JP2012116776A - Production method of phosphonic acid diester derivative - Google Patents

Abstract

(式中、R^a、R^b、R^c、R¹、R²は、明細書に定義されるとおりである。）。
【選択図】なしAn efficient method for producing a phosphonic acid diester derivative is provided.
A process for producing a phosphonic acid diester derivative represented by general formula (I), which comprises deprotecting a compound represented by general formula (II):
[Chemical 1]

(Wherein R ^a , R ^b , R ^c , R ¹ , R ² are as defined in the specification).
[Selection figure] None

Description

  The present invention relates to a method for producing a phosphonic acid diester derivative.

The present inventors have invented a phosphonic acid diester derivative that strongly and selectively inhibits GGT activity (Patent Document 1). This phosphonic acid diester derivative is a safe and highly active GGT inhibitor and is currently sold as a biochemical reagent under the trademark GGsTop. Further, since it has the ability to enhance collagen production in human fibroblast cells, it is extremely promising as a novel cosmetic material (Patent Document 2). Furthermore, it is a promising compound as a medicine, showing a protective effect on renal tissue in an acute renal failure model (Patent Document 3).
Non-Patent Document 1 performs a Michael addition reaction of methyl methyl (vinyl) phosphinate and a glycine derivative.

WO2007 / 066705 Patent application 2010-099957 Japanese Patent Application 2010-032161

N. Minowa, et al. (1997). "Asymmetric Synthesis of (+)-Phosphinothricin and Related Compounds by the Michael Addition of Glycine Schiff Bases to Vinyl Compounds." Bull. Chem. Soc. Jpn. 60 (5): 1761 -1766.

  In Patent Document 1, a phosphonic acid diester derivative was chemically synthesized by a 10-step reaction. This route requires a multi-step reaction such as introducing another protecting group again after hydrolyzing the protecting group of the functional group. Furthermore, while including processes that require cryogenic temperatures (-65 ° C), the overall yield is not satisfactory at 6.3%.

  The main object of the present invention is to provide an efficient process for producing phosphonic acid diester derivatives.

  The present inventor can eliminate the need for removal / reintroduction of protecting groups by using Michael addition reaction of vinylphosphonic acid heteroester and glycine derivative to form the basic skeleton of the desired phosphonic acid diester derivative. I found.

The present invention provides the following methods for producing phosphonic acid diester derivatives.
Item 1. A method for producing a phosphonic acid diester derivative represented by the general formula (I), which comprises deprotecting the compound represented by the general formula (II):

(Wherein R ^a and R ^b are the same or different and may have a substituent, an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, or a substituent. An aryl group, an aralkyl group which may have a substituent, and a heteroaryl group which may have a substituent are shown.

R ^c may have an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, an aryl group which may have a substituent, or a substituent. An aralkyl group and a heteroaryl group which may have a substituent are shown.

R ¹ and R ² are the same or different and each represents an azide group (N ₃ ), —OR ³ , —OCR ⁴ = CR ⁵ R ⁶ , —ON = CR ⁷ R ⁸ , or —SR ⁹ (Here, each of R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ is a hydrogen atom, an optionally substituted alkyl group, or an optionally substituted aryl. And at least one substituent selected from the group consisting of an electron-withdrawing group, and two adjacent substituents among the substituents of R ^{4 to} R ⁸ may be bonded to each other to form a ring. )).
Item 2. A Michael addition reaction is performed on the compound represented by the general formula (1) and the compound represented by the general formula (2) in the presence of a base and, if necessary, a phase transfer catalyst. ) A method for producing a phosphonic acid diester derivative represented by:

(Wherein R ^a and R ^b are the same or different and may have a substituent, an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, or a substituent. An aryl group, an aralkyl group which may have a substituent, and a heteroaryl group which may have a substituent are shown.

R ^c may have an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, an aryl group which may have a substituent, or a substituent. An aralkyl group and a heteroaryl group which may have a substituent are shown.

R ¹ and R ² are the same or different and each represents an azide group (N ₃ ), —OR ³ , —OCR ⁴ = CR ⁵ R ⁶ , —ON = CR ⁷ R ⁸ , or —SR ⁹ (Here, each of R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ is a hydrogen atom, an optionally substituted alkyl group, or an optionally substituted aryl. And at least one substituent selected from the group consisting of an electron-withdrawing group, and two adjacent substituents among the substituents of R ^{4 to} R ⁸ may be bonded to each other to form a ring. )).
Item 3. A compound represented by the general formula (II) by subjecting the compound represented by the general formula (1) and the compound represented by the general formula (2) to a Michael addition reaction in the presence of a base and, if necessary, a phase transfer catalyst. And then deprotecting the compound represented by the general formula (II): A method for producing a phosphonic acid diester derivative represented by the general formula (I):

(Wherein R ^a and R ^b are the same or different and may have a substituent, an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, or a substituent. An aryl group, an aralkyl group which may have a substituent, and a heteroaryl group which may have a substituent are shown.

R ^c may have an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, an aryl group which may have a substituent, or a substituent. An aralkyl group and a heteroaryl group which may have a substituent are shown.

R ¹ and R ² are the same or different and each represents an azide group (N ₃ ), —OR ³ , —OCR ⁴ = CR ⁵ R ⁶ , —ON = CR ⁷ R ⁸ , or —SR ⁹ (Here, each of R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ is a hydrogen atom, an optionally substituted alkyl group, or an optionally substituted aryl. And at least one substituent selected from the group consisting of an electron-withdrawing group, and two adjacent substituents among the substituents of R ^{4 to} R ⁸ may be bonded to each other to form a ring. )).

  The present invention differs from Non-Patent Document 1 in that the Michael acceptor of Non-Patent Document 1 (in this case, methyl (vinyl) methyl phosphinate) is a vinylphosphonic acid heteroester in the present invention.

  In Patent Document 1, a phosphonic acid diester that requires 10 steps of reaction can be synthesized in the present invention at 4 steps and at a reaction temperature of 0 ° C. or higher. Also, the total yield can be improved up to about 30%. Furthermore, the point which used the alkyl (aryl) heteroester of vinyl phosphonate for the reaction agent of the Michael addition reaction which is a key reaction in this invention is mentioned. Phosphonic acid aryl esters are generally highly reactive and are thought to easily react with nucleophiles and decompose, but this Michael addition reaction using a phase transfer catalyst does not have such a reaction temperature of 80 ° C. No significant decomposition reaction was observed, and the intended Michael addition reaction could be performed.

In the present specification, examples of the electron withdrawing group include a halogen atom, a carbamoyl group, an acyl group, a cyano group, an alkylsulfamoyl group, an arylsulfamoyl group, and a carboxy group. Examples of the ring formed by bonding two adjacent substituents among the substituents of R ^{4 to} R ⁸ include an aliphatic cyclic group having 3 to 7 carbon atoms such as a cyclopentane group and a cyclohexane group, and a benzene ring. And aromatic aromatic groups such as pyridine, pyrrole, imidazole, and indole.

  An alkyl group which may have a substituent, an cycloalkyl group which may have a substituent, an aryl group which may have a substituent, an aralkyl group which may have a substituent, a substituent Examples of the substituent of the heteroaryl group which may have a group include alkyl, alkenyl, alkynyl, alkoxy, hydroxy, SH, alkylthio, halogen atom, cyano, amino, monoalkylamino, dialkylamino, acyl, alkylcarbonyloxy , Arylcarbonyloxy, aryl, aryloxy, carboxy, nitro, carbamoyl, alkylsulfamoyl, arylsulfamoyl, guanidino, amide, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkylcarbonylamino, arylcarbonyl Amino, aralkylcarbonylamino, and the like.

As alkylcarbonyloxy, methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy, isobutylcarbonyloxy, tert-butylcarbonyloxy, n-pentylcarbonyloxy, isopentylcarbonyloxy And C _1-6 alkylcarbonyloxy such as _{hexylcarbonyloxy} .

  As arylcarbonyloxy, phenylcarbonyloxy, naphthylcarbonyloxy, fluorenylcarbonyloxy, anthrylcarbonyloxy, biphenylylcarbonyloxy, tetrahydronaphthylcarbonyloxy, chromanylcarbonyloxy, 2,3-dihydro-1,4- Examples include dioxanaphthalenylcarbonyloxy, indanylcarbonyloxy, and phenanthrylcarbonyloxy.

  Aralkylcarbonyloxy includes benzylcarbonyloxy, naphthylmethylcarbonyloxy, fluorenylmethylcarbonyloxy, anthrylmethylcarbonyloxy, biphenylylmethylcarbonyloxy, tetrahydronaphthylmethylcarbonyloxy, chromanylmethylcarbonyloxy, 2,3- Dihydro-1,4-dioxanaphthalenylmethylcarbonyloxy, indanylmethylcarbonyloxy and phenanthrylmethylcarbonyloxy, phenethylcarbonyloxy, naphthylethylcarbonyloxy, fluorenylethylcarbonyloxy, anthrylethylcarbonyloxy, Biphenylylethylcarbonyloxy, tetrahydronaphthylethylcarbonyloxy, chromanylethylcarbonyloxy, , 3-dihydro-1,4-geo Kisana lid les sulfonyl ethylcarbonyloxy include indanyloxycarbonyl ethylcarbonyloxy and phenanthryloxy ethylcarbonyloxy.

Examples of alkylcarbonylamino include methylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, isopropylcarbonylamino, n-butylcarbonylamino, isobutylcarbonylamino, tert-butylcarbonylamino, n-pentylcarbonylamino, isopentylcarbonylamino. And C _1-6 alkylcarbonylamino such as _{hexylcarbonylamino} .

  As arylcarbonylamino, phenylcarbonylamino, naphthylcarbonylamino, fluorenylcarbonylamino, anthrylcarbonylamino, biphenylylcarbonylamino, tetrahydronaphthylcarbonylamino, chromanylcarbonylamino, 2,3-dihydro-1,4- Examples include dioxanaphthalenylcarbonylamino, indanylcarbonylamino and phenanthrylcarbonylamino.

  Aralkylcarbonylamino includes benzylcarbonylamino, naphthylmethylcarbonylamino, fluorenylmethylcarbonylamino, anthrylmethylcarbonylamino, biphenylylmethylcarbonylamino, tetrahydronaphthylmethylcarbonylamino, chromanylmethylcarbonylamino, 2,3- Dihydro-1,4-dioxanaphthalenylmethylcarbonylamino, indanylmethylcarbonylamino and phenanthrylmethylcarbonylamino, phenethylcarbonylamino, naphthylethylcarbonylamino, fluorenylethylcarbonylamino, anthrylethylcarbonylamino, Biphenylylethylcarbonylamino, tetrahydronaphthylethylcarbonylamino, chromanylethylcarbonylamino, , 3-dihydro-1,4-geo Kisana lid les sulfonyl ethyl carbonyl amino, indanyl ethylcarbonylamino and phenanthrylcarbonyl ethylcarbonylamino.

Examples of the alkylthio group include straight chain or branched C _1-6 alkylthio such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio, n-pentylthio, isopentylthio, hexylthio and the like. Groups.

Examples of monoalkylamino include mono C _1-1 such as methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, tert-butylamino, n-pentylamino, isopentylamino, hexylamino and the like. ₆ alkylamino is mentioned.

Examples of dialkylamino include dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, di-n-butylamino, diisobutylamino, ditert-butylamino, di-n-pentylamino, diisopentylamino, dihexylamino and the like. C _1-6 alkylamino is mentioned.

Acyl groups include acetyl, propionyl, n-butyryl, isobutyryl, n-butylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, isopentylcarbonyl, hexylcarbonyl C _1-6 alkylcarbonyl, phenylcarbonyl, naphthyl Such as carbonyl, fluorenylcarbonyl, anthrylcarbonyl, biphenylylcarbonyl, tetrahydronaphthylcarbonyl, chromanylcarbonyl, 2,3-dihydro-1,4-dioxanaphthalenylcarbonyl, indanylcarbonyl and phenanthrylcarbonyl Arylcarbonyl is mentioned.

The alkylsulfamoyl group, C _1-6 alkyl monosubstituted sulfamoyl group, di-substituted sulfamoyl group by C _1-6 alkyl.

The sulfamoyl group mono-substituted with C _1-6 alkyl includes methylsulfamoyl, ethylsulfamoyl, n-propylsulfamoyl, isopropylsulfamoyl, n-butylsulfamoyl, isobutylsulfamoyl, tert -Butylsulfamoyl, n-pentylsulfamoyl, isopentylsulfamoyl, hexylsulfamoyl.

Examples of the sulfamoyl group disubstituted with C _1-6 alkyl include dimethylsulfamoyl, diethylsulfamoyl, di-n-propylsulfamoyl, diisopropylsulfamoyl, di-n-butylsulfamoyl, diisobutylsulfamoyl. Di-tert-butylsulfamoyl, di-n-pentylsulfamoyl, diisopentylsulfamoyl, dihexylsulfamoyl.

  Arylsulfamoyl groups include phenylsulfamoyl, naphthylsulfamoyl, fluorenylsulfamoyl, anthrylsulfamoyl, biphenylylsulfamoyl, tetrahydronaphthylsulfamoyl, chromanylsulfamoyl, 2,3 -Dihydro-1,4-dioxanaphthalenylsulfamoyl, indanylsulfamoyl and phenanthrylsulfamoyl.

Examples of the alkoxy group include linear or branched C _1-6 alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy and hexyloxy.

  The halogen atom means fluorine, chlorine, bromine or iodine, but fluorine, chlorine or bromine is preferred.

Examples of the alkyl group include linear or branched C _1-6 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, hexyl and the like. .

Cycloalkyl groups include C _3-7 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The alkenyl group may be linear, branched or cyclic, and has at least one double bond, such as vinyl, allyl, 1-propenyl, 2-methyl-2-propenyl, Isopropenyl, 1-, 2- or 3-butenyl, 2-, 3- or 4-pentenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 5-hexenyl, 1-cyclopentenyl, 1- C _2-6 alkenyl groups such as cyclohexenyl and 3-methyl-3-butenyl are exemplified.

The alkynyl group may be linear, branched or cyclic, and means one having at least one triple bond, such as ethynyl, 1- or 2-propynyl, 1-, 2- or 3- And C _2-6 alkynyl groups such as butynyl and 1-methyl-2-propynyl.

  The aryl group means a monocyclic or polycyclic group composed of a 5- or 6-membered aromatic hydrocarbon ring. Specific examples include phenyl, naphthyl, fluorenyl, anthryl, biphenylyl, tetrahydronaphthyl, chromanyl, 2 , 3-dihydro-1,4-dioxanaphthalenyl, indanyl and phenanthryl.

  Heteroaryl group means a monocyclic or polycyclic group consisting of a 5- or 6-membered aromatic ring containing 1 to 3 heteroatoms selected from N, O and S. In some cases, at least one ring may be an aromatic ring. Specific examples include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, quinolyl, isoquinolyl, benzo [b] thienyl and benzimidazolyl.

  Aryloxy includes phenyloxy, naphthyloxy, fluorenyloxy, anthryloxy, biphenylyloxy, tetrahydronaphthyloxy, chromanoxy, 2,3-dihydro-1,4-dioxanaphthalenyloxy, inda Nyloxy and phenanthryloxy are mentioned.

  Aralkyl groups include benzyl, naphthylmethyl, fluorenylmethyl, anthrylmethyl, biphenylylmethyl, tetrahydronaphthylmethyl, chromanylmethyl, 2,3-dihydro-1,4-dioxanaphthalenylmethyl, indanyl Methyl and phenanthrylmethyl, phenethyl, naphthylethyl, fluorenylethyl, anthrylethyl, biphenylylethyl, tetrahydronaphthylethyl, chromanylethyl, 2,3-dihydro-1,4-dioxanaphthalenylethyl, Indanylethyl and phenanthrylethyl are mentioned.

As alkylcarbonyloxy, methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy, isobutylcarbonyloxy, tert-butylcarbonyloxy, n-pentylcarbonyloxy, isopentylcarbonyloxy And C _1-6 alkylcarbonyloxy such as _{hexylcarbonyloxy} .

  As arylcarbonyloxy, phenylcarbonyloxy, naphthylcarbonyloxy, fluorenylcarbonyloxy, anthrylcarbonyloxy, biphenylylcarbonyloxy, tetrahydronaphthylcarbonyloxy, chromanylcarbonyloxy, 2,3-dihydro-1,4- Examples include dioxanaphthalenylcarbonyloxy, indanylcarbonyloxy, and phenanthrylcarbonyloxy.

Examples of the alkyl group substituted with a hydroxy group include —CH ₂ OH, —CH (CH ₃ ) OH, and the like. Examples of the alkyl group substituted with a carboxy group include —CH ₂ COOH, —CH ₂ CH ₂ COOH, and the like. Examples of the alkyl group substituted with a carbamoyl group include —CH ₂ CONH ₂ , —CH ₂ CH ₂ CONH _{2, and the} like. Examples of the alkyl group substituted with an amino group include — (CH ₂ ) ₄ NH ₂ . Examples of the alkyl group substituted with a guanidino group include — (CH ₂ ) ₃ NHC (═NH) NH ₂ .

Examples of the alkyl group substituted with SH or alkylthio include —CH ₂ CH ₂ SCH ₃ , —CH ₂ SH, —CH ₂ S) _{2 and the} like. As the alkyl group substituted with an alkoxy _group, and the like -CH 2 ^{OR 12} '. Examples of the alkyl group substituted with an amide group include —CH ₂ NHCOR ¹² ′.

Compounds of general formula (I) can be obtained according to scheme 1 below.
<Scheme 1>

(Wherein R ^a , R ^b , R ^c , R ¹ , R ² are as defined above).

  Compounds (1) and (2) are known compounds, or can be easily produced according to the description of the production method of the present invention and known literature.

  In the present invention, first, compound (1) and compound (2) are subjected to a Michael addition reaction in a solvent in the presence of a base and optionally a phase transfer catalyst to obtain a compound of the general formula (II).

  Either an excess of compound (1) or compound (2) may be used, but 1/1 is preferable in consideration of cost.

When a phase transfer catalyst is not used, the solvent includes ether solvents such as tetrahydrofuran, dioxane, diethyl ether and diisopropyl ether, aromatic hydrocarbon solvents such as toluene and xylene, and aliphatic hydrocarbons such as n-hexane and cyclohexane. A system solvent or the like can be preferably used, and the reaction is preferably under anhydrous conditions. The reaction temperature is about -78 ° C to 100 ° C, preferably about -78 ° C to room temperature. The reaction pressure proceeds sufficiently at 1 to 50 atmospheres, preferably normal pressure. As the base (Base), a bulky strong base such as K [N (SiMe ₃ ) ₂ ] or Li [N (i-Pr) ₂ ] can be preferably used. The base can be used in an amount of 1 to 10 equivalents, preferably about 1 to 2 equivalents. By introducing an asymmetric source into R ² or R ³ , it is possible to make the α-carbon of the amino acid moiety chiral (Bull. Chem. Soc. Jpn., 60, 1761, 1987).

  In the case of using a phase transfer catalyst, water and organic solvents other than water can be widely used. Examples of organic solvents other than water include dichloromethane, chloroform, 1,2-dichloroethane, 1,1,1-trichloroethane, carbon tetrachloride, benzene, toluene, xylene, pentane, hexane, heptane, octane, cyclopentane, cyclohexane, and acetic acid. Ethyl, acetonitrile, ether solvents and the like are used. These organic solvents can be used alone, but two or more solvents including water can be mixed. The reaction proceeds sufficiently at a reaction temperature of about 0 to 150 ° C., preferably about room temperature to 100 ° C., and a reaction pressure of 1 to 50 atm, preferably normal pressure. As the base, inorganic bases such as alkali metal hydroxides, alkali metal carbonates, and alkali metal hydrogen carbonates are used. The inorganic base includes 1 to 10 equivalents, preferably 1 of an inorganic base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate. Up to 5 equivalents can be used. As the phase transfer catalyst, a general catalyst such as a quaternary ammonium salt can be used. It is also possible to make the α-carbon of the amino acid moiety chiral by using a chiral phase transfer catalyst (eg Tetrahedron Lett., 39, 5347, 1998).

Removal of the protecting group can be easily performed by catalytic reduction or using an acid according to a conventional method.
(Peter GM Wuts and Theodora W. Green. “Green's protective groups in organic synthesis (4 ^th edition)” John Wiley & Sons, Inc. (2007))

  In the present invention, crystallization, recrystallization, extraction, chromatography or precipitation, reprecipitation and the like can be used for purification of the reaction product.

Hereinafter, the present invention will be described in more detail with reference to examples. Preparation of methyl vinylphosphonochloride

Vinylphosphonic acid methyl sodium salt

A mixture of dimethyl vinylphosphonate (12.4 g, 91.1 mmol), sodium iodide (13.6 g, 90.7 mmol), and 2-butanone (60 mL) was refluxed for 1 hour. After returning the reaction solution to room temperature, the solid was collected by filtration and washed with ethyl acetate to obtain a deliquescent colorless solid (10.9 g, yield 83%). ^{1 H NMR (300 MHz, D} 2 O) δ H:. 3.51 (3H, d, J = 10.5 Hz), 5.87-6.17 (3H, m) 31 P NMR (121 MHz, D 2 O) δ P: 21.5 .
(Reference) US4339443 (1982).

Methyl hydrogenated phosphonate

Dowex ^™ 50Wx8 (200-400 mesh, 10.0 g) was washed with methanol (50 mL × 3) and then suspended in methanol (50 mL). To this was added vinylphosphonic acid methyl sodium salt (5.37 g, 37.3 mmol), and the mixture was stirred at room temperature for 15 minutes. After the ion exchange resin was filtered off, the filtrate was concentrated under reduced pressure and further azeotroped with toluene (15 mL × 2) to give the title compound (5.02 g, yield: quantitative) as a tan oil. . ^{1 H NMR (300 MHz, CDCl} 3) δ H:. 3.60 (3H, d, J = 10.8 Hz), 5.86-6.25 (3H, m), 9.23 (1H, br.s) 31 P NMR (121 MHz, CDCl ₃ ) δ _P : 18.0.
(Reference) Chem. Eur. J., 15, 2064 (2009).

Methyl vinylphosphonochloride

Dimethyl vinylphosphonate (22.0 g, 162 mmol) was dissolved in anhydrous dichloromethane (80 mL), oxalyl chloride (14.5 mL, 171 mmol) was added dropwise, and the mixture was stirred at room temperature for 14 hours. After further refluxing for 3 days, the reaction solution returned to room temperature was concentrated under reduced pressure, and the resulting single brown oil was subjected to vacuum distillation to give the title compound (12.5 g, yield: 55%) as a colorless oil. Obtained. Bp 92-95 oC / 7 mmHg. ¹ H NMR (300 MHz, CDCl ₃ ) δ _H : 3.92 (3H, d, J = 13.5 Hz), 6.13-6.57 (3H, m). ³¹ P NMR (121 MHz, CDCl ₃ ) δ _P : 29.5.
(Reference) J. Org. Chem., 73, 3103 (2008).

2. Preparation of glycine derivatives

4,4'-dichlorobenzophenone imine

Magnesium (1.06 g, 43.6 mmol) and a catalytic amount of iodine are suspended in anhydrous tetrahydrofuran (15 mL) under an argon atmosphere, and 1-bromo-4-chlorobenzene (7.87 g, 41.1 mmol) is suspended in anhydrous tetrahydrofuran (8.0 mL). A portion of the solution dissolved in was added. After the iodine color disappeared, the remaining solution was added dropwise and refluxed for 23 hours. 4-Chlorobenzonitrile (5.18 g, 37.7 mmol) dissolved in anhydrous tetrahydrofuran (8.0 mL) was added to the reaction solution returned to room temperature, and the mixture was further refluxed for 12 hours. The obtained dark brown suspension was returned to room temperature, anhydrous methanol (20 mL) was added, and the mixture was refluxed again for 30 minutes. The reaction solution returned to room temperature was diluted with dichloromethane (100 mL) and washed with water (30 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the resulting residue was purified by recrystallization (pentane / ether) to obtain the title compound (8.20 g, yield: 87%) as a colorless solid.
(Reference) J. Org. Chem., 33, 2852 (1968); Org. Synth. Coll. Vol., 5, 520-522 (1973).

[Di (4-chlorophenyl) methylene] aminoacetic acid t-butyl

4,4′-Dichlorobenzophenone imine (237 mg, 0.948 mmol) and glycine t-butyl hydrochloride (159 mg, 0.949 mmol) were dissolved in anhydrous dichloromethane (5.0 mL) and stirred at room temperature for 13 hours. The resulting yellow suspension was diluted with dichloromethane (15 mL) and washed successively with water and saturated aqueous sodium bicarbonate (20 mL each). The organic layer was washed with anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (287 mg, yield: 83%) as a yellow oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ _H : 1.46 (9H, s), 4.09 (2H, s), 7.12 (2H, d, J = 8.7 Hz), 7.30 (2H, d, J = 8.7 Hz) , 7.46 (2H, d, J = 8.7 Hz), 7.58 (2H, d, J = 8.7 Hz).
(Reference) J. Org. Chem. 47, 2663 (1982).

Benzhydryl bromoacetate

Benzhydrol (1.90 g, 10.3 mmol) was dissolved in anhydrous dichloromethane (10 mL), anhydrous pyridine (1.0 mL, 12.4 mmol) was added, and the mixture was ice-cooled. Bromoacetyl bromide (0.90 mL, 10.3 mmol) was added dropwise thereto, and the mixture was further stirred at the same temperature for 1 hour. The reaction mixture was diluted with chloroform (30 mL), washed with water and 2N hydrochloric acid (20 mL each), and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (2.42 g, yield: 77%) as a pale yellow oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ _H : 3.92 (2H, s), 6.91 (1H, s), 7.25-7.36 (10H, m).
(Reference) Tetrahedron, 53, 1635 (1997).

(Diphenylmethylene) aminoacetic acid benzhydryl

Benzhydryl bromoacetate (2.41 g, 7.90 mmol) was dissolved in anhydrous acetonitrile (10 mL), ethyldiisopropylamine (1.12 g, 8.67 mmol) and benzophenone imine (1.43 g, 7.89 mmol) were added, and the mixture was stirred for 3 days. The obtained brown reaction solution was concentrated under reduced pressure, and the residue was dissolved in t-butyl methyl ether (50 mL), and washed successively with water (30 mL) and saturated aqueous sodium hydrogen carbonate solution (20 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.The resulting brown oil was purified by silica gel flash column chromatography (hexane / ethyl acetate = 9/1) to give the title compound (1.99 g, yield). : 62%) as a colorless solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ _H : 4.32 (2H, s), 6.96 (1H, s), 7.11-7.15 (2H, m), 7.23-7.43 (16H, m), 7.63-7.68 (2H , m).
(Reference) Eur. J. Org. Chem., 317 (2005).

[Di (4-chlorophenyl) methylene] aminoacetic acid benzhydryl

Dissolve benzhydryl bromoacetate (623 mg, 2.04 mmol) and 4,4'-dichlorobenzophenone imine (510 mg, 2.04 mmol) in acetonitrile (10 mL), add ethyldiisopropylamine (0.34 mL, 1.95 mmol) and add 90 Refluxed for minutes. Benzhydryl bromoacetate (640 mg, 2.10 mmol) was added to the reaction solution and refluxed for 2 hours, and then ethyldiisopropylamine (0.34 mL, 1.95 mmol) was added and refluxed for 1 hour. Furthermore, after adding ethyl diisopropylamine (0.68 mL, 3.90 mmol) and bromoacetate benzhydryl (1.28 g, 4.19 mmol) and refluxing for 4 hours, the reaction solution which was returned to room temperature was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate (50 mL), and washed successively with water and saturated aqueous sodium hydrogen carbonate solution (30 mL each). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.The resulting black oil was purified by silica gel flash column chromatography (hexane / ethyl acetate = 9/1) to give the title compound (532 mg, yield). : 55%) as a yellow oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ _H : 4.29 (2H, s), 6.94 (1H, s), 7.01-7.58 (18H, m).

Bromoacetic acid 4,4'-dichlorobenzhydryl

4,4′-Dichlorobenzhydrol (1.25 g, 4.94 mmol) was dissolved in anhydrous dichloromethane (10 mL), anhydrous pyridine (0.48 mL, 5.93 mmol) was added, and the mixture was ice-cooled. Bromoacetyl bromide (0.43 mL, 4.94 mmol) was added dropwise thereto, and the mixture was further stirred at the same temperature for 50 minutes. The formed reddish brown precipitate was removed by filtration, and diethyl ether (30 mL) was added to the reaction solution. The precipitate formed again was removed by filtration, and the filtrate was washed with water and 2N hydrochloric acid (30 mL each). The organic layer was dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure to give the title compound (1.23 g, yield: 67%) as a yellow oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ _H : 3.90 (2H, s), 6.82 (1H, s), 7.27 (4H, d, J = 9.0 Hz), 7.34 (4H, d, J = 9.0 Hz) .

[Di (4-chlorophenyl) methylene] aminoacetic acid 4,4'-dichlorobenzhydryl

Bromoacetic acid 4,4'-dichlorobenzhydryl (1.23 g, 3.29 mmol) was dissolved in acetonitrile (10 mL), and 4,4'-dichlorobenzophenone imine (415 mg, 1.66 mmol) and ethyldiisopropylamine (0.56 ml) were dissolved. , 3.22 mmol) and refluxed for 4 hours. The resulting brown reaction solution was diluted with ethyl acetate (30 mL) and washed successively with water and saturated aqueous sodium hydrogen carbonate solution (30 mL each). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.The resulting brown oil was purified by silica gel flash column chromatography (hexane / ethyl acetate = 14/1) to give the title compound (543 mg, yield). : 60%) as a yellow oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ _H : 4.27 (2H, s), 6.86 (1H, s), 6.73-7.58 (16H, m).

3. Preparation of phenol derivatives

3-hydroxyphenyl acetate t-butyl

A mixture of 3-hydroxyphenylacetic acid (5.03 g, 33.1 mmo) and anhydrous toluene (50 mL) was heated to 80 ° C., and N, N-dimethylformamide = di-t-butylacetal (25 mL, 104 mmol) was added. After that, the mixture was further stirred at the same temperature for 30 minutes. The reaction solution was returned to room temperature, water was added, and then the organic layer was recovered. The aqueous layer was extracted with toluene (20 mL × 3), and the combined organic layer was washed with saturated brine (20 mL) and then dried over anhydrous magnesium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure, and the resulting yellow oil was purified by silica gel flash column chromatography (hexane / ethyl acetate = 4/1) to give the title compound (3.51 g, yield: 51 %) Was obtained as a colorless solid. ¹ H NMR (300MHz, CDCl ₃ ) δ _H : 1.44 (9H, s), 3.47 (2H, s), 5.95 (1H, br.s), 6.69-6.81 (3H, m), 7.15 (1H, dd, J = 7.8 and 7.8 Hz).
(Reference): US6313107 (2001).

Benzyl 3-hydroxyphenylacetate

3-hydroxyphenylacetic acid (100 g, 657 mmol) was dissolved in anhydrous N, N-dimethylformamide (500 mL), and sodium carbonate (70.0 g, 660 mmol) was added little by little. When sodium carbonate was added, bubbles were generated and the reaction solution changed from transparent to suspended. After adding the total amount of sodium carbonate, the mixture was further stirred at room temperature for 10 minutes. Benzyl bromide (79.0 mL, 664 mmol) was added dropwise thereto, and the mixture was further stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, water (500 mL) was added to the residue, and acidified with concentrated hydrochloric acid (35 mL). When concentrated hydrochloric acid was added, bubbles were generated and the oily residue turned into a solid. The mixture was further stirred at room temperature for 30 minutes, and the resulting solid was collected by filtration and dried under reduced pressure in a desiccator in the presence of calcium chloride to give the title compound (146 g, yield: 92%) as a brown solid. . ¹ H NMR (300MHz, CDCl ₃ ) δ _H : 3.62 (2H, s), 4.32 (1H, br.s), 5.14 (2H, s), 6.73-6.76 (2H, m), 6.83 (1H, d, J = 7.5 Hz), 7.18 (1H, dd, J = 7.5 and 7.5 Hz), 7.28-7.39 (5H, m).

2-hydroxyphenylacetic acid 2-chlorophenyldiphenylmethyl

3-hydroxyphenylacetic acid (1.00 g, 6.57 mmol) was dissolved in ethyl acetate (15 mL), and N-methylmorpholine (665 mg, 6.57 mmol) and chloro (2-chlorophenyl) diphenylmethane (2.05 g, 6.54 mmol) were added. Added sequentially. Further, anhydrous dichloromethane (10 mL) was added, followed by stirring at room temperature for 1 hour. The produced colorless solid was filtered off, and the filtrate was washed successively with saturated aqueous sodium hydrogen carbonate solution (15 mL) and saturated brine (15 mL), and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the resulting brown residue was purified by recrystallization (hexane / ethyl acetate) to give the title compound (350 mg, yield: 12%) as a colorless solid. It was. ¹ H NMR (300 MHz, CDCl ₃ ) δ _H : 3.77 (2H, s), 5.27 (1H, br.s), 6.69-6.86 (3H, m), 7.17-7.41 (15H, m).

4). Preparation of vinylphosphonic acid heterodiester (reference) GB882703 (1961).

3-{[Methoxy (vinyl) phosphoryl] oxy} phenyl acetate t-butyl

Methyl hydrogen phosphonate (1.00 g, 8.79 mmol) was dissolved in toluene (10 mL), oxalyl chloride (1.56 g, 12.3 mmol) was added, and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was concentrated under reduced pressure, and 3-{[methoxy (vinyl) phosphoryl] oxy} phenyl acetate t-butyl (1.50 g, 7.20 mmol) and anhydrous dichloromethane (15 mL) were added to the residue, followed by ice cooling. To this, triethylamine (1.8 mL, 12.9 mmol) was slowly added and then stirred at room temperature for 50 minutes. Silica gel (20 mL) was added to the reaction mixture, the solvent was evaporated under reduced pressure, and the residue was subjected to silica gel flash column chromatography (hexane / ethyl acetate = 1/1) to give the title compound (1.05 g, yield: 47%). ) Was obtained as a colorless oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ _H : 1.44 (9H, s), 3.51 (2H, s), 3.83 (3H, d, J = 11.1 Hz), 6.05-6.49 (3H, m), 7.07- 7.12 (3H, m), 7.27 (1H, dd, J = 7.8 and 7.8 Hz) 31 P NMR (121 MHz, CDCl 3) δ P:. 15.8.

3-{[Methoxy (vinyl) phosphoryl] oxy} phenyl acetate benzyl
a) Method using methyl hydrogen phosphonate as raw material

Methyl hydrogen phosphonate (1.76 g, 14.4 mmol) was dissolved in anhydrous dichloromethane (15 mL), and oxalyl chloride (1.8 mL, 21.3 mmol) was slowly added, followed by stirring at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure and azeotroped with toluene (10 mL), and then the residue was mixed with benzyl 3-{[methoxy (vinyl) phosphoryl] oxy} phenylacetate (3.40 g, 14.0 mmol) and anhydrous dichloromethane (30 mL). In addition, it was ice-cooled. To this, triethylamine (3.0 mL, 21.5 mmol) was slowly added, followed by stirring at room temperature for 1 hour. Silica gel (30 mL) was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel flash column chromatography (hexane / ethyl acetate = 1/1) to give the title compound (3.19 g, yield: 66%). ) Was obtained as a pale yellow oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ _H : 3.66 (2H, s), 3.81 (3H, d, J = 11.4 Hz), 5.13 (2H, s), 6.08-6.48 (3H, m), 7.08- 7.14 (3H, m), 7.25-7.36 (6H, m) 31 P NMR (121 MHz, CDCl 3) δ P:. 15.9.

b) Method using methyl vinylphosphonochloride as raw material

  Benzyl 3-hydroxyphenylacetate (80.0 g, 0.330 mol) was dissolved in anhydrous dichloromethane (500 mL), methyl vinylphosphonochloride (50.0 g, 0.356 mol) was added, and the mixture was ice-cooled. To this was added dropwise triethylamine (50 mL, 0.359 mol) over 1 hour, followed by stirring at room temperature for 16 hours. Insoluble solids were removed from the obtained brown suspension by filtration, and the filtrate was washed successively with saturated aqueous sodium hydrogen carbonate solution (50 mL × 2) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (99.0 g, yield: 87%) as a yellow oil.

3-{[Methoxy (vinyl) phosphoryl] oxy} phenylacetic acid 2-chlorophenyldiphenylmethyl

3-Hydroxyphenylacetic acid (1.01 g, 6.64 mmol) was suspended in anhydrous dichloromethane (25 mL), N-methylmorpholine (0.73 mL, 6.64 mmol) was added slowly, and then chloro (2-chlorophenyl) diphenylmethane (2.08 g , 6.64 mmol) and stirred at room temperature for 3 hours. To this was added methyl vinylphosphonochloridate (2.54 g, 18.1 mmol), and then triethylamine (3.0 mL, 21.5 mmol) was added under ice cooling. The reaction mixture was stirred at room temperature for 12 hours, diluted with chloroform (40 mL), and washed successively with water and saturated brine (20 mL each). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.The resulting brown oil was purified by silica gel flash column chromatography (hexane / ethyl acetate = 1/1) to give the title compound (737 mg, yield). : 21%) as a pale yellow viscous oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ _H : 3.77 (3H, d, J = 11.1 Hz), 3.82 (2H, s), 6.01-6.44 (3H, m), 7.13-7.31 (18H, m). ³¹ P NMR (121 MHz, CDCl ₃ ) δ _P : 15.8.

5. Synthesis of GGsTop protectors by Michael addition reaction (reference) Tetrahedron, 44, 5343 (1988).

4- {3-{(t-Butyloxycarbonylmethyl) phenyl] (methyl) phosphono} -2- (diphenylmethylene) aminobutanoic acid t-butyl

(Diphenylmethylene) aminoacetic acid t-butyl (1.00 g, 3.39 mmol), potassium carbonate (1.38 g, 9.98 mmol), 3-{[methoxy (vinyl) phosphoryl] oxy} phenylacetic acid t-butyl (1.04 g, 3.33 mmol) ), Acetonitrile (20 mL), and benzyltriethylammonium chloride (75 mg, 0.329 mmol) were refluxed for 45 minutes. The reaction mixture was allowed to cool to room temperature, silica gel (15 mL) was added, and the mixture was concentrated under reduced pressure. The residue was subjected to silica gel flash column chromatography (hexane / ethyl acetate = 1/1) to give the title compound (1.16 g, yield: 57%) as a pale yellow oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ _H : 1.43 (18H, s), 1.91-2.04 (2H, m), 2.12-2.34 (2H, m), 3.49 (2H, s), 3.76 (d, J = 11.1 Hz) and 3.77 (d, J = 11.1 Hz) (total 3H), 3.96-4.00 (1H, m), 7.06-7.45 (12H, m), 7.62-7.65 (2H, m). ³¹ P NMR ( 121 MHz, CDCl ₃ ) δ _P : 30.8.

4- {3-[(2-Chlorophenyldiphenylmethoxycarbonylmethyl) phenyl] (methyl) phosphono} -2- (diphenylmethylene) aminobutanoic acid t-butyl

3-{[Methoxy (vinyl) phosphoryl] oxy} phenylacetate 2-chlorophenyldiphenylmethyl (690 mg, 1.29 mmol) and (diphenylmethylene) aminoacetate benzyl (380 mg, 1.29 mmol) were dissolved in acetonitrile (12 mL). , Potassium carbonate (530 mg, 3.83 mmol) and benzyltriethylammonium chloride (30 mg, 0.132 mmol) were added and refluxed for 3 hours. The reaction solution was returned to room temperature, insoluble solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (hexane / ethyl acetate = 3/2) to give the title compound (269 mg, yield: 25%) as a pale-yellow viscous oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ _H : 1.42 (9H, s), 1.90-2.07 (2H, m), 2.13-2.36 (2H, m), 3.67 (3H, d, J = 11.1 Hz), . 3.80 (2H, s), 3.98 (1H, br.s), 7.10-7.42 (26H, m), 7.63 (2H, d, J = 7.2 Hz) 31 P NMR (121 MHz, CDCl 3) δ P: 30.8.

4- {3-[(2-chlorophenyldiphenylmethoxycarbonylmethyl) phenyl] (methyl) phosphono} -2- [di (4-chlorophenyl) methylene] aminobutanoic acid t-butyl

[Di (4-chlorophenyl) methylene] aminoacetic acid t-butyl (287 mg, 0.788 mmol), potassium carbonate (326 mg, 2.36 mmol), 3-{[methoxy (vinyl) phosphoryl] oxy} phenylacetic acid 2-chlorophenyldiphenyl A mixture of methyl (420 mg, 0.788 mmol), acetonitrile (3.0 mL), and benzyltriethylammonium chloride (89 mg, 0.391 mmol) was refluxed for 30 minutes. The reaction solution was returned to room temperature, insoluble solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (hexane / ethyl acetate = 3/2) to give the title compound (241 mg, yield: 34%) as a pale-yellow solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ _H : 1.42 (9H, s), 1.91-2.00 (2H, m), 2.21-2.26 (2H, m), 3.68 (3H, d, J = 11.1 Hz), 3.81 (2H, s), 3.93 (1H, t, J = 5.7 Hz), 7.07-7.33 (22H, m), 7.41 (2H, d, J = 8.6 Hz), 7.54 (2H, d, J = 8.6 Hz) ³¹ P NMR (121 MHz, CDCl ₃ ) δ _P : 34.8.

4- {3-[(Benzyloxycarbonylmethyl) phenyl] (methyl) phosphono} -2- (diphenylmethylene) aminobutanoic acid benzyl ester

3-{[Methoxy (vinyl) phosphoryl] oxy} phenyl acetate benzyl (98.8 g, 285 mmol), potassium carbonate (118 g, 855 mmol), acetonitrile (500 mL), (diphenylmethylene) aminoacetate benzyl (84.8 g, 257 mmol), and a mixture of benzyltriethylammonium chloride (25.1 g, 110 mmol) was refluxed for 90 minutes. After returning the reaction solution to room temperature and removing insolubles by filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel flash column chromatography (hexane / ethyl acetate = 4/1 to 1/1). The title compound (73.4 g, yield: 42%) was obtained as a pale yellow oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ _H : 1.91-2.04 (2H, m), 2.19-2.38 (2H, m), 3.62 (s) and 3.63 (s) (total 2H), 3.71 (d, J = 10.8 Hz) and 3.72 (d, J = 11.4 Hz) (total 3H), 4.13-4.17 (1H, m), 5.11 (2H, s), 5.12 (1H, d, J = 12.0 Hz), 5.18 (1H , d, J = 12.0 Hz) , 7.07-7.14 (5H, m), 7.22-7.44 (17H, m), 7.60-7.65 (2H, m) 31 P NMR (121 MHz, CDCl 3) δ P:. 30.6 .

4- {3-[(2-Chlorophenyldiphenylmethoxycarbonylmethyl) phenyl] (methyl) phosphono} -2- (diphenylmethylene) aminobutanoic acid benzyl ester

(Diphenylmethylene) aminoacetic acid benzyl (831 mg, 2.52 mmol), potassium carbonate (1.04 g, 7.53 mmol), 3-{[methoxy (vinyl) phosphoryl] oxy} phenylacetic acid 2-chlorophenyldiphenylmethyl (1.33 g, 2.50 mmol ), Acetonitrile (5.0 mL), and benzyltriethylammonium chloride (56 mg, 0.246 mmol) were refluxed for 17 hours. The reaction solution was returned to room temperature, insoluble solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (hexane / ethyl acetate = 1/1) to give the title compound (158 mg, yield: 7.3%) as a yellow oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ _H : 1.92-2.04 (2H, m), 2.22-2.32 (2H, m), 3.64 (3H, d, J = 11.1 Hz), 3.79 (2H, s), 4.11 (1H, t, J = 7.2 Hz), 5.12 (1H, d, J = 12.3 Hz), 5.17 (1H, d, J = 12.3 Hz), 7.07-7.37 (33H, m). ³¹ P NMR (121 MHz, CDCl ₃ ) δ _P : 30.5.

4- {3-[(2-Chlorophenyldiphenylmethoxycarbonylmethyl) phenyl] (methyl) phosphono} -2- (diphenylmethylene) aminobutanoic acid benzhydryl

(Diphenylmethylene) aminoacetic acid benzhydryl (800 mg, 1.97 mmol), potassium carbonate (830 mg, 6.01 mmol), 3-{[methoxy (vinyl) phosphoryl] oxy} phenylacetic acid 2-chlorophenyldiphenylmethyl (1.06 g, 1.99 mmol) ), Acetonitrile (10 mL), and benzyltriethylammonium chloride (225 mg, 0.988 mmol) were refluxed for 30 minutes. The reaction solution was returned to room temperature, insoluble solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (hexane / ethyl acetate = 3/2) to give the title compound (882 mg, yield: 48%) as a yellow solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ _H : 1.89-2.08 (2H, m), 2.25-2.35 (2H, m), 3.63 (3H, d, J = 10.8 Hz), 3.79 (2H, s), 4.21 (1H, t, J = 6.0 Hz), 6.81-7.41 (38H, m) 31 P NMR (121 MHz, CDCl 3) δ P:. 30.7.

4- {3-[(2-chlorophenyldiphenylmethoxycarbonylmethyl) phenyl] (methyl) phosphono} -2- [di (4-chlorophenyl) methylene] aminobutanoic acid benzhydryl

[Bis (4-chlorophenyl) methylene] aminoacetic acid benzhydryl (504 mg, 1.06 mmol), potassium carbonate (416 mg, 3.01 mmol), 3-{[methoxy (vinyl) phosphoryl] oxy} phenylacetic acid 2-chlorophenyldiphenylmethyl ( A mixture of 544 mg, 1.02 mmol), acetonitrile (10 mL), and benzyltriethylammonium chloride (114 mg, 0.501 mmol) was refluxed for 1 hour. The reaction solution was returned to room temperature, insoluble solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (hexane / ethyl acetate = 2/1) to give the title compound (230 mg, yield: 23%) as a pale yellow solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ _H : 1.80-2.05 (2H, m), 2.25-2.40 (2H, m), 3.63 (3H, d, J = 12.0 Hz), 3.80 (2H, s), 4.14 (1H, t, J = Hz), 6.88 (1H, s), 6.93-7.74 (36H, m) 31 P NMR (121 MHz, CDCl 3) δ P:. 30.2.

4- {3-[(2-Chlorophenyldiphenylmethoxycarbonylmethyl) phenyl] (methyl) phosphono} -2- [di (4-chlorophenyl) methylene] aminobutanoic acid 4,4'-dichlorobenzhydryl

[Bis (4-chlorophenyl) methylene] aminoacetic acid 4,4'-dichlorobenzhydryl (543 mg, 1.00 mmol), potassium carbonate (394 mg, 2.85 mmol), 3-{[methoxy (vinyl) phosphoryl] oxy} A mixture of 2-chlorophenyldiphenylmethyl phenylacetate (514 mg, 0.964 mmol), acetonitrile (10 mL), and benzyltriethylammonium chloride (108 mg, 0.474 mmol) was refluxed for 1 hour. The reaction solution was returned to room temperature, insoluble solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (hexane / ethyl acetate = 2/1) to give the title compound (256 mg, yield: 26%) as a colorless solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ _H : 1.80-2.00 (2H, m), 2.20-2.40 (2H, m), 3.64 (3H, d, J = 12.0 Hz), 3.81 (2H, s), 4.15 (1H, t, J = 6.0 Hz), 6.79 (1H, s), 6.94-7.55 (34H, m) 31 P NMR (121 MHz, CDCl 3) δ P:. 30.0.

6). Synthesis of GGsTop

2-Amino-4-{[3- ( carboxymethyl) phenyl] (methyl) phosphono} butanoic acid

4- {3-[(Benzyloxycarbonylmethyl) phenyl] (methyl) phosphono} -2- (diphenylmethylene) aminobutanoic acid benzyl (4.95 g, 7.33 mmol) is dissolved in methanol (30 mL), and argon gas is added to the solution. Introduced for 5 minutes. To this was added palladium-carbon (256 mg), and the mixture was stirred at room temperature for 4 hours while introducing hydrogen gas. The catalyst was removed by filtration, the filtrate was concentrated under reduced pressure, water (100 mL) was added, and the mixture was washed with diethyl ether (30 mL × 3). After concentrating the aqueous layer under reduced pressure, the resulting residue was purified by medium pressure column chromatography (water / methanol = 55 / 45-30 / 70) and lyophilized to give the title compound (2.26 g, yield: 93%) was obtained as a colorless solid. ¹ H NMR (300 MHz, D ₂ O) δ _H : 2.14-2.33 (4H, m), 3.74 (2H, s), 3.86 (3H, d, J = 11.1 Hz), 7.15-7.45 (4H, m) ³¹ P NMR (121 MHz, D ₂ O) δ _P : 32.3.

Claims (3)

A method for producing a phosphonic acid diester derivative represented by the general formula (I), which comprises deprotecting the compound represented by the general formula (II):

(Wherein R ^a and R ^b are the same or different and may have a substituent, an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, or a substituent. An aryl group, an aralkyl group which may have a substituent, and a heteroaryl group which may have a substituent are shown.
R ^c may have an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, an aryl group which may have a substituent, or a substituent. An aralkyl group and a heteroaryl group which may have a substituent are shown.
R ¹ and R ² are the same or different and each represents an azide group (N ₃ ), —OR ³ , —OCR ⁴ = CR ⁵ R ⁶ , —ON = CR ⁷ R ⁸ , or —SR ⁹ (Here, each of R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ is a hydrogen atom, an optionally substituted alkyl group, or an optionally substituted aryl. And at least one substituent selected from the group consisting of an electron-withdrawing group, and two adjacent substituents among the substituents of R ^{4 to} R ⁸ may be bonded to each other to form a ring. )). A Michael addition reaction is performed on the compound represented by the general formula (1) and the compound represented by the general formula (2) in the presence of a base and, if necessary, a phase transfer catalyst. ) A method for producing a phosphonic acid diester derivative represented by:

(Wherein R ^a and R ^b are the same or different and may have a substituent, an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, or a substituent. An aryl group, an aralkyl group which may have a substituent, and a heteroaryl group which may have a substituent are shown.
R ^c may have an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, an aryl group which may have a substituent, or a substituent. An aralkyl group and a heteroaryl group which may have a substituent are shown.
R ¹ and R ² are the same or different and each represents an azide group (N ₃ ), —OR ³ , —OCR ⁴ = CR ⁵ R ⁶ , —ON = CR ⁷ R ⁸ , or —SR ⁹ (Here, each of R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ is a hydrogen atom, an optionally substituted alkyl group, or an optionally substituted aryl. And at least one substituent selected from the group consisting of an electron-withdrawing group, and two adjacent substituents among the substituents of R ^{4 to} R ⁸ may be bonded to each other to form a ring. )). A compound represented by the general formula (II) by subjecting the compound represented by the general formula (1) and the compound represented by the general formula (2) to a Michael addition reaction in the presence of a base and, if necessary, a phase transfer catalyst. And then deprotecting the compound represented by the general formula (II): A method for producing a phosphonic acid diester derivative represented by the general formula (I):

(Wherein R ^a and R ^b are the same or different and may have a substituent, an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, or a substituent. An aryl group, an aralkyl group which may have a substituent, and a heteroaryl group which may have a substituent are shown.
R ^c may have an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, an aryl group which may have a substituent, or a substituent. An aralkyl group and a heteroaryl group which may have a substituent are shown.
R ¹ and R ² are the same or different and each represents an azide group (N ₃ ), —OR ³ , —OCR ⁴ = CR ⁵ R ⁶ , —ON = CR ⁷ R ⁸ , or —SR ⁹ (Here, each of R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ is a hydrogen atom, an optionally substituted alkyl group, or an optionally substituted aryl. And at least one substituent selected from the group consisting of an electron-withdrawing group, and two adjacent substituents among the substituents of R ^{4 to} R ⁸ may be bonded to each other to form a ring. )).