CN101636402B - 含磷的脱氢氨基酸的制造方法 - Google Patents
含磷的脱氢氨基酸的制造方法 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 24
- 239000002253 acid Substances 0.000 title description 13
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 title description 2
- 229910052698 phosphorus Inorganic materials 0.000 title description 2
- 239000011574 phosphorus Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 34
- 239000002585 base Substances 0.000 claims description 30
- -1 benzoyl- Chemical group 0.000 claims description 27
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 17
- 238000004519 manufacturing process Methods 0.000 claims description 14
- SMDGVPQREIZILS-UHFFFAOYSA-N $l^{1}-oxidanylmethylbenzene Chemical compound [O]CC1=CC=CC=C1 SMDGVPQREIZILS-UHFFFAOYSA-N 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 claims description 3
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 abstract description 9
- 230000002363 herbicidal effect Effects 0.000 abstract description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 abstract 1
- 239000004009 herbicide Substances 0.000 abstract 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 7
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 7
- 125000003107 substituted aryl group Chemical group 0.000 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 5
- 125000003118 aryl group Chemical group 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 4
- 125000005002 aryl methyl group Chemical group 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 3
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 235000013905 glycine and its sodium salt Nutrition 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- PBRXKNKPUMMYPO-UHFFFAOYSA-N 1-$l^{1}-oxidanyl-2-methylpropane Chemical compound CC(C)C[O] PBRXKNKPUMMYPO-UHFFFAOYSA-N 0.000 description 1
- QOOQLKSEGVNYLA-UHFFFAOYSA-N 1-$l^{1}-oxidanylbutane Chemical group CCCC[O] QOOQLKSEGVNYLA-UHFFFAOYSA-N 0.000 description 1
- JAVBBFXUGDCHLZ-UHFFFAOYSA-N 1-$l^{1}-oxidanylpropane Chemical compound CCC[O] JAVBBFXUGDCHLZ-UHFFFAOYSA-N 0.000 description 1
- VZHOTZFOEWTWKS-UHFFFAOYSA-N 2-[methyl(phenoxy)phosphoryl]acetaldehyde Chemical compound O=CCP(=O)(C)OC1=CC=CC=C1 VZHOTZFOEWTWKS-UHFFFAOYSA-N 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- HFQYJCVJLPOROO-UHFFFAOYSA-N CCC(C)[O] Chemical compound CCC(C)[O] HFQYJCVJLPOROO-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 description 1
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 239000001273 butane Substances 0.000 description 1
- IAQRGUVFOMOMEM-UHFFFAOYSA-N butene Natural products CC=CC IAQRGUVFOMOMEM-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical class FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- HORAABAEVCFTSB-UHFFFAOYSA-N methyl(3-oxobutyl)phosphinic acid Chemical compound CC(=O)CCP(C)(O)=O HORAABAEVCFTSB-UHFFFAOYSA-N 0.000 description 1
- HXZSFRJGDPGVNY-UHFFFAOYSA-N methyl(oxido)phosphanium Chemical compound C[PH2]=O HXZSFRJGDPGVNY-UHFFFAOYSA-N 0.000 description 1
- UPQNPBHYPACBSK-UHFFFAOYSA-N methylsulfinylmethane;sodium Chemical compound [Na].CS(C)=O UPQNPBHYPACBSK-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- CWXOAQXKPAENDI-UHFFFAOYSA-N sodium methylsulfinylmethylide Chemical compound [Na+].CS([CH2-])=O CWXOAQXKPAENDI-UHFFFAOYSA-N 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000009333 weeding Methods 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
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
-
- 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)]
- C07F9/32—Esters thereof
- C07F9/3205—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/3217—Esters of acyclic unsaturated acids
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- Life Sciences & Earth Sciences (AREA)
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- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
相关申请
本申请基于并要求2007年3月19日申请的日本专利申请2007-69958号的优先权,其内容完全被引入作为参考。
技术领域
本发明涉及作为除草剂有用的L-2-氨基-4-(羟基甲基氧膦基)-丁烷酸(以下简记为L-AMPB)的制造中间体即N-取代-2-氨基-4-(取代氧基甲基氧膦基)-2-丁烯酸酯的制造方法。
背景技术
已知N-取代-2-氨基-4-(取代氧基甲基氧膦基)-2-丁烯酸酯是具有除草活性的L-AMPB的合成中间体(特开昭62-226993号公报(专利文献1)、J.Org.Chem.,56,1783-1788(1991)(非专利文献1))。
迄今为止,作为N-取代-2-氨基-4-(取代氧基甲基氧膦基)-2-丁烯酸酯的制造方法,报告了通过使2-氧代-4-(羟基甲基氧膦基)-丁烷酸与乙酰胺缩合来合成的方法、以及通过使氧膦基乙醛衍生物与异氰基乙酸酯缩合来合成的方法(专利文献1)。
通过磷酰基甘氨酸衍生物与醛的Horner-Emmons型的反应来合成脱氢氨基酸的方法是已知的(Synthesis 487(1992)(非专利文献2))。
专利文献1:特开昭62-226993号公报
非专利文献1:J.Org.Chem.,56,1783-1788(1991)
非专利文献2:Synthesis 487(1992)
发明内容
本发明进行下述分析。上述专利文献1、以及非专利文献1和2的全部记载引入到本说明书中。
但是,在专利文献1、非专利文献1等的方法中,存在工序数多、收率低、试药昂贵等的问题,因此期望确立更有效率的制造方法。
另外,在非专利文献2中,应用于与具有磷那样的极性取代基的醛化合物的反应的例子是未知的。
本发明的目的是提供以短工序、有效率地制造作为除草剂有用的L-AMPB的制造中间体N-取代-2-氨基-4-(取代氧基甲基氧膦基)-2-丁烯酸酯的方法。
本发明者对磷酰基甘氨酸衍生物与含磷的醛衍生物的反应进行了详细研究,结果发现,如果使用碱进行反应,则可以以高收率获得N-取代-2-氨基-4-(取代氧基甲基氧膦基)-2-丁烯酸酯,从而完成了本发明。
即,在本发明的第1方案中,提供下式(3)所示的化合物的制造方法,包括将下式(1)所示的化合物在碱的存在下与下式(2)所示的化合物反应的操作,
[式中、R1表示C1-4烷基、芳基、取代芳基、芳基甲基或取代芳基甲基,
R3表示C1-4烷基、芳基甲基或取代芳基甲基,
R4表示C2-4烷酰基、苯甲酰基、苄基、C1-4烷基氧基羰基或苄基氧基羰基],
[式中、R1表示与上述定义相同的含义]
[式中、R2、R2′可以相同,也可以不同,表示C1-4烷基、芳基、取代芳基、芳基甲基或取代芳基甲基,R3和R4表示与上述定义相同的含义]。
通过本发明的制造方法,可以制造作为除草剂L-AMPB的制造中间体的N-取代-2-取代氨基-4-(取代氧基甲基氧膦基)-2-丁烯酸酯。本发明的制造方法与现有的制造方法比较,廉价、短工序并且可以以高效率合成,该方法是优异的。因此,本发明特别在要求除草效果的药物的领域,在工业上是非常有用的。
具体实施方式
对式(1)~式(3)所示的化合物中R1、R2、R2′、R3、R4所示的基团进行说明。
R1、R2、R2′和R3表示的C1-4烷基是碳数1~4的直链或分枝状的烷基,更具体来说,可以列举出甲基、乙基、正丙基、异丙基、正丁基、2-丁基、异丁基、叔丁基等。
作为R1、R2、R2′和R3表示的基团或基团上的芳基,可以列举出苯基、或萘基等。
R1、R2、R2′和R3表示的芳基甲基,是指被1~3个芳基取代的甲基,更具体来说,可以列举出苄基、二苯基甲基、芴基、三苯基甲基等。
R1、R2和R2′表示的取代芳基,是指其苯环上的1个以上的氢原子、优选1~3个氢原子被取代,作为具体的取代基,可以列举出甲基、乙基、正丙基、异丙基、正丁基、2-丁基、异丁基、叔丁基等的直链或分枝状的C1-4烷基、氟基、氯原子、溴原子等的卤素原子、甲氧基等的C1-4烷氧基。
R1、R2、R2′和R3表示的取代芳基甲基,是指其苯环上的1以上的氢原子、优选1~3个氢原子被取代,作为具体的取代基,可以列举出甲基、乙基、正丙基、异丙基、正丁基、2-丁基、异丁基、叔丁基等的直链或分枝状的C1-4烷基、氟基、氯原子、溴原子等的卤素原子、甲氧基等的C1-4烷氧基。
R4表示的C2-4烷酰基,是指碳数2~4的直链或分枝状的烷酰基,更具体来说,可以列举出乙酰基、正丙酰基、正丁酰基、异丁酰基等。
R4表示的C1-4烷基氧基羰基,是指具有碳数1~4的直链或分枝状的烷基的烷基氧基羰基,更具体来说,可以列举出甲氧基羰基、乙氧基羰基、正丙基氧基羰基、异丙基氧基羰基、正丁基氧基羰基、2-丁基氧基羰基、异丁基氧基羰基、叔丁基氧基羰基等。
式(1)和式(3)的化合物中,R1优选C1-4烷基,更优选甲基和乙基。
作为式(1)所示的化合物的具体例,可以列举出
2-(甲氧基(甲基)氧膦基)-乙醛、
2-(乙氧基(甲基)氧膦基)-乙醛、
2-(正丙基氧基(甲基)氧膦基)-乙醛、
2-(正丁基氧基(甲基)氧膦基)-乙醛、
2-(苯氧基(甲基)氧膦基)-乙醛、
2-(对甲苯基氧基(甲基)氧膦基)-乙醛
2-(苄基氧基(甲基)氧膦基)-乙醛或
2-(对氯苄基氧基(甲基)氧膦基)-乙醛,优选2-(乙氧基(甲基)氧膦基)-乙醛。
式(1)的化合物可以通过Zu.Obshch.Khim.,46,243(1977)记载的方法来合成(在本说明书中引入该文献的公开内容)。
式(2)的化合物中,R2、R2′相同或不同,优选为C1-4烷基、芳基,更优选都为C1-4烷基。
式(2)和式(3)的化合物中,R3优选C1-4烷基,R4优选C2-4烷酰基、C1-4烷基氧基羰基或苄基氧基羰基、更优选苄基氧基羰基。
因此更优选,式(2)中,R2和R2′为C1-4烷基、R3为C1-4烷基、R4为C2-4烷酰基、C1-4烷基氧基羰基或苄基氧基羰基的化合物。
更优选式(3)中R1为C1-4烷基、R3为C1-4烷基、R4为C2-4烷酰基、C1-4烷基氧基羰基或苄基氧基羰基的化合物。
进而,作为本发明的优选的形态,可以列举出式(1)中的R1为C1-4烷基、式(2)中的R2、R2′和R3为C1-4烷基、R4为苄基氧基羰基、式(3)中的R1、R3和R4为与它们对应的基团的方法。
作为式(2)所示的化合物的具体例,可以列举出下示的化合物。具体例中、Ph表示苯基,Me表示甲基,Et表示乙基。
优选下示的化合物。
式(2)的化合物可以通过Liebigs Ann.Chem.,599(1983)记载的方法来合成。(本说明书中引入该文献的公开内容)
作为式(3)的化合物的具体例,可以列举出下示的化合物。具体例中、Ph表示苯基,Me表示甲基,Et表示乙基。
优选下示的化合物。
在由式(1)的化合物和式(2)的化合物来制造式(3)的化合物的方法中,作为所使用的溶剂,可以列举出二氯甲烷、氯仿等的卤化烃系溶剂、苯、甲苯等的芳香族烃系溶剂、四氢呋喃、二甲氧基乙烷、二噁烷等的醚系溶剂、N、N-二甲基甲酰胺、二甲亚砜等的非质子性极性有机溶剂或甲醇等的碳数1~4的烷醇溶剂,优选为二氯甲烷、氯仿、四氢呋喃。
作为所使用的碱,可以列举出氢化钠、氢化钾、正丁基锂、二异丙基氨基锂、二甲亚砜钠盐(dimsyl sodium)、甲醇钠、乙醇钠、叔丁醇钾、四甲基胍等,优选叔丁醇钾、四甲基胍。
碱的使用量,以式(1)的化合物的量为基准,使用1~1.4当量。
式(2)所示的化合物的使用量优选为,以式(1)的化合物的量为基准,使用1~1.4当量,式(2)和碱的使用量为相同的当量。
作为在式(2)的化合物的溶液中加入碱和式(1)的化合物时的反应温度,在-78~0℃、优选-78~-30℃的范围内进行。反应时间通常为10分钟~2小时、优选30分钟~1小时的范围内进行。然后将反应温度升至0℃~50℃、优选升至15~30℃。升温后的反应时间为2~8小时、优选3~5小时。
反应结束后,通过将反应液减压浓缩,使用硅胶柱色谱等进行精制,可以分离式(3)的化合物。
本发明中获得的N-取代-2-氨基-4-(取代氧基甲基氧膦基)-2-丁烯酸酯可以利用特开昭62-226993号公报、国际公开第2006/104120号、国际公开第2008/029754号等记载的方法变换为L-AMPB(本说明书中引用这些文献的公开内容)。
实施例
下面,列举实施例来具体说明本发明,但是本发明不限于这些实施例。N-(苄基氧基羰基)-α-膦酰基甘氨酸三甲基酯可以使用从アルドリツチ购买的产品。2-(乙氧基(甲基)氧膦基)-乙醛依据Zu.Obshch.Khim.,46,243(1977)记载的方法来合成。
实施例1 甲基(Z)-N-(苄基氧基羰基)-2-氨基-4-(乙氧基(甲基)氧膦 基)-2-丁烯酸酯的制造
在将N-(苄基氧基羰基)-α-膦酰基甘氨酸三甲基酯214mg溶解在二氯甲烷5ml中后,加入叔丁醇钾74mg,在-78℃搅拌30分钟。在该反应溶液中缓慢滴加2-(乙氧基(甲基)氧膦基)-乙醛76.5mg的二氯甲烷溶液(1ml),搅拌1小时。缓慢升温至室温后,进而搅拌3小时。用TLC确认原料消失后,减压馏去溶剂。将残渣用硅胶柱色谱(氯仿-甲醇(100∶1~50∶1))精制,获得标记化合物168mg(收率93%)。
本化合物的物理化学的性状
1H NMR(CDCl3)δ:1.24(t,3H,J=7.5Hz),1.41(d,3H,J=15Hz),2.68(q,1H,J=7.5Hz),2.73(q,1H,J=7.5Hz),3.68(s,3H),3.99(m,2H),5.16(s,2H),6.37(dd,1H,J=7.5Hz,15Hz),7.28(m,5H).
FABMASS:m/z 356[M+H]+
以上的记载基于实施例,但是本发明不限于上述实施例。本发明的全部公开内容(包括权利要求书)中,进而基于其基本技术思想,可以变更和调节实施方式或实施例。本发明的权利要求书中,可以进行各种公开要素的多种组合、取代或选择。本说明书中参照的专利和发行物的公开内容引用到本说明书中。
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Hans-Joachim Zeiss.Enantioselective Synthesis of Both Enantiomers of Phosphinothricin via Asymmetric Hydrogenation of a-Acylamido Acrylates..《J. Org. Chem.》.1991,第56卷(第5期),1783-1788. * |
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