CN109796368B - Synthesis method of N' - [ (2S,3S) -2- (benzyloxy) pentan-3-yl ] formylhydrazine - Google Patents
Synthesis method of N' - [ (2S,3S) -2- (benzyloxy) pentan-3-yl ] formylhydrazine Download PDFInfo
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- CN109796368B CN109796368B CN201811619219.4A CN201811619219A CN109796368B CN 109796368 B CN109796368 B CN 109796368B CN 201811619219 A CN201811619219 A CN 201811619219A CN 109796368 B CN109796368 B CN 109796368B
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- benzyloxy
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- formylhydrazine
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- carbohydrazide
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- LNEGZKZTVLXZFX-AAEUAGOBSA-N n-[[(2s,3s)-2-phenylmethoxypentan-3-yl]amino]formamide Chemical compound O=CNN[C@@H](CC)[C@H](C)OCC1=CC=CC=C1 LNEGZKZTVLXZFX-AAEUAGOBSA-N 0.000 title claims abstract description 13
- 238000001308 synthesis method Methods 0.000 title claims description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 64
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 58
- 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 36
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 28
- 239000001257 hydrogen Substances 0.000 claims abstract description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 27
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 23
- LRRGYHJHSLSATF-VIFPVBQESA-N (2s)-2-phenylmethoxypropanal Chemical compound O=C[C@H](C)OCC1=CC=CC=C1 LRRGYHJHSLSATF-VIFPVBQESA-N 0.000 claims abstract description 21
- 238000001914 filtration Methods 0.000 claims abstract description 21
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical group CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims abstract description 16
- 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 15
- 239000007818 Grignard reagent Substances 0.000 claims abstract description 15
- 150000004795 grignard reagents Chemical class 0.000 claims abstract description 15
- XZBIXDPGRMLSTC-UHFFFAOYSA-N formohydrazide Chemical compound NNC=O XZBIXDPGRMLSTC-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000002904 solvent Substances 0.000 claims abstract description 14
- 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
- 238000010992 reflux Methods 0.000 claims abstract description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 8
- 229940078552 o-xylene Drugs 0.000 claims abstract description 8
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 7
- 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 30
- 238000003756 stirring Methods 0.000 claims description 26
- 239000011541 reaction mixture Substances 0.000 claims description 23
- 239000000047 product Substances 0.000 claims description 18
- 238000010438 heat treatment Methods 0.000 claims description 17
- XVIXWWBNDGAMAC-JQWIXIFHSA-N CC[C@@H]([C@H](C)OCC1=CC=CC=C1)N(C(NN)=O)N Chemical compound CC[C@@H]([C@H](C)OCC1=CC=CC=C1)N(C(NN)=O)N XVIXWWBNDGAMAC-JQWIXIFHSA-N 0.000 claims description 16
- 230000015572 biosynthetic process Effects 0.000 claims description 13
- 238000003786 synthesis reaction Methods 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 10
- 239000002244 precipitate Substances 0.000 claims description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 10
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 239000012044 organic layer Substances 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 239000003208 petroleum Substances 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 239000011630 iodine Substances 0.000 claims description 4
- 229910052749 magnesium Inorganic materials 0.000 claims description 4
- 239000011777 magnesium Substances 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- SIOVKLKJSOKLIF-HJWRWDBZSA-N trimethylsilyl (1z)-n-trimethylsilylethanimidate Chemical compound C[Si](C)(C)OC(/C)=N\[Si](C)(C)C SIOVKLKJSOKLIF-HJWRWDBZSA-N 0.000 claims description 4
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 2
- 239000000706 filtrate Substances 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000006722 reduction reaction Methods 0.000 claims description 2
- 230000010933 acylation Effects 0.000 abstract description 5
- 238000005917 acylation reaction Methods 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 5
- 239000000243 solution Substances 0.000 description 14
- 239000000203 mixture Substances 0.000 description 10
- 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
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical group C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 206010007134 Candida infections Diseases 0.000 description 3
- 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 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 3
- 201000003984 candidiasis Diseases 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 238000003747 Grignard reaction Methods 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
- 239000010413 mother solution Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- -1 1,2, 4-triazol-1-ylmethyl Chemical group 0.000 description 1
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 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
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 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
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007613 environmental effect Effects 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
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 229940099075 noxafil Drugs 0.000 description 1
- 229940100692 oral suspension Drugs 0.000 description 1
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000126 substance Substances 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 method for synthesizing N' - [ (2S,3S) -2- (benzyloxy) pentan-3-yl ] formylhydrazine comprises the following steps: reacting (S) -2-benzyloxy propionic acid with an acylating reagent to obtain (S) -2-benzyloxy propionyl chloride; adding a palladium barium sulfate catalyst into o-xylene, and reacting for 15-30 minutes in a hydrogen atmosphere; adding (S) -2-benzyloxy propionyl chloride hydrogen to carry out reflux reaction until hydrogen is not absorbed; after the reaction is finished, filtering the catalyst to remove the o-xylene to obtain (S) -2-benzyloxy propionaldehyde; reacting (S) -2-benzyloxy propionaldehyde with formylhydrazine, removing the solvent after the reaction is finished, and performing post-treatment to obtain (S) -N' - (2-benzyloxy propylene) formylhydrazine; reacting (S) -N '- (2-benzyloxy propylene) formylhydrazine with a Grignard reagent, and carrying out post-treatment to obtain the N' - [ (2S,3S) -2- (benzyloxy) pentan-3-yl ] formylhydrazine. According to the invention, the acylation reagent which is low in price and safer and more environment-friendly in reaction and the palladium barium sulfate catalyst which can be recycled for multiple times are used as reaction raw materials, so that the reaction process is more in line with the atom economy principle, and the reaction is milder.
Description
Technical Field
The invention relates to the technical field of posaconazole intermediate synthesis, and particularly designs a synthesis method of N' - [ (2S,3S) -2- (benzyloxy) pent-3-yl ] formhydrazide.
Background
Posaconazole (chemical name: 4- [4- [4- [ [ (3R,5R) -5- (2, 4-difluorophenyl) -5- (1,2, 4-triazol-1-ylmethyl) oxolan-3-yl ] methoxy ] phenyl ] piperazin-1-yl ] phenyl ] -2- [ (2S,3S) -2-hydroxypentan-3-yl ] -1,2, 4-triazol-3-one, english name: Posaconazole) having the following structural formula:
developed by Mr. Probaba company in America, approved by FDA in US in 2006 and 9 months, and is a high-lipophilicity broad-spectrum triazole antifungal agent. The product is Noxafil (Nocofei), and is an oral suspension for preventing invasive Aspergillus and Candida infections in thirteen or more years old, and treating oropharyngeal Candida infections and fluconazole and voriconazole-resistant oropharyngeal Candida infections.
N' - [ (2S,3S) -2- (benzyloxy) pent-3-yl ] carbohydrazide is an intermediate in the synthesis of posaconazole, and has the following structural formula:
international PCT patent application WO 2013042138 discloses the synthesis of N' - [ (2S,3S) -2- (benzyloxy) pent-3-yl ] carbohydrazide from (S) -2-benzyloxypropionic acid, as shown in the following formula:
the method has the advantages that the preparation steps are long (up to five steps), so that side reactions are more, the yield is low, more prominently, diisobutylaluminum hydride which is expensive and easy to catch fire during aftertreatment is used in the preparation process, and anhydrous conditions are required to be harsh, so that the production risk of the N' - [ (2S,3S) -2- (benzyloxy) pent-3-yl ] formylhydrazine is high, the cost is high, and the operation difficulty is high.
Chinese patent application No. 201711474200.0 discloses a method for synthesizing (S) -N' - (2-benzyloxypropylene) carbohydrazide as shown below, which avoids the use of diisobutylaluminum hydride, but the whole reaction route is not highly atom-economical, and the use and post-treatment of ethylenediamine cause a certain environmental pressure:
therefore, a new method for synthesizing N '- [ (2S,3S) -2- (benzyloxy) pent-3-yl ] carbohydrazide is needed to meet the requirement of important intermediate N' - [ (2S,3S) -2- (benzyloxy) pent-3-yl ] carbohydrazide needed by the synthesis of posaconazole.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a synthesis method of N' - [ (2S,3S) -2- (benzyloxy) pentan-3-yl ] carbohydrazide, which does not need diisobutylaluminum hydride which is easy to catch fire in the post-treatment process as a reaction raw material, but adopts an acylation reagent which is low in price and safer and more environmentally-friendly in reaction and a palladium barium sulfate catalyst which can be recycled for multiple times as the reaction raw material, so that the reaction process better conforms to the atom economy principle, the reaction steps are short, and the reaction is milder.
In order to solve the technical problems, the invention adopts the technical scheme that: a method for synthesizing N' - [ (2S,3S) -2- (benzyloxy) pent-3-yl ] formylhydrazine comprises the following specific synthetic route:
the invention relates to a synthesis method of N' - [ (2S,3S) -2- (benzyloxy) pent-3-yl ] formylhydrazine, which comprises the following specific steps:
(1) firstly, (S) -2-benzyloxy propionic acid (CAS login number: 100836-85-9) reacts with an acylation reagent to obtain (S) -2-benzyloxy propionyl chloride;
(2) then adding a palladium barium sulfate catalyst (Rosenmon catalyst) into o-xylene, and then carrying out reduction reaction for 15-30 minutes in a hydrogen atmosphere; then adding (S) -2-benzyloxy propionyl chloride, and continuously heating and refluxing in a hydrogen atmosphere to react until the reaction mixture does not absorb hydrogen; after the reaction is finished, filtering the catalyst, and removing o-xylene to obtain (S) -2-benzyloxy propionaldehyde;
(3) reacting (S) -2-benzyloxy propionaldehyde with formylhydrazine, removing a solvent after the reaction is finished, and then carrying out post-treatment to obtain (S) -N' - (2-benzyloxy propylene) formylhydrazine;
(4) reacting (S) -N '- (2-benzyloxy propylene) formylhydrazine with a Grignard reagent, and carrying out post-treatment after the reaction is finished to obtain the product N' - [ (2S,3S) -2- (benzyloxy) pentan-3-yl ] formylhydrazine.
The molar ratio of the (S) -2-benzyloxypropionic acid to the acylating agent in step (1) of the present invention is 1:1.0 to 1.5, preferably 1:1 to 1.2; by adopting the raw material collocation of the proportioning structure, the yield and the reaction completion degree of the intermediate product can be improved, and the generation of byproducts is reduced.
The acylating agent in step (1) of the present invention may be one of thionyl chloride, oxalyl chloride and phosphorus trichloride.
In the step (1), toluene is used as a solvent, wherein the reaction time is 4-8 hours, and the reaction temperature adopts reflux temperature (the boiling point of toluene) for reaction.
In the step (2), the hydrogen atmosphere is kept at a pressure of 0.05-0.15MPa in the reaction system.
The step (2) of the invention is heated and refluxed to react until the reaction mixture does not absorb hydrogen, namely, the pressure of the hydrogen in the reaction system is not changed.
The palladium barium sulfate catalyst in the step (2) of the invention has a mass percent of palladium in the catalyst of 8-12%.
The molar ratio of palladium to (S) -2-benzyloxypropionyl chloride in the palladium barium sulfate catalyst in step (2) of the present invention is 1:8 to 12, and more preferably 1:9 to 10.
In step (3) of the present invention, the molar ratio of (S) -2-benzyloxypropanal to formylhydrazine is 1:0.8 to 1.5, and more preferably 1:1 to 1.2.
The post-treatment in the step (3) of the invention comprises the following steps: adding ethyl acetate into the reactant after the solvent is removed, stirring for 0.5-2 hours at 25-30 ℃, filtering, removing the ethyl acetate from the obtained filtrate, adding petroleum ether, stirring for 0.5-2 hours at 25-30 ℃, filtering out the precipitate, and drying the precipitate to obtain the product (S) -N' - (2-benzyloxypropylene) formylhydrazine.
The Grignard reagent in the step (4) of the invention is prepared before use, namely the Grignard reagent is prepared in situ, and the specific preparation process comprises the following steps: mixing magnesium, iodine and methyl tert-butyl ether, heating to 35-45 ℃ under the protection of nitrogen, then dropwise adding bromoethane, and adding methyl tert-butyl ether after dropwise adding; heating the reaction mixture to 50-55 ℃, and stirring for reaction for 1.5-2.5 hours; and after the reaction is finished, cooling to 0-10 ℃ to obtain a reaction mixture containing the Grignard reagent.
Dissolving (S) -N' - (2-benzyloxypropylene) formylhydrazine in methyl tert-butyl ether in the step (4), adding N, O-bis (trimethylsilyl) acetamide, and stirring at 25-30 ℃ for reaction for 0.5-1.5 hours; and then adding the reaction solution into a reaction mixture containing the Grignard reagent, and stirring and reacting for 6-10 hours at 25-30 ℃.
The post-treatment in the step (4) of the invention comprises the following steps: cooling the reacted solution to-5-5 ℃, adding an acetic acid solution, stirring, mixing and separating an organic layer, washing the organic layer with saturated saline solution and water for 1-3 times respectively, then drying, filtering and removing methyl tert-butyl ether to obtain the product N' - [ (2S,3S) -2- (benzyloxy) pentan-3-yl ] formylhydrazine.
The invention has the advantages and beneficial effects that:
1. the method comprises the steps of firstly, using palladium barium sulfate as a catalyst, using (S) -2-benzyloxy propionic acid and an acylation reagent as raw materials, preparing (S) -2-benzyloxy propionaldehyde in two steps, and then reacting with formylhydrazine and a Grignard reagent to prepare a target product; the palladium barium sulfate catalyst adopted by the invention can be recycled, and the utilization efficiency is equivalent to the effect of directly adopting the catalyst, so that the synthesis cost can be effectively reduced; and diisobutyl aluminum hydride which is expensive and easy to catch fire during post-treatment is not adopted in the preparation process, so that the operation safety is fully improved, the production cost is reduced, the preparation process is mild, the operation is easy, and the industrial production is easy to realize.
2. The method has high atom economy and simple post-treatment, and can obtain (S) -2-benzyloxy propionaldehyde only by filtering and removing the solvent; then reacting with formylhydrazine, washing, filtering, reacting with a Grignard reagent, extracting, washing with water, drying and filtering to obtain a target product; without recrystallization, column chromatography and other steps which are difficult to operate industrially, and the like, has the advantages of high yield, easy operation and easy industrial production.
3. The invention provides a brand-new method for preparing N '- [ (2S,3S) -2- (benzyloxy) pent-3-yl ] formhydrazide, which provides a good solution for obtaining the product and can ensure that the N' - [ (2S,3S) -2- (benzyloxy) pent-3-yl ] formhydrazide which is an intermediate for synthesizing posaconazole is obtained by a more ideal method; the invention also provides a more economical and environment-friendly method for obtaining the N' - [ (2S,3S) -2- (benzyloxy) pentan-3-yl ] formylhydrazine which is an important intermediate of posaconazole, by firstly using an acylation reagent, then using a palladium barium sulfate catalyst, then using formylhydrazine and finally using a Grignard reagent reaction mode and an integrated way.
Detailed Description
The present invention will be described in further detail below by way of examples, but the present invention is not limited to only the following examples.
Example 1
1. A250 ml round bottom flask was charged with (S) -2-benzyloxypropionic acid (18.02 g, 0.10mol), thionyl chloride (14.16 g, 0.12mol) and 150ml of toluene, heated under reflux, and the tail gas was taken up in sodium hydroxide solution. After 6 hours of reaction, heating was stopped, and toluene and excess thionyl chloride were removed by rotary evaporation to give 18.87 g (0.095mol) of (S) -2-benzyloxypropionyl chloride in 95% yield.
2. Adding 10.00 g (reduced to 0.01mol of metallic palladium) of palladium barium sulfate catalyst with 10 percent of palladium content into 100ml of o-xylene, refluxing for 20 minutes under hydrogen atmosphere (0.1MPa pressure), and then cooling to room temperature; then, 19.86 g (0.10mol) of the (S) -2-benzyloxypropionyl chloride prepared in step (1) was added, and then, hydrogenation was continued under a hydrogen atmosphere of 0.1MPa and refluxed until the reaction mixture did not absorb hydrogen (the hydrogen pressure in the reaction system did not decrease). After the reaction is finished, the mixture is cooled to room temperature, the catalyst is removed by filtration, and the solvent o-xylene is removed by rotary evaporation to obtain 14.76 g of (S) -2-benzyloxy propionaldehyde with the yield of 90%;
3. dissolving 9.01 g (0.15mol) of formylhydrazine in 130ml of methanol, cooling to 0 ℃, adding 130ml of toluene solution in which 24.63 g (0.15mol) of (S) -2-benzyloxy propionaldehyde is dissolved, slowly heating to 25-30 ℃, and continuing to stir at the temperature for reaction for 3 hours; after the reaction is finished, removing the solvent by rotary evaporation, adding 60ml of ethyl acetate into the residue, stirring for 1.5 hours at 25-30 ℃, filtering out the precipitate, adding 60ml of petroleum ether into the semisolid product obtained after the ethyl acetate of the mother solution is removed, stirring for 1.5 hours at 25-30 ℃, filtering out the precipitate, and drying to obtain 26.28 g (0.128mol) of (S) -N' - (2-benzyloxypropylidene) formylhydrazine, wherein the yield is 85%;
4. 20 g of magnesium strip (0.83mol), 0.0325 g of iodine (0.13mmol) and 150ml of methyl tert-butyl ether are added to a 500ml three-neck round-bottom flask, the mixture is heated to 40 ℃ under nitrogen protection, and 90.53 g of bromoethane (0.83mol) are slowly added dropwise. After the dropwise addition, adding 60ml of methyl tert-butyl ether, heating the reaction mixture to 55 ℃, and stirring for reaction for 2 hours; after the reaction is finished, cooling to 5 ℃ to obtain a reaction mixture containing the Grignard reagent;
and adding 81.2 g (0.4mol) of N, O-bis (trimethylsilyl) acetamide slowly into 150ml of methyl tert-butyl ether dissolved with 40 g (0.2mol) of (S) -N' - (2-benzyloxypropylene) formylhydrazine, stirring at 25-30 ℃ for reaction for 1 hour, adding the obtained solution into the Grignard reaction mixture under the protection of nitrogen at 5 ℃, heating the reaction mixture to 25-30 ℃ after the addition is finished, and stirring for reaction for 8 hours. After the reaction, an acetic acid solution having a concentration of 8% was added to the reaction mixture at 0 ℃ and stirred for 30 minutes, followed by separation of an organic layer, washing with saturated brine once and washing with water once again, drying over anhydrous sodium sulfate and filtration, and removal of methyl t-butyl ether to obtain 31.17 g (0.132mol) of N' - [ (2S,3S) -2- (benzyloxy) pent-3-yl ] carbohydrazide in a yield of 66%.
And (3) comparison: the step (2) is repeated, the catalyst is changed into the palladium barium sulfate catalyst recovered in the step (2), and 14.76 g of the product (S) -2-benzyloxy propionaldehyde is obtained, and the yield is 90%. The activity of the catalyst is not reduced, and the catalyst can be repeatedly utilized, so that the production cost is reduced.
(S) -2-Benzyloxypropionaldehyde MS (M/z):164(M +), 135, 107, 91, 77.
Infrared analysis of (S) -2-benzyloxypropanal: a benzene ring skeleton vibration peak exists at 1454cm-1, and a benzene ring-CH out-of-plane bending vibration peak exists at 698cm-1 and 738 cm-1; a C-O-C stretching peak exists at 1094cm < -1 >, a carbonyl stretching vibration peak exists at 1733cm < -1 >, and a frequency doubling peak of C-H stretching vibration and fundamental frequency Fermi resonance generated by the C-H stretching vibration of the carbonyl exist at 1374cm < -1 >; the peak of stretching vibration of-CH 3 is at 2870 cm-1.
Example 2
1. A250 ml round bottom flask was charged with (S) -2-benzyloxypropionic acid (18.02 g, 0.10mol), oxalyl chloride (12.70 g, 0.10mol) and 150ml toluene, heated under reflux, and the tail gas was taken up in sodium hydroxide solution. After 8 hours of reaction, heating was stopped, and toluene and excess oxalyl chloride were removed by rotary evaporation to give 18.27 g (0.092mol) of (S) -2-benzyloxypropionyl chloride in 92% yield.
2. 10.00 g of palladium barium sulfate catalyst (reduced to 0.01mol of metallic palladium) with 10 percent of palladium content is added into 100ml of toluene, the mixture is refluxed for 20 minutes under the hydrogen atmosphere (0.1MPa) and then cooled to room temperature, 19.86 g (0.10mol) of (S) -2-benzyloxy propionyl chloride is added, and then hydrogenation is continued under the hydrogen atmosphere of 0.1MPa and the mixture is refluxed until the reaction mixture does not absorb hydrogen (the hydrogen pressure in the reaction system is not reduced). After the reaction is finished, the mixture is cooled to room temperature, the catalyst is removed by filtration, and the solvent toluene is removed by rotary evaporation to obtain 14.76 g of (S) -2-benzyloxy propionaldehyde with the yield of 90%;
3. dissolving 9.61 g (0.16mol) of formylhydrazine in 150ml of methanol, cooling to 0 ℃, adding 150ml of toluene solution dissolved with 28.90 g (0.176mol) of (S) -2-benzyloxy propionaldehyde, slowly heating to 25-30 ℃, and continuing to stir at the temperature for reaction for 3 hours; after the reaction is finished, removing the solvent by rotary evaporation, adding 70ml of ethyl acetate into the residue, stirring for 2 hours at 25-30 ℃, filtering out the precipitate, adding 70ml of petroleum ether into the semisolid product obtained after the ethyl acetate of the mother solution is removed, stirring for 2 hours at 25-30 ℃, filtering out the precipitate, and drying to obtain 30.47 g (0.148mol) of (S) -N' - (2-benzyloxypropylidene) formylhydrazine, wherein the yield is 84%;
4. 22.59 g (0.94mol) of magnesium strip, 0.0375 g (0.15mmol) of iodine and 160ml of methyl tert-butyl ether are added into a 500ml three-neck round-bottom flask, the mixture is heated to 12 ℃ under the protection of nitrogen, and 92.71 g (0.85mol) of ethyl bromide is slowly added dropwise. Adding 70ml of methyl tert-butyl ether after the dropwise addition is finished, then heating the reaction mixture to 55 ℃, and stirring for reaction for 2 hours; after the reaction is finished, cooling to 5 ℃ to obtain a reaction mixture containing the Grignard reagent;
and slowly adding 101.15 g (0.5mol) of N, O-bis (trimethylsilyl) acetamide into 150ml of methyl tert-butyl ether dissolved with 50 g (0.25mol) of (S) -N' - (2-benzyloxypropylene) formylhydrazine, stirring at 25-30 ℃ for reaction for 1 hour, adding the obtained solution into the Grignard reaction mixture at 5 ℃ under the protection of nitrogen, heating the reaction mixture to 25-30 ℃ after the addition is finished, and stirring for reaction for 9 hours. After the reaction, an acetic acid solution having a concentration of 8% was added to the reaction mixture at 0 ℃ and stirred for 30 minutes, followed by separation of an organic layer, washing with saturated brine once and washing with water once again, drying over anhydrous sodium sulfate and filtration, and removal of methyl t-butyl ether to obtain 29.68 g (0.155mol) of N' - [ (2S,3S) -2- (benzyloxy) pent-3-yl ] carbohydrazide in 62% yield.
And (3) comparison: the step 2 is repeated, the catalyst is changed into the palladium barium sulfate catalyst recovered in the step 2, and 14.76 g of the product (S) -2-benzyloxy propionaldehyde is obtained, and the yield is 90%. Indicating that the catalyst activity did not decrease.
Example 3
1. A250 ml round bottom flask was charged with (S) -2-benzyloxypropionic acid (18.02 g, 0.10mol), phosphorus trichloride (15.07 g, 0.11mol) and 150ml of toluene, heated under reflux, and the tail gas was taken up in sodium hydroxide solution. After 7 hours of reaction, heating was stopped, and toluene and excess thionyl chloride were removed by rotary evaporation to give 19.06 g (0.096mol) of (S) -2-benzyloxypropionyl chloride in 96% yield.
2. 12 g of palladium barium sulfate catalyst with 10 percent of palladium content (calculated as 0.012mol of metal palladium) is added into 100ml of toluene, the mixture is refluxed for 20 minutes under the hydrogen atmosphere (0.1MPa) and then cooled to room temperature, 21.41 g (0.108mol) of (S) -2-benzyloxy propionyl chloride is added, and then hydrogenation is continued under the hydrogen atmosphere of 0.1MPa and the mixture is refluxed until the reaction mixture does not absorb hydrogen (the hydrogen pressure in the reaction system does not decrease). After the reaction is finished, the mixture is cooled to room temperature, the catalyst is removed by filtration, and the solvent toluene is removed by rotary evaporation to obtain 16.13 g (0.098mol) of the product (S) -2-benzyloxy propionaldehyde with the yield of 91 percent;
3. dissolving 9.61 g (0.15mol) of formylhydrazine in 150ml of methanol, cooling to 0 ℃, adding 150ml of toluene solution dissolved with 29.56 g (0.18mol) of (S) -2-benzyloxy propionaldehyde, slowly heating to 25-30 ℃, and continuing to stir at the temperature for reaction for 3 hours; after the reaction is finished, the solvent is removed by rotary evaporation, 80ml of ethyl acetate is added into the residue, the mixture is stirred for 2 hours at 25-30 ℃, the precipitate is filtered out, 80ml of petroleum ether is added into a semisolid product obtained after the ethyl acetate of the mother liquor is removed, the precipitate is filtered out after the stirring for 2 hours at 25-30 ℃, and the product (S) -N' - (2-benzyloxypropylidene) formylhydrazine is 31.90 g (0.155mol) and the yield is 86 percent after drying.
The subsequent step 4 was performed in the same manner as in example 2.
And (3) comparison: the step 2 is repeated, the catalyst is changed into the palladium barium sulfate catalyst recovered in the step 2, and the product (S) -2-benzyloxy propionaldehyde is 16.13 g, and the yield is 91%. Indicating that the catalyst activity did not decrease.
The above yields of the present invention are set by rounding off in a manner conventional in the industry.
The embodiments show that the method of the invention has high atom economy, simple and safe post-reaction treatment, easy operation and easy industrial production.
Claims (10)
2. the process for the synthesis of N' - [ (2S,3S) -2- (benzyloxy) pent-3-yl ] carbohydrazide as claimed in claim 1, wherein: the synthesis method comprises the following specific steps:
(1) firstly, reacting (S) -2-benzyloxy propionic acid with an acylating reagent to obtain (S) -2-benzyloxy propionyl chloride;
(2) then adding a palladium barium sulfate catalyst into o-xylene, and then carrying out reduction reaction for 15-30 minutes in a hydrogen atmosphere; then adding (S) -2-benzyloxy propionyl chloride, and continuously heating and refluxing in a hydrogen atmosphere to react until the reaction mixture does not absorb hydrogen; after the reaction is finished, filtering the catalyst, and removing o-xylene to obtain (S) -2-benzyloxy propionaldehyde;
(3) reacting (S) -2-benzyloxy propionaldehyde with formylhydrazine, removing a solvent after the reaction is finished, and then carrying out post-treatment to obtain (S) -N' - (2-benzyloxy propylene) formylhydrazine;
(4) reacting (S) -N '- (2-benzyloxy propylene) formylhydrazine with a Grignard reagent, and carrying out post-treatment after the reaction is finished to obtain the product N' - [ (2S,3S) -2- (benzyloxy) pentan-3-yl ] formylhydrazine.
3. The process for the synthesis of N' - [ (2S,3S) -2- (benzyloxy) pent-3-yl ] carbohydrazide as claimed in claim 2, wherein: the molar ratio of the (S) -2-benzyloxy propionic acid to the acylating agent in the step (1) is 1: 1.0-1.5; the acylating reagent in the step (1) is one of thionyl chloride, oxalyl chloride and phosphorus trichloride; in the step (1), toluene is used as a solvent, wherein the reaction time is 4-8 hours, and the reaction temperature adopts reflux temperature for reaction.
4. The process for the synthesis of N' - [ (2S,3S) -2- (benzyloxy) pent-3-yl ] carbohydrazide as claimed in claim 3, wherein: the molar ratio of the (S) -2-benzyloxy propionic acid to the acylating agent in the step (1) is 1: 1-1.2.
5. The process for the synthesis of N' - [ (2S,3S) -2- (benzyloxy) pent-3-yl ] carbohydrazide as claimed in claim 2, wherein: in the step (2), the hydrogen atmosphere is to keep the pressure in the reaction system at 0.05-0.15 MPa; heating reflux reaction is carried out until the reaction mixture does not absorb hydrogen, namely the pressure of the hydrogen in the reaction system is unchanged; the palladium barium sulfate catalyst in the step (2), wherein the mass percentage of palladium in the catalyst is 8-12%; the molar ratio of palladium to (S) -2-benzyloxypropionyl chloride in the palladium barium sulfate catalyst in the step (2) is 1: 8-12.
6. The method of synthesizing N' - [ (2S,3S) -2- (benzyloxy) pent-3-yl ] carbohydrazide as claimed in claim 5, wherein: the molar ratio of palladium to (S) -2-benzyloxypropionyl chloride in the palladium barium sulfate catalyst in the step (2) is 1: 9-10.
7. The process for the synthesis of N' - [ (2S,3S) -2- (benzyloxy) pent-3-yl ] carbohydrazide as claimed in claim 2, wherein: in the step (3), the molar ratio of the (S) -2-benzyloxy propionaldehyde to the formylhydrazine is 1: 0.8-1.5; the post-treatment in the step (3) is as follows: adding ethyl acetate into the reactant after the solvent is removed, stirring for 0.5-2 hours at 25-30 ℃, filtering, removing the ethyl acetate from the obtained filtrate, adding petroleum ether, stirring for 0.5-2 hours at 25-30 ℃, filtering out the precipitate, and drying the precipitate to obtain the product (S) -N' - (2-benzyloxypropylene) formylhydrazine.
8. The process for the synthesis of N' - [ (2S,3S) -2- (benzyloxy) pent-3-yl ] carbohydrazide as claimed in claim 2, wherein: the Grignard reagent in the step (4) is prepared before use, and the specific preparation process comprises the following steps: mixing magnesium, iodine and methyl tert-butyl ether, heating to 35-45 ℃ under the protection of nitrogen, then dropwise adding bromoethane, and adding methyl tert-butyl ether after dropwise adding; heating the reaction mixture to 50-55 ℃, and stirring for reaction for 1.5-2.5 hours; and after the reaction is finished, cooling to 0-10 ℃ to obtain a reaction mixture containing the Grignard reagent.
9. The process for the synthesis of N' - [ (2S,3S) -2- (benzyloxy) pent-3-yl ] carbohydrazide as claimed in claim 2, wherein: dissolving (S) -N' - (2-benzyloxypropylene) formylhydrazine in methyl tert-butyl ether, adding N, O-bis (trimethylsilyl) acetamide, and stirring at 25-30 ℃ for reaction for 0.5-1.5 hours; and then adding the reaction solution into a reaction mixture containing the Grignard reagent, and stirring and reacting for 6-10 hours at 25-30 ℃.
10. The process for the synthesis of N' - [ (2S,3S) -2- (benzyloxy) pent-3-yl ] carbohydrazide as claimed in claim 9, wherein: the post-treatment in the step (4) is as follows: cooling the reacted solution to-5-5 ℃, adding an acetic acid solution, stirring, mixing and separating an organic layer, washing the organic layer with saturated saline solution and water for 1-3 times respectively, then drying, filtering and removing methyl tert-butyl ether to obtain the product N' - [ (2S,3S) -2- (benzyloxy) pentan-3-yl ] formylhydrazine.
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Non-Patent Citations (2)
Title |
---|
Synthesis of (-)-(E,S)-3-(benzyloxy)-1-butenyl phenyl sulfone via a Horner-Wadsworth-Emmons reaction of (-)-(S)-2-(benzyloxy)propanal;D. Enders等;《Organic Syntheses》;20021231;第78卷;第177-181页 * |
SYNTHESIS OF REGIOISOMERIC NAPHTHO-FURANS VIA NAPHTHYLOXYALKANALS;H. Kwiecień等;《Chemistry of Heterocyclic Compounds》;20101231;第46卷(第1期);第20-29页 * |
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