CN114644577A - Environment-friendly preparation method of substituted isonitrile compound - Google Patents
Environment-friendly preparation method of substituted isonitrile compound Download PDFInfo
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- CN114644577A CN114644577A CN202011508780.2A CN202011508780A CN114644577A CN 114644577 A CN114644577 A CN 114644577A CN 202011508780 A CN202011508780 A CN 202011508780A CN 114644577 A CN114644577 A CN 114644577A
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- dehydrating agent
- halide reagent
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- -1 isonitrile compound Chemical class 0.000 title claims abstract description 88
- 238000002360 preparation method Methods 0.000 title abstract description 20
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 49
- 239000012024 dehydrating agents Substances 0.000 claims abstract description 39
- 238000006243 chemical reaction Methods 0.000 claims abstract description 33
- 238000000034 method Methods 0.000 claims abstract description 31
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 28
- 150000001266 acyl halides Chemical class 0.000 claims abstract description 28
- 150000003003 phosphines Chemical class 0.000 claims abstract description 28
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 28
- 150000001412 amines Chemical class 0.000 claims abstract description 22
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 17
- AUONHKJOIZSQGR-UHFFFAOYSA-N oxophosphane Chemical class P=O AUONHKJOIZSQGR-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000006227 byproduct Substances 0.000 claims abstract description 8
- 239000011574 phosphorus Substances 0.000 claims abstract description 6
- 229910052698 phosphorus Inorganic materials 0.000 claims abstract description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 36
- 150000001875 compounds Chemical class 0.000 claims description 33
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- 239000002253 acid Substances 0.000 claims description 23
- 125000003118 aryl group Chemical group 0.000 claims description 23
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 22
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 21
- 239000012074 organic phase Substances 0.000 claims description 17
- 150000004820 halides Chemical class 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 16
- 238000004821 distillation Methods 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 10
- 150000002431 hydrogen Chemical class 0.000 claims description 10
- 239000012071 phase Substances 0.000 claims description 10
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical group C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 6
- LWYAOXMPTVOERN-UHFFFAOYSA-N ethyl 2-formamidopropanoate Chemical compound CCOC(=O)C(C)NC=O LWYAOXMPTVOERN-UHFFFAOYSA-N 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 5
- 239000011780 sodium chloride Substances 0.000 claims description 5
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical group CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical group ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- ASWXNYNXAOQCCD-UHFFFAOYSA-N dichloro(triphenyl)-$l^{5}-phosphane Chemical group C=1C=CC=CC=1P(Cl)(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 ASWXNYNXAOQCCD-UHFFFAOYSA-N 0.000 claims description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- 125000003107 substituted aryl group Chemical group 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- OCXGTPDKNBIOTF-UHFFFAOYSA-N dibromo(triphenyl)-$l^{5}-phosphane Chemical compound C=1C=CC=CC=1P(Br)(C=1C=CC=CC=1)(Br)C1=CC=CC=C1 OCXGTPDKNBIOTF-UHFFFAOYSA-N 0.000 claims description 3
- 238000003786 synthesis reaction Methods 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 claims description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- 229940049953 phenylacetate Drugs 0.000 claims description 2
- 150000003017 phosphorus Chemical class 0.000 claims description 2
- MDDUHVRJJAFRAU-YZNNVMRBSA-N tert-butyl-[(1r,3s,5z)-3-[tert-butyl(dimethyl)silyl]oxy-5-(2-diphenylphosphorylethylidene)-4-methylidenecyclohexyl]oxy-dimethylsilane Chemical class C1[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)C(=C)\C1=C/CP(=O)(C=1C=CC=CC=1)C1=CC=CC=C1 MDDUHVRJJAFRAU-YZNNVMRBSA-N 0.000 claims description 2
- 125000005270 trialkylamine group Chemical group 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- IJMLGTYJAKFUEG-UHFFFAOYSA-N butyl 2-formamido-2-phenylacetate Chemical compound CCCCOC(C(C1=CC=CC=C1)NC=O)=O IJMLGTYJAKFUEG-UHFFFAOYSA-N 0.000 claims 1
- XYAQYTADJIMJOD-UHFFFAOYSA-N butyl 2-formamidopropanoate Chemical compound CCCCOC(=O)C(C)NC=O XYAQYTADJIMJOD-UHFFFAOYSA-N 0.000 claims 1
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 abstract description 12
- 239000002351 wastewater Substances 0.000 abstract description 9
- 239000000047 product Substances 0.000 abstract description 8
- 239000003795 chemical substances by application Substances 0.000 abstract description 5
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 abstract description 5
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 abstract description 5
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 abstract description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 abstract description 3
- 239000004471 Glycine Substances 0.000 abstract description 3
- 239000000543 intermediate Substances 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000007858 starting material Substances 0.000 abstract description 2
- 229960001701 chloroform Drugs 0.000 description 11
- 239000002994 raw material Substances 0.000 description 8
- 239000011259 mixed solution Substances 0.000 description 6
- 238000001514 detection method Methods 0.000 description 4
- FKRCODPIKNYEAC-UHFFFAOYSA-N propionic acid ethyl ester Natural products CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 4
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 description 4
- 238000005292 vacuum distillation Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 230000018044 dehydration Effects 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- 150000002527 isonitriles Chemical class 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000012433 hydrogen halide Substances 0.000 description 2
- 229910000039 hydrogen halide Inorganic materials 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 2
- 238000005086 pumping Methods 0.000 description 2
- RADKZDMFGJYCBB-UHFFFAOYSA-N pyridoxal hydrochloride Natural products CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 239000011726 vitamin B6 Substances 0.000 description 2
- 235000019158 vitamin B6 Nutrition 0.000 description 2
- 229940011671 vitamin b6 Drugs 0.000 description 2
- AZTYHYHSDPMHRA-UHFFFAOYSA-N 2-formamido-2-phenylacetic acid Chemical compound O=CNC(C(=O)O)C1=CC=CC=C1 AZTYHYHSDPMHRA-UHFFFAOYSA-N 0.000 description 1
- SRBATDDRZARFDZ-UHFFFAOYSA-N 2-formamidopropanoic acid Chemical compound OC(=O)C(C)NC=O SRBATDDRZARFDZ-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 239000003674 animal food additive Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000002912 waste gas Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C291/00—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00
- C07C291/10—Isocyanides
Abstract
The invention provides an environment-friendly preparation method of a substituted isonitrile compound, which uses N-formyl-alpha-R2The substituted glycine ester is used as a starting material, and is subjected to dehydration reaction under the action of a dehydrating agent such as trisubstituted phosphine dihalide, a combination of trisubstituted phosphine dihalide and an acyl halide reagent or a combination of trisubstituted phosphine oxide and an acyl halide reagent and organic amine to obtain the substituted isonitrile compound. The obtained substituted isonitrile compound is synthesized VB6An important intermediate of (2). The invention can be carried out in a continuous flow mode, improves the production efficiency and reduces the operation. The by-product trisubstituted phosphine oxide in the reaction process can be recycled, so that the cost is reduced; the method does not use phosphorus oxychloride and phosphorus pentoxide which are high in price and large in wastewater amount in the preparation process as dehydrating agents, does not need high-temperature dehydration reaction, and is simple and convenient in process and operation, free of phosphorus-containing wastewater discharge in the process, green, environment-friendly and low in cost; high atom economy, high yield and purity of target products and suitability for industrial application.
Description
Technical Field
The invention relates to an environment-friendly preparation method of a substituted isonitrile compound, belonging to the technical field of pharmaceutical biochemical industry.
Background
Substituted isonitrile compounds, namely isonitrile alkyl acid ester compounds, are important intermediates for preparing 4-methyl-5-alkoxy oxazole (US20030120082), and 4-methyl-5-alkoxy oxazole is an important intermediate for synthesizing vitamin B6. Vitamin B6 is one of essential vitamins for human and animals, plays a key role in the growth process of animals and human bodies, and is widely used in the fields of medicine, food, feed additives, cosmetics industry and the like.
At present, the synthesis of isonitrile alkyl acid ester compounds mainly adopts N-formamido alkyl acid ester as a raw material, and the reaction route is as follows:
with regard to the synthesis of isonitrile alkanoate compounds, the documents "Chemische berg 108, 1580-; in the existing method, organic base such as triethylamine is generally used as an acid-removing agent, and phosphorus oxychloride, phosphorus pentachloride, acetyl chloride, acetic anhydride and the like are used as dehydrating agents; however, the reaction yield (60 to 70%) is low.
Patent document DE3029231 discloses the preparation of isonitrile alkanoate compounds in yields of 90% or more by high temperature reaction in the presence of organic amines using phosphorus pentoxide as a dehydrating agent. But the industrial use of the phosphorus pentoxide is difficult; the reaction temperature is high, heat release is severe during hydrolysis, and the safety risk is high; meanwhile, a large amount of phosphorus-containing wastewater is generated and is difficult to treat.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides an environment-friendly preparation method of a substituted isonitrile compound. The substituted isonitrile compound is prepared by taking N-formamidoalkyl ester as an initial raw material and utilizing easily obtained tri-substituted phosphine dihalide, the combination of tri-substituted phosphine dihalide and acyl halide reagent or the combination of tri-substituted phosphine oxide and acyl halide reagent as a dehydrating agent, and the by-product tri-substituted phosphine oxide can be recycled, so that the cost is reduced. The method does not use dehydrating agents such as phosphorus oxychloride and phosphorus pentoxide and the like which are high in price, large in preparation process wastewater amount and high in safety risk, does not need high-temperature dehydration reaction, is short in reaction time, simple and convenient to operate, does not discharge phosphorus-containing wastewater in the process, only contains sodium chloride monosalt in the wastewater, is green, safe and environment-friendly, and is low in cost; the target product has high yield and purity, and is suitable for industrial application.
Description of terms:
a compound of formula I: an isonitrile alkanoic acid ester, i.e., a substituted isonitrile compound;
a compound of formula II: N-formyl-alpha-R2A substituent glycine ester.
The technical scheme of the invention is as follows:
a method for preparing a substituted isonitrile compound, comprising the steps of:
preparing a substituted isonitrile compound (I) by a compound of a formula II through a dehydration reaction in a solvent A under the action of a dehydrating agent and organic amine; the dehydrating agent is trisubstituted phosphine dihalide, the combination of trisubstituted phosphine dihalide and acyl halide reagent, or the combination of trisubstituted phosphine oxide and acyl halide reagent;
wherein, the compound of formula I and II has the structural formula:
R1is hydrogen, CnH2n+1A linear or branched group of 1 ≦ n ≦ 10, an aromatic group or a substituted aromatic group;
R2is hydrogen, CnH2n+11 < n < 10, an aromatic group or a substituted aromatic group.
Preferred according to the invention are compounds of the formulae I and II in which R1Is C1-4 alkyl, preferably ethyl or butyl.
According to the invention, the compounds of formula I and II are preferably represented by the formula,R2is methyl or phenyl.
Preferably, according to the invention, the compound of formula ii is: ethyl N-formyl-alpha-methylglycine, butyl N-formyl-alpha-methylglycine or butyl N-formyl-alpha-phenylglycine.
According to a preferred embodiment of the invention, the compound of the formula I is ethyl α -isonitrile propionate, butyl α -isonitrile propionate or butyl α -isonitrile phenylacetate.
Preferably, the solvent A is one or a combination of dichloromethane, chloroform, n-hexane, cyclohexane, petroleum ether, n-heptane, xylene, chlorobenzene, benzene, toluene, dimethyl sulfoxide, trichloromethane, trichloroethane or dichloroethane; the mass ratio of the solvent A to the compound shown in the formula II is (0.5-20.0) to 1; preferably, the mass ratio of the solvent A to the compound of the formula II is (3.0-15.0): 1.
According to a preferred embodiment of the invention, the organic amine is a trialkylamine and the alkyl group has the general formula CnH2n+11 ≦ n ≦ 10; preferably, the alkyl group is methyl, ethyl, isopropyl, n-propyl, isobutyl or n-butyl; further preferably, the organic amine is triethylamine; the molar ratio of the organic amine to the compound of the formula II is (1.8-4.0) to 1; preferably (2.0-3.0): 1.
Preferably, according to the present invention, the trisubstituted phosphine dihalide has the structural formula shown in formula III:
wherein in the compound of formula III, Ra、Rb、RcSelected from methyl, ethyl, C3-C10 straight chain or branched chain alkyl, aryl or substituted aryl; preferably, Ra、Rb、RcSelected from phenyl or isobutyl; r isa、Rb、RcThe same or different;
X1、X2is halogen, X1、X2Preferably chlorine or bromine; x1、X2Identical or different, preferably identical.
Preferably, in the compound of formula III, when R isa、Rb、RcWhen the aryl is aryl, the structure is shown as the following formula IV;
in the structural formula shown in the formula IV, m is 0, 1, 2, 3, 4 or 5, R4Is hydrogen, CnH2n+1A linear or branched alkyl group, 1 ≦ n ≦ 10, or a halogen; further preferably, R4Is hydrogen. The structural formula shown in formula IV: with m radicals R4Respectively and randomly connecting six carbon atoms of a benzene ring; and m substituents may be the same or different.
Preferably, the trisubstituted phosphine dihalide is triphenylphosphine dichloride or triphenylphosphine dibromide.
Preferably according to the invention, the acid halide reagent is a sulfuryl halide, a thionyl halide, an oxalyl halide, a carbonyl halide or triphosgene; preferably, the acid halide reagent is an acid chloride reagent; further preferably, the acid halide reagent is phosgene or triphosgene.
According to the invention, the trisubstituted phosphine oxide has a structural formula: rdReRfP＝O；
Wherein R isd、Re、RfSelected from C1-10 straight chain or branched chain alkyl, aryl or substituted aryl; rd、Re、RfThe same or different.
Preferably, in the trisubstituted phosphine oxide formula, when R isd、Re、RfWhen the aryl is aryl, the structure is shown as the following formula V;
in the structural formula shown in the formula V, m is 0, 1, 2, 3, 4 or 5, R4Is hydrogen, CnH2n+1A linear or branched alkyl group, 1 ≦ n ≦ 10, orHalogen; further preferably, R4Is hydrogen or methyl. The structural formula shown in formula V represents: with m radicals R4Respectively and randomly connecting six carbon atoms of a benzene ring; and m substituents may be the same or different.
Preferably, the trisubstituted phosphine oxide is triphenylphosphine oxide or tris-p-methylphenylphosphine oxide.
Preferably according to the invention, when the dehydrating agent is a trisubstituted phosphine dihalide, the molar ratio of trisubstituted phosphine dihalide to compound of formula II is (0.01-5.0): 1; preferably, the molar ratio of trisubstituted phosphine dihalide to compound of formula II is (0.1-1.5): 1.
Preferably according to the invention, when the dehydrating agent is a combination of a tri-substituted phosphine oxide and an acid halide reagent, the molar ratio of the acid halide reagent to the compound of formula II is (0.1-2.0):1, the molar ratio of the tri-substituted phosphine oxide to the compound of formula II is (0.01-5.0): 1; preferably, the molar ratio of the acyl halide reagent to the compound of formula II is (0.3-1):1, and the molar ratio of the trisubstituted phosphine oxide to the compound of formula II is (0.1-1.5): 1.
Preferably according to the invention, when the dehydrating agent is a combination of a trisubstituted phosphine dihalide and an acid halide reagent, the molar ratio of the acid halide reagent to the compound of formula II is (0.1-2.0):1, and the molar ratio of the trisubstituted phosphine dihalide to the compound of formula II is (0.01-5.0): 1; preferably, the molar ratio of the acid chloride reagent to the compound of formula II is (0.5-1.5):1, and the molar ratio of the trisubstituted phosphine dihalide to the compound of formula II is (0.05-1.0): 1.
According to the invention, the preferable dehydration reaction temperature is-100-30 ℃; preferably-10 to 10 ℃. The dehydration reaction time is 0.2 to 10 hours, preferably 0.2 to 5 hours.
Preferably, according to the present invention, when a combination of a tri-substituted phosphorus oxide and an acid halide reagent or a combination of a tri-substituted phosphine dihalide and an acid halide reagent, which is added dropwise to the system, is used as the dehydrating agent, the substituted isonitrile compound can be synthesized in a batch manner.
When a combination of a tri-substituted phosphorus oxide and an acid halide reagent or a combination of a tri-substituted phosphine dihalide and an acid halide reagent is used as the dehydrating agent, it is preferable according to the present invention to synthesize the substituted isonitrile compound in a continuous flow manner by feeding the dehydrating agent/organic amine/the compound of formula ii alone or in combination of any two thereof continuously.
Preferably, according to the present invention, when a trisubstituted phosphorus dihalide is used as the dehydrating agent, the substituted isonitrile compound can be synthesized in a continuous flow manner by feeding the dehydrating agent/organic amine/compound of formula II alone or in combination with any two of them continuously.
According to the present invention, the continuous flow method used for synthesizing the substituted isonitrile compound can be: kettle type continuous reaction, pipeline type continuous reaction, tower type continuous reaction, microchannel reactor and the like.
According to the invention, the compound shown in the formula II is dehydrated to obtain a reaction liquid, and the obtained reaction liquid is subjected to post-treatment to obtain the substituted isonitrile compound (I), wherein the post-treatment method comprises the following steps: adding water into the obtained reaction liquid, layering, extracting the obtained water layer by using a solvent A, and combining organic phases to obtain a water phase and an organic phase; distilling the organic phase to recover the solvent A, and then carrying out reduced pressure distillation to obtain a substituted isonitrile compound (I); the obtained water phase or the residues of reduced pressure distillation contain trisubstituted phosphine oxide, and the trisubstituted phosphine dihalide can be prepared by reacting with acyl halide reagent to be used as dehydrating agent or directly recycled to be used as dehydrating agent; the obtained water phase can be neutralized by sodium hydroxide, and then organic amine is recovered by distillation, and sodium chloride is a byproduct.
According to the invention, when the dehydrating agent is the combination of the tri-substituted phosphine oxide and the acyl halide reagent, the tri-substituted phosphine oxide and the acyl halide reagent can generate the tri-substituted phosphine dihalide in situ, and then the dehydrating effect is further realized.
According to the method, organic amine is used as an acid-binding agent to generate organic amine hydrochloride with byproduct hydrogen chloride in the reaction process, then sodium hydroxide and the organic amine hydrochloride are used for neutralization, and finally, the organic amine is recovered and the byproduct sodium chloride is produced.
The preparation method of the substituted isonitrile compound has the following reaction route:
wherein, the compound of formula I and II has the structural formula: r1Is hydrogen, CnH2n+1A linear or branched group of 1 ≦ n ≦ 10, an aromatic group or a substituted aromatic group; r2Is hydrogen, CnH2n+11 < n < 10, an aromatic group or a substituted aromatic group.
The invention has the technical characteristics and beneficial effects that:
1. the invention provides a novel environment-friendly method for preparing substituted isonitrile compounds by dehydration; with N-formyl-alpha-R2Taking substituent glycine ester (II) as an initial raw material, and carrying out dehydration reaction under the action of a tri-substituted phosphine dihalide, a combination of the tri-substituted phosphine dihalide and an acyl halide reagent or a combination of the tri-substituted phosphine oxide and the acyl halide reagent as a dehydrating agent and an organic amine to obtain a substituted isonitrile compound (I).
2. The whole reaction process of the invention can be understood as follows: removing one molecule of water from the compound shown in the formula II through dehydration reaction, reacting the water with tri-substituted phosphine dihalide to generate tri-substituted phosphine oxide and two molecules of hydrogen halide, and reacting the two molecules of hydrogen halide with organic amine serving as an acid-binding agent to generate organic amine hydrochloride. The dehydrating agent used in the method is trisubstituted phosphine dihalide, the combination of trisubstituted phosphine dihalide and acyl halide reagent or the combination of trisubstituted phosphine oxide and acyl halide reagent; when the dehydrating agent is the combination of trisubstituted phosphine dihalide and acyl halide reagent, the trisubstituted phosphine dihalide is converted into trisubstituted phosphine oxide after dehydration reaction, and the trisubstituted phosphine oxide and the acyl halide reagent react in situ to generate the trisubstituted phosphine dihalide which can continuously participate in the dehydration reaction; when the dehydrating agent is the combination of the trisubstituted phosphine oxide and the acyl halide reagent, the acyl halide reagent enables the trisubstituted phosphine oxide to generate the trisubstituted phosphine dihalide in situ, and then the dehydrating reaction is carried out. In the preparation process, only sodium chloride and byproduct gas such as sulfur dioxide or carbon dioxide are generated, and the production amount of waste water and waste gas is less, so that the preparation method is green and environment-friendly. The dehydrating agent is easy to prepare; the byproduct tri-substituted phosphine oxide can be recycled when the substituted isonitrile compound is prepared for reaction, and the tri-substituted phosphine oxide is easy to be quantitatively converted into tri-substituted phosphine dihalide, so that the cost is reduced, the recycling of materials is realized, and the concept of environmental protection and atom economy is met. The preparation of the substituted isonitrile compound can be carried out in a continuous flow mode, so that the production efficiency is improved, and the operation is reduced; the method does not use dehydrating agents such as phosphorus oxychloride and phosphorus pentoxide with high price, large wastewater amount of the preparation process and high safety risk, does not need high-temperature dehydration reaction, and has the advantages of simple process, simple and convenient operation, no discharge of phosphorus-containing wastewater in the process, environmental protection and low cost.
3. The method has the advantages of high reaction activity, good reaction selectivity, high atom economy, high product yield and purity, high yield of more than 95 percent and high purity of more than 99 percent, and is suitable for industrial application.
Detailed Description
The present invention is described in detail below with reference to examples, but the present invention is not limited thereto.
In the examples, "%" is a mass percentage unless otherwise specified.
The yields in the examples are all molar yields.
The starting materials and reagents used in the examples are either commercially available products or are prepared according to the prior art.
Performing gas phase detection by using Shimadzu Gas Chromatograph (GC) with instrument model of GC-1020PLUS for reaction monitoring and purity detection; some of the purity was measured by high performance liquid chromatography and is indicated as HPLC.
Example 1: preparation of alpha-Isonitrilopropionic acid ethyl ester
Adding 6215g of triphenylphosphine dichloride toluene solution (containing 1000g of triphenylphosphine dichloride) into a mixing kettle, adding 435g (3mol) of N-formyl-alpha-methylglycine ethyl ester, and uniformly mixing; and (2) adopting a kettle type continuous reaction, enabling the obtained mixed solution to enter a continuous reactor at the speed of 110g/min, pumping 665 g of triethylamine into the continuous reactor at the speed of 11g/min for reaction, controlling the reaction temperature to be-10-0 ℃, keeping the reaction time for 15-35 minutes, allowing a solid-liquid mixture to flow out of the reactor, adding 2000ml of water for hydrolysis, layering, and adding 2000ml of toluene into a water phase for extraction. The toluene phases were combined, the solvent was recovered by distillation under reduced pressure, and 371 g of ethyl α -isonitrile propionate was obtained by high vacuum distillation with a GC purity of 99% and a yield of 96.3%.
The main component of the residue after high vacuum distillation is triphenylphosphine oxide, and the method can be repeatedly used for preparing the dehydrating agent.
The nuclear magnetic data of the product obtained are as follows:
1HNMR:1.29(3H,t)，1.62(3H,d)，4.21(2H,q)，4.53(1H,q)。
example 2: preparation of n-butyl alpha-isonitrile propionate
Adding 6130g of triphenyl phosphorus dibromide dichloromethane solution (containing 1300g of triphenyl phosphorus dibromide) into a mixing kettle, adding 519.6g of N-formyl-alpha-methyl glycine N-butyl ester, and uniformly mixing; and (2) adopting a kettle type continuous reaction, enabling the obtained mixed solution to enter a continuous reactor at the speed of 110g/min, pumping 660 g of triethylamine into the continuous reactor at the speed of 11g/min for reaction, controlling the reaction temperature to be-10-0 ℃, keeping the reaction time for 55-65 minutes, allowing a solid-liquid mixture to flow out of the reactor, adding 2000ml of water for hydrolysis and layering, and adding 2000ml of dichloromethane into a water phase for extraction. The organic phases were combined, the solvent was recovered by distillation, and high vacuum distillation was carried out to give 453.84 g of n-butyl α -isonitrile propionate with a GC purity of 99% and a yield of 96.5%.
The main component of the residue after high vacuum distillation is triphenylphosphine oxide, and the method can be repeatedly used for preparing the dehydrating agent.
The nuclear magnetic data of the product obtained are as follows:
1HNMR:0.98(3H,t)，1.33(2H,m)，1.55(2H,m)，1.62(3H,d)，4.22(2H,t)，4.46(1H,q)。
example 3: preparation of alpha-isonitrile ethyl propionate
Adding 100 g of toluene, 3.4 g (0.01 mol) of triphenylphosphine dichloride, 14.5 g (0.1 mol) of ethyl N-formyl-alpha-methylglycinate, 20.8 g (0.206 mol) of triethylamine, dropwise adding a mixed solution of 9.9 g (0.1 mol) of phosgene and 50 g of toluene at-10-5 ℃, finishing dropwise adding within 2 hours, reacting at 0-5 ℃ for 1 hour, detecting that the raw materials are reacted, adding 30g of water, layering, extracting the obtained water layer twice (using 30g in total) by using toluene, combining organic phases, distilling and recovering the toluene at normal pressure from the organic phases, and then distilling under reduced pressure to obtain 12 g of ethyl alpha-isonitrile propionate, wherein the yield is 94%, and the GC purity is 99%; the main component of the residue after reduced pressure distillation is triphenylphosphine oxide, which can be repeatedly used for preparing the dehydrating agent.
Example 4: preparation of alpha-isonitrile ethyl propionate
100 g of toluene, the residue after reduced pressure distillation in example 3 (the main component is triphenyl phosphorus oxide), 0.4 g of triphenyl phosphorus oxide, 14.5 g (0.1 mol) of ethyl N-formyl-alpha-methylglycinate, 20.8 g (0.206 mol) of triethylamine in example 3, 9.9 g (0.1 mol) of a mixed solution of phosgene and 50 g of toluene are dropwise added between 10 ℃ and 5 ℃, dropwise addition is completed within 2 hours, reaction is completed at 0 ℃ to 5 ℃, detection is performed on the reaction of raw materials, 30g of water is added for layering, an obtained water layer is extracted twice by toluene (30 g is used in total), organic phases are combined, the organic phase is distilled at normal pressure to recover toluene, and then reduced pressure distillation is performed to obtain 12 g of ethyl alpha-isonitrile propionate, the yield is 94%, and the GC purity is 99%.
Example 5: preparation of n-butyl alpha-isonitrile propionate
Adding 100 g of chloroform, 2.78 g (0.01 mol) of triphenylphosphine oxide, 17.3 g (0.1 mol) of N-formyl-alpha-methylglycine N-butyl ester, dropwise adding a mixed solution of 30g of chloroform and 10.0 g (0.034 mol) of triphosgene into a 500 ml four-neck flask within 2 hours at the temperature of-15-5 ℃, simultaneously dropwise adding 24.3 g (0.24 mol) of triethylamine, reacting at the temperature of 0-5 ℃ for 2 hours after double dropwise adding, detecting the reaction of raw materials, adding 30g of water, layering, extracting an obtained water layer twice (using 40 g in total) by using chloroform, combining organic phases, distilling the organic phases at normal pressure to recover solvents and other impurities, and then distilling under reduced pressure to obtain 15.05 g of alpha-isonitrile N-butyl propionate, wherein the yield is 96%, and the GC purity is 99%; the main component of the residue after reduced pressure distillation is triphenylphosphine oxide which can be repeatedly used as a dehydration catalyst.
Example 6: preparation of alpha-isonitrile n-butyl phenylacetate
Adding 100 g of chloroform, 3.2 g (0.01 mol) of tri-p-methylphenyl phosphine oxide, 23.5 g (0.1 mol) of N-formyl-alpha-phenylglycine N-butyl ester into a 500 ml four-neck flask, dropwise adding a mixed solution of 30g of chloroform and 10.0 g (0.034 mol) of triphosgene into the flask within 2 hours at the temperature of-15-5 ℃, simultaneously dropwise adding 24.3 g (0.24 mol) of triethylamine, reacting at the temperature of 0-5 ℃ for 2 hours, detecting the reaction of raw materials, adding 30g of water, layering, extracting an obtained water layer twice (using 40 g in total) by using chloroform, combining organic phases, distilling the organic phase at normal pressure to recover solvents and other impurities, and then distilling under reduced pressure to obtain 20.42 g of alpha-isonitrile phenylacetic acid N-butyl ester, wherein the yield is 94%, and the GC purity is 99%; the main component of the residue after reduced pressure distillation is triphenylphosphine oxide which can be repeatedly used as a dehydration catalyst.
The nuclear magnetic data of the product obtained are as follows:
1HNMR:0.98(3H,t)，1.33(2H,m)，1.55(2H,m)，4.21(2H,m)，5.64(1H,s)，7.29(2H,dd)，7.33(1H,dd)，7.44(2H,d)。
comparative example 1: preparation of alpha-isonitrile ethyl propionate
100 g of trichloromethane, 15.6 g of phosphorus oxychloride and 14.5 g (0.1 mol) of N-formyl-alpha-methylglycine ethyl ester are added into a 500 ml flask, 25 g of triethylamine is dropwise added at 10-30 ℃ within 2 hours, then the reaction is carried out for 1 hour at 65 ℃, 30g of water is added after the detection of the completion of the reaction of the raw materials, the layers are separated, the obtained water layer is extracted twice by 30g of trichloromethane, the organic phase is combined, the trichloromethane is recovered by atmospheric distillation of the organic phase, then 9.1 g of alpha-isonitrile ethyl propionate is obtained by reduced pressure distillation, the GC purity is 99%, and the yield is 71.57%.
As can be seen from this comparative example, the yield of the product is low by using phosphorus oxychloride as the dehydrating agent.
Claims (10)
1. A method for preparing a substituted isonitrile compound, comprising the steps of:
preparing a substituted isonitrile compound (I) by a compound of a formula II through a dehydration reaction in a solvent A under the action of a dehydrating agent and organic amine; the dehydrating agent is trisubstituted phosphine dihalide, the combination of trisubstituted phosphine dihalide and acyl halide reagent, or the combination of trisubstituted phosphine oxide and acyl halide reagent;
wherein, the compound of formula I and II has the structural formula:
R1is hydrogen, CnH2n+1A linear or branched group of 1 ≦ n ≦ 10, an aromatic group or a substituted aromatic group;
R2is hydrogen, CnH2n+1A linear or branched group of 1 ≦ n ≦ 10, an aromatic group or a substituted aromatic group;
preferably, R1Is C1-4 alkyl, more preferably ethyl or butyl;
preferably, R2Is methyl or phenyl.
2. The method of claim 1, wherein the compound of formula ii is ethyl N-formyl- α -methylglycinate, butyl N-formyl- α -methylglycinate, or butyl N-formyl- α -phenylglycinate.
3. The method of claim 1, wherein the compound of formula i is ethyl α -isonitrile propionate, butyl α -isonitrile propionate, or butyl α -isonitrile phenylacetate.
4. The method of claim 1, wherein the solvent A is one or a combination of dichloromethane, chloroform, n-hexane, cyclohexane, petroleum ether, n-heptane, xylene, chlorobenzene, benzene, toluene, dimethylsulfoxide, chloroform, trichloroethane, or dichloroethane.
5. The method of claim 1, wherein the organic amine is a trialkylamine, and the alkyl group has the formula CnH2n+11 ≦ n ≦ 10; preferably, the alkyl group is methyl, ethyl, isopropyl, n-propyl, isobutyl or n-butyl; further preferably, the organic amine is triethylamine.
6. The method for preparing a substituted isonitrile compound according to claim 1, wherein the trisubstituted phosphine dihalide has a structural formula shown in formula III:
wherein, in the compound of formula III, Ra、Rb、RcSelected from methyl, ethyl, C3-C10 straight chain or branched chain alkyl, aryl or substituted aryl; preferably, Ra、Rb、RcSelected from phenyl or isobutyl; ra、Rb、RcThe same or different;
X1、X2is halogen, X1、X2Preferably chlorine or bromine; x1、X2Identical or different, preferably identical;
preferably, in the compound of formula III, when R isa、Rb、RcWhen it is aryl, it has the structure shown in formula IV；
In the structural formula shown in the formula IV, m is 0, 1, 2, 3, 4 or 5, R4Is hydrogen, CnH2n+1A linear or branched alkyl group, 1 ≦ n ≦ 10, or a halogen; further preferably, R4Is hydrogen;
preferably, the trisubstituted phosphine dihalide is triphenylphosphine dichloride or triphenylphosphine dibromide.
7. The method of claim 1, wherein the acid halide reagent is a sulfuryl halide, a thionyl halide, an oxalyl halide, a carbonyl halide or triphosgene; preferably, the acid halide reagent is an acid chloride reagent; further preferably, the acid halide reagent is phosgene or triphosgene.
8. The method of claim 1, wherein the trisubstituted phosphine oxide has the following structural formula: rdReRfP＝O；
Wherein R isd、Re、RfSelected from C1-10 straight chain or branched chain alkyl, aryl or substituted aryl; rd、Re、RfThe same or different;
preferably, in the trisubstituted phosphine oxide formula, when R isd、Re、RfWhen the aryl is aryl, the structure is shown as the following formula V;
in the structural formula shown in the formula V, m is 0, 1, 2, 3, 4 or 5, R4Is hydrogen, CnH2n+1A linear or branched alkyl group, 1 ≦ n ≦ 10, or a halogen; further preferably, R4Is hydrogen or methyl；
Preferably, the trisubstituted phosphine oxide is triphenylphosphine oxide or tris-p-methylphenylphosphine oxide.
9. The method of claim 1, wherein the method comprises one or more of the following conditions:
a) the mass ratio of the solvent A to the compound shown in the formula II is (0.5-20.0): 1; preferably, the mass ratio of the solvent A to the compound of the formula II is (3.0-15.0): 1;
b) the molar ratio of the organic amine to the compound shown in the formula II is (1.8-4.0): 1; preferably (2.0-3.0): 1;
c) when the dehydrating agent is trisubstituted phosphine dihalide, the molar ratio of the trisubstituted phosphine dihalide to the compound in the formula II is (0.01-5.0): 1; preferably, the molar ratio of the trisubstituted phosphine dihalide to the compound of formula II is (0.1-1.5): 1;
d) when the dehydrating agent is the combination of the tri-substituted phosphine oxide and the acyl halide reagent, the molar ratio of the acyl halide reagent to the compound of the formula II is (0.1-2.0) to 1, and the molar ratio of the tri-substituted phosphine oxide to the compound of the formula II is (0.01-5.0) to 1; preferably, the molar ratio of the acyl halide reagent to the compound of formula II is (0.3-1):1, and the molar ratio of the trisubstituted phosphine oxide to the compound of formula II is (0.1-1.5): 1;
e) when the dehydrating agent is the combination of the tri-substituted phosphine dihalide and the acyl halide reagent, the molar ratio of the acyl halide reagent to the compound of the formula II is (0.1-2.0):1, and the molar ratio of the tri-substituted phosphine dihalide to the compound of the formula II is (0.01-5.0): 1; preferably, the molar ratio of the acid chloride reagent to the compound of formula II is (0.5-1.5) to 1, and the molar ratio of the trisubstituted phosphine dihalide to the compound of formula II is (0.05-1.0) to 1;
f) when a combination of a tri-substituted phosphorus oxide and an acid halide reagent or a combination of a tri-substituted phosphine dihalide and an acid halide reagent added dropwise to a system is used as a dehydrating agent, a substituted isonitrile compound can be synthesized in a batch manner;
g) when the combination of the tri-substituted phosphorus oxide and the acyl halide reagent or the combination of the tri-substituted phosphine dihalide and the acyl halide reagent is used as the dehydrating agent, the substituted isonitrile compound can be synthesized in a continuous flow mode by adopting a mode of continuously feeding the dehydrating agent/the organic amine/the compound shown in the formula II alone or after mixing any two of the dehydrating agent/the organic amine/the compound shown in the formula II;
h) when trisubstituted phosphorus dihalide is used as the dehydrating agent, the substituted isonitrile compound can be synthesized in a continuous flow mode by adopting a mode of continuously feeding the dehydrating agent/organic amine/compound shown in the formula II alone or after any two of the dehydrating agent/organic amine/compound shown in the formula II are mixed;
i) the synthesis of the continuous flow used was: kettle type continuous reaction, pipeline type continuous reaction, tower type continuous reaction or microchannel reactor.
10. The method for preparing a substituted isonitrile compound according to claim 1, wherein the dehydration reaction temperature is-100 to 30 ℃; preferably-10 to 10 ℃;
preferably, the dehydration reaction time is 0.2 to 10 hours, preferably 0.2 to 5 hours;
preferably, the compound of formula ii is dehydrated to obtain a reaction solution, and the obtained reaction solution is post-treated to obtain the substituted isonitrile compound (i), wherein the post-treatment method comprises the following steps: adding water into the obtained reaction liquid, layering, extracting the obtained water layer by using a solvent A, and combining organic phases to obtain a water phase and an organic phase; distilling the organic phase to recover the solvent A, and then carrying out reduced pressure distillation to obtain a substituted isonitrile compound (I); the obtained water phase or the residues of reduced pressure distillation contain trisubstituted phosphine oxide, and the trisubstituted phosphine dihalide can be prepared by reacting with acyl halide reagent to be used as dehydrating agent or directly recycled to be used as dehydrating agent; the obtained water phase can be neutralized by sodium hydroxide, and then organic amine is recovered by distillation, and sodium chloride is a byproduct.
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| TAKASHI MATSUO等: ""Meso-Unsubstituted Iron Corrole in Hemoproteins: Remarkable Differences in Effects on Peroxidase Activities between Myoglobin and Horseradish Peroxidase"", 《J. AM., CHEM. SOC.》 * |
| WANG XIA等: ""Synthesis of Isonitriles from N-Substituted Formamides Using Triphenylphosphine and Iodine"", 《SYNTHESIS》 * |
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| Publication number | Publication date |
|---|---|
| WO2022126947A1 (en) | 2022-06-23 |
| CN114644577B (en) | 2023-06-27 |
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Denomination of invention: An environmentally friendly preparation method for substituted isonitrile compounds Effective date of registration: 20231130 Granted publication date: 20230627 Pledgee: Dongying Branch of China CITIC Bank Co.,Ltd. Pledgor: Xinfa pharmaceutical Co.,Ltd. Registration number: Y2023980068537 |