are the flexible peaks of C-O-C, in 1733cm-1
There are the stretching vibration peaks of carbonyl at place, and there are the C-H stretching vibrations at the frequency multiplication peak of C-H stretching vibration and carbonyl at 1374cm-1
The fundamental frequency Fermi resonance of generation；The stretching vibration peak for being-CH3 at 2870cm-1.
Embodiment 2
1, (S) -2- benzyloxypropionic acid (18.02 grams, 0.10mol), oxalyl chloride are added in 250ml round-bottomed flask
(12.70 grams, 0.10mol) and 150ml toluene, are heated to reflux, tail gas is absorbed with sodium hydroxide solution.Reaction stops after 8 hours
Heating, rotary evaporation remove toluene and excessive oxalyl chloride, obtain 18.27 grams of propionyl chloride of (S) -2- benzyloxy (0.092mol), produce
Rate 92%.
2, it is 10.00 grams of palladium barium sulphate catalyst (being converted to Metal Palladium 0.01mol) of 10% for palladium content to be added to
In 100ml toluene, room temperature is down in (0.1MPa) reflux after twenty minutes under atmosphere of hydrogen, and (S) -2- benzyloxy propionyl chloride is added
19.86 grams (0.10mol), then continues under 0.1MPa atmosphere of hydrogen plus hydrogen and be back to until reaction mixture do not inhale hydrogen
(Hydrogen Vapor Pressure does not decline in reaction system).Mixture is cooled to room temperature, Filtration of catalyst after completion of the reaction, and rotary evaporation removes
14.76 grams of propionic aldehyde of (S) -2- benzyloxy are obtained after removing solvent toluene, yield 90%；
3, it is dissolved in 150ml methanol for 9.61 grams of formylhydrazine (0.16mol), is added after being cooled to 0 DEG C dissolved with 28.90 grams
The toluene solution 150ml of (0.176mol) (S) -2- benzyloxy propionic aldehyde, continues to stir at such a temperature after being slowly warming up to 25-30 DEG C
Mix reaction 3 hours；Rotary evaporation removes solvent after completion of the reaction, and 70ml ethyl acetate is added in residue, stirs at 25-30 DEG C
It mixes 2 hours, filters off precipitating, 70ml petroleum ether is added in gained semi-solid product after mother liquor removing ethyl acetate, is stirred at 25-30 DEG C
Precipitating is filtered out after mixing 2 hours, obtains 30.47 grams of formylhydrazine (0.148mol) of (S)-N '-(2- benzyloxy propylidene) after drying, yield
84%；
4, by 22.59 grams of magnesium rod (0.94mol), 0.0375 gram of iodine (0.15mmol), methyl tertiary butyl ether(MTBE) 160ml is added
Into 500ml three neck round bottom flask, nitrogen protection, mixture is slowly added dropwise 92.71 grams of bromoethane after being heated to 12 DEG C
(0.85mol).70ml methyl tertiary butyl ether(MTBE) is added after being added dropwise, and reaction mixture is then warming up to 55 DEG C, stirring is anti-
It answers 2 hours；5 DEG C are cooled to after completion of the reaction, obtain the reaction mixture containing Grignard Reagent；
N separately is taken, 101.15 grams of bis- trimethyl silicane yl acetamides of O- (0.5mol) are slowly added into dissolved with (S)-N '-(2- benzyl
Oxygroup propylidene) in 50 grams of formylhydrazine (0.25mol) of 150ml methyl tertiary butyl ether(MTBE), after 1 hour is stirred to react at 25~30 DEG C
Resulting solution is added in above-mentioned grignard reaction mixture at nitrogen protection, 5 DEG C, is added rear reaction mixture and is warming up to 25
It~30 DEG C and is stirred to react 9 hours.The acetum that concentration is 8% is added at 0 DEG C into reaction mixture after completion of the reaction, stirs
Organic layer is separated after mixing 30 minutes, saturated salt solution washed once, then wash once, filters, removes after anhydrous sodium sulfate is dry
Methyl tertiary butyl ether(MTBE) obtains 29.68 grams of formylhydrazine (0.155mol) of product N '-[the amyl- 3- yl of (2S, 3S) -2- (benzyloxy)], yield
62%.
Comparison: repeating the above steps 2, and catalyst is changed to the palladium barium sulphate catalyst of step 2 recycling, obtains product (S) -2-
14.76 grams of benzyloxy propionic aldehyde, yield 90%.Show that catalyst activity does not decline.
Embodiment 3
1, (S) -2- benzyloxypropionic acid (18.02 grams, 0.10mol), phosphorus trichloride are added in 250ml round-bottomed flask
(15.07 grams, 0.11mol) and 150ml toluene, are heated to reflux, tail gas is absorbed with sodium hydroxide solution.Reaction stops after 7 hours
Heating, rotary evaporation remove toluene and excessive thionyl chloride, obtain 19.06 grams of propionyl chloride of (S) -2- benzyloxy (0.096mol),
Yield 96%.
2, palladium content is 12 grams of palladium barium sulphate catalyst (being converted to Metal Palladium 0.012mol) of 10% and is added to 100ml
In toluene, room temperature is down in (0.1MPa) reflux after twenty minutes under atmosphere of hydrogen, is added 21.41 grams of propionyl chloride of (S) -2- benzyloxy
(0.108mol) then continues to add hydrogen under 0.1MPa atmosphere of hydrogen and is back to (reactant until reaction mixture does not inhale hydrogen
Hydrogen Vapor Pressure does not decline in system).Mixture is cooled to room temperature, Filtration of catalyst after completion of the reaction, and rotary evaporation removes solvent
16.13 grams of propionic aldehyde of product (S) -2- benzyloxy (0.098mol), yield 91% are obtained after toluene；
3, it is dissolved in 150ml methanol for 9.61 grams of formylhydrazine (0.15mol), is added after being cooled to 0 DEG C dissolved with 29.56 grams
The toluene solution 150ml of (0.18mol) (S) -2- benzyloxy propionic aldehyde, continues to stir at such a temperature after being slowly warming up to 25-30 DEG C
Mix reaction 3 hours；Rotary evaporation removes solvent after completion of the reaction, and 80ml ethyl acetate is added in residue, stirs at 25-30 DEG C
It mixes 2 hours, filters off precipitating, 80ml petroleum ether is added in gained semi-solid product after mother liquor removing ethyl acetate, is stirred at 25-30 DEG C
Filter out precipitating after mixing 2 hours, after drying 31.90 grams of formylhydrazine of product (S)-N '-(2- benzyloxy propylidene)
(0.155mol), yield 86%.
The preparation process of subsequent step 4 is the same as embodiment 2.
Comparison: repeating the above steps 2, and catalyst is changed to the palladium barium sulphate catalyst of step 2 recycling, obtains product (S) -2-
16.13 grams of benzyloxy propionic aldehyde, yield 91%.Show that catalyst activity does not decline.
The above-mentioned yield of the present invention is all made of what the mode that industry routinely rounds up was set.
From above-described embodiment it is found that method Atom economy of the invention is high, post-reaction treatment is simple, safe, is easy to grasp
Make, it is easy to industrialized production.
Claims (10)
1. a kind of synthetic method of N '-[the amyl- 3- yl of (2S, 3S) -2- (benzyloxy)] formylhydrazine, it is characterised in that: this method
Specific synthesis path are as follows:
2. the synthetic method of N '-[the amyl- 3- yl of (2S, 3S) -2- (benzyloxy)] formylhydrazine according to claim 1, special
Sign is: the specific steps of the synthetic method include:
(1) (S) -2- benzyloxypropionic acid is reacted first with acylating reagent, obtains (S) -2- benzyloxy propionyl chloride；
(2) then palladium barium sulphate catalyst is added in ortho-xylene, then reduction reaction 15-30 divides under an atmosphere of hydrogen
Clock；(S) -2- benzyloxy propionyl chloride is added, continues heating reflux reaction to reaction mixture under an atmosphere of hydrogen and does not inhale hydrogen；Instead
Catalyst is filtered off after answering, and obtains (S) -2- benzyloxy propionic aldehyde after removing ortho-xylene；
(3) by (S) -2- benzyloxy propionic aldehyde and formyl hydrazine reaction, solvent is removed after the reaction was completed, and then post-processing obtains (S) -
N '-(2- benzyloxy propylidene) formylhydrazine；
(4) (S)-N '-(2- benzyloxy propylidene) formylhydrazine is reacted with Grignard Reagent, carries out post-processing acquisition after the reaction was completed
Product N '-[the amyl- 3- yl of (2S, 3S) -2- (benzyloxy)] formylhydrazine.
3. the synthetic method of N '-[the amyl- 3- yl of (2S, 3S) -2- (benzyloxy)] formylhydrazine according to claim 2, special
Sign is: the molar ratio of (S) -2- benzyloxypropionic acid and acylating reagent is 1:1.0-1.5 in step (1)；Described in step (1)
Acylating reagent is one of thionyl chloride, oxalyl chloride and phosphorus trichloride；Step (1) uses toluene as solvent, therein anti-
It is 4-8 hours between seasonable, reaction temperature is reacted using reflux temperature.
4. the synthetic method method of N '-[the amyl- 3- yl of (2S, 3S) -2- (benzyloxy)] formylhydrazine according to claim 3,
Be characterized in that: the molar ratio of (S) -2- benzyloxypropionic acid and acylating reagent is 1:1-1.2 in step (1).
5. the synthetic method of N '-[the amyl- 3- yl of (2S, 3S) -2- (benzyloxy)] formylhydrazine according to claim 2, special
Sign is: step (2) atmosphere of hydrogen is that the pressure inside holding reaction system is 0.05-0.15MPa；Step (2) is heated to reflux
It is constant to react the Hydrogen Vapor Pressure that do not inhale in hydrogen i.e. reaction system to reaction mixture；Palladium barium sulphate catalyst in step (2),
The mass percentage content of middle palladium in the catalyst is 8-12%；Palladium and (S) -2- in palladium barium sulphate catalyst in step (2)
The molar ratio of benzyloxy propionyl chloride is 1:8-12.
6. according to claim 5 (synthetic method of N '-[the amyl- 3- yl of (2S, 3S) -2- (benzyloxy)] formylhydrazine, it is special
Sign is: the molar ratio of palladium and (S) -2- benzyloxy propionyl chloride is 1:9-10 in the palladium barium sulphate catalyst in step (2).
7. the synthetic method of N '-[the amyl- 3- yl of (2S, 3S) -2- (benzyloxy)] formylhydrazine according to claim 2, special
Sign is: the molar ratio of (S) -2- benzyloxy propionic aldehyde and formylhydrazine is 1:0.8-1.5, further preferably 1:1- in step (3)
1.2；Post-processing in step (3) are as follows: ethyl acetate is added into the reactant after removal solvent, stirs 0.5-2 at 25-30 DEG C
Hour, petroleum ether is added after removing ethyl acetate in filtering, obtained filtrate, and it is heavy to filter out after stirring 0.5-2 hours at 25-30 DEG C
It forms sediment, obtains product (S)-N '-(2- benzyloxy propylidene) formylhydrazine after precipitating drying.
8. the synthetic method of N '-[the amyl- 3- yl of (2S, 3S) -2- (benzyloxy)] formylhydrazine according to claim 2, special
Sign is: step (4) Grignard Reagent is prepared again using preceding, and specific preparation process includes: by magnesium, iodine and methyl- tert fourth
The mixing of base ether, is heated to 35-45 DEG C under nitrogen protection, bromoethane is then added dropwise, add methyl tertbutyl after being added dropwise to complete
Ether；Reaction mixture is 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
To the reaction mixture containing Grignard Reagent.
9. the synthetic method of N '-[the amyl- 3- yl of (2S, 3S) -2- (benzyloxy)] formylhydrazine according to claim 2, special
Sign is: (S)-N '-(2- benzyloxy 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 synthetic method of N '-[the amyl- 3- yl of (2S, 3S) -2- (benzyloxy)] formylhydrazine according to claim 9, special
Sign is: the post-processing in step (4) are as follows: the 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- yl of (2S, 3S) -2- (benzyloxy)] formylhydrazine.
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| CN115260055A (en) * | 2022-09-13 | 2022-11-01 | 济南大学 | Preparation method of chiral isomer of posaconazole side chain intermediate |
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