WO2023109757A1 - L-草铵膦衍生物、包含其的组合物及其制备方法和用途 - Google Patents
L-草铵膦衍生物、包含其的组合物及其制备方法和用途 Download PDFInfo
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- WO2023109757A1 WO2023109757A1 PCT/CN2022/138391 CN2022138391W WO2023109757A1 WO 2023109757 A1 WO2023109757 A1 WO 2023109757A1 CN 2022138391 W CN2022138391 W CN 2022138391W WO 2023109757 A1 WO2023109757 A1 WO 2023109757A1
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- 238000002360 preparation method Methods 0.000 title claims description 4
- IAJOBQBIJHVGMQ-BYPYZUCNSA-N glufosinate-P Chemical class CP(O)(=O)CC[C@H](N)C(O)=O IAJOBQBIJHVGMQ-BYPYZUCNSA-N 0.000 title abstract 2
- 238000000034 method Methods 0.000 claims abstract description 28
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- 125000004432 carbon atom Chemical group C* 0.000 claims description 73
- 238000006243 chemical reaction Methods 0.000 claims description 59
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- 125000000217 alkyl group Chemical group 0.000 claims description 32
- 239000002904 solvent Substances 0.000 claims description 23
- 125000003118 aryl group Chemical group 0.000 claims description 21
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- 125000003342 alkenyl group Chemical group 0.000 claims description 15
- 125000000623 heterocyclic group Chemical group 0.000 claims description 15
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 13
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 12
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- 239000012442 inert solvent Substances 0.000 claims description 8
- 125000000304 alkynyl group Chemical group 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
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- 150000007530 organic bases Chemical class 0.000 claims description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 5
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
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- FYGHSUNMUKGBRK-UHFFFAOYSA-N 1,2,3-trimethylbenzene Chemical compound CC1=CC=CC(C)=C1C FYGHSUNMUKGBRK-UHFFFAOYSA-N 0.000 claims description 4
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical group CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 4
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- 239000004210 ether based solvent Substances 0.000 claims description 4
- 150000008282 halocarbons Chemical class 0.000 claims description 4
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 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
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- MVPPADPHJFYWMZ-IDEBNGHGSA-N chlorobenzene Chemical group Cl[13C]1=[13CH][13CH]=[13CH][13CH]=[13CH]1 MVPPADPHJFYWMZ-IDEBNGHGSA-N 0.000 claims description 3
- 239000003759 ester based solvent Substances 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
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- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
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- 150000003462 sulfoxides Chemical class 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims 3
- 229940125904 compound 1 Drugs 0.000 claims 1
- 239000007787 solid Substances 0.000 description 31
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 24
- 238000003756 stirring Methods 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- -1 3-pentenyl Chemical group 0.000 description 11
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- UTZAXPKCGJZGLB-UHFFFAOYSA-N diethyl methyl phosphite Chemical compound CCOP(OC)OCC UTZAXPKCGJZGLB-UHFFFAOYSA-N 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 6
- ZBMRKNMTMPPMMK-UHFFFAOYSA-N 2-amino-4-[hydroxy(methyl)phosphoryl]butanoic acid;azane Chemical compound [NH4+].CP(O)(=O)CCC(N)C([O-])=O ZBMRKNMTMPPMMK-UHFFFAOYSA-N 0.000 description 5
- 125000002619 bicyclic group Chemical group 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 125000002950 monocyclic group Chemical group 0.000 description 5
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- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
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- 239000012043 crude product Substances 0.000 description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- CFXLTWWKEOMXOK-YFKPBYRVSA-N ethyl (2S)-2-(chloroamino)-4-hydroxybutanoate Chemical compound CCOC(=O)[C@H](CCO)NCl CFXLTWWKEOMXOK-YFKPBYRVSA-N 0.000 description 3
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- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
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- 238000004458 analytical method Methods 0.000 description 2
- 125000005605 benzo group Chemical group 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
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- 229920006395 saturated elastomer Polymers 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 238000010025 steaming Methods 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- IAJOBQBIJHVGMQ-UHFFFAOYSA-N 2-amino-4-[hydroxy(methyl)phosphoryl]butanoic acid Chemical compound CP(O)(=O)CCC(N)C(O)=O IAJOBQBIJHVGMQ-UHFFFAOYSA-N 0.000 description 1
- 125000006022 2-methyl-2-propenyl group Chemical group 0.000 description 1
- 125000006024 2-pentenyl group Chemical group 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000006041 3-hexenyl group Chemical group 0.000 description 1
- 125000006042 4-hexenyl group Chemical group 0.000 description 1
- 125000003119 4-methyl-3-pentenyl group Chemical group [H]\C(=C(/C([H])([H])[H])C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000006043 5-hexenyl group Chemical group 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- WYZXVBWBNFHLDO-LURJTMIESA-N CC(C)N([C@@H](CCO)C(O)=O)Cl Chemical compound CC(C)N([C@@H](CCO)C(O)=O)Cl WYZXVBWBNFHLDO-LURJTMIESA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 description 1
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- 108010081348 HRT1 protein Hairy Proteins 0.000 description 1
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- 238000001816 cooling Methods 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002720 diazolyl group Chemical group 0.000 description 1
- CDPKWOKGVUHZFR-UHFFFAOYSA-N dichloro(methyl)phosphane Chemical compound CP(Cl)Cl CDPKWOKGVUHZFR-UHFFFAOYSA-N 0.000 description 1
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- 150000002148 esters Chemical class 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
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- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
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- 125000005004 perfluoroethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
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- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
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- 239000002244 precipitate Substances 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/46—Phosphinous acids [R2POH], [R2P(= O)H]: Thiophosphinous acids including[R2PSH]; [R2P(=S)H]; Aminophosphines [R2PNH2]; Derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
- C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
Definitions
- the present invention relates to an L-glufosinate-ammonium derivative, a composition containing it, a preparation method and an application thereof.
- Glufosinate is a highly efficient, broad-spectrum, low-toxic, non-selective (killing) organophosphorus herbicide developed by Hearst in the 1980s. It can be used to control annual and perennial dicotyledonous and gramineous weeds.
- Glufosinate-ammonium has two enantiomers of L-type and D-type. L-type glufosinate-ammonium is the essence of glufosinate-ammonium, and its herbicidal activity is twice that of racemic DL-type glufosinate-ammonium.
- the invention provides a preparation method of a compound of formula (I),
- Y is -OR 1 , -NH 2 , -NHR 2 or -N(R 2 )(R 3 );
- R is H, substituted or unsubstituted alkyl having 1-6 carbon atoms, substituted or unsubstituted alkenyl having 2-6 carbon atoms, substituted or unsubstituted alkyne having 2-6 carbon atoms A substituted or unsubstituted cycloalkyl group having 3-10 carbon atoms, a substituted or unsubstituted heterocyclic group having 2-10 carbon atoms, a substituted or unsubstituted aromatic group having 6-20 carbon atoms A group, a substituted or unsubstituted aralkyl group having 6-20 carbon atoms, or a substituted or unsubstituted heteroaryl group having 2-10 carbon atoms; preferably, R is H or has 1-6 carbon atoms A substituted or unsubstituted alkyl group of atoms; more preferably, R is H (at this time ROH is water), methyl (at this time ROH is methanol) or ethyl (
- R 1 , R 2 and R 3 are each independently a substituted or unsubstituted alkyl group having 1-6 carbon atoms, a substituted or unsubstituted alkenyl group having 2-6 carbon atoms, a substituted or unsubstituted alkenyl group having 2-6 carbon atoms, Atom substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl with 3-10 carbon atoms, substituted or unsubstituted heterocyclic group with 2-10 carbon atoms, substituted or unsubstituted heterocyclic group with 6-20 carbon atoms Atomic substituted or unsubstituted aryl, substituted or unsubstituted aralkyl having 6-20 carbon atoms, or substituted or unsubstituted heteroaryl having 2-10 carbon atoms, or -Si(R 4 )(R 5 )(R 6 );
- R 4 , R 5 and R 6 are each independently a substituted or unsubstituted alkyl group having 1-6 carbon atoms or a substituted or unsubstituted aryl group having 6-20 carbon atoms;
- the substituents of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, aralkyl and heteroaryl are each independently halogen, carboxyl (-COOH), amino (-NH 2 ) , nitro (-NO 2 ), cyano (-CN), alkyl having 1-6 carbon atoms, aryl having 6-10 carbon atoms or cycloalkyl having 3-10 carbon atoms.
- the reaction of the compound of formula (III) with ROH is carried out at a temperature of 0°C to 100°C, for example at 0°C to 80°C, 0°C to 60°C, 0°C to 40°C, 0°C °C to 30°C, 0°C to 20°C, 30°C to 80°C, or 30°C to 60°C.
- reaction of the compound of formula (III) with ROH is carried out in the absence of acid and/or base.
- the compound of formula (III) is prepared from a compound of formula (V):
- X is halogen, -OTs or Hal
- Hal is independently at each occurrence a halogen selected from F, Cl, Br or I;
- Y is as defined above;
- R is hydrogen , substituted or unsubstituted alkyl having 1 to 6 carbon atoms, substituted or unsubstituted alkenyl having 2 to 6 carbon atoms, or substituted or unsubstituted having 2 to 6 carbon atoms Alkynyl, the substituents of the alkyl, alkenyl and alkynyl are each independently halogen, carboxyl, amino, nitro, cyano, alkyl with 1-6 carbon atoms, alkyl with 6-10 carbon atoms An aryl group or a cycloalkyl group having 3-10 carbon atoms.
- the compound of formula (V) is derived from the compound of formula (II)
- the mixture is a mixture comprising one or more compounds of formula (IV)-1 and one or more compounds of formula (IV)-2; or, comprising one or more compounds of formula (IV)-1 A mixture of a compound and one or more compounds of formula (IV); or, a mixture comprising one or more compounds of formula (IV)-2 and one or more compounds of formula (IV); or, comprising a mixture of one or more compounds of formula (IV), one or more compounds of formula (IV)-1 and one or more compounds of formula (IV)-2;
- any order of feeding can smoothly obtain the product. If the compound of formula (II) is added to the compound of formula (IV) or said mixture, the compound of formula (IV) or said mixture can also be added to the compound of formula (II).
- the salt (such as hydrochloride) of the compound of formula (II) can also be reacted smoothly.
- R 1 , R 2 and R 3 are each independently methyl, ethyl, propyl (such as n-propyl, isopropyl), butyl (such as n-butyl, isobutyl or tert-butyl ), pentyl, hexyl, benzyl, phenyl or naphthyl, preferably ethyl, n-propyl, isopropyl or n-butyl, more preferably ethyl.
- Y is -NHCH 2 CH 2 CH 2 CH 3 , -N(CH 3 ) 2 , -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 ) 2 , - OCH 2 CH 2 CH 2 CH 3 , —OCH 2 CH(CH 3 ) 2 or —OBn.
- R 7 is methyl, ethyl, propyl, butyl, pentyl or hexyl, preferably ethyl.
- the reaction temperature is -30-30°C, such as -10-20°C, -10-10°C, and the more preferred temperature is -10°C.
- the reaction time may be 0.1 to 20 hours.
- reaction temperature is -30-30°C.
- the mixture is a mixture of one or more compounds of formula (IV)-1 and one or more compounds of formula (IV), the formula ( The molar ratio of IV)-1 compound and formula (IV) compound is (0.9 ⁇ 1.1): 1 or (0.05 ⁇ 1.1): 1; Or described mixture is one or more formula (IV)-2 compounds and A mixture of one or more compounds of formula (IV), the molar ratio of the compound of formula (IV)-2 to the compound of formula (IV) is (0.9 ⁇ 1.1): 1 or (0.05 ⁇ 1.1): 1; or the The mixture is a mixture comprising one or more compounds of formula (IV)-1 and one or more compounds of formula (IV)-2, and the mole of compound of formula (IV)-1 and compound of formula (IV)-2 The ratio is (0.9 ⁇ 1.1):1.
- the base in the aforementioned reaction for preparing the compound of formula (V) is an organic base or ammonia.
- the organic base is selected from organic amines, pyridine or pyridine derivatives having 1 to 3 substituents connected to one or more carbon atoms of the heterocycle , piperidine or a piperidine derivative having 1 to 3 substituents connected to one or more carbon atoms of the heterocycle;
- the above substituents are selected from halogen, -OH, -O-(C 1 -C 6 alkyl), -NH 2 , -NO 2 , -CN, C 1 -C 6 alkyl, C 3-10 ring Alkyl and C 6-10 aryl.
- the organic base is selected from N,N-dimethylaniline, triethylamine, piperidine or pyridine.
- the reaction for preparing the compound of formula (V) is carried out under solvent-free conditions or in an inert solvent;
- the inert solvent is selected from benzene solvents, amide solvents, hydrocarbon solvents, halogenated hydrocarbon solvents, sulfones or Any one or more of sulfoxide solvents, ether solvents or ester solvents; preferably, the inert solvent is selected from benzene solvents, amide solvents, halogenated hydrocarbon solvents, ether solvents or esters Any one or more kinds of solvents.
- the inert solvent is selected from chlorobenzene, trimethylbenzene, 1,4-dioxane, 1,2-dichloroethane, dimethyl sulfoxide, nitrogen methyl pyrrolidone, N,N-dimethyl Any one or more of formamide, petroleum ether, n-heptane, tetrahydrofuran, methyltetrahydrofuran, benzene, toluene, ethyl acetate, and butyl acetate.
- the molar ratio of the compound of formula (IV) or the mixture to the compound of formula (II) is 1: (0.5-10), preferably 1: (1-3 ); or the molar ratio of the compound of formula (II) to the compound of formula (IV) or the mixture is 1: (0.5-10), preferably 1: (1-3).
- a slight excess of the compound of formula (IV) or the mixture is beneficial to the yield of the reaction, for example, an excess of 5% to 10%.
- the aforementioned reaction for preparing the compound of formula (III) includes heating the compound of formula (V) at a temperature of 50-150° C. to convert it into the compound of formula (III).
- the preferred temperature is 60-120°C or 90-100°C.
- the reaction time may be 0.5 to 40 hours.
- the reaction to prepare the compound of formula (III) can be carried out in the presence of an organic solvent, such as 1,4-dioxane, acetonitrile, 1,2-dichloroethane, tetrahydrofuran, chlorobenzene , more preferred organic solvent is chlorobenzene.
- an organic solvent such as 1,4-dioxane, acetonitrile, 1,2-dichloroethane, tetrahydrofuran, chlorobenzene , more preferred organic solvent is chlorobenzene.
- reaction for preparing the compound of formula (V) and the reaction for preparing the compound of formula (III) are carried out in one pot, that is, the intermediate compound of formula (V) is not isolated.
- the ee value of the aforementioned compound of formula (I) is greater than 50%.
- the ee value of the aforementioned compound of formula (I) is greater than 90%.
- alkyl is defined as a linear or branched saturated aliphatic hydrocarbon.
- the alkyl group has 1 to 12, eg, 1 to 6 carbon atoms.
- alkyl having 1 to 6 carbon atoms refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl base, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl), which are optionally replaced by 1 or more (such as 1 to 3) Suitable substituents are such as halogen substitution (in which case the group is referred to as "haloalkyl”) (eg CH2F , CHF2 , CF3 , CCl3 , C
- alkyl having 1 to 4 carbon atoms refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (i.e. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).
- alkenyl means a linear or branched monovalent hydrocarbon group containing one or more double bonds and having 2-6 carbon atoms (“ C2-6 alkenyl”).
- the alkenyl is, for example, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-butenyl, -hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl.
- the compound of the present invention contains an alkenyl group, the compound may exist in pure E (ent ought) form, pure Z (zusammen) form, or any mixture thereof.
- alkynyl denotes a monovalent hydrocarbon group containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, eg ethynyl or propynyl.
- cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (eg monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl , cyclooctyl, cyclononyl, or bicyclic, including spiro, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decahydronaphthyl, etc.), which are optionally substituted by 1 or more (such as 1 to 3) suitable substituents.
- monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl , cyclooctyl, cycl
- the cycloalkyl preferably has 3 to 10 Carbon atoms.
- C 3-6 cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (such as cyclopropyl, cyclobutyl, cyclopentyl) of 3 to 6 ring-forming carbon atoms radical or cyclohexyl) optionally substituted with 1 or more (such as 1 to 3) suitable substituents, eg methyl substituted cyclopropyl.
- heterocyclic groups having 2-10 carbon atoms are, for example but not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, Tetrahydrofuryl, dioxolinyl, pyrrolidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithia Alkyl (dithianyl), thiomorpholinyl, piperazinyl or trithianyl.
- aryl refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated ⁇ -electron system.
- aryl group having 6-20 carbon atoms means an aromatic group containing 6 to 20 carbon atoms, such as phenyl or naphthyl.
- Aryl is optionally substituted with 1 or more (such as 1 to 3) suitable substituents (eg, halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.).
- aralkyl preferably denotes an aryl-substituted alkyl group, wherein the aryl and the alkyl are as defined herein.
- the aryl group may have 6-10 carbon atoms
- the alkyl group may have 1-6 carbon atoms.
- Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.
- heteroaryl refers to a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, In particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms and which contain at least one heteroatom which may be the same or different (the heteroatom is for example oxygen, nitrogen or sulfur), and, in addition May be benzo-fused in each case.
- heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl, Diazolyl, etc., and their benzo derivatives; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives.
- halogen group is defined to include F, Cl, Br or I.
- substituted means that one or more (eg, one, two, three or four) hydrogens on the indicated atom are replaced by a selection from the indicated group, provided that no more than Atoms are designated at their normal valences at the present situation and such substitutions result in stable compounds. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
- chlorohomoserine alkyl esters in the following examples can be prepared by a method similar to the method disclosed in CN 110845347 A.
- the remaining reagents, such as MDP and MDEP, are commercially available.
- the product content recorded in the examples is the absolute content of the pure product in the obtained product, which is detected by HPLC (external standard method).
- the product structure analysis data are as follows:
- Chlorine of isopropyl chlorohomoserine (82.0g, 433.6mmol, 1.0eq, 95% purity, ee value 99%) and triethylamine (53.8g, 520.5mmol, 1.2eq, 98% purity) were added dropwise thereto.
- Benzene (300g) solution the rate of addition is 4d/s, continue to stir for 30min after the dropwise addition, raise the temperature to room temperature and stir for 1h, continue to react at 90°C for 3h, the reaction is complete, naturally cool to room temperature, suction filter, chlorobenzene (150mL x 3 ) to wash the filter cake, take the filtrate and spin-evaporate to dryness of chlorobenzene to obtain a light yellow viscous liquid, namely the crude product of MPO-iPr.
- the product structure analysis data are as follows:
- Chlorobenzene ( 167g) solution the dropping speed is 4d/s, continue to stir for 30min after the dropwise addition is completed, heat up to room temperature and stir for 1h, continue to react for 3h at 90°C, the reaction is complete, naturally cool to room temperature, suction filter, wash with chlorobenzene (50mL x 3) filter cake.
- the reaction solution was added dropwise to the chlorobenzene (232kg) solution of chlorohomoserine ethyl ester (50kg, 96% purity, ee value 99%) and triethylamine (35.8kg, 98% purity), and the dropping time was controlled at 5h After completion of the dropwise addition, the temperature was raised to 90°C to continue the reaction for 3 hours, the reaction was complete, cooled naturally to room temperature, centrifuged, and the filter cake was fully washed with chlorobenzene.
- the reaction solution was added dropwise to a chlorobenzene (232kg) solution of chlorohomoserine ethyl ester (25kg, 96% purity, ee value 99%), and at the same time, 3kg of ammonia gas was introduced for neutralization, and the dropping time was controlled within 3h.
- the temperature was raised to 90° C. to continue the reaction for 3 h, and the reaction was complete, cooled naturally to room temperature, centrifuged, and the filter cake was fully washed with chlorobenzene.
- Chlorobenzene ( 167g) solution the dropping speed is 4d/s, continue to stir for 30min after the dropwise addition is completed, heat up to room temperature and stir for 1h, continue to react for 3h at 90°C, the reaction is complete, naturally cool to room temperature, suction filter, wash with chlorobenzene (50mL x 3) filter cake.
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Abstract
提供了一种式(I)的L-草铵膦或其衍生物的制备方法。
Description
本发明涉及L-草铵膦衍生物、包含其的组合物及其制备方法和用途。
发明背景
草铵膦是(Glufosinate)由赫斯特公司于上世纪80年代开发的一种具有部分内吸作用的高效、广谱、低毒、非选择性(灭生性)有机磷类除草剂。可用于防除一年和多年生双子叶及禾本科杂草。草铵膦具有L型和D型两种对映异构体,L-型草铵膦即精草铵膦,其除草活性为外消旋DL-型草铵膦的两倍。
仍需开发草铵膦的衍生物,以获得具有改善的除草效果、降低的抗药性和/或在长期储存时具有更高物理/化学稳定性的化合物。
发明概述
本发明提供了一种式(I)的化合物的制备方法,
其中所述方法包括将式(III)的化合物与ROH反应,
其中:
Y为-OR
1、-NH
2、-NHR
2或-N(R
2)(R
3);
R为H、具有1-6个碳原子的取代或未取代的烷基、具有2-6个碳原子的取代或未取代的烯基、具有2-6个碳原子的取代或未取代的炔基,具有3-10个碳原子的取代或未取代的环烷基、具有2-10个碳原子的取代或未取代的杂环基、具有6-20个碳原子的取代或未取代的芳基、具有6-20个碳原子的取代或未取代的芳烷基、或具有2-10个碳原子的取 代或未取代的杂芳基;优选地,R为H或具有1-6个碳原子的取代或未取代的烷基;更优选地,R为H(此时ROH为水)、甲基(此时ROH为甲醇)或乙基(此时ROH为乙醇);
R
1、R
2和R
3各自独立地为具有1-6个碳原子的取代或未取代的烷基、具有2-6个碳原子的取代或未取代的烯基、具有2-6个碳原子的取代或未取代的炔基,具有3-10个碳原子的取代或未取代的环烷基、具有2-10个碳原子的取代或未取代的杂环基、具有6-20个碳原子的取代或未取代的芳基、具有6-20个碳原子的取代或未取代的芳烷基、或具有2-10个碳原子的取代或未取代的杂芳基、或-Si(R
4)(R
5)(R
6);
R
4、R
5和R
6各自独立地为具有1-6个碳原子的取代或未取代的烷基或具有6-20个碳原子的取代或未取代的芳基;
所述烷基、烯基、炔基、环烷基、杂环基、芳基、芳烷基和杂芳基的取代基各自独立地为卤素、羧基(-COOH)、氨基(-NH
2)、硝基(-NO
2)、氰基(-CN)、具有1-6个碳原子的烷基、具有6-10个碳原子的芳基或具有3-10个碳原子的环烷基。
在优选的实施方案中,所述式(III)的化合物与ROH反应在0℃至100℃的温度下进行,例如在0℃至80℃、0℃至60℃、0℃至40℃、0℃至30℃、0℃至20℃、30℃至80℃或30℃至60℃的温度下进行。
所述式(III)的化合物与ROH的反应在没有酸和/或碱的存在下进行。
在一些实施方案中,所述式(III)的化合物由式(V)化合物制备:
其中:
Hal在每次出现时各自独立地为选自F、Cl、Br或I的卤素;
Y如前述定义;
R
7为氢、具有1至6个碳原子的取代或未取代的烷基、具有2-6个碳原子的取代或未取代的烯基或具有2-6个碳原子的取代或未取代的炔基,所述烷基、烯基和炔基的取代基各自独立地为卤素、羧基、氨基、硝基、氰基、具有1-6个碳原子的烷基、具有6- 10个碳原子的芳基或具有3-10个碳原子的环烷基。
在一些实施方案中,所述式(V)化合物由式(II)化合物
与一种或更多种式(IV)化合物或混合物反应;
所述混合物为包含一种或更多种式(IV)-1化合物与一种或更多种式(IV)-2化合物的混合物;或,包含一种或更多种式(IV)-1化合物与一种或更多种式(IV)化合物的混合物;或,包含一种或更多种式(IV)-2化合物与一种或更多种式(IV)化合物的混合物;或,包含一种或更多种式(IV)化合物、一种或更多种式(IV)-1化合物与一种或更多种式(IV)-2化合物的混合物;
其中X、Hal和R
7如上文所定义。
在制备所述式(V)化合物的反应中,任意的投料顺序均可以顺利得到产物。如将式(II)化合物投入式(IV)化合物或所述混合物中,也可以将式(IV)化合物或所述混合物投入到式(II)化合物中。
在制备所述式(V)化合物的反应中,以式(II)化合物的盐(如盐酸盐)也可以顺利进行反应。
进一步地,前述R
1、R
2和R
3各自独立地为甲基、乙基、丙基(例如正丙基、异丙基)、丁基(例如正丁基、异丁基或叔丁基)、戊基、己基、苄基、苯基或萘基,优选乙基、正丙基、异丙基或正丁基,更优选乙基。
优选地,Y为-NHCH
2CH
2CH
2CH
3、-N(CH
3)
2、-OCH
3、-OCH
2CH
3、-OCH
2CH
2CH
3、-OCH(CH
3)
2、-OCH
2CH
2CH
2CH
3、-OCH
2CH(CH
3)
2或-OBn。
进一步地,前述R
7为甲基、乙基、丙基、丁基、戊基或己基,优选乙基。
进一步地,前述制备所述式(V)化合物的反应中,反应的温度为-30~30℃,如-10~20℃、-10~10℃,较优选的温度为-10℃。反应的时间可以是0.1~20小时。
进一步地,前述制备所述式(V)化合物的反应中,反应的温度为-30~30℃。
进一步地,在制备所述式(V)化合物的反应中,所述混合物为一种或更多种式(IV)-1 化合物与一种或更多种式(IV)化合物的混合物,式(IV)-1化合物与式(IV)化合物的摩尔比为(0.9~1.1)∶1或者(0.05~1.1)∶1;或者所述混合物为一种或更多种式(IV)-2化合物与一种或更多种式(IV)化合物的混合物,式(IV)-2化合物与式(IV)化合物的摩尔比为(0.9~1.1)∶1或者(0.05~1.1)∶1;或者所述混合物为包含一种或更多种式(IV)-1化合物与一种或更多种式(IV)-2化合物的混合物,式(IV)-1化合物与式(IV)-2化合物的摩尔比为(0.9~1.1)∶1。
进一步地,前述制备所述式(V)化合物的反应在碱的存在下进行。
进一步地,前述制备所述式(V)化合物的反应中的碱为有机碱或氨。
进一步地,前述制备所述式(V)化合物的反应中,有机碱选自有机胺、吡啶或具有1~3个连接到该杂环的一个或多个碳原子上的取代基的吡啶衍生物、哌啶或具有1~3个连接到该杂环的一个或多个碳原子上的取代基的哌啶衍生物;
优选地,上述取代基选自卤素、-OH、-O-(C
1-C
6烷基)、-NH
2、-NO
2、-CN、C
1-C
6烷基、C
3-10环烷基和C
6-10芳基。
进一步地,前述制备所述式(V)化合物的反应中,所述有机碱选自N,N-二甲基苯胺、三乙胺、哌啶或吡啶。
进一步地,制备所述式(V)化合物的反应在无溶剂条件下或惰性溶剂中进行;所述惰性溶剂选自苯类溶剂、酰胺类溶剂、烃类溶剂、卤代烃类溶剂、砜或亚砜类溶剂、醚类溶剂或酯类溶剂中的任一种或一种以上;优选地,所述惰性溶剂选自苯类溶剂、酰胺类溶剂、卤代烃类溶剂、醚类溶剂或酯类溶剂中的任一种或一种以上。
进一步地,所述惰性溶剂选自氯苯、三甲苯、1,4-二氧六环、1,2-二氯乙烷、二甲亚砜、氮甲基吡咯烷酮、N,N-二甲基甲酰胺、石油醚、正庚烷、四氢呋喃、甲基四氢呋喃、苯、甲苯、乙酸乙酯、乙酸丁酯中的任一种或一种以上。
进一步地,前述制备所述式(V)化合物的反应中,式(IV)化合物或所述混合物与式(II)化合物的摩尔比为1∶(0.5~10),优选1∶(1~3);或者式(II)化合物与式(IV)化合物或所述混合物的摩尔比为1∶(0.5~10),优选1∶(1~3)。略过量的式(IV)化合物或所述混合物对反应的收率是有利的,例如过量5%~10%。
进一步地,前述制备所述式(III)化合物的反应包括将式(V)化合物在50~150℃的温度下加热,以转化为式(III)化合物。优选的温度为60~120℃或90~100℃。反应的时间可以是0.5~40小时。
在一些实施方案中,制备所述式(III)化合物的反应可以在有机溶剂的存在下进行, 如1,4-二氧六环、乙腈、1,2-二氯乙烷、四氢呋喃、氯苯,较优选的有机溶剂为氯苯。
进一步地,前述制备所述式(V)化合物的反应和制备所述式(III)化合物的反应一锅进行,即不分离中间体式(V)化合物。
进一步地,前述式(I)的化合物的ee值大于50%。
进一步地,前述式(I)的化合物的ee值大于90%。
定义
除非另有定义,本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术,包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解,但仍然阐述以下定义以更好地解释本发明。
如本文中所使用,术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的,且不排除其它未列举的元素或方法步骤。
如本文中所使用,术语“烷基”定义为线性或支化饱和脂肪族烃。在一些实施方案中,烷基具有1至12个,例如1至6个碳原子。例如,如本文中所使用,术语“具有1至6个碳原子的烷基”指1至6个碳原子的线性或支化的基团(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基或正己基),其任选地被1或多个(诸如1至3个)适合的取代基如卤素取代(此时该基团被称作“卤代烷基”)(例如CH
2F、CHF
2、CF
3、CCl
3、C
2F
5、C
2Cl
5、CH
2CF
3、CH
2Cl或-CH
2CH
2CF
3等)。术语“具有1至4个碳原子的烷基”指1至4个碳原子的线性或支化的脂肪族烃链(即甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)。
如本文中所使用,术语“烯基”意指线性的或支化的单价烃基,其包含一个或多个双键,且具有2-6个碳原子(“C
2-6烯基”)。所述烯基为例如乙烯基、1-丙烯基、2-丙烯基、2-丁烯基、3-丁烯基、2-戊烯基、3-戊烯基、4-戊烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、2-甲基-2-丙烯基和4-甲基-3-戊烯基。当本发明的化合物含有烯基时,所述化合物可以纯E(异侧(entgegen))形式、纯Z(同侧(zusammen))形式或其任意混合物形式存在。
如本文中所使用,术语“炔基”表示包含一个或多个三键的单价烃基,其优选具有2、3、4、5或6个碳原子,例如乙炔基或丙炔基。
如本文中所使用,术语“环烷基”指饱和的单环或多环(诸如双环)烃环(例如单环,诸如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基,或双环,包括螺环、稠合或桥连系统(诸如双环[1.1.1]戊基、双环[2.2.1]庚基、双环[3.2.1]辛基或双环[5.2.0]壬基、十 氢化萘基等),其任选地被1或多个(诸如1至3个)适合的取代基取代。所述环烷基优选具有3至10个碳原子。例如,术语“C
3-6环烷基”指3至6个成环碳原子的饱和的单环或多环(诸如双环)烃环(例如环丙基、环丁基、环戊基或环己基),其任选地被1或多个(诸如1至3个)适合的取代基取代,例如甲基取代的环丙基。
如本文中所使用,术语“杂环基”指饱和或不饱和的一价单环或双环基团,其在环中具有2、3、4、5、6、7、8、9或10个碳原子和一个或多个(例如一个、两个、三个或四个)选自C(=O)、O、S、S(=O)、S(=O)
2和NR
d的含杂原子的基团,其中R
d表示氢原子或C
1-6烷基或卤代-C
1-6烷基;所述杂环基可以通过所述碳原子中的任一个或氮原子(如果存在的话)与分子的其余部分连接。特别地,具有2-10个碳原子的杂环基为例如但不限于环氧乙烷基、氮丙啶基、氮杂环丁烷基(azetidinyl)、氧杂环丁烷基(oxetanyl)、四氢呋喃基、二氧杂环戊烯基(dioxolinyl)、吡咯烷基、吡咯烷酮基、咪唑烷基、吡唑烷基、吡咯啉基、四氢吡喃基、哌啶基、吗啉基、二噻烷基(dithianyl)、硫吗啉基、哌嗪基或三噻烷基(trithianyl)。
如本文中所使用,术语“芳基”指具有共轭π电子系统的全碳单环或稠合环多环芳族基团。例如,如本文中所使用,术语“具有6-20个碳原子的芳基”意指含有6至20个碳原子的芳族基团,诸如苯基或萘基。芳基任选地被1或多个(诸如1至3个)适合的取代基(例如卤素、-OH、-CN、-NO
2、C
1-6烷基等)取代。
如本文中所使用,术语“芳烷基”优选表示芳基取代的烷基,其中所述芳基和所述烷基如本文中所定义。通常,所述芳基可具有6-10个碳原子,并且所述烷基可具有1-6个碳原子。示例性芳烷基包括但不限于苄基、苯基乙基、苯基丙基、苯基丁基。
如本文中所使用,术语“杂芳基”指一价单环、双环或三环芳族环系,其具有5、6、8、9、10、11、12、13或14个环原子,特别是1或2或3或4或5或6或9或10个碳原子,且其包含至少一个可以相同或不同的杂原子(所述杂原子是例如氧、氮或硫),并且,另外在每一种情况下可为苯并稠合的。特别地,杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基等,以及它们的苯并衍生物;或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等,以及它们的苯并衍生物。
如本文中所使用,术语“卤素”基团定义为包括F、Cl、Br或I。
如本文中所使用,术语“取代”指所指定的原子上的一个或多个(例如一个、两个、三个或四个)氢被从所指出的基团的选择代替,条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成 稳定的化合物时才是允许的。
发明详述
以下实施例中的氯代高丝氨酸烷基酯可通过与CN 110845347 A中所公开的方法类似的方法制备获得。其余试剂(例如MDP和MDEP)均可商购获得。
实施例中记载的产物含量是所获得产物中产物纯品的绝对含量,通过HPLC(外标法)检测得到。
实施例1
在氮气氛围下,-10℃下,在圆底烧瓶中加入甲基亚磷酸二乙酯(MDEP,68.8g,455.4mmol,0.53eq,90%纯度)的氯苯(300g)溶液,用恒压滴液漏斗滴加甲基二氯化磷(MDP,54.4g,455.4mmol,0.53eq,98%纯度)的氯苯(200g)溶液,滴加速度1d/s,滴加完毕后继续搅拌10min(此时反应液中有MCP生成)。向其中滴加氯代高丝氨酸乙酯(150g,867.5mmol,1.0eq,96%纯度,ee值99%)和三乙胺(107.5g,1041mmol,1.2eq,98%纯度)的氯苯(500g)溶液,滴加速度4d/s,滴加完毕后继续搅拌30min,升温至室温下搅拌1h,90℃下继续反应3h反应完全,自然冷却至室温,抽滤,氯苯(150mL x 3)洗滤饼,取滤液旋蒸干氯苯,得到浅黄色黏稠液体,即MPO粗产物。
在10℃下,向MPO粗产物中滴加水(62.5g,3470mmol)和乙腈(125g)的混合物,搅拌反应1h,至有固体析出,再继续加入乙腈(594g),在室温(约15℃)下搅拌,有大量固体析出。将固体过滤,烘干,得MPN(白色固体,145.9g,含量90%)。
产物结构分析数据如下:
MS(ESI):m/z[M+H]
+calcd for C7H17NO4P:210.09;found:210.1.
1H NMR(400MHz,DMSO-d
6)δ:4.34-4.11(m,2H),4.00(t,J=5.8Hz,1H),2.28-1.92(m,2H),1.77-1.48(m,2H),1.23(t,J=7.1Hz,3H),1.17(d,J=13.8Hz,3H).
13C NMR(100MHz,DMSO-d
6)δ169.5,61.7,52.4,52.3,27.6,26.7,23.8,16.3,15.3, 14.0.
31P NMR(160MHz,DMSO-d
6)δ38.9.
实施例2
在氮气氛围下,-10℃下,在圆底烧瓶中加入甲基亚磷酸二乙酯(MDEP,34.7g,227.6mmol,0.53eq,90%纯度)的氯苯(300g)溶液,用恒压滴液漏斗滴加甲基二氯化磷(MDP,27.2g,227.6mmol,0.53eq,98%纯度)的氯苯(200g)溶液,滴加速度1d/s,滴加完毕后继续搅拌10min(此时反应液中有MCP生成)。向其中滴加氯代高丝氨酸异丙酯(82.0g,433.6mmol,1.0eq,95%纯度,ee值99%)和三乙胺(53.8g,520.5mmol,1.2eq,98%纯度)的氯苯(300g)溶液,滴加速度4d/s,滴加完毕后继续搅拌30min,升温至室温下搅拌1h,90℃下继续反应3h反应完全,自然冷却至室温,抽滤,氯苯(150mL x 3)洗滤饼,取滤液旋蒸干氯苯,得到浅黄色黏稠液体,即MPO-iPr粗产物。
在10℃下,向MPO-iPr粗产物中滴加水(31.2g,1734.4mmol)和乙腈(62.4g)的混合物,搅拌反应1h,至有固体析出,再继续加入乙腈(296.4g),在室温(约15℃)下搅拌,有大量固体析出。将固体过滤,烘干,得MPN-iPr(白色固体,79.4g,含量91%)。
产物结构分析数据如下:
MS(ESI):m/z[M+H]
+calcd for C8H19NO4P:224.10;found:224.1.
1H NMR(600MHz,Chloroform-d)δ5.10(p,J=6.3Hz,1H),3.82(dd,J=7.5,2.9Hz,1H),2.41-2.31(m,1H),2.26(dddq,J=15.6,11.9,8.0,4.5,4.0Hz,1H),1.77-1.60(m,2H),1.31-1.23(m,9H).
13C NMR(150MHz,Chloroform-d)δ169.2,70.0,53.1,29.1,28.5,23.8,21.9,17.1,16.5.
31P NMR(240MHz,Chloroform-d)δ36.8.
实施例3
在氮气氛围下,-10℃下,在圆底烧瓶中加入甲基亚磷酸二乙酯(MDEP,22.9g,151.8mmol,0.53eq,90%纯度)的氯苯(100g)溶液,用恒压滴液漏斗滴加甲基二氯化磷(MDP,18.1g,151.8mmol,0.53eq,98%纯度)的氯苯(67g)溶液,滴加速度1d/s,滴加完毕后继续搅拌10min(此时反应液中有MCP生成)。向其中滴加氯代高丝氨酸乙酯(50g,289.1mmol,1.0eq,96%纯度,ee值99%)和三乙胺(35.8g,347.0mmol,1.2eq,98%纯度)的氯苯(167g)溶液,滴加速度4d/s,滴加完毕后继续搅拌30min,升温至室温下搅拌1h,90℃下继续反应3h反应完全,自然冷却至室温,抽滤,氯苯(50mL x 3)洗滤饼。
取MPO滤液,加入水(20.8g,1156.4mmol)和乙腈(20.8g)的混合溶液,旋蒸至有固体析出,停止旋蒸,再加入含5重量%水的乙腈(250g)搅拌,有大量固体析出。将固体过滤,烘干,得MPN(白色固体,41.8g,含量94%)。
实施例4
在氮气氛围下,-10至-15℃下,往反应釜中加入甲基亚磷酸二乙酯(MDEP,22.9kg,95%纯度)的氯苯(80kg)溶液,滴加入甲基二氯化磷(MDP,19.1kg,98%纯度),滴加时间控制在2h内,滴加完毕后继续搅拌30min(此时反应液中有MCP生成)。将反应液滴加至氯代高丝氨酸乙酯(50kg,96%纯度,ee值99%)和三乙胺(35.8kg,98%纯度)的氯苯(232kg)溶液,滴加时间控制在5h内,滴加完毕后升温至90℃下继续反应3h反应完全,自然冷却至室温,离心,用氯苯充分洗滤饼。
于60℃下,往MPO滤液中加入水(10kg)和乙腈(20kg),搅拌30min后,蒸馏溶剂至有固体析出,再加入含5重量%水的乙腈(25kg)搅拌,有大量固体析出。将固体过滤,烘干,得MPN(白色固体,57.5kg,含量96%,收率91%,ee99%),母液残留MPN3.2%。
实施例5
在氮气氛围下,-10至-15℃下,往反应釜中加入甲基亚磷酸二乙酯(MDEP,11.5kg,95%纯度)的氯苯(40kg)溶液,滴加入甲基二氯化磷(MDP,10.1kg,98%纯度),滴加时间控制在1h内,滴加完毕后继续搅拌30min(此时反应液中有MCP生成)。将反应液滴加至氯代高丝氨酸乙酯(25kg,96%纯度,ee值99%)的氯苯(232kg)溶液中,同时通入3kg氨气中和,滴加时间控制在3h内,滴加完毕后升温至90℃下继续反应3h反应完全,自然冷却至室温,离心,用氯苯充分洗滤饼。
于40℃下,往MPO滤液中加入水(5kg)和乙腈(25kg),搅拌30min后,蒸馏溶剂至有大量固体析出。将固体过滤烘干,得MPN(白色固体,28.1kg,含量96%,收率89%,ee99%),母液残留MPN 2.8%。
实施例6
在氮气氛围下,-10℃下,在圆底烧瓶中加入甲基亚磷酸二乙酯(MDEP,22.9g,151.8mmol,0.53eq,90%纯度)的氯苯(100g)溶液,用恒压滴液漏斗滴加甲基二氯化磷(MDP,18.1g,151.8mmol,0.53eq,98%纯度)的氯苯(67g)溶液,滴加速度1d/s,滴加完毕后继续搅拌10min(此时反应液中有MCP生成)。向其中滴加氯代高丝氨酸乙酯(50g,289.1mmol,1.0eq,96%纯度,ee值99%)和三乙胺(35.8g,347.0mmol,1.2eq,98%纯度)的氯苯(167g)溶液,滴加速度4d/s,滴加完毕后继续搅拌30min,升温至室温下搅拌1h,90℃下继续反应3h反应完全,自然冷却至室温,抽滤,氯苯(50mL x 3)洗滤饼。
取MPO滤液,在10℃下,向MPO滤液中加入无水乙醇(40g,867.3mmol),搅拌反应1h,减压蒸馏得MPN-Et(淡黄色粘稠液体,76.8g,含量75%,收率84%,ee 98.7%)。
实施例7
在圆底烧瓶中加入MPN(70g,301.2mmol,90%纯度),滴加36%的浓盐酸(315mL),缓慢加热至回流反应,至原料反应完毕,蒸干溶剂,加入95%乙醇(240mL)和水(24mL)回流直至产物完全溶解,冷却以使固体析出。将固体过滤,干燥得到L-草铵膦盐酸盐(白色固体,纯品收率92.4%,含量96.6%,ee值98%)。
实施例8
在圆底烧瓶中加入MPN(70g,301.2mmol,90%纯度),滴加36%的浓盐酸(315mL),缓慢加热至回流反应,至原料反应完毕,蒸干溶剂,加入水(63g)和滴加氨水(59g),调节pH至7-8,再蒸干溶剂,加入甲醇溶解,过滤,除去氯化铵,滤液回流2h,冷却至15℃以使固体析出。将固体过滤,干燥得到L-草铵膦铵盐(白色固体,纯品收率84.4%,含量96%,ee值98%)。
实施例9
在圆底烧瓶中加入MPN-Et(70g,221.4mmol,75%纯度),滴加36%的浓盐酸(315mL),缓慢加热至回流反应,至原料反应完毕,蒸干溶剂,加入95%乙醇(200mL)和水(20mL)回流直至产物完全溶解,冷却以使固体析出。将固体过滤,干燥得到L-草铵膦盐酸盐(白色固体,纯品收率91.3%,含量93.2%,ee值97%)。
实施例10
在反应釜中加入MPN(28.7kg,96%纯度),加入30%的浓盐酸(143.5kg),缓慢加热至100℃下反应,同时在该温度下边反应边蒸馏,至原料反应完全,反应结束后蒸干溶剂,加入95%乙醇(72kg)搅拌,冷却后有大量白色固体析出。将固体过滤,干燥得到L-草铵膦盐酸盐(白色固体,28.4kg,纯品收率91.7%,含量96.2%,ee值99%),母液残留L-草铵膦盐酸盐3.6%。
除本文中描述的那些外,根据前述描述,本发明的各种修改对本领域技术人员而言会是显而易见的。这样的修改也意图落入所附权利要求书的范围内。本申请中所引用的各参考文献(包括所有专利、专利申请、期刊文章、书籍及任何其它公开)均以其整体援引加入本文。
Claims (19)
- 一种式(I)的化合物的制备方法,其中所述方法包括将式(III)的化合物与ROH反应,其中:Y为-OR 1、-NH 2、-NHR 2或-N(R 2)(R 3);R为H、具有1-6个碳原子的取代或未取代的烷基、具有2-6个碳原子的取代或未取代的烯基、具有2-6个碳原子的取代或未取代的炔基,具有3-10个碳原子的取代或未取代的环烷基、具有2-10个碳原子的取代或未取代的杂环基、具有6-20个碳原子的取代或未取代的芳基、具有6-20个碳原子的取代或未取代的芳烷基、或具有2-10个碳原子的取代或未取代的杂芳基;优选地,R为H或具有1-6个碳原子的取代或未取代的烷基;更优选地,R为H、甲基或乙基;R 1、R 2和R 3各自独立地为具有1-6个碳原子的取代或未取代的烷基、具有2-6个碳原子的取代或未取代的烯基、具有2-6个碳原子的取代或未取代的炔基,具有3-10个碳原子的取代或未取代的环烷基、具有2-10个碳原子的取代或未取代的杂环基、具有6-20个碳原子的取代或未取代的芳基、具有6-20个碳原子的取代或未取代的芳烷基、或具有2-10个碳原子的取代或未取代的杂芳基、或-Si(R 4)(R 5)(R 6);R 4、R 5和R 6各自独立地为具有1-6个碳原子的取代或未取代的烷基或具有6-20个碳原子的取代或未取代的芳基;所述烷基、烯基、炔基、环烷基、杂环基、芳基、芳烷基和杂芳基的取代基各自独立地为卤素、羧基、氨基、硝基、氰基、具有1-6个碳原子的烷基、具有6-10个碳原子的芳基或具有3-10个碳原子的环烷基。
- 根据权利要求1-3任一项所述的方法,其中所述R 1、R 2和R 3各自独立地为甲基、乙基、丙基(例如正丙基、异丙基)、丁基(例如正丁基、异丁基或叔丁基)、戊基、己基、苄基、苯基或萘基,优选乙基、正丙基、异丙基或正丁基,更优选乙基;优选地,Y为-NHCH 2CH 2CH 2CH 3、-N(CH 3) 2、-OCH 3、-OCH 2CH 3、-OCH 2CH 2CH 3、-OCH(CH 3) 2、-OCH 2CH 2CH 2CH 3、-OCH 2CH(CH 3) 2或-OBn。
- 根据权利要求2-4任一项所述的方法,其中所述R7为甲基、乙基、丙基、丁基、戊基或己基,优选乙基。
- 根据权利要求3-5任一项所述的方法,其中在制备所述式(V)化合物的反应中,反应的温度为-30~30℃。
- 根据权利要求3-6任一项所述的方法,其中在制备所述式(V)化合物的反应中,所述混合物为一种或更多种式(IV)-1化合物与一种或更多种式(IV)化合物的混合物,式(IV)-1化合物与式(IV)化合物的摩尔比为(0.9~1.1)∶1或者(0.05~1.1)∶1;或者所述混合物为一种或更多种式(IV)-2化合物与一种或更多种式(IV)化合物的混合物,式(IV)-2化合物与式(IV)化合物的摩尔比为(0.9~1.1)∶1或者(0.05~1.1)∶1;或者所述混合物为包含一种或更多种式(IV)-1化合物与一种或更多种式(IV)-2化合物的混合物,式(IV)-1化合物与式(IV)-2化合物的摩尔比为(0.9~1.1)∶1。
- 根据权利要求3-7任一项所述的方法,其中制备所述式(V)化合物的反应在碱的存在下进行。
- 根据权利要求8所述的方法,其中制备所述式(V)化合物的反应中的碱为有机碱或氨。
- 根据权利要求9所述的方法,其中制备所述式(V)化合物的反应中,有机碱选自有机胺、吡啶或具有1~3个连接到该杂环的一个或多个碳原子上的取代基的吡啶衍生物、哌啶或具有1~3个连接到该杂环的一个或多个碳原子上的取代基的哌啶衍生物;优选地,上述取代基选自卤素、-OH、-O-(C 1-C 6烷基)、-NH 2、-NO 2、-CN、C 1-C 6烷基、C 3-10环烷基和C 6-10芳基。
- 根据权利要求10所述的方法,其中所述有机碱选自N,N-二甲基苯胺、三乙胺、哌啶或吡啶。
- 根据权利要求3-11任一项所述的方法,其中制备所述式(V)化合物的反应在无溶剂条件下或惰性溶剂中进行;所述惰性溶剂选自苯类溶剂、酰胺类溶剂、烃类溶剂、卤代烃类溶剂、砜或亚砜类溶剂、醚类溶剂或酯类溶剂中的任一种或一种以上;优选地,所述惰性溶剂选自苯类溶剂、酰胺类溶剂、卤代烃类溶剂、醚类溶剂或酯类溶剂中的任一种或一种以上。
- 根据权利要求12所述的方法,其中所述惰性溶剂选自氯苯、三甲苯、1,4-二氧 六环、1,2-二氯乙烷、二甲亚砜、氮甲基吡咯烷酮、N,N-二甲基甲酰胺、石油醚、正庚烷、四氢呋喃、甲基四氢呋喃、苯、甲苯、乙酸乙酯、乙酸丁酯中的任一种或一种以上。
- 根据权利要求3-13中任一项所述的方法,其中在制备所述式(V)化合物的反应中,式(IV)化合物或所述混合物与式(II)化合物的摩尔比为1∶(0.5~10),优选1∶(1~3);或者式(II)化合物与式(IV)化合物或所述混合物的摩尔比为1∶(0.5~10),优选1∶(1~3)。
- 根据权利要求2-14任一项所述的方法,其中制备所述式(III)化合物的反应包括将式(V)化合物在50~150℃的温度下加热。
- 根据权利要求3-15任一项所述的方法,其中制备所述式(V)化合物的反应和制备所述式(III)化合物的反应一锅进行。
- 根据权利要1-16任一项所述的方法,其中所述式(I)的化合物的ee值大于50%。
- 根据权利要求17所述的方法,其中所述式(I)的化合物的ee值大于90%。
- 根据权利要求1所述的方法,其中所述式(III)的化合物与ROH反应在0℃至100℃的温度下进行,例如在0℃至80℃、0℃至60℃、0℃至40℃、0℃至30℃、0℃至20℃、30℃至80℃或30℃至60℃的温度下进行。
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