CN113248537B - 草铵膦的制备方法 - Google Patents
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- 238000002360 preparation method Methods 0.000 title claims abstract description 6
- 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 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 11
- 239000002841 Lewis acid Substances 0.000 claims abstract description 10
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 5
- 239000001257 hydrogen Substances 0.000 claims abstract description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 21
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical group C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 17
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 12
- IAJOBQBIJHVGMQ-BYPYZUCNSA-N glufosinate-P Chemical compound CP(O)(=O)CC[C@H](N)C(O)=O IAJOBQBIJHVGMQ-BYPYZUCNSA-N 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 239000012442 inert solvent Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 abstract description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 9
- 125000003118 aryl group Chemical group 0.000 abstract description 5
- 125000006239 protecting group Chemical group 0.000 abstract description 5
- 125000003342 alkenyl group Chemical group 0.000 abstract description 4
- 229910052736 halogen Inorganic materials 0.000 abstract description 4
- 150000002367 halogens Chemical class 0.000 abstract description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 4
- 239000005561 Glufosinate Substances 0.000 abstract description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 abstract description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 abstract description 2
- 125000004663 dialkyl amino group Chemical group 0.000 abstract description 2
- 150000002431 hydrogen Chemical group 0.000 abstract description 2
- 238000006467 substitution reaction Methods 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 239000012043 crude product Substances 0.000 description 16
- 239000007858 starting material Substances 0.000 description 16
- 239000002904 solvent Substances 0.000 description 14
- 238000010992 reflux Methods 0.000 description 11
- NSSMTQDEWVTEKN-UHFFFAOYSA-N diethoxy(methyl)phosphane Chemical compound CCOP(C)OCC NSSMTQDEWVTEKN-UHFFFAOYSA-N 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 229940125904 compound 1 Drugs 0.000 description 8
- 239000013078 crystal Substances 0.000 description 8
- 230000008034 disappearance Effects 0.000 description 8
- 238000001704 evaporation Methods 0.000 description 8
- 239000012299 nitrogen atmosphere Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- NYYLZXREFNYPKB-UHFFFAOYSA-N 1-[ethoxy(methyl)phosphoryl]oxyethane Chemical compound CCOP(C)(=O)OCC NYYLZXREFNYPKB-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- -1 boron halides Chemical class 0.000 description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 5
- FYGHSUNMUKGBRK-UHFFFAOYSA-N 1,2,3-trimethylbenzene Chemical compound CC1=CC=CC(C)=C1C FYGHSUNMUKGBRK-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 229910052782 aluminium Inorganic materials 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- 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 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- YNLAOSYQHBDIKW-UHFFFAOYSA-M diethylaluminium chloride Chemical compound CC[Al](Cl)CC YNLAOSYQHBDIKW-UHFFFAOYSA-M 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 150000007970 thio esters Chemical class 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- PVKVBDZRILNPJY-UHFFFAOYSA-N 1-butoxybutane;trifluoroborane Chemical compound FB(F)F.CCCCOCCCC PVKVBDZRILNPJY-UHFFFAOYSA-N 0.000 description 1
- AWONIZVBKXHWJP-UHFFFAOYSA-N 1-methoxy-2,3,5-trimethylbenzene Chemical compound COC1=CC(C)=CC(C)=C1C AWONIZVBKXHWJP-UHFFFAOYSA-N 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 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
- 229910015900 BF3 Inorganic materials 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- OTYYBJNSLLBAGE-UHFFFAOYSA-N CN1C(CCC1)=O.[N] Chemical compound CN1C(CCC1)=O.[N] OTYYBJNSLLBAGE-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- ZDQWVKDDJDIVAL-UHFFFAOYSA-N catecholborane Chemical compound C1=CC=C2O[B]OC2=C1 ZDQWVKDDJDIVAL-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 description 1
- UAIZDWNSWGTKFZ-UHFFFAOYSA-L ethylaluminum(2+);dichloride Chemical compound CC[Al](Cl)Cl UAIZDWNSWGTKFZ-UHFFFAOYSA-L 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 description 1
- 229910001623 magnesium bromide Inorganic materials 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- JTBKFHQUYVNHSR-UHFFFAOYSA-N propan-2-yloxyalumane Chemical compound CC(C)O[AlH2] JTBKFHQUYVNHSR-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
- NFMWFGXCDDYTEG-UHFFFAOYSA-N trimagnesium;diborate Chemical class [Mg+2].[Mg+2].[Mg+2].[O-]B([O-])[O-].[O-]B([O-])[O-] NFMWFGXCDDYTEG-UHFFFAOYSA-N 0.000 description 1
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229940102001 zinc bromide Drugs 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
Classifications
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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
- C07F9/28—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)]
- C07F9/301—Acyclic saturated acids which can have further substituents on alkyl
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及草铵膦(I)的制备方法,包括使对映体纯的式(II)化合物与式(III)化合物在路易斯酸的存在下反应的步骤,其中:Hal为卤素;PG为氢或氨基保护基;Z为OX或OY;R1为C1‑C16的烷基、环己基、环戊基或苯基,其中每个基团可被氢、C1‑C6烷基、C1‑C6烷氧基或二烷基氨基取代;R2为C1‑C8烷基、C1‑C8醚基或苯基;X和Y各自独立地为烷基、烯基或芳香基;手性碳原子标有*。本发明的方法可以高收率得到高纯度的草铵膦。
Description
技术领域
本发明涉及草铵膦的制备方法。
背景技术
草铵膦是一种重要的除草剂。
发明内容
本发明提供了一种制备对映体纯的式(I)化合物及其盐的方法,
所述方法包括以下步骤:
使对映体纯的式(II)化合物
与式(III)化合物在路易斯酸的存在下反应,
其中:
Hal为卤素;
PG为氢或氨基保护基;
Z为OX或OY;
R1为C1-C16的烷基、环己基、环戊基或苯基,其中每个基团可被氢、C1-C6烷基、C1-C6烷氧基或二烷基氨基取代;
R2为C1-C8烷基、C1-C8醚基或苯基;
X和Y各自独立地为烷基、烯基或芳香基;
手性碳原子标有*。
进一步地,前述R2为C1-C6烷基,优选C1-C4烷基。
进一步地,前述路易斯酸选自三氟化硼醚合物,铁、锌、铝、镁或硼的卤化物,锌、铝或镁的硼酸盐,有机铝化合物中的一种或一种以上,优选三氟化硼醚合物。
进一步地,前述三氟化硼醚合物选自三氟化硼甲醚、三氟化硼乙醚、三氟化硼丁醚中一种或一种以上,优选三氟化硼乙醚。
进一步地,前述有机铝化合物选自二乙基氯化铝、乙基氯化铝、异丙氧基铝、三甲基铝中的一种或一种以上。
进一步地,前述R1为苯基或C1-C6烷基,优选C1-C4烷基,更优选甲基。
进一步地,前述X和Y各自独立的为C1-C6烷基,优选C1-C4烷基。
进一步地,前述R1为甲基,X为乙基,Y为乙基。
进一步地,前述对映体比值是50.5∶49.5至99.5∶0.5的(L)∶(D)-对映体或(D)∶(L)-对映体。
进一步地,前述对映体比值是50.5∶49.5至99.5∶0.5的(L)∶(D)-对映体。
反应在室温下即可发生,反应的温度可以是20~200℃,考虑到反应的效率,优选90~140℃。温度过低反应速率过慢,温度过高会有副产物生成。
前述反应可以在无溶剂条件下或惰性溶剂中进行。加入溶剂可以减少杂质的产生,增长反应时间。惰性溶剂可选自苯类溶剂、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。
作为具体实施方式,惰性溶剂可选自氯苯、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。溶剂对反应效果有一定影响,优选苯、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。
前述反应可采取多种投料方式,可以先将式(II)化合物与式(III)化合物混合,向其中加入路易斯酸;先将式(II)化合物与路易斯酸混合,向其中加入式(III)化合物。
进一步地,前述路易斯酸与式(II)化合物的摩尔比为1∶(1~100),优选1∶(2~10)。
前述式(II)化合物与式(III)化合物的摩尔比为1∶(1~10),优选1∶(1.3~2)。
反应时间可在较宽范围内变化,根据温度、操作条件和批次的大小,可以是0.5~48小时。
本发明还提供了一种制备L-草铵膦的方法,该方法包括以下步骤:
按照前述的方法制备得到式(Ia)化合物,
使所得式(Ia)化合物在酸性条件下水解,得到L-草铵膦;
其中,PG、Z和R2如前述所定义。
本发明还提供了式(I)化合物或其盐、对映异构体或所有比例的对映异构体的混合物,
其中,PG、Z、R1和R2如前述定义;
手性碳原子标有*。
本发明方法通过加入路易斯酸,可以有效保持原料的ee值。
除非有相反陈述,下列用在说明书和权利要求书中的术语具有下述含义。
术语“氨基保护基”指可连接至氨基上的氮原子从而保护所述氨基不参与反应并且其可在后面的反应中容易地除去的基团。合适的氨基保护基包括,但不限于下述保护基:
式-C(O)O-R的氨基甲酸酯基团,其中R例如甲基、乙基、叔丁基、苄基、苯乙基、CH2=CH-CH2-,等等;式-C(O)-R′的酰胺基团,其中R′例如甲基、乙基、苯基、三氟甲基,等等;式-SO2-R″的N-磺酰基衍生物-基团,其中R″例如甲苯基、苯基、三氟甲基、2,2,5,7,8-五甲基色满-6-基-、2,3,6-三甲基-4-甲氧基苯,等等。
术语“烷基”指饱和的脂族烃基团,包括1至18个碳原子的直链和支链基团。优选含有1至6个碳原子的烷基,例如甲基、乙基、丙基、2-丙基、正丁基、异丁基、叔丁基、戊基等。烷基可以是取代的或未取代的,当被取代时,取代基可以为卤素、硝基、磺酰基、醚氧基、醚硫基、酯基、硫代酯基或氰基。
术语“烯基”指由至少两个碳原子和至少一个碳-碳双键组成的如上述定义的烷基。例如乙烯基、1-丙烯基、2-丙烯基、1-,2-或3-丁烯基等。烯基可以是取代的或未取代的,当被取代时,取代基可以为卤素、硝基、磺酰基、醚氧基、醚硫基、酯基、硫代酯基或氰基。
术语“芳香基”指具有至少一个芳环结构的基团。芳香基优选苯基或苄基。苯基和苄基可以是取代的或未取代的。
C1-C4烷基是直链的或支链的,包含1至4个碳原子的饱和烃链。它可以是甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基或叔丁基基团。
具体实施方式
实施例中,ee值为水解完全后,反应液ee值,通过重结晶分离后L-草铵膦ee值95%-97%。
实施例1
在氮气氛围下,往三口瓶中分别加入化合物1(40.0g,242.4mmol,1.0eq)和1,4-二氧六环(64g,727.2mmol,3.0eq),三氟化硼乙醚(6.9g,48.5mmol,0.2eq),滴加甲基亚膦酸二乙酯(36.8g,290.9mmol,1.2eq),室温下搅拌30h后,升温至100℃下,反应20h,MS检测原料消失,减压蒸馏出1,4-二氧六环和多余的甲基亚膦酸二乙酯,得到白色粗产物,直接下一步。
在圆底烧瓶中加入上步粗产物,滴加36%HCl(294.9mL)加热回流至原料反应完全,蒸干溶剂后,加入95%乙醇(200mL)和水(20mL)回流直至产物完全溶解,冷却结晶,过滤,干燥得到L-草铵膦(白色晶体,36.2g,两步的分离收率83%,96.5%ee)。
实施例2
在氮气氛围下,往三口瓶中分别加入化合物1(40.0g,242.4mmol,1.0eq)和氯苯(81.8g,727.2mmol,3.0eq),三氟化硼乙醚(6.9g,48.5mmol,0.2eq),滴加甲基亚膦酸二乙酯(36.8g,290.9mmol,1.2eq),室温下搅拌30h后,升温至100℃下,反应20h,MS检测原料消失,减压蒸馏出氯苯和多余的甲基亚膦酸二乙酯,得到白色粗产物,直接下一步。
在圆底烧瓶中加入上步粗产物,滴加36%HCl(294.9mL)加热回流至原料反应完全,蒸干溶剂后,加入95%乙醇(200mL)和水(20mL)回流直至产物完全溶解,冷却结晶,过滤,干燥得到L-草铵膦(白色晶体,32.3g,两步的分离收率74%,91%ee)。
实施例3
在氮气氛围下,往三口瓶中分别加入化合物1(40.0g,242.4mmol,1.0eq)和1,4-二氧六环(64g,727.2mmol,3.0eq),三氯化硼(5.7g,48.5mmol,0.2eq),滴加甲基亚膦酸二乙酯(36.8g,290.9mmol,1.2eq),室温下搅拌30h后,升温至100℃下,反应20h,MS检测原料消失,减压蒸馏出1,4-二氧六环和多余的甲基亚膦酸二乙酯,得到白色粗产物,直接下一步。
在圆底烧瓶中加入上步粗产物,滴加36%HCl(294.9mL)加热回流至原料反应完全,蒸干溶剂后,加入95%乙醇(200mL)和水(20mL)回流直至产物完全溶解,冷却结晶,过滤,干燥得到L-草铵膦(白色晶体,33.2g,两步的分离收率76%,94%ee)。
实施例4
在氮气氛围下,往三口瓶中分别加入化合物1(40.0g,242.4mmol,1.0eq)和1,4-二氧六环(64g,727.2mmol,3.0eq),溴化锌(10.9g,48.5mmol,0.2eq),滴加甲基亚膦酸二乙酯(36.8g,290.9mmol,1.2eq),室温下搅拌30h后,升温至100℃下,反应20h,MS检测原料消失,减压蒸馏出1,4-二氧六环和多余的甲基亚膦酸二乙酯,得到白色粗产物,直接下一步。
在圆底烧瓶中加入上步粗产物,滴加36%HCl(294.9mL)加热回流至原料反应完全,蒸干溶剂后,加入95%乙醇(200mL)和水(20mL)回流直至产物完全溶解,冷却结晶,过滤,干燥得到L-草铵膦(白色晶体,34.0g,两步的分离收率78%,95%ee)。
实施例5
在氮气氛围下,往三口瓶中分别加入化合物1(40.0g,242.4mmol,1.0eq)和1,4-二氧六环(64g,727.2mmol,3.0eq),溴化镁(8.9g,48.5mmol,0.2eq),滴加甲基亚膦酸二乙酯(36.8g,290.9mmol,1.2eq),室温下搅拌30h后,升温至100℃下,反应20h,MS检测原料消失,减压蒸馏出1,4-二氧六环和多余的甲基亚膦酸二乙酯,得到白色粗产物,直接下一步。
在圆底烧瓶中加入上步粗产物,滴加36%HCl(294.9mL)加热回流至原料反应完全,蒸干溶剂后,加入95%乙醇(200mL)和水(20mL)回流直至产物完全溶解,冷却结晶,过滤,干燥得到L-草铵膦(白色晶体,29.2g,两步的分离收率67%,94%ee)。
实施例6
在氮气氛围下,往三口瓶中分别加入化合物1(40.0g,242.4mmol,1.0eq)和1,4-二氧六环(64g,727.2mmol,3.0eq),氯化锌(6.6g,48.5mmol,0.2eq),滴加甲基亚膦酸二乙酯(36.8g,290.9mmol,1.2eq),室温下搅拌30h后,升温至100℃下,反应20h,MS检测原料消失,减压蒸馏出1,4-二氧六环和多余的甲基亚膦酸二乙酯,得到白色粗产物,直接下一步。
在圆底烧瓶中加入上步粗产物,滴加36%HCl(294.9mL)加热回流至原料反应完全,蒸干溶剂后,加入95%乙醇(200mL)和水(20mL)回流直至产物完全溶解,冷却结晶,过滤,干燥得到L-草铵膦(白色晶体,29.1g,两步的分离收率67%,95%ee)。
实施例7
在氮气氛围下,往三口瓶中分别加入化合物1(40.0g,242.4mmol,1.0eq)和1,4-二氧六环(64g,727.2mmol,3.0eq),二乙基氯化铝(甲苯溶液0.9mol/L,54mL,48.5mmol,0.2eq),滴加甲基亚膦酸二乙酯(36.8g,290.9mmol,1.2eq),室温下搅拌30h后,升温至100℃下,反应20h,MS检测原料消失,减压蒸馏出1,4-二氧六环和多余的甲基亚膦酸二乙酯,得到白色粗产物,直接下一步。
在圆底烧瓶中加入上步粗产物,滴加36%HCl(294.9mL)加热回流至原料反应完全,蒸干溶剂后,加入95%乙醇(200mL)和水(20mL)回流直至产物完全溶解,冷却结晶,过滤,干燥得到L-草铵膦(白色晶体,27.5g,两步的分离收率63%,93%ee)。
实施例8
在氮气氛围下,往三口瓶中分别加入化合物1(40.0g,242.4mmol,1.0eq)和1,4-二氧六环(64g,727.2mmol,3.0eq),儿茶酚硼烷(5.8g,48.5mmol,0.2eq),滴加甲基亚膦酸二乙酯(36.8g,290.9mmol,1.2eq),室温下搅拌30h后,升温至100℃下,反应20h,MS检测原料消失,减压蒸馏出1,4-二氧六环和多余的甲基亚膦酸二乙酯,得到白色粗产物,直接下一步。
在圆底烧瓶中加入上步粗产物,滴加36%HCl(294.9mL)加热回流至原料反应完全,蒸干溶剂后,加入95%乙醇(200mL)和水(20mL)回流直至产物完全溶解,冷却结晶,过滤,干燥得到L-草铵膦(白色晶体,27.9g,两步的分离收率64%,95%ee)。
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