CN117603151A - Synthesis method of topiramate intermediate - Google Patents
Synthesis method of topiramate intermediate Download PDFInfo
- Publication number
- CN117603151A CN117603151A CN202311637228.7A CN202311637228A CN117603151A CN 117603151 A CN117603151 A CN 117603151A CN 202311637228 A CN202311637228 A CN 202311637228A CN 117603151 A CN117603151 A CN 117603151A
- Authority
- CN
- China
- Prior art keywords
- reaction
- chlorobromination
- synthesizing
- glyoxylate
- temperature
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000001308 synthesis method Methods 0.000 title claims abstract description 7
- KJADKKWYZYXHBB-XBWDGYHZSA-N Topiramic acid Chemical compound C1O[C@@]2(COS(N)(=O)=O)OC(C)(C)O[C@H]2[C@@H]2OC(C)(C)O[C@@H]21 KJADKKWYZYXHBB-XBWDGYHZSA-N 0.000 title description 2
- 229960004394 topiramate Drugs 0.000 title description 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 86
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 claims abstract description 37
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical compound CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 claims abstract description 21
- PBZUAIHRZUBBAJ-UHFFFAOYSA-N 2-hydroxyiminoacetic acid Chemical compound ON=CC(O)=O PBZUAIHRZUBBAJ-UHFFFAOYSA-N 0.000 claims abstract description 11
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000006482 condensation reaction Methods 0.000 claims abstract description 7
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 36
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 33
- 239000000460 chlorine Substances 0.000 claims description 33
- 229910052801 chlorine Inorganic materials 0.000 claims description 33
- 238000000034 method Methods 0.000 claims description 25
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 18
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 12
- OMKAMTCDOWAJAA-UHFFFAOYSA-N 3-bromo-5,5-dimethyl-4h-1,2-oxazole Chemical group CC1(C)CC(Br)=NO1 OMKAMTCDOWAJAA-UHFFFAOYSA-N 0.000 claims description 11
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 11
- YMCWJQIZJIKFHO-UHFFFAOYSA-N 3-chloro-5,5-dimethyl-4h-1,2-oxazole Chemical compound CC1(C)CC(Cl)=NO1 YMCWJQIZJIKFHO-UHFFFAOYSA-N 0.000 claims description 10
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 10
- 230000002194 synthesizing effect Effects 0.000 claims description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 9
- 238000007363 ring formation reaction Methods 0.000 claims description 8
- ZNBNBTIDJSKEAM-UHFFFAOYSA-N 4-[7-hydroxy-2-[5-[5-[6-hydroxy-6-(hydroxymethyl)-3,5-dimethyloxan-2-yl]-3-methyloxolan-2-yl]-5-methyloxolan-2-yl]-2,8-dimethyl-1,10-dioxaspiro[4.5]decan-9-yl]-2-methyl-3-propanoyloxypentanoic acid Chemical group C1C(O)C(C)C(C(C)C(OC(=O)CC)C(C)C(O)=O)OC11OC(C)(C2OC(C)(CC2)C2C(CC(O2)C2C(CC(C)C(O)(CO)O2)C)C)CC1 ZNBNBTIDJSKEAM-UHFFFAOYSA-N 0.000 claims description 7
- 229910000378 hydroxylammonium sulfate Inorganic materials 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 238000005893 bromination reaction Methods 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 230000001105 regulatory effect Effects 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 10
- YHSAMQAMZAWZPE-UHFFFAOYSA-N butyl 2-[4-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]oxyphenoxy]propanoate Chemical group C1=CC(OC(C)C(=O)OCCCC)=CC=C1OC1=NC=C(C(F)(F)F)C=C1Cl YHSAMQAMZAWZPE-UHFFFAOYSA-N 0.000 abstract description 9
- 239000004009 herbicide Substances 0.000 abstract description 4
- 230000002363 herbicidal effect Effects 0.000 abstract description 3
- 239000000543 intermediate Substances 0.000 description 39
- 238000004811 liquid chromatography Methods 0.000 description 16
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 230000035484 reaction time Effects 0.000 description 9
- MFSWTRQUCLNFOM-SECBINFHSA-N haloxyfop-P-methyl Chemical group C1=CC(O[C@H](C)C(=O)OC)=CC=C1OC1=NC=C(C(F)(F)F)C=C1Cl MFSWTRQUCLNFOM-SECBINFHSA-N 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 229910052794 bromium Inorganic materials 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 230000001276 controlling effect Effects 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000004321 preservation Methods 0.000 description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 3
- 241000196324 Embryophyta Species 0.000 description 3
- RRKHIAYNPVQKEF-UHFFFAOYSA-N Pyriftalid Chemical compound COC1=CC(OC)=NC(SC=2C=3C(=O)OC(C)C=3C=CC=2)=N1 RRKHIAYNPVQKEF-UHFFFAOYSA-N 0.000 description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- -1 glyoxime carboxylic acid Chemical class 0.000 description 3
- 239000013067 intermediate product Substances 0.000 description 3
- 239000007791 liquid phase Substances 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- CASLETQIYIQFTQ-UHFFFAOYSA-N 3-[[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazol-4-yl]methylsulfonyl]-5,5-dimethyl-4h-1,2-oxazole Chemical compound CN1N=C(C(F)(F)F)C(CS(=O)(=O)C=2CC(C)(C)ON=2)=C1OC(F)F CASLETQIYIQFTQ-UHFFFAOYSA-N 0.000 description 2
- VTNQPKFIQCLBDU-UHFFFAOYSA-N Acetochlor Chemical compound CCOCN(C(=O)CCl)C1=C(C)C=CC=C1CC VTNQPKFIQCLBDU-UHFFFAOYSA-N 0.000 description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
- 230000006978 adaptation Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 2
- CRWJEUDFKNYSBX-UHFFFAOYSA-N sodium;hypobromite Chemical compound [Na+].Br[O-] CRWJEUDFKNYSBX-UHFFFAOYSA-N 0.000 description 2
- 238000012795 verification Methods 0.000 description 2
- WVQBLGZPHOPPFO-UHFFFAOYSA-N 2-chloro-N-(2-ethyl-6-methylphenyl)-N-(1-methoxypropan-2-yl)acetamide Chemical compound CCC1=CC=CC(C)=C1N(C(C)COC)C(=O)CCl WVQBLGZPHOPPFO-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 239000005580 Metazachlor Substances 0.000 description 1
- 239000005592 Penoxsulam Substances 0.000 description 1
- SYJGKVOENHZYMQ-UHFFFAOYSA-N Penoxsulam Chemical compound N1=C2C(OC)=CN=C(OC)N2N=C1NS(=O)(=O)C1=C(OCC(F)F)C=CC=C1C(F)(F)F SYJGKVOENHZYMQ-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- SXDBWCPKPHAZSM-UHFFFAOYSA-M bromate Inorganic materials [O-]Br(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-M 0.000 description 1
- SXDBWCPKPHAZSM-UHFFFAOYSA-N bromic acid Chemical compound OBr(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-N 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- VXIVSQZSERGHQP-UHFFFAOYSA-N chloroacetamide Chemical compound NC(=O)CCl VXIVSQZSERGHQP-UHFFFAOYSA-N 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 230000000442 meristematic effect Effects 0.000 description 1
- STEPQTYSZVCJPV-UHFFFAOYSA-N metazachlor Chemical compound CC1=CC=CC(C)=C1N(C(=O)CCl)CN1N=CC=C1 STEPQTYSZVCJPV-UHFFFAOYSA-N 0.000 description 1
- MFSWTRQUCLNFOM-UHFFFAOYSA-N methyl 2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]oxy}phenoxy)propanoate Chemical group C1=CC(OC(C)C(=O)OC)=CC=C1OC1=NC=C(C(F)(F)F)C=C1Cl MFSWTRQUCLNFOM-UHFFFAOYSA-N 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a synthesis method of a haloxyfop-butyl intermediate, which belongs to the technical field of herbicide intermediate preparation, and comprises the steps of generating 2- (hydroxyimino) acetic acid through condensation reaction of glyoxylic acid and hydroxylamine, generating a chlorobrominated intermediate through chlorobrominated reaction of the 2- (hydroxyimino) acetic acid, and generating the haloxyfop-butyl intermediate with isobutene.
Description
Technical Field
The invention relates to the technical field of herbicide intermediate preparation, in particular to a synthesis method of a haloxyfop-R-methyl intermediate.
Background
The chemical name of the haloxyfop-butyl is 3- [5- (difluoromethoxy) -1-methyl-3- (trifluoromethyl) pyrazol-4-ylmethyl sulfonyl ] -4, 5-dihydro-5, 5-dimethyl-1, 2-isoxazole, the molecular formula is C12H14F5N3O4S, the molecular weight is 391.32, and the CAS registration number is 447399-55-5. The haloxyfop-methyl is an isoxazole herbicide which is researched and developed by Japanese chemical combination Co-Ltd, is used as a pre-emergence treatment agent for a plurality of crop fields, can inhibit the growth of roots and buds of weeds after being applied, thus inhibiting the early growth of seedlings of the weeds, damaging meristematic tissues and coleoptile, is an important potential inhibitor in the biosynthesis of VLCFA (very long side chain fatty acid) in plants, has wide application range and high biological activity compared with acetochlor and metolachlor, and has the unit area dosage which is about 9 times lower than that of the acetochlor and chloroacetamide herbicides. The structural formula of the fenpyrad is shown as follows:
3-bromo-5, 5-dimethyl-4, 5-dihydroisoxazole and 3-chloro-5, 5-dimethyl-4, 5-dihydroisoxazole are important intermediates for synthesizing halofop-butyl.
The main method for preparing 3-bromo-5, 5-dimethyl-4, 5-dihydro isoxazole at present comprises the following steps: glyoxylate is used as a starting material and reacts with hydroxylamine to generate 2- (hydroxyimino) acetic acid, dibromoaldoxime is obtained through bromination reaction, and 3-bromo-5, 5-dimethyl-4, 5-dihydro isoxazole is finally generated through reaction with isobutene.
The solution of the patent document is to use sodium bisulphite for reaction, so that the problems of unstable reaction and liquid bromine carried away by the gas are solved, but meanwhile, the sodium bisulphite reaction produces more side salts, the yield and purity are reduced, and the later-stage waste treatment workload is increased.
To solve the problem of excessive secondary salt, the related technicians adoptIn step 2, "adding sodium bromide and hydrogen peroxide into glyoxime carboxylic acid, brominating to obtain dibromoaldoxime", wherein the reaction relies on intermediate NaBrO to be oxidized by hydrogen peroxide to form Br 2 The quantitative bromine release is carried out to reduce the waste and consumption of liquid bromine, but excessive hydrogen peroxide is needed to oxidize to reduce the existence of NaBrO in the aqueous solution of the product, so that the purity of a large amount of byproducts produced influences the subsequent separation of dibromoaldoxime, and the reaction yield and the product purity are not good.
Disclosure of Invention
In view of the above, the invention provides a synthesis method of a metazachlor intermediate, which can improve the yield and the purity of the intermediate product while keeping the reaction environment stable.
The invention provides a synthesis method of a haloxyfop-butyl intermediate, which comprises the steps of generating 2- (hydroxyimino) acetic acid through condensation reaction of glyoxylic acid and hydroxylamine, generating a chlorobrominated intermediate through a chlorobrominated reaction of the 2- (hydroxyimino) acetic acid, and generating the haloxyfop-butyl intermediate through the chlorobrominated intermediate and isobutene.
The technical scheme of the invention is that the 2- (hydroxyimino) acetic acid is subjected to a chlorobromination reaction, and is subjected to bromination, the generated chlorobromination intermediate is a mixture, two halofop-butyl intermediates are generated by the subsequent reaction with isobutene, the prior art is mostly 3-bromo-5, 5-dimethyl-4, 5-dihydro isoxazole, and the 3-chloro-5, 5-dimethyl-4, 5-dihydro isoxazole is not generated, so that the gradual replacement of liquid bromine or bromine element by chlorine element is greatly improved in the preparation of the halofop-butyl intermediate, and as sodium chloride is only generated after the reaction, one side salt is very easy to remove, the subsequent purification process is greatly improved, compared with liquid bromine, chlorine is easier to remove, and the purity of the prepared product is further increased by the excessive chlorine gas due to the gas characteristics of the chlorine gas itself.
The dibromoaldoxime and 2-chloro-2-bromoaldoxime produced in the above steps are cyclized with isobutylene to produce a mixture of 3-bromo-5, 5-dimethyl-4, 5-dihydro-isoxazole and 3-chloro-5, 5-dimethyl-4, 5-dihydro-isoxazole, the latter 3-chloro-5, 5-dimethyl-4, 5-dihydro-isoxazole being the sole intermediate of the fenpyrad in the present application.
Further, the temperature of the chlorobromination reaction is 0-30 ℃.
Further, the temperature of the chlorobromination reaction is 0-5 ℃.
Further, the molar ratio of glyoxylic acid to sodium bromide is 1: 2-1: 3, the mol ratio of the glyoxylate to the chlorine is 1: 1.5-1: 3.
further, the molar ratio of glyoxylic acid to sodium bromide is 1: 2.0-1: 2.1, the molar ratio of glyoxylate to chlorine is 1: 1.5-1: 2.
further, the method further comprises the step of adjusting the pH of the reaction system to 3.44 by sodium carbonate after the condensation reaction and before the cyclization reaction.
Further, the molar ratio of glyoxylic acid to hydroxylamine is 1:2.9-1:4.0, and is optimized to be 1:2.9-1:3.5.
Further, the hydroxylamine is hydroxylamine sulfate or hydroxylamine hydrochloride, and the molar ratio of the glyoxylic acid to the hydroxylamine sulfate is 1: 0.8-1: 1.5, the molar ratio of glyoxylate to hydroxylamine hydrochloride is 1: 1-1: 2.
further, the molar ratio of glyoxylic acid to hydroxylamine sulfate is 1: 0.8-1: 1.1, the molar ratio of glyoxylate to hydroxylamine hydrochloride is 1: 1-1: 1.5.
further, the cyclization reaction is carried out in the presence of a basic catalyst, wherein the basic catalyst is sodium carbonate or potassium carbonate, and the molar ratio of the glyoxylate to the basic catalyst is 1: 1-1: 4.
further, the reaction environment of the condensation reaction is water, the chlorobromination intermediate is dibromoaldoxime and 2-chloro-2-bromoaldoxime, the halofop-butyl intermediate is 3-bromo-5, 5-dimethyl-4, 5-dihydro isoxazole and 3-chloro-5, 5-dimethyl-4, 5-dihydro isoxazole, the reaction environment of the chlorobromination reaction is an organic solvent, and the organic solvent is one of dichloroethane, chloroform and methyl isobutyl ketone.
Further, the molar ratio of the chlorobrominated intermediate to the isobutene is 1:1-1:3, preferably 1:1-1:1.5.
Further, the intermediate of the penoxsulam is then reacted with thiourea in the presence of hydrobromic acid to produce 5, 5-dimethyl-4, 5-dihydro-isoxazol-3-yl thiourea bromate.
Further, the molar ratio of the chlorobrominated intermediate to hydrobromic acid is 1:1.2-1:1.8, preferably 1:1.2-1:1.5.
Further, the molar ratio of the chlorobrominated intermediate to the thiourea is 1:1.2-1:1.7, preferably 1:1.2-1:1.3.
Further, the cyclization reaction temperature, that is, the addition temperature of isobutene is 0 to 40 ℃, preferably 0 to 10 ℃.
In summary, compared with the prior art, the method has at least one of the following beneficial technical effects:
1. according to the invention, the chlorine bromination reaction environment is changed, and then the chlorine is used in an organic environment, so that the use of bromine is greatly reduced, the waste of liquid bromine is avoided, the bromine does not pollute the environment, in the subsequent reaction, the generated byproduct salt is less sodium chloride, and in the organic solvent, the sodium chloride is only slightly dissolved in the alcohol organic solvent, so that the method is extremely easy to separate, has a better effect on the subsequent separation and purification of intermediates, and the yield and purity of the final product are improved to a certain extent.
2. The invention has the advantages of reducing the use of liquid bromine, greatly saving the cost, greatly promoting the process and being capable of being applied in large scale and carrying out industrial production.
3. The method slowly releases bromine through the reaction of sodium bromide and chlorine, has mild and controllable reaction and higher expensive bromine utilization rate, and does not need secondary recovery.
Drawings
FIG. 1 is a schematic illustration of the preparation process of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to fig. 1 of the embodiments of the present invention. It will be apparent that the described embodiments are some, but not all, embodiments of the invention. All other embodiments, which are obtained by a person skilled in the art based on the described embodiments of the invention, fall within the scope of protection of the invention.
Example 1
The preparation method of the intermediate of the paraquat sulfone in the experiment is as follows:
55g of hydroxylamine sulfate (0.34 mol) and 300g of water were put into a 1000ml four-necked flask, stirring was started, the temperature was lowered to 23℃after stirring uniformly, 60g of glyoxylate solution (0.41 mol, 50%) was added, and the mixture was kept at 25℃for 2 hours after the completion of the addition.
After the heat preservation is finished, the temperature is reduced to 3 ℃, 122.8g of sodium carbonate (1.13 mol) is slowly added, the pH value is regulated to about 3.5, a large amount of bubbles are generated during the feeding process, and the feeding speed is noted. And stirring for 10min, and then regulating the pH value to 3.5-4 by using 20% sodium carbonate solution.
120g of methyl isobutyl ketone (1.2 mol) and 150g of sodium bromide (1.46 mol) are added into a reaction system, the temperature is reduced to 5 ℃ after stirring for 0.5h, the chlorine is introduced for about 43.6g (0.61 mol), the reaction time is 2h, the temperature of the system is controlled to be 0-5 ℃, and the system turns green. The control was performed by Liquid Chromatography (LC) until the reaction was complete.
After heat preservation, layering, adding 66g of sodium carbonate into an organic phase, controlling the temperature to be 0-5 ℃ and introducing 22.9g of isobutene for cyclization reaction, after the reaction is completed for 1h at the temperature of 0-5 ℃, then heating to be 20 ℃ for reaction for 2h, carrying out suction filtration after the liquid phase detection reaction is qualified, evaporating mother liquor to dryness, and obtaining 126g of a mixture of 3-bromo-5, 5-dimethyl-4, 5-dihydro isoxazole and 3-chloro-5, 5-dimethyl-4, 5-dihydro isoxazole, wherein the total purity of the two substances is 96.5%, and the yield is 92.7%.
Taking a 1L four-mouth bottle, adding 50g acetonitrile and 401g MIBK at room temperature, adding 46g thiourea and 101g 48% hydrobromic acid, stirring for 1h at 20 ℃ after complete dissolution, then controlling the temperature below 35 ℃, dropwise adding 126g of a mixture of 3-bromo-5, 5-dimethyl-4, 5-dihydro-isoxazole and 3-chloro-5, 5-dimethyl-4, 5-dihydro-isoxazole, keeping the temperature at 35 ℃ after the dropwise adding is finished for 3h, precipitating white solid, heating to 50-55 ℃, distilling half of the solvent under reduced pressure, adding 561g clear water for complete dissolution, standing for layering, and obtaining 147g of 5, 5-dimethyl-4, 5-dihydro-isoxazole-3-thiourea bromate as a water phase.
Example two
The difference between this example and example one is that the amount of chlorine used was changed, and by increasing the amount of chlorine input, it was investigated how the different amounts of chlorine input affect the purity and yield of the intermediate, i.e. the intermediate, of pyriftalid, with the following changes:
after methyl isobutyl ketone and sodium bromide are added into the reaction system, the reaction system is stirred for 0.5h, then cooled to 5 ℃, and then chlorine is introduced for about 58.2g, the reaction time is 2h, and the temperature of the system is controlled to be 0-5 ℃, so that the system turns green. The control was performed by Liquid Chromatography (LC) until the reaction was complete.
After heat preservation, layering, adding 66g of sodium carbonate into an organic phase, controlling the temperature to be 0-5 ℃ and introducing 22.9g of isobutene for cyclization reaction, after the reaction is completed for 1h at the temperature of 0-5 ℃, then heating to be 20 ℃ for reaction for 2h, carrying out suction filtration after the liquid phase detection reaction is qualified, evaporating mother liquor to dryness, and obtaining 120g of a mixture of 3-bromo-5, 5-dimethyl-4, 5-dihydro isoxazole and 3-chloro-5, 5-dimethyl-4, 5-dihydro isoxazole, wherein the total purity of the two substances is 95.3%, and the yield is 87.6%.
Example III
The difference between this example and example one is that the amount of chlorine used was changed, and by reducing the amount of chlorine input, it was investigated how the different amounts of chlorine input affect the purity and yield of the intermediate, i.e. the intermediate, of pyriftalid, with the following changes:
after methyl isobutyl ketone and sodium bromide are added into the reaction system, the reaction system is stirred for 0.5h, then cooled to 5 ℃, and then chlorine is introduced into the reaction system for about 75.6g, the reaction time is 2h, and the temperature of the system is controlled to be 0-5 ℃, so that the system turns green. The control was performed by Liquid Chromatography (LC) until the reaction was complete.
After heat preservation, layering, adding 66g of sodium carbonate into an organic phase, controlling the temperature to be 0-5 ℃ and introducing 22.9g of isobutene for cyclization reaction, after the reaction is completed for 1h at the temperature of 0-5 ℃, then heating to be 20 ℃ for reaction for 2h, carrying out suction filtration after the liquid phase detection reaction is qualified, evaporating mother liquor to dryness, and obtaining 118g of a mixture of 3-bromo-5, 5-dimethyl-4, 5-dihydro isoxazole and 3-chloro-5, 5-dimethyl-4, 5-dihydro isoxazole, wherein the total purity of the two substances is 94.2%, and the yield is 85.8%.
Example IV
The difference between this example and example one is that the temperature of the chlorobromination reaction was changed by gradually increasing the chlorobromination reaction temperature, thereby exploring the effect of the chlorobromination temperature on yield and purity, and the specific changes are as follows:
after methyl isobutyl ketone and sodium bromide are added into the reaction system, the reaction system is stirred for 0.5h, then cooled to 10 ℃, and then chlorine is introduced for about 43.6g, the reaction time is 2h, and the temperature of the system is controlled between 5 and 10 ℃ so that the system turns green. The control was performed by Liquid Chromatography (LC) until the reaction was complete.
Example five
The difference between this example and example one is that the temperature of the chlorobromination reaction was changed by gradually increasing the chlorobromination reaction temperature, thereby exploring the effect of the chlorobromination temperature on yield and purity, and the specific changes are as follows:
after methyl isobutyl ketone and sodium bromide are added into the reaction system, the reaction system is stirred for 0.5h, then cooled to 15 ℃, and then chlorine is introduced for about 43.6g, the reaction time is 2h, and the temperature of the system is controlled to be 10-15 ℃ so that the system turns green. The control was performed by Liquid Chromatography (LC) until the reaction was complete.
Example six
The difference between this example and example one is that the temperature of the chlorobromination reaction was changed by gradually increasing the chlorobromination reaction temperature, thereby exploring the effect of the chlorobromination temperature on yield and purity, and the specific changes are as follows:
after methyl isobutyl ketone and sodium bromide are added into the reaction system, the reaction system is stirred for 0.5h, then cooled to 20 ℃, and then chlorine is introduced for about 43.6g, the reaction time is 2h, and the temperature of the system is controlled between 15 and 20 ℃ so that the system turns green. The control was performed by Liquid Chromatography (LC) until the reaction was complete.
Example seven
The difference between this example and example one is that the temperature of the chlorobromination reaction was changed by gradually increasing the chlorobromination reaction temperature, thereby exploring the effect of the chlorobromination temperature on yield and purity, and the specific changes are as follows:
after methyl isobutyl ketone and sodium bromide are added into the reaction system, the reaction system is stirred for 0.5h, then cooled to 25 ℃, and then chlorine is introduced for about 43.6g, the reaction time is 2h, and the temperature of the system is controlled to be 20-25 ℃, so that the system turns green. The control was performed by Liquid Chromatography (LC) until the reaction was complete.
Example eight
The difference between this example and example one is that the temperature of the chlorobromination reaction was changed by gradually increasing the chlorobromination reaction temperature, thereby exploring the effect of the chlorobromination temperature on yield and purity, and the specific changes are as follows:
after methyl isobutyl ketone and sodium bromide are added into the reaction system, the reaction system is stirred for 0.5h, then cooled to 30 ℃, and then chlorine is introduced for about 43.6g, the reaction time is 2h, and the system temperature is controlled to be 25-30 ℃ so that the system turns green. The control was performed by Liquid Chromatography (LC) until the reaction was complete.
Yield data between the different temperatures of example one and example four to example eight are as follows:
the reaction range of the chlorobromination temperature is found to be much higher than that of the prior art in the range of about 5 ℃ only, so that further example verification is required in a range of effect equivalent to that of the prior art.
Example nine
The embodiment accurately changes the above chlorobromination reaction temperature, accurately implements at about 5 ℃, sets a temperature interval between-5 ℃ and 10 ℃ for verification, and the specific implementation preparation method is basically the same as that of the embodiment one, and the specific implementation temperature and data are as follows:
comparative example one
The difference between this comparative example and example one is that the molar ratio of glyoxylic acid to chlorine is less than 1:1.5, and is carried out to investigate the effect on the yield or purity of the intermediate product of pyriftalid, the preparation method carried out is basically the same as that of example one, and the temperature and data carried out are as follows:
comparative example two
The difference between this comparative example and example one is that the molar ratio of glyoxylic acid to chlorine is greater than 1:3, and carrying out the implementation to explore the influence on the yield or purity of the intermediate product of the pyrifos-methyl, wherein the implementation preparation method is basically the same as that of the first embodiment, and the implementation of the chlorine consumption and the data are as follows:
comparative example three
The difference between this comparative example and example I is that the chlorobromination reaction is carried out at a reaction temperature of greater than 30℃and the preparation process is essentially the same as in example I, with the following temperatures and data:
comparative example four
The comparative example differs from example one in that the chlorobromination reaction is carried out at a reaction temperature below 0 c, and the preparation process is essentially the same as in example one, with the following temperatures and data:
analysis
According to the first to third examples, the purity of the intermediate of the haloxyfop-R-methyl prepared by the method is up to 94.2%, compared with the conventional intermediate of the bromohaloxynil, the feasibility of the intermediate of the haloxyfop-R-methyl is proved, and the purity of the intermediate of the haloxyfop-R-methyl is extremely similar to that of the prior art, and the yield is greatly improved.
Through the data analysis of the first embodiment and the fourth embodiment to the eighth embodiment, the technical solution of the present application has obvious improvement on the yield at about 5 ℃, the purity is not changed greatly in the process of gradually increasing the temperature, the yield is obviously reduced, and based on the finding, in the ninth further embodiment, the reaction temperature lower than 0 ℃ is found to cause obvious yield reduction of the intermediate of the fenpyr, and the reduction range is larger than the reduction range from 5 ℃ to 7 ℃.
According to the first comparison example, the yield of the intermediate of the haloxyfop-R-methyl can be obviously reduced by reducing the input of chlorine, but the purity of the intermediate of the haloxyfop-R-methyl is slightly influenced, because the chlorine amount is small, the reaction is most complete in the reaction of the whole system, and the rest 2- (hydroxyimino) acetic acid and sodium bromide can not be completely converted into the intermediate of the haloxyfop-R-methyl, so that the yield is reduced, and more impurity salts are not generated without redundant chlorine, so that the purity influence is not great.
Through the second comparison example, the purity of the intermediate of the haloxyfop-butyl is obviously reduced by improving the input amount of the chlorine, but the yield of the intermediate of the haloxyfop-butyl is not greatly influenced, because a large amount of the chlorine completely reacts the residual 2- (hydroxyimino) acetic acid with sodium bromide, the yield is increased, but the purity of the intermediate of the haloxyfop-butyl is not increased due to the auxiliary salt generated by the redundant chlorine, and the yield of the intermediate of the haloxyfop-butyl is slightly changed.
It is known from the comparative examples three and four that too high a chlorobromination reaction temperature results in reaction stagnation, so that the reaction cannot continue, and that a reaction temperature lower than 0 ℃ also results in incomplete reaction within a reaction time of 2 hours due to too slow reaction, so that the yield is lower than a normal level, and that at too high a temperature, the contact time of chlorine gas with 2- (hydroxyimino) acetic acid and sodium bromide is too short to effectively form a chlorobromination intermediate, and at too low a temperature, the reaction speed is reduced due to slow movement between activated molecules, so that the yield and purity are reduced.
While the foregoing is directed to the preferred embodiments of the present invention, it will be appreciated by those skilled in the art that various modifications and adaptations can be made without departing from the principles of the present invention, and such modifications and adaptations are intended to be comprehended within the scope of the present invention.
Claims (10)
1. The synthesis method of the halofop-butyl intermediate comprises the steps of performing condensation reaction on glyoxylic acid and hydroxylamine to generate 2- (hydroxyimino) acetic acid, performing a chlorobromination reaction on the 2- (hydroxyimino) acetic acid to generate a chlorobromination intermediate, and further performing a chlorobromination reaction on the chlorobromination intermediate and isobutene to generate the halofop-butyl intermediate, wherein the chlorobromination reaction is performed in the presence of sodium bromide and chlorine.
2. The method for synthesizing the intermediate of the metazopyr as claimed in claim 1, wherein the method comprises the following steps: the temperature of the chlorination-bromination reaction is 0-30 ℃.
3. The method for synthesizing the intermediate of the pyrifos-methyl according to claim 2, which is characterized in that: the temperature of the chlorination-bromination reaction is 0-5 ℃.
4. The method for synthesizing the intermediate of the metazopyr as claimed in claim 1, wherein the method comprises the following steps: the molar ratio of glyoxylate to sodium bromide is 1: 2-1: 3, the mol ratio of the glyoxylate to the chlorine is 1: 1.5-1: 3.
5. the method for synthesizing the intermediate of the metazopyr as claimed in claim 4, wherein the method comprises the following steps: the molar ratio of glyoxylate to sodium bromide is 1: 2.0-1: 2.1, the molar ratio of glyoxylate to chlorine is 1: 1.5-1: 2.
6. the method for synthesizing the intermediate of the metazopyr as claimed in claim 1, wherein the method comprises the following steps: the pH of the reaction system is regulated to 3.44 by sodium carbonate after the condensation reaction and before the cyclization reaction.
7. The method for synthesizing the intermediate of the metazopyr as claimed in claim 1, wherein the method comprises the following steps: the hydroxylamine is hydroxylamine sulfate or hydroxylamine hydrochloride, and the mol ratio of the glyoxylic acid to the hydroxylamine sulfate is 1: 0.8-1: 1.5, the molar ratio of glyoxylate to hydroxylamine hydrochloride is 1: 1-1: 2.
8. the method for synthesizing the intermediate of the pyrifos-methyl according to claim 7, which is characterized in that: the mol ratio of the glyoxylate to the hydroxylamine sulfate is 1: 0.8-1: 1.1, the molar ratio of glyoxylate to hydroxylamine hydrochloride is 1: 1-1: 1.5.
9. the method for synthesizing the intermediate of the metazopyr as claimed in claim 1, wherein the method comprises the following steps: the cyclization reaction is carried out in the presence of an alkaline catalyst, wherein the alkaline catalyst is sodium carbonate or potassium carbonate, and the molar ratio of the glyoxylate to the alkaline catalyst is 1: 1-1: 4.
10. the method for synthesizing the intermediate of the metazopyr as claimed in claim 1, wherein the method comprises the following steps: the reaction environment of the condensation reaction is water, the chlorobromination intermediate is dibromoaldoxime and 2-chloro-2-bromoaldoxime, the halofop-butyl intermediate is 3-bromo-5, 5-dimethyl-4, 5-dihydro isoxazole and 3-chloro-5, 5-dimethyl-4, 5-dihydro isoxazole, the reaction environment of the chlorobromination reaction is an organic solvent, and the organic solvent is one of dichloroethane, chloroform and methyl isobutyl ketone.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311637228.7A CN117603151A (en) | 2023-12-01 | 2023-12-01 | Synthesis method of topiramate intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311637228.7A CN117603151A (en) | 2023-12-01 | 2023-12-01 | Synthesis method of topiramate intermediate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117603151A true CN117603151A (en) | 2024-02-27 |
Family
ID=89954511
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311637228.7A Pending CN117603151A (en) | 2023-12-01 | 2023-12-01 | Synthesis method of topiramate intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117603151A (en) |
-
2023
- 2023-12-01 CN CN202311637228.7A patent/CN117603151A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN113135867B (en) | S- (5, 5-dimethyl-4, 5-dihydroisoxazol-3-yl) ethyl acetate and synthetic method and application thereof | |
| CN113336716B (en) | Preparation method of topramezone intermediate | |
| CN111393427A (en) | Synthetic method of sulfuryl pyraflufen | |
| CN113754648B (en) | Preparation method of xaflufen and intermediate thereof | |
| CN113754647B (en) | Synthesis method of sulfuryl pyraflufen-ethyl and intermediate thereof | |
| US20160318859A1 (en) | Florfenicol synthesizing method | |
| CN113831333B (en) | Synthesis method of pyrifos | |
| NO159274B (en) | ANALOGUE PROCEDURE FOR THE PREPARATION OF PHENYL-ALIFATIC-ISOXAZOLS FOR FIGHTING VIRUSES. | |
| CN112079848A (en) | Synthesis method of baroxavir key intermediate | |
| CN117603151A (en) | Synthesis method of topiramate intermediate | |
| CN117417333A (en) | Synthesis process of pyribenzoxim sulfone | |
| CN100506820C (en) | (S)-nifuratel, preparation method and application thereof | |
| CN115073441B (en) | Synthesis method of topiramate intermediate | |
| CN114957233A (en) | Sulfoxapyrazole and preparation method thereof | |
| CN114292228A (en) | Synthetic method of clodinafop-propargyl | |
| CN106565560A (en) | Synthesis process of mesotrione | |
| JPS62192372A (en) | Manufacture of 2-((2-chlorophenyl)methyl)-4,4-dimethyl-3- isoxazolidinone | |
| CN109232456B (en) | 3-methyl-4-nitro-5- (2-aryl-2-trifluoromethyl) cyclopropyl isoxazole compound and preparation method thereof | |
| CN117229273B (en) | Preparation method of metazachlor and intermediate thereof | |
| CN102304125B (en) | Intermediate for preparing linezolid | |
| CN105924400B (en) | The preparation method of Azilsartan impurity A and B | |
| CN105669613B (en) | The production method of highy potent herbicide flurtamone | |
| CN106748919A (en) | A kind of synthesis technique of mesotrione | |
| CN106631736A (en) | Method for preparing 3,5-dichloro-2-pentanone | |
| SU189434A1 (en) | METHOD OF OBTAINING 3,5-DESIGNED ISOXAZOL-4-CARBONIC ACIDS |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |