JP2000016998A - New diphosphonate compound, its production intermediate and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new diphosphonate compound useful as an intermediate for producing optically active phosphine compounds constituting excellent catalysts for asymmetric reactions. SOLUTION: A compound of formula I (R1 and R2 are each an alkyl, phenyl or the like), for example, diphenyl(3,4-methylenedioxyphenyl) phosphonate. The compound of formula I is obtained by reacting a chlorophosphate compound of formula II with a Grignard reagent or lithium reagent prepared from a compound of formula III (X is a halogen), treating the obtained phosphonate compound of formula IV with a base (preferably an organic lithium compound or an organic magnesium compound) preferably in an amount of 1.2-2.0 equivalents preferably in tetrahydrofuran at -78 to -15 deg.C, and subsequently dimerizing the treated compound with an oxidizing agent, preferably an oxidizing metal compound (preferably an iron compound, a copper compound or the like) preferably in an amount of 1.2-2.0 equivalents preferably at -5 to 15 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel diphosphonate compound, an intermediate for producing the same and a method for producing them, and more particularly, to a method for producing an optically active phosphine compound constituting an excellent catalyst for asymmetric reaction. The present invention relates to a diphosphonate compound as a production intermediate, a production intermediate of the diphosphonate compound, and a novel production method for easily synthesizing diphosphonate.

[0002]

2. Description of the Related Art There have been many reports on transition metal complexes which can be used for asymmetric synthesis such as asymmetric hydrogenation, asymmetric isomerization, and asymmetric hydrosilylation. In particular, a complex in which an optically active tertiary phosphine compound is coordinated with a transition metal complex such as ruthenium, rhodium, iridium, or palladium has excellent performance as a catalyst for an asymmetric synthesis reaction.

In order to further enhance the performance of the transition metal complex catalyst, a large number of phosphine compounds having various structures have been developed so far (Chemical Review 32, Chemistry of Organometallic Complexes, edited by The Chemical Society of Japan, pp. 23-238). , 1982; "Asymmet
ric Catalysis In Organic Synthesis ", by Ryoji Noyori,
A Wiley-Interscience Publication). Among these phosphine compounds, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (hereinafter “BINAP”)
That. ) Is one of particularly excellent optically active phosphines, and rhodium complexes (JP-A-55-61973) and ruthenium complexes (JP-A-61-6390) using this BINAP as a ligand have already been reported. ing.

Heretofore, as a method for synthesizing these phosphine compounds, racemic binaphthol has been prepared at a high temperature (240 ° C.-320 ° C.) using triphenylphosphine-dibromide.
° C) and lead to a Digrignard reagent, then condensed with a diarylphosphinyl chloride compound to form a diphosphine oxide compound, and after optical resolution, a tertiary diphosphine compound (BINAPs) using a trichlorosilane reducing agent. The method is known as an industrial method. (H. Takaya, K. Mashima, K. Koyano, M. Ya
gi, H. Kumobayashi, T. Taketomi, S. Akutagawa, R. N
(oyori, J. Org. Chem., 1986, 51, 629)

As a method for synthesizing a diarylphosphinyl chloride compound, a Grignard reagent prepared from aryl bromide is reacted with diethylaminophosphinic dichloride to form a diarylphosphinic acid compound, which is then reacted with thionyl chloride. A method for synthesizing a diarylphosphinyl chloride compound is known. (K. Mashima, K. Kusano, N. Sato, Y.
Matsumura, K. Nozaki, H. Kumobayashi, N. Sayo, Y. H
ori, T. Ishizaki, S. Akutagawa, H. Takaya, J. Org.
Chem., 1994, 59, 3064.)

[0006] Other methods for synthesizing phosphine compounds include:
Reduction of a substituted (2-nitrophenyl) diphenylphosphine oxide compound to give (2-aminophenyl)
A diphenylphosphine oxide compound was obtained, followed by diazotization and iodination to obtain a (2-iodophenyl) diphenylphosphine oxide compound having a substituent, followed by dimerization in the presence of copper to obtain a bisphosphine oxide compound, which was optically resolved. A method is known in which a tertiary diphosphine compound is later formed using a trichlorosilane reducing agent. (Japanese Unexamined Patent Publication No. 5-507503)

On the other hand, catalysts using BINAP as a ligand have excellent properties, but their selectivity (chemical selectivity, enantioselectivity) and catalytic activity are not sufficient depending on the target reaction or its reaction substrate. There are cases. The present inventors have solved ((5, 6), (5 ′,
6 ′)-bis (methylenedioxy) biphenyl-2,
2′-diyl) bis (diphenylphosphine) (hereinafter, referred to as “
It is called "SEGPHOS". ) Or a derivative thereof using a ligand as a ligand was developed and filed earlier (Japanese Patent Application No. 8-359818). This transition metal complex is
Asymmetric hydrogenation of hydroxyacetone, α-substituted-β-
It exhibits excellent catalytic activity and enantio- or diastereoselective asymmetric hydrogenation of ketoesters. However, these diphosphine compounds have a problem that the production process is long depending on the production intermediate, the yield of the required optically active compound is low, or the yield of the intermediate is poor. Not a satisfactory way. For this reason, improvement of the manufacturing method is desired.

[0008]

DISCLOSURE OF THE INVENTION The present invention provides a SEG having excellent performance (chemoselectivity, enantioselectivity, catalytic activity) as a catalyst for asymmetric synthesis reactions, particularly asymmetric hydrogenation reactions.
An object of the present invention is to provide a novel production intermediate useful for producing a diphosphine compound such as PHOS. Another object of the present invention is to provide a method for producing the production intermediate simply and with high yield.

[0009]

Means for Solving the Problems The present inventors have made intensive developments to solve the above problems, and as a result, ((5, 5)
6) A diphosphonate compound such as (5 ′, 6 ′)-bis (methylenedioxy) biphenyl-2,2′-diyl) bis (diphenylphosphonate) (hereinafter referred to as “PhO-SEGPHOSO”) is SEGPHOS.
Is found to be a useful intermediate for the production of diphosphine compounds such as PhO-SEGPHOSO,
Conventionally, diphenyl (3,4-methylenedioxyphenyl) phosphonate is treated with a base such as lithium diisopropylamide and then treated with an oxidizing agent such as iron trichloride. Although a step reaction was required, the present inventors have found that it can be produced simply and with high yield by a one-step reaction, and completed the present invention.

That is, the first aspect of the present invention relates to the general formula (1)

Embedded image (Wherein R ¹ and R ² are each independently an alkyl group,
A phenyl group or an alkyl group having 1 to 4 carbon atoms, an alkoxyl group having 1 to 4 carbon atoms, a substituted phenyl group substituted with a halogen atom or a dialkylamino group. )
Is a diphosphonate compound represented by

Further, the second aspect of the present invention provides a compound represented by the following general formula (2):

Embedded image (Wherein R ¹ and R ² represent the same as described above).

Further, the third aspect of the present invention provides a compound represented by the following general formula (3):

Embedded image (Wherein, R ¹ and R ² represent the same as described above) and a chlorophosphate compound represented by the general formula (4)

Embedded image (Wherein X represents a halogen atom), and reacted with a Grignard reagent or lithium reagent prepared from a compound represented by the general formula (2):

Embedded image (Wherein R ¹ and R ² represent the same as defined above), followed by treatment with a base, followed by dimerization using an oxidizing agent. Equation (1)

Embedded image (Wherein R ¹ and R ² represent the same as described above).

[0013] The fourth invention is the method for producing a diphosphonate compound represented by the general formula (1), wherein the base is an organic lithium compound or an organomagnesium compound according to the third invention. is there.

[0014] In a fifth aspect of the present invention based on the third or fourth aspect, the oxidizing agent is a metal compound having an oxidizing property. Specifically, the metal compound is iron, copper, ruthenium, cobalt, or the like. , Nickel, vanadium, molybdenum, manganese, titanium, or a metal complex or a metal complex compound thereof is a method for producing a diphosphonate compound represented by the general formula (1).

Hereinafter, the present invention will be described in more detail. In the general formula (1), the alkyl group of R ¹ and R ² in the formula is preferably a C _{1 to} C ₅ alkyl group. Examples of the preferable alkyl group include a methyl group, an ethyl group and a propyl group. Group, butyl group and pentyl group. The substituent in the substituted phenyl group is a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkoxyl group, a halogen atom or a di (lower alkyl) amino group. Also the lower alkyl herein is an alkyl group of C ₁ -C _5.

Among these compounds, preferred compounds are those represented by the general formula (5)

Embedded image (Wherein, Ar ¹ is

Embedded image R ⁴ and R ⁵ are each independently a hydrogen atom, C
₁ -C alkyl or alkoxyl group C ₁ -C ₄ of _4, R ⁶ represents a hydrogen atom, an alkyl group or a C ₁ -C ₄ alkoxyl group C ₁ -C _4. )

Further preferred compounds are those represented by the general formula (6)

Embedded image (Where Ar ² is

Embedded image R ⁷ and R ⁸ are the same and are a hydrogen atom, t-
R ⁹ represents a butyl group, n-butyl group, n-propyl group, isopropyl group, ethyl group or methyl group; R ⁹ represents a hydrogen atom, t-butoxy group, isopropoxy group, ethoxy group or methoxy group. ).

Among the above compounds,

Embedded image (In the formula, Ph represents a phenyl group.) Is a particularly preferred compound.

The phosphonate compound represented by the above general formula (2) of the present invention is used as a production intermediate for producing the diphosphonate compound represented by the above general formula (1).

Hereinafter, an example of a method for producing the compound represented by the general formula (1) via the compound represented by the general formula (2) will be described. The synthesis is performed by the following route.

Embedded image (In the formula, R ¹ , R ² and X represent the same as described above.)

First, a Grignard reagent or lithium reagent prepared from the compound represented by the formula (4) and a compound represented by the formula (3)
Is reacted with a chlorophosphate compound represented by the formula (2) to produce a phosphonate compound represented by the formula (2). Adjustment of the Grignard reagent or lithium reagent is carried out in a conventional manner, for example, in a solvent such as tetrahydrofuran, dioxane, ether, toluene, and hexane.
It can be easily carried out by reacting an alkyl halide or an aryl halide with a magnesium metal or a lithium metal. In addition, the reaction of the compound represented by the formula (3) with a Grignard reagent or a lithium reagent can be performed by a conventional method, for example, by adding a Grignard reagent or a lithium reagent in a solution of tetrahydrofuran, dioxane, ether, toluene, hexane or the like by the formula (3) It can be easily carried out by dropping and reacting the compound represented at room temperature.

Next, a diphosphonate compound represented by the formula (1) is produced from the phosphonate compound represented by the formula (2). In this production, first, the phosphonate compound is anionized with a base, and the anion can be adjusted by a method known per se. For example, a phosphonate compound represented by the formula (2)
One or more equivalents, preferably 1.2 to 2.0 equivalents, of a base selected from organolithium reagents such as lithium alkylamides, alkyllithiums and allyllithiums, and organomagnesium reagents such as Grignard reagents, preferably lithium diethylamide and lithium diamide Propylamide (hereinafter, referred to as
"LDA". ), Methyl lithium, butyl lithium, phenyl lithium, alkyl magnesium halide of C ₁ -C _5, unsubstituted or substituted phenyl magnesium halide, a base such as magnesium amide, more preferably a LDA, ethers, aliphatic or aromatic hydrocarbon Solvents such as a system solvent or a mixed solvent thereof, preferably tetrahydrofuran (hereinafter referred to as “THF”), dioxane, diethyl ether, toluene, hexane, heptane or a mixed solvent thereof, more preferably −5 in THF.
The reaction is carried out at a temperature of not more than ℃, preferably -78 ℃ to -15 ℃.

The method for producing the diphosphonate compound represented by the general formula (1) from an anion can be carried out as follows. That is, the anion solution prepared by the above method is used in an amount of 1 equivalent or more, preferably 1.2 to
An oxidizing metal compound having 2.0 equivalents (the number of equivalents may be the same as or different from the equivalent of the base);
The reaction is carried out in THF or a mixed solvent of THF and an aliphatic or aromatic hydrocarbon at 50 ° C or lower, preferably -5 ° C to 15 ° C. If desired, the reaction can also be carried out at a low temperature, preferably -78 ° C to -40 ° C, by adding the oxidizing agent directly into the anion solution. The oxidizing metal compound is iron, copper, ruthenium, cobalt, nickel, vanadium, molybdenum,
Manganese, selected from oxidizing compounds such as titanium, these compounds are preferably trivalent iron, divalent copper, trivalent ruthenium, trivalent cobalt, divalent nickel, tri, four or Oxidants selected from pentavalent vanadium, tri-, tetra-, 5- or hexavalent molybdenum, tri-, tetra-, 5- or hexavalent manganese, tri- or tetravalent titanium metal salts or metal complex compounds, more preferably Metal chlorides, bromides, iodides, nitrates, sulfates, perchlorates, acetates, oxalates, acetylacetone complexes, bipyridyl and phenanthrene complexes of these metal salts, more preferably iron trichloride, iron tribromide , Iron triiodide, copper dichloride, copper dibromide,
And copper diiodide.

In order to avoid complication, among the compounds included in the present invention, compounds represented by the above general formula (7);
((5,6), (5 ′, 6 ′)-Bis (methylenedioxy) biphenyl-2,2′-diyl) bis (diphenylphosphonate) (PhO-SEGPHOSO) A typical example of the production method will be specifically described. However, the present invention is not limited to this example.

Embedded image

That is, a magnesium piece is reacted with 3,4-methylenedioxybromobenzene (8) to give a Grignard reagent, which is reacted with diphenylphosphoryl chloride to give diphenyl (3,4-methylenedioxyphenyl) phosphonate. (9) is synthesized. Reacting this compound with LDA, followed by the action of iron trichloride,
The target PhO-SEGPHOSO (7) can be manufactured with high efficiency.

Further, in the diphosphonate compound of the present invention, the diphosphonate compound having a substituent on the phenyl group can be prepared by using a diarylphosphoryl chloride having a phenyl group having a substituent instead of diphenylphosphoryl chloride. it can.

A diphosphonate compound having an alkyl group instead of a phenyl group can be prepared by using a dialkyl phosphoryl chloride having an alkyl group instead of diphenyl phosphoryl chloride.

[0028]

The novel diphosphonate compound represented by the above general formula (1) of the present invention is particularly useful as an intermediate for synthesizing diphosphine compounds such as SEGPHOS.
The novel phosphonate compound represented by the general formula (2) is useful as a synthetic intermediate of the diphosphonate compound represented by the general formula (1). In addition, the novel production method of the present invention can produce a novel diphosphonate compound simply and in good yield, and is extremely useful industrially.

[0029]

The present invention will be described in detail with reference to examples and reference examples, but the present invention is not limited to these examples. In addition, the apparatus used for the measurement of the physical property in each Example is as follows. Nuclear Magnetic Resonance ¹ H NMR Bruker AM400 (400 MHz) ³¹ P NMR Bruker AM400 (162 MHz) Melting point Yanaco MP-500D Optical rotation JASCO DIP-4 Gas chromatography-GLC Hewlett Packard 5890-II High-performance liquid chromatography HPLC 10A Shimadzu PD LCA Shimadzu & LC MASS Hitachi M-80B

Example 1 Synthesis of diphenyl (3,4-methylenedioxyphenyl) phosphonate 51 g (2.10 mol) of magnesium under a nitrogen stream
While stirring THF (100 ml) and iodine (catalytic amount) and stirring, 405.9 g (2.02 mol) of 1-bromo- (3,4) -methylenedioxybenzene was added to THF (2).
L) After the addition of a small amount of the solution and the formation of the Grignard reagent was confirmed, the dropwise addition was continued while maintaining the reaction temperature at 25 to 30 ° C. After stirring overnight at room temperature, the resulting Grignard reagent was added dropwise to a solution of 580 g (2.05 mol) of diphenylphosphoryl chloride in THF (1 L) cooled to -5 ° C. After stirring at room temperature overnight, THF was distilled off under reduced pressure, and ethyl acetate (3 L) and 1 N hydrochloric acid (1.5 L) were added and stirred. The organic layer was separated, washed with water and a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product (746.48 g).
The crude product was recrystallized from ethyl acetate to give the title compound 5
74.9 g were obtained.

Yield 80% mp: 55.5 ° C. ¹ H-NMR (CDCl ₃ ): δ 6.04 (2H,
s), 6.90 (1H, dd, J = 7.8, 3.9H)
z), 7.12-7.20 (5H, m), 7.27-
7.31 (4H, m), 7.35 (1H, dd, J = 1
3.6, 1.3 Hz), 7.52 (1H, ddd, J =
14.7, 8.0, 1.5 Hz) ³¹ P-NMR (CDCl ₃ ): δ12.5

Example 2 ((5, 6), (5 ',
6 ′)-bis (methylenedioxy) biphenyl-2,
Synthesis of 2′-diyl) bis (diphenylphosphonate) Diisopropylamine 11 cooled in an ice bath under a nitrogen stream
In 5 ml (0.88 mol) of THF 600 ml solution,
500 ml of 1.6N normal butyl lithium solution (0.
80 mol) was added dropwise, and after the addition was completed, the mixture was further stirred for 2 hours to prepare LDA. Then, at -60 ° C, diphenyl (3,4-methylenedioxyphenyl) phosphonate 2
34 g (0.66 mol) of a 1.5 L THF solution was added with the adjusted LDA, and stirred for 45 minutes.
Then, 128 g (0.80 mol) of iron trichloride was added thereto, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and ethyl acetate (2
L) 1N hydrochloric acid (1.5 L) was added and stirred. The organic layer was separated, washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product (230 g).
I got The crude product is recrystallized from acetonitrile,
91.7 g of the title compound were obtained.

Yield 40% mp: 119-123 ° C. ¹ H-NMR (CDCl ₃ ): δ 5.54 (2H,
d, J = 1.4 Hz), 5.90 (2H, d, J = 1.
4 Hz), 6.77-6.94 (8H, m), 6.97
(2H, dd, J = 8.1, 3.5 Hz), 7.01-
7.08 (4H, m), 7.08-7.20 (8H,
m), 7.82 (2H, dd, J = 15.7, 8.1H
z) ³¹ P-NMR (CDCl ₃ ): δ10.5

Example 3 Synthesis of diethyl (3,4-methylenedioxyphenyl) phosphonate 6.05 g of magnesium was placed in a four-necked flask under a nitrogen stream.
(0.25 mol), weigh out THF (15 ml),
After activating magnesium with a small amount of dibromoethane,
50 g of 4-bromo-1,2-methylenedioxybenzene
(0.25 mol) of 235 ml of THF was added dropwise while maintaining the reaction temperature at 25 to 30 ° C. After stirring at room temperature for 1.5 hours, the mixture was stirred in an ice bath for 35 hours.
9 ml (o. 25 mol) was added dropwise, and the mixture was stirred for 1 hour, returned to room temperature, and stirred for 2 hours. THF was distilled off under reduced pressure, a saturated aqueous solution of ammonium chloride was added, and the mixture was stirred, and ethyl acetate was added for extraction. The organic layer was separated, washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. The crude product was distilled under reduced pressure (20 mmHg, 1
45 ° C.) and 42.45 g (0.165 mol) of the title compound
1) was obtained as a colorless liquid.

Yield 66.3% ¹ H-NMR (CDCl ₃ ): δ 1.27 (6H,
t, J = 7.1 Hz), 4.06 (4H, m), 6.0
1 (2H, d, J = 2.0 Hz), 6.86 (1H, d
d, J = 8.0, 3.6 Hz), 7.22 (1H, d
d, J = 12.9, 1.4 Hzm), 7.38 (1H,
ddd, J = 13.9, 7.9, 1.4 Hzm) ³¹ P-NMR (CDCl ₃ ): δ 19.6

Embodiment 4 ((5, 6), (5 ',
6 ′)-bis (methylenedioxy) biphenyl-2,
Synthesis of 2′-diyl) bis (diethylphosphonate) Diethyl (3,4) was placed in a 1 L four-necked flask under a nitrogen stream.
-Methylenedioxyphenyl) phosphonate 42.0 g
(0.163 mol) and THF (210 ml) were weighed and placed in a dry ice-acetone bath (−72 ° C.) at 0.7
280 ml of a solution of M LDA in THF (0.196 mo
l) was added dropwise, and the mixture was further stirred for 2 hours. Next, in a nitrogen stream, 31.75 g of ferric chloride was placed in a 1 L four-necked flask.
(0.1957 mol), 209 ml of THF was added dropwise, and the mixture was stirred and dried in a dry ice-acetone bath (−7).
(2 ° C.), the above solution was added dropwise, and the mixture was stirred and reacted overnight. The solvent was distilled off from the reaction mixture, a saturated aqueous ammonium chloride solution was added, and the mixture was stirred and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated. After purification on a silica gel column, recrystallization was performed from chloroform-hexane, and the obtained crystals were dried under reduced pressure to obtain 22.7 g of the title compound.

Yield 54.1% mp: 189 ° C. ¹ H-NMR (CDCl ₃ ): δ 1.13 (6H,
t, J = 7.1 Hz), 1.19 (6H, t, J = 7.
1 Hz), 3.77 (2H, m), 3.97 (6H,
m), 5.96 (2H, d, J = 1.4 Hz), 6.0
1 (2H, d, J = 1.4 Hz), 6.87 (2H, d
d, J = 8.0, 3.0 Hz), 7.56 (2H, d
d, J = 14.1, 8.1 Hz) ³¹ P-NMR (CDCl ₃ ): δ 18.1

Reference Example 1 (±) − ((5, 6),
Synthesis of (5 ′, 6 ′)-bis (methylenedioxy) biphenyl-2,2′-diyl) bis (diphenylphosphine oxide) ((5,6), (5 ′, 6 ′)- Bis (methylenedioxy) biphenyl-2,2'-diyl) bis (diphenylphosphonate) 1.0 g (1.42 mmol)
l) in 10 ml of THF was added 28 m of a 0.5N phenylmagnesium bromide (14 mmol) THF solution.
1 was added dropwise at room temperature. After that, the reaction was stirred at room temperature overnight,
Water was added to quench excess Grignard reagent. The solvent was distilled off under reduced pressure, and ethyl acetate (100 ml) and 1N hydrochloric acid (100 ml) were added and stirred. The organic layer was separated, washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. Purification by a silica gel column gave the title compound (0.73 g).

Yield 81% mp: 230-232 ° C. ¹ H-NMR (CDCl ₃ ): δ 5.26 (2H,
d, J = 1.5 Hz), 5.72 (2H, d, J = 1.
6 Hz), 6.65 (2H, dd, J = 8.1, 2.1)
Hz), 6.77 (2H, dd, J = 14.1, 8.1)
Hz), 7.28-7.72 (20H, m) ³¹ P-NMR (CDCl ₃ ): δ 29.6

Reference Example 2 (±) − ((5, 6),
Synthesis of (5 ′, 6 ′)-bis (methylenedioxy) biphenyl-2,2′-diyl) bis (bis (3,5-dimethylphenyl) phosphine oxide) Under a nitrogen stream, ((5,6), 1.0 g of (5 ', 6')-bis (methylenedioxy) biphenyl-2,2'-diyl) bis (diphenylphosphonate) (1.42 mmol)
l) in 10 ml of THF was added 3,5-dimethylphenylmagnesium bromide (14 mmol) in THF2
0 ml solution was added dropwise at room temperature. Thereafter, the reaction was stirred overnight at room temperature, and water was added to quench the excess Grignard reagent. The solvent was distilled off under reduced pressure, and ethyl acetate (100 m
l) 1N hydrochloric acid (100 ml) was added and stirred. The organic layer was separated, washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. Purify on a silica gel column to give the title compound (0.90 g)
I got

Yield 85% mp: 256-258 ° C. ¹ H-NMR (CDCl ₃ ): δ 2.11 (12H,
s), 2.30 (12H, s), 5.43 (2H, d,
J = 1.6 Hz), 5.77 (2H, d, J = 1.6H)
z), 6.65 (2H, dd, J = 8.1, 2.0H
z), 6.92 (2H, dd, J = 14.0, 8.1H
z), 6.95 (2H, s) 7.09 (2H, s),
7.14 (4H, d, J = 12.2 Hz), 7.37
(4H, d, J = 12.1 Hz) ³¹ P-NMR (CDCl ₃ ): δ30.5

Reference Example 3 (±) − ((5, 6),
Synthesis of (5 ′, 6 ′)-bis (methylenedioxy) biphenyl-2,2′-diyl) bis (bis (4-methylphenyl) phosphine oxide) 4.3 g of magnesium in a four-necked flask under a nitrogen stream.
(0.178 mol), THF (8 ml) and iodine (catalytic amount) were added and stirred at room temperature for 1 hour.
A solution of 9.6 g (0.17 mol) in THF (150 ml) was added dropwise, and the mixture was stirred at room temperature for 3 hours. ((5,6),
(5 ′, 6 ′)-bis (methylenedioxy) biphenyl-2,2′-diyl) bis (diphenylphosphonate)
20.0 g (0.0283 mol) of THF (140 m
l) The THF solution of 4-methylphenylmagnesium bromide prepared above was added dropwise to the solution in an ice bath, and the mixture was stirred and reacted at room temperature overnight. The solvent was distilled off from the reaction mixture, a saturated aqueous ammonium chloride solution was added, and the mixture was stirred and extracted with ethyl acetate. The organic layer was washed three times with a 3N aqueous sodium hydroxide solution, then with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated. After purification on a silica gel column, recrystallization was performed from ethyl acetate, and the obtained crystals were dried under reduced pressure to obtain the title compound (19.4 g).

Yield 98% mp: 156-158 ° C. ¹ H-NMR (CDCl ₃ ): δ 2.27 (6H,
s), 2.38 (6H, s), 5.37 (2H, d, J
= 1.6 Hz), 5.75 (2H, d, J = 1.6H)
z), 6.65 (2H, dd, J = 8.1, 2.0H
z), 6.78 (2H, dd, J = 14.0, 8.1H
z), 7.04 (2H, dd, J = 8.0, 2.2H
z), 7.19 (2H, dd, J = 8.0, 2.2H
z), 7.43 (4H, dd, J = 11.9, 8.1H
z), 7.57 (4H, dd, J = 11.7, 8.1H
z) ³¹ P-NMR (CDCl ₃ ): δ 29.6

Reference Example 4 (±) − ((5, 6),
Synthesis of (5 ′, 6 ′)-bis (methylenedioxy) biphenyl-2,2′-diyl) bis (bis (4-chlorophenyl) phosphine oxide) After replacing the inside of a 100 mL three-necked flask with nitrogen. , Magnesium 0.76 g (32 mmol), THF
Measure 2 ml. After adding a small amount of dibromoethane and stirring vigorously to activate magnesium, 1-bromo-
5.43 g (28 mmol) of 4-chlorobenzene in TH
After 24 ml of F24 solution was added dropwise in a water bath, the mixture was stirred at room temperature for 3 hours. Next, ((5,6), (5 ′, 6 ′)-bis (methylenedioxy) biphenyl-2,2′-diyl)
2.01 g of bis (diphenylphosphonate) (2.8 m
mol) and THF (16 ml), and weighed at 50-60 ° C.
Then, the prepared Grignard reagent was dropped into the solution. 3 /
After 4 drops, the completion of the reaction was confirmed, and the excess reagent was crushed with water to terminate the reaction. The solvent was distilled off under reduced pressure, 100 ml of methylene chloride was added, and 100 ml of a 1.2N hydrochloric acid aqueous solution was added.
1 × 2 times, 1N aqueous solution of sodium hydroxide 100 ml × 2
After washing twice with 100 ml of water twice and drying with magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 3.2 g of a crude target product. The title compound (1.56 g) was obtained by washing with ethyl acetate and methanol.

Mp: 310-313 ° C. (decomposition) ¹ H-NMR (CDCl ₃ ): δ 5.41 (2H,
d, J = 1.4 Hz), 5.80 (2H, d, J = 1.
5 Hz)), 6.67-6.73 (4H, m), 7.2
9 (4H, dd, J = 8.6, 2.2 Hz), 7.41
(4H, dd, J = 8.7, 2.2 Hz), 7.46
(4H, dd, J = 11.7, 8.5 Hz), 7.57
(4H, dd, J = 11.3, 8.5 Hz) ³¹ P-NMR (CDCl ₃ ): δ28.7

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Noboru Sayo, Inventor No. 1-4-11, Nishi-Hachiman, Hiratsuka-shi, Kanagawa Prefecture Inside the Research Institute of Takasago International Co., Ltd. 1-4-11, Yawata Takasago International Corporation F-term (reference) 4H050 AA01 AA02 AB84 AC20 BD70 WA15 WA26

Claims (6)

[Claims] 1. A compound of the general formula (1) (Wherein R ¹ and R ² are each independently an alkyl group,
A phenyl group or an alkyl group having 1 to 4 carbon atoms, an alkoxyl group having 1 to 4 carbon atoms, a substituted phenyl group substituted with a halogen atom or a dialkylamino group. )
A diphosphonate compound represented by the formula: 2. A compound of the general formula (2) (Wherein R ¹ and R ² are each independently an alkyl group,
A phenyl group or an alkyl group having 1 to 4 carbon atoms, an alkoxyl group having 1 to 4 carbon atoms, a substituted phenyl group substituted with a halogen atom or a dialkylamino group. )
A phosphonate compound represented by the formula: 3. A compound of the general formula (3) (Wherein R ¹ and R ² are each independently an alkyl group,
A phenyl group or an alkyl group having 1 to 4 carbon atoms, an alkoxyl group having 1 to 4 carbon atoms, a substituted phenyl group substituted with a halogen atom or a dialkylamino group. )
And a chlorophosphate compound represented by the general formula (4): (Wherein X represents a halogen atom) by reacting with a Grignard reagent or a lithium reagent prepared from a compound represented by the following general formula (2): (Wherein R ¹ and R ² represent the same as defined above), followed by treatment with a base, followed by dimerization using an oxidizing agent. Formula (1) (Wherein, R ¹ and R ² represent the same as described above). 4. The method for producing a diphosphonate compound according to claim 3, wherein the base is an organic lithium compound or an organic magnesium compound. 5. The method for producing a diphosphonate compound according to claim 3, wherein the oxidizing agent is a metal compound having an oxidizing property. 6. The diphosphonate according to claim 5, wherein the oxidizing metal compound is at least one selected from metal salts or metal complex compounds of iron, copper, ruthenium, cobalt, nickel, vanadium, molybdenum, manganese, titanium. A method for producing a compound.