CN108586214A - A kind of synthetic method of the chloro- 2 pentanones of medicine intermediate 5- - Google Patents
A kind of synthetic method of the chloro- 2 pentanones of medicine intermediate 5- Download PDFInfo
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- CN108586214A CN108586214A CN201711246067.3A CN201711246067A CN108586214A CN 108586214 A CN108586214 A CN 108586214A CN 201711246067 A CN201711246067 A CN 201711246067A CN 108586214 A CN108586214 A CN 108586214A
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- 239000003814 drug Substances 0.000 title claims abstract description 22
- 238000010189 synthetic method Methods 0.000 title claims abstract description 19
- MGTGUEKJBFTQQW-UHFFFAOYSA-N 1-chloropentan-2-one Chemical class CCCC(=O)CCl MGTGUEKJBFTQQW-UHFFFAOYSA-N 0.000 title claims description 27
- 238000006243 chemical reaction Methods 0.000 claims abstract description 54
- 239000002131 composite material Substances 0.000 claims abstract description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000002360 preparation method Methods 0.000 claims abstract description 17
- VQKFNUFAXTZWDK-UHFFFAOYSA-N 2-Methylfuran Chemical class CC1=CC=CO1 VQKFNUFAXTZWDK-UHFFFAOYSA-N 0.000 claims abstract description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000003756 stirring Methods 0.000 claims abstract description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000001257 hydrogen Substances 0.000 claims abstract description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 9
- 239000000706 filtrate Substances 0.000 claims abstract description 8
- 239000000203 mixture Substances 0.000 claims abstract description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 8
- 239000012044 organic layer Substances 0.000 claims abstract description 8
- 238000010992 reflux Methods 0.000 claims abstract description 8
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 36
- BGCWDXXJMUHZHE-UHFFFAOYSA-N 5-methyl-2,3-dihydrofuran Chemical compound CC1=CCCO1 BGCWDXXJMUHZHE-UHFFFAOYSA-N 0.000 claims description 24
- APUPEJJSWDHEBO-UHFFFAOYSA-P ammonium molybdate Chemical compound [NH4+].[NH4+].[O-][Mo]([O-])(=O)=O APUPEJJSWDHEBO-UHFFFAOYSA-P 0.000 claims description 16
- 229940010552 ammonium molybdate Drugs 0.000 claims description 16
- 235000018660 ammonium molybdate Nutrition 0.000 claims description 16
- 239000011609 ammonium molybdate Substances 0.000 claims description 16
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 claims description 15
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 14
- 239000007864 aqueous solution Substances 0.000 claims description 14
- 229910052700 potassium Inorganic materials 0.000 claims description 14
- 239000011591 potassium Substances 0.000 claims description 14
- 229910052750 molybdenum Inorganic materials 0.000 claims description 12
- 235000006408 oxalic acid Nutrition 0.000 claims description 12
- 229910052802 copper Inorganic materials 0.000 claims description 7
- 239000010949 copper Substances 0.000 claims description 7
- XTVVROIMIGLXTD-UHFFFAOYSA-N copper(II) nitrate Chemical compound [Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XTVVROIMIGLXTD-UHFFFAOYSA-N 0.000 claims description 7
- IRXRGVFLQOSHOH-UHFFFAOYSA-L dipotassium;oxalate Chemical compound [K+].[K+].[O-]C(=O)C([O-])=O IRXRGVFLQOSHOH-UHFFFAOYSA-L 0.000 claims description 7
- 238000004090 dissolution Methods 0.000 claims description 7
- 229910052748 manganese Inorganic materials 0.000 claims description 7
- 239000011572 manganese Substances 0.000 claims description 7
- MIVBAHRSNUNMPP-UHFFFAOYSA-N manganese(2+);dinitrate Chemical compound [Mn+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O MIVBAHRSNUNMPP-UHFFFAOYSA-N 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 6
- XEEVLJKYYUVTRC-UHFFFAOYSA-N oxomalonic acid Chemical compound OC(=O)C(=O)C(O)=O XEEVLJKYYUVTRC-UHFFFAOYSA-N 0.000 claims description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims 1
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 abstract description 14
- 239000000047 product Substances 0.000 abstract description 12
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 abstract description 7
- 238000005292 vacuum distillation Methods 0.000 abstract description 6
- 239000006227 byproduct Substances 0.000 abstract description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 abstract 2
- 239000000460 chlorine Substances 0.000 abstract 2
- 229910052801 chlorine Inorganic materials 0.000 abstract 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract 2
- 239000000543 intermediate Substances 0.000 description 10
- 238000000034 method Methods 0.000 description 9
- 239000002994 raw material Substances 0.000 description 7
- 238000001914 filtration Methods 0.000 description 6
- 150000002431 hydrogen Chemical class 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 5
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 description 5
- 238000005660 chlorination reaction Methods 0.000 description 5
- 239000011733 molybdenum Substances 0.000 description 5
- 241000224016 Plasmodium Species 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- AEUAEICGCMSYCQ-UHFFFAOYSA-N 4-n-(7-chloroquinolin-1-ium-4-yl)-1-n,1-n-diethylpentane-1,4-diamine;dihydrogen phosphate Chemical compound OP(O)(O)=O.ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 AEUAEICGCMSYCQ-UHFFFAOYSA-N 0.000 description 3
- -1 acetyl normal propyl alcohol Chemical compound 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229960002328 chloroquine phosphate Drugs 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 210000003936 merozoite Anatomy 0.000 description 2
- 239000012450 pharmaceutical intermediate Substances 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 description 1
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- CDIIZULDSLKBKV-UHFFFAOYSA-N 4-chlorobutanoyl chloride Chemical class ClCCCC(Cl)=O CDIIZULDSLKBKV-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 230000004543 DNA replication Effects 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229940111121 antirheumatic drug quinolines Drugs 0.000 description 1
- YWTGENIJAPJWEG-UHFFFAOYSA-N bromomethane;phosphane Chemical compound P.BrC YWTGENIJAPJWEG-UHFFFAOYSA-N 0.000 description 1
- YIKMRTHKLRXOBU-UHFFFAOYSA-N bromomethane;triphenylphosphane Chemical compound BrC.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YIKMRTHKLRXOBU-UHFFFAOYSA-N 0.000 description 1
- 229930188620 butyrolactone Natural products 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229960003677 chloroquine Drugs 0.000 description 1
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 1
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical class C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000010924 continuous production Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000012202 endocytosis Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 239000010970 precious metal Substances 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 210000001563 schizont Anatomy 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- 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
- C07C45/57—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom
- C07C45/59—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom in five-membered rings
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
- B01J23/002—Mixed oxides other than spinels, e.g. perovskite
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
- B01J23/70—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of the iron group metals or copper
- B01J23/76—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of the iron group metals or copper combined with metals, oxides or hydroxides provided for in groups B01J23/02 - B01J23/36
- B01J23/84—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of the iron group metals or copper combined with metals, oxides or hydroxides provided for in groups B01J23/02 - B01J23/36 with arsenic, antimony, bismuth, vanadium, niobium, tantalum, polonium, chromium, molybdenum, tungsten, manganese, technetium or rhenium
- B01J23/889—Manganese, technetium or rhenium
- B01J23/8898—Manganese, technetium or rhenium containing also molybdenum
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J35/00—Catalysts, in general, characterised by their form or physical properties
- B01J35/60—Catalysts, in general, characterised by their form or physical properties characterised by their surface properties or porosity
- B01J35/61—Surface area
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J37/00—Processes, in general, for preparing catalysts; Processes, in general, for activation of catalysts
- B01J37/08—Heat treatment
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J37/00—Processes, in general, for preparing catalysts; Processes, in general, for activation of catalysts
- B01J37/08—Heat treatment
- B01J37/082—Decomposition and pyrolysis
- B01J37/088—Decomposition of a metal salt
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/28—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2523/00—Constitutive chemical elements of heterogeneous catalysts
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Inorganic Compounds Of Heavy Metals (AREA)
Abstract
The invention discloses a kind of synthetic methods of 5 chlorine of medicine intermediate, 2 pentanone, include the following steps：2 methylfurans are placed in reaction kettle, it is passed through nitrogen, Cu Mn Mo composite oxides are added later, controlled at 20 30 DEG C, it is passed through hydrogen, control pressure is 0.25 0.3MPa, after reaction carries out 30 45min, stops reaction, the mixture of preparation is filtered, filtrate is collected, 2 methyl, 4,5 dihydrofuran is made；2 methyl, 4,5 dihydrofuran of preparation is mixed with ether and is added in reaction kettle, controlled at 70 80 DEG C, FeCl is added3, stir evenly, control pressure is 0.05 0.08Mpa, after carrying out 30 45min of microwave treatment, 2 3h of reaction are stirred at reflux, after reaction, water is added and is uniformly mixed, after being stirred to react 1 2h, restore Room pressure, collected organic layer, 5 chlorine, 2 pentanone is made in vacuum distillation.The synthetic method of the application is easy to operate, and mild condition, by-product is less, and product purity is high, and product yield is higher.
Description
Technical field
The present invention relates to medicine intermediate fields, more particularly to a kind of synthesis side of the chloro- 2 pentanones of medicine intermediate 5-
Method.
Background technology
The chloro- 2 pentanones of 5- are a kind of emerging pharmaceutical intermediates, can be as the starting original of a variety of chemical classes pharmaceutical synthesis
Material, such as chloroquine phosphate is synthesized, 5- lignocaines -2 pentanone, or it is used for indirect synthesis Ciprofloxacin class drug and quinoline
Promise ketone drug is a kind of very pharmaceutical intermediate with development potentiality and development prospect.Wherein, chloroquine phosphate is 4 ammonia
The schizont of the base quinolines intracellular phase red to plasmodium plays the role of destruction and inhibition, for its this machine
Reason, it may be possible to required DNA replication dna and transcription when Plasmodium merozoite can be interfered to breed due to the active constituent of the drug,
To hinder the endocytosis of Plasmodium merozoite, and then plasmodium body is made to maintain transcription and replication DNA must by lacking
The amino acid two of palpus is dead complete.Chloroquine phosphate can also be treated to the nauseous cruel of chloroquine-sensitive, and can be used for the suppression of malaria symptoms
Property processed prevents and treats over-the-counter amcbiasis etc..
Existing research is it has been reported that 4 synthetic routes of the chloro- 2 pentanones of 5-：(1) α-acetyl group-γ-is used
Butyrolactone is raw material, and target product is obtained through hydrochloric acid water solution, and although this method has higher yield, but raw material is costly,
Source is more difficult, is not appropriate for industrialized production；(2) using 5- chlorine pentyne as raw material, by catalyst, in acid condition into
Target product is made in row reaction, and not only yield is relatively low but also expensive raw material price for this method；(3) it is that starting is former with 4- chlorobutanoylchlorides
Material, prepares amide, then reacted with triphenylphosphine bromomethane and prepare target product first, and this method uses butyl lithium, triphenyl
The raw materials such as phosphine bromomethane, and severe reaction conditions, operation are complex；(4) it uses acetyl normal propyl alcohol for starting material, passes through
Target product is made in chlorination, and there are still the relatively low problems of product yield for this method.
Chinese patent CN201610756869.8 discloses a kind of method of the chloro- 2 pentanones of continuous production 5-, belongs to organic
Synthesis technology field includes the process of chlorination-azeotropic distillation-grease split-phase-dehydration；Chlorination in chlorination process
Hydrogen enters from reactor-bottom, and 3- acetylpropyl alcohols enter from reactor head, and reactor interior reaction temperature is 48 DEG C -55
DEG C, reaction pressure 0.3Mpa-0.5MPa, the material hybrid reaction time is 165min-180min；It is sufficiently mixed reaction in material
Afterwards, reactor bottom material delivers into azeotrope tower.The invention using hydrogen chloride gas as chloro raw material, hydrogen chloride gas from
Reactor bottom enters, and 3- acetylpropyl alcohols enter from reactor top, and the two is sufficiently mixed in counter-current process, then one is risen and fallen
Enter reactor bottom and carry out chlorination, the temperature needed for the chlorination of the invention is relatively low, and energy consumption is small, and not will produce height
Chloride wastewater, product quality are stablized.
Invention content
The object of the present invention is to provide a kind of synthetic method of the chloro- 2 pentanones of medicine intermediate 5-, synthetic method operations
Simply, mild condition, by-product is less, and product purity is high, and product yield is higher.
To achieve the above object, the present invention uses following technical scheme：
A kind of synthetic method of the chloro- 2 pentanones of medicine intermediate 5-, includes the following steps：
(1) by ammonium molybdate, copper nitrate and manganese nitrate mixed dissolution in water, CTAB is added and is uniformly mixed, is heated to 40-
60 DEG C, oxalic acid aqueous solutions of potassium is added dropwise under stirring condition thereto, it is 10 to keep pH, after being added dropwise to complete, is persistently stirred to react 4-6h,
12-16h is stood later, is filtered later, after washing 2-3 times, is dried under the conditions of 110 DEG C, is roasted under the conditions of 480 DEG C later
4-5h is burnt, Cu-Mn-Mo composite oxides are made；
(2) 2- methylfurans are placed in reaction kettle, are passed through nitrogen, Cu-Mn-Mo composite oxides, control are added later
Temperature is 20-30 DEG C, is passed through hydrogen, and control pressure 0.25-0.3MPa after reaction carries out 30-45min, stops reaction, will make
Standby mixture filtering, collects filtrate, 2- methyl -4,5- dihydrofuran is made；
(3) 2- methyl -4,5- dihydrofuran of preparation is mixed with ether and is added in reaction kettle, controlled at 70-80
DEG C, FeCl is added3, stir evenly, control pressure 0.05-0.08Mpa, after carrying out microwave treatment 30-45min, be stirred at reflux
2-3h is reacted, after reaction, water is added and is uniformly mixed, after being stirred to react 1-2h, restore Room pressure, collected organic layer subtracts
Pressure distillation, is made the chloro- 2 pentanones of 5-.
Preferably, the molar ratio of Cu, Mn, Mo are 3 in the Cu-Mn-Mo composite oxides prepared in the step (1):5:
1。
Preferably, the mass ratio of CTAB and ammonium molybdate is 18 in the step (1):47.
Preferably, a concentration of 1.2-1.6mol/L of step (1) the mesoxalic acid aqueous solutions of potassium, the usage amount of potassium oxalate with
The usage amount molar ratio of ammonium molybdate is 10:1.
Preferably, 2- methylfurans and Cu-Mn-Mo composite oxides use quality ratio are 9 in the step (2):7.
Preferably, the usage amount molar ratio of 2- methyl -4,5- dihydrofuran and ether is 1 in the step (3):2.
Preferably, FeCl in the step (3)3Usage amount molar ratio with 2- methyl -4,5- dihydrofuran is 1:1.
The invention has the advantages that using Cu-Mn-Mo composite oxides as catalyst, by 2- methylfurans
Catalytic hydrogenation is made 2- methyl -4,5- dihydrofuran and has saved cost instead of the use of precious metals pd, and achieves preferably
Transformation efficiency, product obtained have higher yield.In Cu-Mn-Mo composite oxides preparation process, by adding CTAB
So that composite oxides obtained have more holes, the specific surface area of composite oxides is improved, convenient for raw material and catalysis
The contact of agent, improves reaction efficiency so that reaction is more abundant.The preparation method of the application, it is easy to operate, cost of material compared with
To be cheap, product yield is higher, is very suitable for industrialized production use.
Specific implementation mode
In order to better understand the present invention, below by embodiment, the present invention is further described, and embodiment is served only for solving
The present invention is released, any restriction will not be constituted to the present invention.
Embodiment 1
A kind of synthetic method of the chloro- 2 pentanones of medicine intermediate 5-, includes the following steps：
(1) by ammonium molybdate, copper nitrate and manganese nitrate mixed dissolution in water, CTAB is added and is uniformly mixed, is heated to 40
DEG C, oxalic acid aqueous solutions of potassium is added dropwise under stirring condition thereto, it is 10 to keep pH, after being added dropwise to complete, is persistently stirred to react 4h, later
12h is stood, is filtered later, after washing 2 times, is dried under the conditions of 110 DEG C, roasts 4h under the conditions of 480 DEG C later, is made
Cu-Mn-Mo composite oxides；
(2) 2- methylfurans are placed in reaction kettle, are passed through nitrogen, Cu-Mn-Mo composite oxides, control are added later
Temperature is 20 DEG C, is passed through hydrogen, and control pressure 0.25MPa after reaction carries out 30min, stops reaction, by the mixture of preparation
Filtrate is collected in filtering, and 2- methyl -4,5- dihydrofuran is made；
(3) 2- methyl -4,5- dihydrofuran of preparation is mixed with ether and is added in reaction kettle, controlled at 70 DEG C,
FeCl is added3, stir evenly, control pressure 0.05Mpa, after carrying out microwave treatment 30min, be stirred at reflux reaction 2h, reaction
After, water is added and is uniformly mixed, after being stirred to react 1h, restores Room pressure, collected organic layer, it is chloro- that 5- is made in vacuum distillation
2 pentanone.
The molar ratio of Cu, Mn, Mo are 3 in the Cu-Mn-Mo composite oxides prepared in excellent step (1):5:1；CTAB and molybdenum
The mass ratio of sour ammonium is 18:47；A concentration of 1.2mol/L of oxalic acid aqueous solutions of potassium, the usage amount of potassium oxalate and the use of ammonium molybdate
It is 10 to measure molar ratio:1.
2- methylfurans and Cu-Mn-Mo composite oxides use quality ratio are 9 in step (2):7.
The usage amount molar ratio of 2- methyl -4,5- dihydrofuran and ether is 1 in step (3):2；FeCl3With 2- methyl-
The usage amount molar ratio of 4,5- dihydrofuran is 1:1.
The chloro- 2 pentanone yields of 5- obtained are 92.3%, purity 99.1%.1HNMR is analyzed, δ 1.86 (m, 2H), and 2.17
(s, 3H), 2.64 (t, 2H), 3.57 (t, 2H).
Embodiment 2
A kind of synthetic method of the chloro- 2 pentanones of medicine intermediate 5-, includes the following steps：
(1) by ammonium molybdate, copper nitrate and manganese nitrate mixed dissolution in water, CTAB is added and is uniformly mixed, is heated to 60
DEG C, oxalic acid aqueous solutions of potassium is added dropwise under stirring condition thereto, it is 10 to keep pH, after being added dropwise to complete, is persistently stirred to react 6h, later
16h is stood, is filtered later, after washing 3 times, is dried under the conditions of 110 DEG C, roasts 5h under the conditions of 480 DEG C later, is made
Cu-Mn-Mo composite oxides；
(2) 2- methylfurans are placed in reaction kettle, are passed through nitrogen, Cu-Mn-Mo composite oxides, control are added later
Temperature is 30 DEG C, is passed through hydrogen, and control pressure 0.3MPa after reaction carries out 45min, stops reaction, by the mixture of preparation
Filtrate is collected in filtering, and 2- methyl -4,5- dihydrofuran is made；
(3) 2- methyl -4,5- dihydrofuran of preparation is mixed with ether and is added in reaction kettle, controlled at 80 DEG C,
FeCl is added3, stir evenly, control pressure 0.08Mpa, after carrying out microwave treatment 45min, be stirred at reflux reaction 3h, reaction
After, water is added and is uniformly mixed, after being stirred to react 2h, restores Room pressure, collected organic layer, it is chloro- that 5- is made in vacuum distillation
2 pentanone.
The molar ratio of Cu, Mn, Mo are 3 in the Cu-Mn-Mo composite oxides prepared in excellent step (1):5:1；CTAB and molybdenum
The mass ratio of sour ammonium is 18:47；A concentration of 1.6mol/L of oxalic acid aqueous solutions of potassium, the usage amount of potassium oxalate and the use of ammonium molybdate
It is 10 to measure molar ratio:1.
2- methylfurans and Cu-Mn-Mo composite oxides use quality ratio are 9 in step (2):7.
The usage amount molar ratio of 2- methyl -4,5- dihydrofuran and ether is 1 in step (3):2；FeCl3With 2- methyl-
The usage amount molar ratio of 4,5- dihydrofuran is 1:1.
The chloro- 2 pentanone yields of 5- obtained are 92.7%, purity 99.2%.
Embodiment 3
A kind of synthetic method of the chloro- 2 pentanones of medicine intermediate 5-, includes the following steps：
(1) by ammonium molybdate, copper nitrate and manganese nitrate mixed dissolution in water, CTAB is added and is uniformly mixed, is heated to 40
DEG C, oxalic acid aqueous solutions of potassium is added dropwise under stirring condition thereto, it is 10 to keep pH, after being added dropwise to complete, is persistently stirred to react 6h, later
12h is stood, is filtered later, after washing 3 times, is dried under the conditions of 110 DEG C, roasts 4h under the conditions of 480 DEG C later, is made
Cu-Mn-Mo composite oxides；
(2) 2- methylfurans are placed in reaction kettle, are passed through nitrogen, Cu-Mn-Mo composite oxides, control are added later
Temperature is 30 DEG C, is passed through hydrogen, and control pressure 0.25MPa after reaction carries out 45min, stops reaction, by the mixture of preparation
Filtrate is collected in filtering, and 2- methyl -4,5- dihydrofuran is made；
(3) 2- methyl -4,5- dihydrofuran of preparation is mixed with ether and is added in reaction kettle, controlled at 70 DEG C,
FeCl is added3, stir evenly, control pressure 0.08Mpa, after carrying out microwave treatment 30min, be stirred at reflux reaction 3h, reaction
After, water is added and is uniformly mixed, after being stirred to react 1h, restores Room pressure, collected organic layer, it is chloro- that 5- is made in vacuum distillation
2 pentanone.
The molar ratio of Cu, Mn, Mo are 3 in the Cu-Mn-Mo composite oxides prepared in excellent step (1):5:1；CTAB and molybdenum
The mass ratio of sour ammonium is 18:47；A concentration of 1.6mol/L of oxalic acid aqueous solutions of potassium, the usage amount of potassium oxalate and the use of ammonium molybdate
It is 10 to measure molar ratio:1.
2- methylfurans and Cu-Mn-Mo composite oxides use quality ratio are 9 in step (2):7.
The usage amount molar ratio of 2- methyl -4,5- dihydrofuran and ether is 1 in step (3):2；FeCl3With 2- methyl-
The usage amount molar ratio of 4,5- dihydrofuran is 1:1.
The chloro- 2 pentanone yields of 5- obtained are 93.4%, purity 99.3%.
Embodiment 4
A kind of synthetic method of the chloro- 2 pentanones of medicine intermediate 5-, includes the following steps：
(1) by ammonium molybdate, copper nitrate and manganese nitrate mixed dissolution in water, CTAB is added and is uniformly mixed, is heated to 60
DEG C, oxalic acid aqueous solutions of potassium is added dropwise under stirring condition thereto, it is 10 to keep pH, after being added dropwise to complete, is persistently stirred to react 4h, later
16h is stood, is filtered later, after washing 2 times, is dried under the conditions of 110 DEG C, roasts 5h under the conditions of 480 DEG C later, is made
Cu-Mn-Mo composite oxides；
(2) 2- methylfurans are placed in reaction kettle, are passed through nitrogen, Cu-Mn-Mo composite oxides, control are added later
Temperature is 20 DEG C, is passed through hydrogen, and control pressure 0.3MPa after reaction carries out 30min, stops reaction, by the mixture of preparation
Filtrate is collected in filtering, and 2- methyl -4,5- dihydrofuran is made；
(3) 2- methyl -4,5- dihydrofuran of preparation is mixed with ether and is added in reaction kettle, controlled at 80 DEG C,
FeCl is added3, stir evenly, control pressure 0.05Mpa, after carrying out microwave treatment 45min, be stirred at reflux reaction 2h, reaction
After, water is added and is uniformly mixed, after being stirred to react 2h, restores Room pressure, collected organic layer, it is chloro- that 5- is made in vacuum distillation
2 pentanone.
The molar ratio of Cu, Mn, Mo are 3 in the Cu-Mn-Mo composite oxides prepared in excellent step (1):5:1；CTAB and molybdenum
The mass ratio of sour ammonium is 18:47；A concentration of 1.2mol/L of oxalic acid aqueous solutions of potassium, the usage amount of potassium oxalate and the use of ammonium molybdate
It is 10 to measure molar ratio:1.
2- methylfurans and Cu-Mn-Mo composite oxides use quality ratio are 9 in step (2):7.
The usage amount molar ratio of 2- methyl -4,5- dihydrofuran and ether is 1 in step (3):2；FeCl3With 2- methyl-
The usage amount molar ratio of 4,5- dihydrofuran is 1:1.
The chloro- 2 pentanone yields of 5- obtained are 94.3%, purity 99.2%.
Embodiment 5
A kind of synthetic method of the chloro- 2 pentanones of medicine intermediate 5-, includes the following steps：
(1) by ammonium molybdate, copper nitrate and manganese nitrate mixed dissolution in water, CTAB is added and is uniformly mixed, is heated to 50
DEG C, oxalic acid aqueous solutions of potassium is added dropwise under stirring condition thereto, it is 10 to keep pH, after being added dropwise to complete, is persistently stirred to react 5h, later
14h is stood, is filtered later, after washing 3 times, is dried under the conditions of 110 DEG C, roasts 5h under the conditions of 480 DEG C later, is made
Cu-Mn-Mo composite oxides；
(2) 2- methylfurans are placed in reaction kettle, are passed through nitrogen, Cu-Mn-Mo composite oxides, control are added later
Temperature is 20 DEG C, is passed through hydrogen, and control pressure 0.28MPa after reaction carries out 45min, stops reaction, by the mixture of preparation
Filtrate is collected in filtering, and 2- methyl -4,5- dihydrofuran is made；
(3) 2- methyl -4,5- dihydrofuran of preparation is mixed with ether and is added in reaction kettle, controlled at 80 DEG C,
FeCl is added3, stir evenly, control pressure 0.06Mpa, after carrying out microwave treatment 45min, be stirred at reflux reaction 3h, reaction
After, water is added and is uniformly mixed, after being stirred to react 1h, restores Room pressure, collected organic layer, it is chloro- that 5- is made in vacuum distillation
2 pentanone.
The molar ratio of Cu, Mn, Mo are 3 in the Cu-Mn-Mo composite oxides prepared in excellent step (1):5:1；CTAB and molybdenum
The mass ratio of sour ammonium is 18:47；A concentration of 1.4mol/L of oxalic acid aqueous solutions of potassium, the usage amount of potassium oxalate and the use of ammonium molybdate
It is 10 to measure molar ratio:1.
2- methylfurans and Cu-Mn-Mo composite oxides use quality ratio are 9 in step (2):7.
The usage amount molar ratio of 2- methyl -4,5- dihydrofuran and ether is 1 in step (3):2；FeCl3With 2- methyl-
The usage amount molar ratio of 4,5- dihydrofuran is 1:1.
The chloro- 2 pentanone yields of 5- obtained are 93.2%, purity 99.2%.
Claims (7)
1. a kind of synthetic method of the chloro- 2 pentanones of medicine intermediate 5-, which is characterized in that include the following steps：
(1) by ammonium molybdate, copper nitrate and manganese nitrate mixed dissolution in water, CTAB is added and is uniformly mixed, is heated to 40-60
DEG C, oxalic acid aqueous solutions of potassium is added dropwise under stirring condition thereto, it is 10 to keep pH, after being added dropwise to complete, is persistently stirred to react 4-6h, it
After stand 12-16h, filtered later, washing 2-3 times after, dry under the conditions of 110 DEG C, roasted under the conditions of 480 DEG C later
Cu-Mn-Mo composite oxides are made in 4-5h；
(2) 2- methylfurans are placed in reaction kettle, are passed through nitrogen, Cu-Mn-Mo composite oxides are added later, control temperature
It is 20-30 DEG C, is passed through hydrogen, control pressure 0.25-0.3MPa after reaction carries out 30-45min, stops reaction, by preparation
Mixture filters, and collects filtrate, and 2- methyl -4,5- dihydrofuran is made；
(3) 2- methyl -4,5- dihydrofuran of preparation is mixed with ether and is added in reaction kettle, controlled at 70-80 DEG C, added
Enter FeCl3, stir evenly, control pressure 0.05-0.08Mpa, after carrying out microwave treatment 30-45min, be stirred at reflux reaction 2-
3h is added water and is uniformly mixed after reaction, after being stirred to react 1-2h, restores Room pressure, and collected organic layer is evaporated under reduced pressure,
The chloro- 2 pentanones of 5- are made.
2. the synthetic method of the chloro- 2 pentanones of medicine intermediate 5- according to claim 1, it is characterised in that：The step
(1) molar ratio of Cu, Mn, Mo are 3 in the Cu-Mn-Mo composite oxides prepared in:5:1.
3. the synthetic method of the chloro- 2 pentanones of medicine intermediate 5- according to claim 1, it is characterised in that：The step
(1) mass ratio of CTAB and ammonium molybdate is 18 in:47.
4. the synthetic method of the chloro- 2 pentanones of medicine intermediate 5- according to claim 1, it is characterised in that：The step
(1) a concentration of 1.2-1.6mol/L of mesoxalic acid aqueous solutions of potassium, the usage amount of potassium oxalate and the usage amount molar ratio of ammonium molybdate are
10:1。
5. the synthetic method of the chloro- 2 pentanones of medicine intermediate 5- according to claim 1, it is characterised in that：The step
(2) 2- methylfurans and Cu-Mn-Mo composite oxides use quality ratio are 9 in:7.
6. the synthetic method of the chloro- 2 pentanones of medicine intermediate 5- according to claim 1, it is characterised in that：The step
(3) the usage amount molar ratio of 2- methyl -4,5- dihydrofuran and ether is 1 in:2.
7. the synthetic method of the chloro- 2 pentanones of medicine intermediate 5- according to claim 1, it is characterised in that：The step
(3) FeCl in3Usage amount molar ratio with 2- methyl -4,5- dihydrofuran is 1:1.
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