CN114644577B - Environment-friendly preparation method of substituted isonitrile compound - Google Patents
Environment-friendly preparation method of substituted isonitrile compound Download PDFInfo
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- CN114644577B CN114644577B CN202011508780.2A CN202011508780A CN114644577B CN 114644577 B CN114644577 B CN 114644577B CN 202011508780 A CN202011508780 A CN 202011508780A CN 114644577 B CN114644577 B CN 114644577B
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- -1 isonitrile compound Chemical class 0.000 title claims abstract description 56
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 62
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 52
- 150000001266 acyl halides Chemical class 0.000 claims abstract description 43
- 239000012024 dehydrating agents Substances 0.000 claims abstract description 40
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 40
- 238000006243 chemical reaction Methods 0.000 claims abstract description 38
- AUONHKJOIZSQGR-UHFFFAOYSA-N oxophosphane Chemical class P=O AUONHKJOIZSQGR-UHFFFAOYSA-N 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 26
- 150000001412 amines Chemical class 0.000 claims abstract description 20
- 150000003003 phosphines Chemical class 0.000 claims abstract description 18
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 17
- 238000004519 manufacturing process Methods 0.000 claims abstract description 10
- 239000006227 byproduct Substances 0.000 claims abstract description 8
- 239000011574 phosphorus Substances 0.000 claims abstract description 8
- 229910052698 phosphorus Inorganic materials 0.000 claims abstract description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 36
- 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 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- 150000001875 compounds Chemical class 0.000 claims description 23
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 22
- 125000003118 aryl group Chemical group 0.000 claims description 21
- 238000004821 distillation Methods 0.000 claims description 21
- 239000012074 organic phase Substances 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 10
- 239000002253 acid Substances 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
- 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
- LWYAOXMPTVOERN-UHFFFAOYSA-N ethyl 2-formamidopropanoate Chemical compound CCOC(=O)C(C)NC=O LWYAOXMPTVOERN-UHFFFAOYSA-N 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([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
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 239000011780 sodium chloride Substances 0.000 claims description 5
- 125000003107 substituted aryl group Chemical group 0.000 claims description 5
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 5
- 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
- 230000015572 biosynthetic process Effects 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)-$l^{5}-phosphane Chemical group C=1C=CC=CC=1P(Cl)(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 ASWXNYNXAOQCCD-UHFFFAOYSA-N 0.000 claims description 4
- 150000004820 halides Chemical class 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- 150000003017 phosphorus Chemical class 0.000 claims description 4
- 229910001392 phosphorus oxide Inorganic materials 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- VSAISIQCTGDGPU-UHFFFAOYSA-N tetraphosphorus hexaoxide Chemical class O1P(O2)OP3OP1OP2O3 VSAISIQCTGDGPU-UHFFFAOYSA-N 0.000 claims description 4
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 claims description 3
- OCXGTPDKNBIOTF-UHFFFAOYSA-N dibromo(triphenyl)-$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
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 229940049953 phenylacetate Drugs 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 125000005270 trialkylamine group Chemical group 0.000 claims description 3
- 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
- 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 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
- 150000001263 acyl chlorides Chemical class 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
- 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 description 2
- XYAQYTADJIMJOD-UHFFFAOYSA-N butyl 2-formamidopropanoate Chemical compound CCCCOC(=O)C(C)NC=O XYAQYTADJIMJOD-UHFFFAOYSA-N 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 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
- 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
- 239000008096 xylene Substances 0.000 claims description 2
- 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 10
- 239000000047 product Substances 0.000 abstract description 8
- DHMQDGOQFOQNFH-UHFFFAOYSA-M Aminoacetate Chemical class NCC([O-])=O DHMQDGOQFOQNFH-UHFFFAOYSA-M 0.000 abstract description 7
- 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
- 239000000543 intermediate Substances 0.000 abstract description 3
- 239000007858 starting material Substances 0.000 abstract description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- 239000002994 raw material Substances 0.000 description 7
- 239000011259 mixed solution Substances 0.000 description 6
- 238000005292 vacuum distillation Methods 0.000 description 5
- 150000002527 isonitriles Chemical class 0.000 description 4
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical group ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 3
- 230000018044 dehydration Effects 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
- 239000000203 mixture Substances 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-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
- 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
- 238000001514 detection method Methods 0.000 description 2
- 150000002148 esters Chemical class 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
- RADKZDMFGJYCBB-UHFFFAOYSA-N pyridoxal hydrochloride Natural products CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 description 2
- 125000001424 substituent group Chemical group 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
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 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
- 239000003513 alkali Substances 0.000 description 1
- 239000003674 animal food additive Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000010364 biochemical engineering Methods 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
- 230000006837 decompression Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000032798 delamination Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 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
- MPQXHAGKBWFSNV-UHFFFAOYSA-N oxidophosphanium Chemical class [PH3]=O MPQXHAGKBWFSNV-UHFFFAOYSA-N 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
- 150000003839 salts Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000002128 sulfonyl halide group Chemical group 0.000 description 1
- 230000002194 synthesizing effect Effects 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-R 2 The substituted glycinate is used as a starting material, and the substituted isonitrile compound is obtained through dehydration reaction under the action of a dehydrating agent such as trisubstituted phosphine dihalide, a combination of trisubstituted phosphine dihalide and acyl halide reagent or a combination of trisubstituted phosphine oxide and acyl halide reagent and organic amine. The obtained substituted isonitrile compound is synthesized VB 6 Is an important intermediate of (a). The invention can be carried out in a continuous flow mode, thereby improving the production efficiency and reducing the operation. The byproduct trisubstituted phosphine oxide in the reaction process can be recycled, so that the cost is reduced; the invention 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, has simple and convenient process and operation, has no discharge of phosphorus-containing wastewater in the process, is environment-friendly and has low cost; the atomic economy is high, the yield and purity of the target product are high, and the method is suitable 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 engineering.
Background
Substituted isonitrile compounds, i.e. isonitrile alkanoate compounds, are an important intermediate for the preparation of 4-methyl-5-alkoxyoxazoles (US 20030120082), which are important intermediates for the synthesis of vitamin B6. Vitamin B6 is one of vitamins essential for humans and animals, plays a key role in the growth process of animals and humans, and is thus widely used in the fields of medicine, food, feed additives, cosmetics industry, and the like.
At present, N-formamido alkyl acid ester is mainly used as a raw material for the synthesis of the isonitrile alkyl acid ester compound, and the reaction route is as follows:
regarding the synthesis of isonitrile alkanoate compounds, the literature "Chemischeberichte 108, pages 1580-1592 (1975)", "Chemical Reports 93, pages 239-248 (1960)", "Angewandte Chemie, pages 492-504 (1965)", etc. have been reported; the existing method generally adopts organic alkali such as triethylamine as a fourier acid agent and phosphorus oxychloride, phosphorus pentachloride, acetyl chloride, acetic anhydride and the like as dehydrating agents; however, the reaction yield (60-70%) is low.
Patent document DE3029231 discloses the preparation of isonitrile alkanoate compounds by high temperature reaction in the presence of organic amine using phosphorus pentoxide as a dehydrating agent, with a yield of over 90%. However, the industrial use of phosphorus pentoxide is difficult; the reaction temperature is high, the heat release is severe during hydrolysis, and the safety risk is high; and a large amount of phosphorus-containing wastewater is produced, so that the wastewater is difficult to treat.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention provides an environment-friendly preparation method of a substituted isonitrile compound. The invention takes N-formamido alkyl acid ester as an initial raw material, utilizes the combination of trisubstituted dihalide phosphine, trisubstituted dihalide phosphine and acyl halide reagent or the combination of trisubstituted phosphine oxide and acyl halide reagent which are easy to obtain as a dehydrating agent to prepare the substituted isonitrile compound, and the byproduct trisubstituted phosphine oxide can be recycled, thereby reducing the cost. The invention does not use the dehydrating agents such as phosphorus oxychloride, phosphorus pentoxide and the like which have high price, large wastewater amount and high safety risk in the preparation process, does not need high-temperature dehydration reaction, has short reaction time, is simple and convenient to operate, does not discharge phosphorus-containing wastewater in the process, only has single salt of sodium chloride in the wastewater, is green, safe and environment-friendly, and has low cost; the yield and purity of the target product are high, and the method is suitable for industrial application.
Description of the terminology:
a compound of formula i: isonitrile alkanoates, i.e., substituted isonitrile compounds;
a compound of formula ii: N-formyl-alpha-R 2 The substituent glycine ester.
The technical scheme of the invention is as follows:
a process for producing a substituted isonitrile compound, comprising the steps of:
in a solvent A, under the action of a dehydrating agent and organic amine, preparing a substituted isonitrile compound (I) by a dehydration reaction of a compound of a formula II; the dehydrating agent is trisubstituted phosphine dihalide, a combination of trisubstituted phosphine dihalide and acyl halide reagent, or a combination of trisubstituted phosphine oxide and acyl halide reagent;
wherein, in the structural formulas of the compounds of the formulas I and II:
R 1 is hydrogen, C n H 2n+1 Straight or branched chain groups of (2), 1.ltoreq.n.ltoreq.10, aromatic groups or substituted aromatic groups;
R 2 is hydrogen, C n H 2n+1 Straight or branched chain groups, 1.ltoreq.n.ltoreq.10, aromatic groups or substituted aromatic groups.
According to the invention, preference is given to compounds of the formulae I, II in which R 1 Alkyl of C1-4 is preferably ethyl or butyl.
According to the invention, the compounds of the formulae I, II,R 2 is methyl or phenyl.
According to a preferred embodiment of the invention, the compound of formula II is: ethyl N-formyl- α -methylglycinate, butyl N-formyl- α -methylglycinate or butyl N-formyl- α -phenylglycinate.
According to a preferred embodiment of the invention, the compound of formula I is ethyl alpha-isonitrile propionate, butyl alpha-isonitrile propionate or butyl alpha-isonitrile phenylacetate.
According to a preferred embodiment of the present invention, the solvent a is one or a combination of dichloromethane, chloroform, n-hexane, cyclohexane, petroleum ether, n-heptane, xylene, chlorobenzene, benzene, toluene, dimethyl sulfoxide, chloroform, trichloroethane or dichloroethane; the mass ratio of the solvent A to the compound of the formula II is (0.5-20.0): 1; preferably, the mass ratio of the solvent A to the compound of formula II is (3.0-15.0): 1.
According to a preferred embodiment of the invention, the organic amine is a trialkylamine, the alkyl group having the formula C n H 2n+1 1.ltoreq.n.ltoreq.10; preferably, the alkyl 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 formula II is (1.8-4.0): 1; preferably (2.0-3.0): 1.
According to the invention, the trisubstituted dihalide phosphine has a structural formula shown in formula III:
wherein, in the compound of formula III, R a 、R b 、R c A linear or branched alkyl, aryl or substituted aryl group selected from methyl, ethyl, C3-C10; preferably, R a 、R b 、R c Selected from phenyl or isobutyl; r is R a 、R b 、R c The same or different;
X 1 、X 2 is halogen, X 1 、X 2 Preferably chlorine or bromine; x is X 1 、X 2 The same or different, preferably the same.
Preferably, in the compounds of formula III, when R a 、R b 、R c When 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, R 4 Is hydrogen, C n H 2n+1 A linear or branched alkyl group, 1+.n+.10, or halogen; further preferably, R 4 Is hydrogen. The structural formula shown in the formula IV is shown as follows: having m radicals R 4 Each of which is optionally connected with six carbon atoms of the 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 acyl halide reagent is a sulfonyl halide, thionyl halide, oxalyl halide, carbonyl halide or triphosgene; preferably, the acyl halide reagent is an acyl chloride reagent; further preferably, the acid halide reagent is phosgene or triphosgene.
According to the invention, the trisubstituted phosphine oxide has a structural formula: r is R d R e R f P＝O；
Wherein R is d 、R e 、R f A linear or branched alkyl group selected from C1-10, an aromatic group or a substituted aromatic group; r is R d 、R e 、R f The same or different.
Preferably, in the trisubstituted phosphine oxides of the formula, R d 、R e 、R f When 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, R 4 Is hydrogen, C n H 2n+1 Linear or branched alkyl groups, 1.ltoreq.n.ltoreq.10, orHalogen; further preferably, R 4 Is hydrogen or methyl. Formula V is represented by the structural formula: having m radicals R 4 Each of which is optionally connected with six carbon atoms of the benzene ring; and m substituents may be the same or different.
Preferably, the trisubstituted phosphine oxide is triphenylphosphine oxide or tri-p-methylphenyl phosphine oxide.
According to the invention, preferably, when the dehydrating agent is a trisubstituted dihalide phosphine, the molar ratio of trisubstituted dihalide phosphine to compound of formula II is (0.01-5.0): 1; preferably, the molar ratio of trisubstituted dihalide to compound of formula II is (0.1-1.5): 1.
According to the invention, preferably, when the dehydrating agent is a combination of a trisubstituted phosphine oxide and an acyl halide reagent, the molar ratio of the acyl halide reagent to the compound of formula II is (0.1-2.0): 1, and the molar ratio of the trisubstituted 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.
According to the invention, preferably, when the dehydrating agent is a combination of a trisubstituted dihalide phosphine and an acyl halide reagent, the molar ratio of the acyl halide reagent to the compound of formula II is (0.1-2.0): 1, and the molar ratio of the trisubstituted dihalide phosphine 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 from (0.5 to 1.5): 1 and the molar ratio of the trisubstituted dihalide phosphine to the compound of formula II is from (0.05 to 1.0): 1.
According to the invention, preferably, the 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.
According to the present invention, preferably, when a combination of trisubstituted phosphorus oxide and an acyl halide reagent or a combination of trisubstituted phosphorus dihalide and an acyl halide reagent is used as a dehydrating agent, a substituted isonitrile compound can be synthesized in a batch manner, the acyl halide reagent being added dropwise to the system.
According to the present invention, preferably, when a combination of trisubstituted phosphorus oxide and an acid halide reagent or a combination of trisubstituted phosphine dihalide and an acid halide reagent is used as the dehydrating agent, the substituted isonitrile compound may be synthesized in a continuous flow manner by using a method of continuously feeding the dehydrating agent/organic amine/compound of formula II alone or after mixing any two.
According to the present invention, when trisubstituted phosphorus dihalide is used as the dehydrating agent, the substituted isonitrile compound can be synthesized in a continuous flow manner by using a continuous feed manner after the dehydrating agent/organic amine/compound of formula II is singly or in any combination of two.
According to the invention, the continuous flow mode adopted for synthesizing the substituted isonitrile compound can be as follows: kettle type continuous reaction, pipeline type continuous reaction, tower type continuous reaction, micro-channel reactor, etc.
According to the present invention, preferably, the compound of formula II is dehydrated to obtain a reaction solution, and the obtained reaction solution is subjected to post-treatment to obtain the substituted isonitrile compound (I), and the post-treatment method comprises the steps of: 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; the organic phase is distilled to recover the solvent A, and then reduced pressure distillation is carried out to obtain the substituted isonitrile compound (I); the obtained water phase or reduced pressure distillation residue contains trisubstituted phosphine oxide, and can be used as a dehydrating agent or directly recycled as the dehydrating agent together with acyl halide reagent to prepare trisubstituted phosphine dihalide; the obtained water phase can be further neutralized by sodium hydroxide, and organic amine is recovered by distillation, and sodium chloride is also a byproduct.
According to the present invention, when the dehydrating agent is a combination of a trisubstituted phosphine oxide and an acyl halide reagent, the trisubstituted phosphine oxide is capable of forming a trisubstituted dihalide phosphine with the acyl halide reagent in situ, and then further dehydrating.
According to the invention, organic amine is used as an acid binding agent, hydrogen chloride which is a byproduct in the reaction process is used for generating organic amine hydrochloride, then sodium hydroxide and the organic amine hydrochloride are used for neutralization, and finally the byproduct sodium chloride is generated while the organic amine is recovered.
The preparation method of the substituted isonitrile compound has the following reaction route:
wherein, in the structural formulas of the compounds of the formulas I and II: r is R 1 Is hydrogen, C n H 2n+1 Straight or branched chain groups of (2), 1.ltoreq.n.ltoreq.10, aromatic groups or substituted aromatic groups; r is R 2 Is hydrogen, C n H 2n+1 Straight or branched chain groups, 1.ltoreq.n.ltoreq.10, aromatic groups or substituted aromatic groups.
The invention has the technical characteristics and beneficial effects that:
1. the invention provides a novel environment-friendly method for preparing a substituted isonitrile compound by dehydration; by N-formyl-alpha-R 2 The substituted glycinate (II) is used as a starting material, and the substituted isonitrile compound (I) is obtained through dehydration reaction under the action of a dehydrating agent and organic amine which are the trisubstituted phosphine dihalide, the combination of trisubstituted phosphine dihalide and acyl halide reagent or the combination of trisubstituted phosphine oxide and acyl halide reagent.
2. The whole reaction process of the invention can be understood as follows: the compound of formula II is dehydrated to remove one molecule of water, the water reacts with trisubstituted dihalide phosphine to generate trisubstituted phosphine oxide and two molecules of hydrogen halide, and the two molecules of hydrogen halide react with organic amine of acid binding agent to generate organic amine hydrochloride. The dehydrating agent used in the method is a combination of trisubstituted dihalide phosphine, trisubstituted dihalide phosphine and acyl halide reagent or a combination of trisubstituted phosphine oxide and acyl halide reagent; when the dehydrating agent is the combination of the trisubstituted dihalide phosphine and the acyl halide reagent, the trisubstituted dihalide phosphine is converted into trisubstituted phosphine oxide after the dehydration reaction, and the trisubstituted phosphine oxide and the acyl halide reagent react in situ to generate trisubstituted dihalide phosphine which can continuously participate in the dehydration reaction; when the dehydrating agent is a combination of trisubstituted phosphine oxide and an acyl halide reagent, the acyl halide reagent enables the trisubstituted phosphine oxide to generate 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, the waste water and waste gas are less in production, and the environment is protected. The dehydrating agent of the invention is easy to prepare; the substituted isonitrile compound is prepared and the byproduct trisubstituted phosphine oxide can be recycled, so that the trisubstituted phosphine oxide is easy to quantitatively convert into trisubstituted dihalide phosphine, the cost is reduced, the recycling of materials is realized, and the environment-friendly and atomic economy concepts are 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 invention does not use the dehydrating agents such as phosphorus oxychloride, phosphorus pentoxide and the like which have high price, large wastewater amount and high safety risk in the preparation process, does not need high-temperature dehydration reaction, has simple process, simple and convenient operation, no discharge of phosphorus-containing wastewater in the process, and is green, safe and environment-friendly and low in cost.
3. The method has the advantages of high reaction activity, good reaction selectivity, high atom economy, high product yield and purity, the yield can reach more than 95 percent, the purity is more than 99 percent, and the method 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 mass percent unless otherwise specified.
The yields in the examples are all molar yields.
The raw materials and reagents used in the examples are all commercially available products or are prepared according to the prior art.
The gas phase detection uses a Shimadzu Gas Chromatograph (GC) for reaction monitoring and purity detection, and the model of the instrument is GC-1020PLUS; part of the purity was detected by high performance liquid chromatography, indicated as HPLC.
Example 1: preparation of ethyl alpha-isonitrile propionate
Adding 6215g of triphenyl phosphorus dichloride toluene solution (containing 1000g of triphenyl phosphorus dichloride) into a mixing kettle, adding 435g (3 mol) of ethyl N-formyl-alpha-methylglycinate, and uniformly mixing; the kettle type continuous reaction is adopted, the obtained mixed solution enters a continuous reactor at the speed of 110g/min, simultaneously 665 g of triethylamine is pumped into the continuous reactor at the speed of 11g/min for reaction, the reaction temperature is controlled to be between-10 and 0 ℃, the reaction residence time is controlled to be between 15 minutes and 35 minutes, the solid-liquid mixture flows out of the reactor, 2000ml of water is added for hydrolysis, layering is carried out, and 2000ml of toluene is added for extraction of the water phase. The toluene phases were combined, the solvent was recovered by distillation under reduced pressure, 371 g of ethyl alpha-isonitrile propionate was obtained by high vacuum distillation, and the GC purity was 99%, and the yield was 96.3%.
The main component of the residue after high vacuum distillation is triphenylphosphine oxide, which can be repeatedly used for preparing dehydrating agent.
The nuclear magnetic data of the obtained product are as follows:
1 HNMR: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; the kettle type continuous reaction is adopted, the obtained mixed solution enters a continuous reactor at the speed of 110g/min, 660 g of triethylamine is pumped into the continuous reactor at the speed of 11g/min for reaction, the reaction temperature is controlled to be between 10 ℃ below zero and 0 ℃, the reaction residence time is controlled to be between 55 minutes and 65 minutes, the solid-liquid mixture flows out of the reactor, 2000ml of water is added for hydrolysis and delamination, and 2000ml of dichloromethane is added for extraction of the water phase. The organic phases were combined, the solvent was recovered by distillation, and 453.84 g of n-butyl alpha-isonitrile propionate was obtained by high vacuum distillation, and the GC purity was 99% and the yield was 96.5%.
The main component of the residue after high vacuum distillation is triphenylphosphine oxide, which can be repeatedly used for preparing dehydrating agent.
The nuclear magnetic data of the obtained product are as follows:
1 HNMR: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 ethyl alpha-isonitrile propionate
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, a mixed solution of 9.9 g (0.1 mol) of phosgene and 50 g of toluene are added dropwise between 10 ℃ and 5 ℃ for 2 hours, after the completion of the dropwise addition, the reaction is carried out for 1 hour at 0 ℃ to 5 ℃, 30g of water is added for layering, the obtained water layer is extracted twice with toluene (30 g are used in total), an organic phase is combined, toluene is recovered by atmospheric distillation from the organic phase, and then 12 g of ethyl alpha-isonitrile propionate is obtained by reduced pressure distillation, 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 reused as a dehydrating agent.
Example 4: preparation of ethyl alpha-isonitrile propionate
100 g of toluene was added to a 500 ml four-necked flask, the residue obtained after distillation under reduced pressure in example 3 (the main component was triphenylphosphine oxide), 0.4 g of triphenylphosphine oxide, 14.5 g (0.1 mol) of ethyl N-formyl- α -methylglycinate, 20.8 g (0.206 mol) of triethylamine, a mixed solution of 9.9 g (0.1 mol) of phosgene and 50 g of toluene was added dropwise between-10 and 5℃for 2 hours, the reaction was carried out at 0 to 5℃for 1 hour, the reaction of the raw materials was detected, 30g of water was added, the layers were separated, the obtained aqueous layer was extracted twice with toluene (30 g was used in total), the organic phase was combined, toluene was recovered by distillation under normal pressure, and then ethyl α -isonitrile propionate was obtained in a yield of 94% and GC purity of 99% was obtained by distillation under reduced pressure.
Example 5: preparation of n-butyl alpha-isonitrile propionate
100 g of chloroform, 2.78 g (0.01 mol) of triphenylphosphine oxide, 17.3 g (0.1 mol) of N-butyl N-formyl-alpha-methylglycinate, a mixed solution of 30g of chloroform and 10.0 g (0.034 mol) of triphosgene is added into a 500 ml four-neck flask in a dropwise manner within 2 hours at the temperature of-15-5 ℃, 24.3 g (0.24 mol) of triethylamine is added dropwise at the same time, the reaction is carried out for 2 hours at the temperature of 0-5 ℃, 30g of water is added after the reaction of the raw materials is detected, the mixture is layered, the obtained water layer is extracted twice with chloroform (40 g is used), an organic phase is combined, the solvent and other impurities are recovered by normal pressure distillation of the organic phase, then 15.05 g of alpha-N-butyl isonitrile propionate is obtained by vacuum distillation, the yield is 96%, and the GC purity is 99%; the residue after reduced pressure distillation contains triphenylphosphine oxide as main component, and can be reused as dehydration catalyst.
Example 6: preparation of n-butyl alpha-isonitrile phenylacetate
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-phenyl glycine N-butyl ester, a mixed solution of 30g of chloroform and 10.0 g (0.034 mol) of triphosgene is added into a 500 ml four-neck flask in a dropwise manner within 2 hours at the temperature of-15-5 ℃, 24.3 g (0.24 mol) of triethylamine is simultaneously added dropwise, the reaction is carried out for 2 hours at the temperature of 0-5 ℃, after the reaction of the raw materials is detected, 30g of water is added, layering is carried out, the obtained water layer is extracted twice (40 g is used in total), an organic phase is combined, the solvent and other impurities are recovered by normal pressure distillation of the organic phase, then 20.42 g of alpha-isonitrile N-butyl phenylacetate is obtained by decompression distillation, and the yield is 94% and the GC purity is 99%; the residue after reduced pressure distillation contains triphenylphosphine oxide as main component, and can be reused as dehydration catalyst.
The nuclear magnetic data of the obtained product are as follows:
1 HNMR: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 ethyl alpha-isonitrile propionate
100 g of chloroform, 15.6 g of phosphorus oxychloride and 14.5 g (0.1 mol) of ethyl N-formyl-alpha-methylglycinate are added into a 500 ml flask, 25 g of triethylamine is dropwise added in 2 hours at the temperature of 10-30 ℃, after the reaction of the raw materials is detected for 1 hour at the temperature of 65 ℃, 30g of water is added for layering, the obtained water layer is extracted twice with 30g of chloroform, the organic phases are combined, the chloroform is recovered by normal pressure distillation of the organic phases, and then 9.1 g of ethyl alpha-isonitrile propionate is obtained by reduced pressure distillation, the GC purity is 99%, and the yield is 71.57%.
As is clear from the comparative example, phosphorus oxychloride is used as a dehydrating agent, and the product yield is low.
Claims (16)
1. A process for producing a substituted isonitrile compound, comprising the steps of:
in a solvent A, under the action of a dehydrating agent and organic amine, preparing a substituted isonitrile compound (I) by a dehydration reaction of a compound of a formula II; the dehydrating agent is trisubstituted phosphine dihalide, a combination of trisubstituted phosphine dihalide and acyl halide reagent, or a combination of trisubstituted phosphine oxide and acyl halide reagent; the organic amine is trialkylamine, and the general formula of alkyl is C n H 2n+1 ，1≦n≦10；
Wherein, in the structural formulas of the compounds of the formulas I and II:
R 1 is hydrogen, C n H 2n+1 Straight or branched chain groups of (2), 1.ltoreq.n.ltoreq.10, aromatic groups or substituted aromatic groups;
R 2 is hydrogen, C n H 2n+1 Straight or branched chain groups of (2), 1.ltoreq.n.ltoreq.10, aromatic groups or substituted aromatic groups;
the trisubstituted dihalide phosphine has a structural formula shown in a formula III:
wherein, in the compound of formula III, R a 、R b 、R c Selected from aryl or substituted aryl; r is R a 、R b 、R c The same or different; the aryl or substituted aryl has a structure shown in the following formula IV;
in the structural formula shown in the formula IV, m is 0, 1, 2, 3, 4 or 5, R 4 Is hydrogen, C n H 2n+1 A linear or branched alkyl group, 1+.n+.10, or halogen;
X 1 、X 2 is chlorine or bromine; x is X 1 、X 2 The same or different;
the trisubstituted phosphine oxide has the structural formula: r is R d R e R f P＝O；
Wherein R is d 、R e 、R f Selected from aryl or substituted aryl; r is R d 、R e 、R f The same or different;
the aryl or substituted aryl has a structure shown in the following formula V;
in the structural formula shown in the formula V, m is 0, 1, 2, 3, 4 or 5, R 4 Is hydrogen, C n H 2n+1 A linear or branched alkyl group, 1+.n+.10, or halogen;
the acyl halide reagent is carbonyl halide or triphosgene.
2. The process for the preparation of a substituted isonitrile compound according to claim 1, wherein the compounds of formula i, ii are of formula i: r is R 1 Alkyl of C1-4; r is R 2 Is methyl or phenyl.
3. The process for the preparation of a substituted isonitrile compound according to claim 1, wherein the compound of formula ii is N-formyl- α -methylglycine ethyl ester, N-formyl- α -methylglycine butyl ester or N-formyl- α -phenylglycine butyl ester.
4. The process for the preparation of a substituted isonitrile compound according to claim 1, wherein the compound of formula i is ethyl α -isonitrile propionate, butyl α -isonitrile propionate or butyl α -isonitrile phenylacetate.
5. The method for producing a substituted isonitrile compound according to 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, dimethyl sulfoxide, trichloroethane, and dichloroethane.
6. The method for producing a substituted isonitrile compound according to claim 1, wherein the alkyl group in the trialkylamine is methyl, ethyl, isopropyl, n-propyl, isobutyl or n-butyl.
7. The process for producing a substituted isonitrile compound according to claim 1, wherein in the compound of formula III, R a 、R b 、R c Selected from phenyl groups.
8. The method for producing a substituted isonitrile compound according to claim 1, wherein the trisubstituted dihalide phosphine is triphenylphosphine dichloride or triphenylphosphine dibromide.
9. The method for producing a substituted isonitrile compound according to claim 1, wherein the acid halide reagent is an acid chloride reagent.
10. The method for producing a substituted isonitrile compound according to claim 1, wherein the trisubstituted phosphine oxide is triphenylphosphine oxide or tri-p-methylphenyl phosphine oxide.
11. The method for producing a substituted isonitrile compound according to claim 1, characterized by comprising any one of the following conditions:
a) The mass ratio of the solvent A to the compound of the formula II is (0.5-20.0): 1;
b) The molar ratio of the organic amine to the compound of formula II is (1.8-4.0): 1;
c) When the dehydrating agent is a trisubstituted phosphine dihalide, the molar ratio of the trisubstituted phosphine dihalide to the compound of formula II is (0.01-5.0): 1;
d) When the dehydrating agent is a combination of trisubstituted phosphine oxide and an acyl halide reagent, the molar ratio of the acyl halide reagent to the compound of formula II is (0.1-2.0): 1, and the molar ratio of trisubstituted phosphine oxide to the compound of formula II is (0.01-5.0): 1;
e) When the dehydrating agent is a combination of a trisubstituted dihalide phosphine and an acyl halide reagent, the molar ratio of the acyl halide reagent to the compound of formula II is (0.1-2.0): 1, and the molar ratio of the trisubstituted dihalide phosphine to the compound of formula II is (0.01-5.0): 1;
f) When a combination of trisubstituted phosphorus oxide and an acyl halide reagent or a combination of trisubstituted phosphorus dihalide and an acyl halide reagent is used as a dehydrating agent, a substituted isonitrile compound can be synthesized in a batch manner, and the acyl halide reagent is added into the system in a dropwise manner;
g) When a combination of trisubstituted phosphorus oxide and acyl halide reagent or a combination of trisubstituted phosphine dihalide and acyl halide reagent is used as a dehydrating agent, a continuous flow mode is adopted to synthesize the substituted isonitrile compound by adopting a mode of continuously feeding after singly or arbitrarily mixing the dehydrating agent/the organic amine/the compound of the formula II;
h) When trisubstituted phosphorus dihalide is used as a dehydrating agent, a continuous flow mode is adopted to synthesize the substituted isonitrile compound by adopting a mode of continuous feeding after the dehydrating agent/organic amine/compound of the formula II is singly or arbitrarily mixed;
i) The synthesis mode of the adopted continuous flow is as follows: kettle type continuous reaction, pipeline type continuous reaction, tower type continuous reaction or micro-channel reactor.
12. The method for producing a substituted isonitrile compound according to claim 11, characterized by comprising any one of the following conditions:
a) 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 of formula II is (2.0-3.0): 1;
c) When the dehydrating agent is a trisubstituted phosphine dihalide, 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 a combination of trisubstituted phosphine oxide and acyl halide reagent, the molar ratio of the acyl halide reagent to the compound of formula II is (0.3-1): 1, and the molar ratio of trisubstituted phosphine oxide to the compound of formula II is (0.1-1.5): 1;
e) When the dehydrating agent is a combination of a trisubstituted dihalide phosphine and an acyl halide reagent, the molar ratio of the acyl chloride reagent to the compound of formula II is (0.5-1.5): 1, and the molar ratio of the trisubstituted dihalide phosphine to the compound of formula II is (0.05-1.0): 1.
13. The process for producing a substituted isonitrile compound according to claim 1, wherein the dehydration reaction temperature is-100 to 30 ℃.
14. The process for producing a substituted isonitrile compound according to claim 13, wherein the dehydration reaction temperature is-10 to 10 ℃.
15. The process for producing a substituted isonitrile compound according to claim 1, wherein the dehydration reaction time is 0.2 to 10 hours.
16. The process for producing a substituted isonitrile compound according to claim 1, wherein 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), the process for post-treatment comprising the steps of: 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; the organic phase is distilled to recover the solvent A, and then reduced pressure distillation is carried out to obtain the substituted isonitrile compound (I); the obtained water phase or reduced pressure distillation residue contains trisubstituted phosphine oxide, and can be used as a dehydrating agent or directly recycled as the dehydrating agent together with acyl halide reagent to prepare trisubstituted phosphine dihalide; the obtained water phase can be further neutralized by sodium hydroxide, and organic amine is recovered by distillation, and sodium chloride is also a byproduct.
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| "A Novel Method for Preparing Isocyanides from N-Substituted Formamides with Chlorophosphate Compounds";Genki Kobayashi等;《Synthesis》;20110907;第20卷;第10867-10874页 * |
| "Meso-Unsubstituted Iron Corrole in Hemoproteins: Remarkable Differences in Effects on Peroxidase Activities between Myoglobin and Horseradish Peroxidase";Takashi Matsuo等;《J. Am., Chem. Soc.》;20091007;第131卷;Supporting Information第2页, Scheme S1 * |
| "One-pot preparation of isocyanides from amines and their multicomponent reactions: crucial role of dehydrating agent and base";Sankar K. Guchhait等;《RSC Advances》;20130412;第3卷;第49-54页 * |
| "Reaktionen zwischen Triphenylphosphin-dibromidund substituierten Saureamiden";Darstellungsmethoden fur Carbodiimide等;《Liebigs Ann. Chem.》;19681231;第718卷;第25-26页 * |
| "Synthesis of Isonitriles from N-Substituted Formamides Using Triphenylphosphine and Iodine";Wang Xia等;《Synthesis》;20140917;第47卷;第3225-3234页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2022126947A1 (en) | 2022-06-23 |
| CN114644577A (en) | 2022-06-21 |
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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 |