JP4572391B2 - Process for producing bisphosphinoylaminomethanes - Google Patents

Description

  The present invention relates to a process for producing bisphosphinoylaminomethanes that are industrially useful as intermediates for pharmaceuticals and the like.

Phosphorus compounds having two phosphorus substituents, for example, the general formula R ¹ NHCH [P (O) R ² R ³ ] [P (O) R ⁴ R ⁵ ] (wherein R ^{1 to} R ⁵ are substituted) The bisphosphinoylmethanes represented by the above-mentioned hydrocarbon group are compounds that form the basic skeleton of an osteoporosis therapeutic agent.
Conventionally, such bisphosphinoylmethanes are produced by the following method.
(1) Reaction of dimethoxymethyldimethylamine with diphenylphosphine oxide (Non-patent Document 1)
(2) Method using imine and diphenylphosphine oxide (3) Method of substituting dimethylaminodiphenylphosphinylmethoxymethane with diphenylphosphine oxide (Non-patent Document 3)
(4) Manufactured by a method of replacing dipropyl (ethoxy (dimethylamino) methyl) phosphine oxide with dibutylphosphine oxide (Non-patent Document 4).
However, each method has a drawback that the raw material (substrate) to be used is difficult to obtain and the reaction efficiency is not so good.

J. Prakt. Chem. 1969, 311, 577-585. J. Prakt. Chem. 1972, 314, 969-974. J. Prakt. Chem. 1969, 311, 925-929. Zh.Obshch.Khim.1993, 63, 1902-1903.

  An object of this invention is to provide the simple manufacturing method of bisphosphinoylaminomethane industrially useful as intermediates, such as a pharmaceutical.

  In the process of studying chemical conversion of PH bonds using transition metal catalysts, the inventor has conducted intensive research on the reaction of readily available disubstituted phosphine oxides with isocyanides, and in the presence of specific transition metal catalysts. As a result, the inventors have found that bisphosphinoylaminomethanes can be obtained in a high yield, and the present invention has been completed based on these findings.

That is, according to this case, the following invention is provided.
(1) Isocyanide represented by general formula (1) R ¹ NC, and represented by general formula (2) R ² R ³ P (OH) or general formula (3) R ⁴ R ⁵ P (O) H A disubstituted phosphine oxide is reacted in the presence of a catalyst containing a group 9 or group 10 transition metal. General formula (4) R ¹ NHCH [P (O) PR ² R ³ ] [P (O) A process for producing bisphosphinoylaminomethanes represented by R ⁴ R ⁵ ] (wherein R ^{1 to} R ⁵ are an alkyl group having 1 to 18 carbon atoms, a cycloalkyl group having 5 to 18 carbon atoms, and a carbon number; A heteroaryl group selected from an aryl group having 1 to 14 carbon atoms, an aralkyl group having 7 to 13 carbon atoms, a thienyl group having 4 to 12 carbon atoms, a furyl group, a pyridyl group, and pyrrolyl; an alkenyl group having 2 to 18 carbon atoms represents a ^.R 1 to R ³ is a group selected from Serial groups are methoxy, cyano, dimethylamino, fluoro, chloro, may be substituted by a group selected from hydroxy.).
(2) The method for producing bisphosphinoylaminomethanes according to (1) above, wherein the transition metal is palladium or rhodium.

  According to the present invention, bisphosphinoylaminomethanes represented by the general formula (1) can be obtained simply and in high yield.

The method for producing bisphosphinoylaminomethanes represented by the general formula (4) R ¹ NHCH [P (O) R ² R ³ ] [P (O) R ⁴ R ⁵ ] of the present invention is represented by the general formula (1 ) An isocyanide represented by R ¹ NC and a disubstituted phosphine oxide represented by the general formula (2) R ² R ³ P (O) H and the general formula (3) R ⁴ R ⁵ P (O) H, The reaction is performed in the presence of a catalyst containing a Group 9 or Group 10 transition metal.
(In formula, R < ¹ > -R < ⁵ > shows the hydrocarbon group which may be substituted.)

R ^{1 to} R ⁵ are alkyl groups, cycloalkyl groups, aryl groups or aralkyl groups, heteroaryl groups, alkenyl groups, and the like.

The alkyl group has 1 to 18 carbon atoms, preferably 1 to 10 carbon atoms. Specific examples thereof include methyl, ethyl, propyl, hexyl, decyl and the like.
The cycloalkyl group has 5 to 18 carbon atoms, preferably 5 to 10 carbon atoms. Specific examples thereof include cyclohexyl, cyclooctyl, cyclododecyl and the like.

  The aryl group has 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms. Specific examples thereof include phenyl, naphthyl, alkyl or aralkyl substituents thereof (tolyl, naphthyl, benzylphenyl, etc.).

  The heteroaryl group is derived from various cyclic compounds containing heteroatoms (oxygen, nitrogen, sulfur, etc.), and the number of atoms contained therein is 4 to 12, preferably 4 to 8. Specific examples thereof include thienyl group, furyl group, pyridyl group, pyrrolyl group and the like.

The aralkyl group has 7 to 13 carbon atoms, preferably 7 to 9 carbon atoms. Specific examples thereof include benzyl, phenethyl, phenylbenzyl, naphthylmethyl and the like.
The alkenyl group has 2 to 18 carbon atoms, preferably 2 to 10 carbon atoms. Specific examples thereof include vinyl and 3-butenyl.

R ^{1 to} R ³ may be further substituted with a functional group inert to the reaction, for example, methoxy, cyano, dimethylamino, fluoro, chloro, hydroxy and the like.

  Examples of the isocyanide compound represented by the general formula (1) preferably used in the present invention include 2,6-dimethylphenyl isocyanide, 1,1,3,3-tetramethylbutyl isocyanide, 1-pentyl isocyanide, 2,5 -Dimethylphenyl isocyanide, 2-naphthyl isocyanide, 4-diethylaminophenyl isocyanide, 4-methoxyphenyl isocyanide, benzyl isocyanide, cyclohexyl isocyanide, t-butyl isocyanide and the like, but are not limited thereto.

  Examples of the disubstituted phosphine oxide represented by the general formula (2) or (3) preferably used in the present invention include diphenylphosphine oxide, bis (4-chlorophenyl) phosphine oxide, bisnaphthylphosphine oxide, phenylbutylphosphine oxide, dibutyl Although phosphine oxide, dimethylphosphine oxide, etc. are mentioned, it is not limited to these.

  In the present invention, it is necessary to use a catalyst containing a Group 9 (chromium, rhodium, iridium) or Group 10 (nickel, palladium, platinum) transition metal in order to efficiently cause the reaction. The catalyst preferably used in the present invention contains palladium or rhodium.

As the catalyst containing palladium, those having various structures can be used. That is, metallic palladium black powder, supported palladium such as silica, alumina, activated carbon, and various organic and inorganic palladium-containing compounds can be used.
Specific examples of the palladium-containing inorganic compound include palladium oxide, palladium acetate, palladium trifluoroacetate, palladium sulfate, palladium nitrate, palladium hydroxide and the like.
Examples of the palladium-containing organic complex include a palladium complex coordinated and stabilized by tertiary phosphine or tertiary phosphite. Further, a complex not containing tertiary phosphine or tertiary phosphite as a ligand is mixed with tertiary phosphine or phosphite in the reaction system, and tertiary phosphine or phosphite is used as the ligand in the reaction system. Complexes and the like are also preferred catalysts.
Examples of ligands that can be suitably used include triphenylphosphine, diphenylmethylphosphine, phenyldimethylphosphine, 1,4-bis (diphenylphosphino) butane, 1,4-bis (diphenylphosphino) propane, 1 , 4-bis (diphenylphosphino) ethane, 1,1′-bis (diphenylphosphino) ferrocene, trimethyl phosphite, triphenyl phosphite and the like.
Examples of the phosphine or phosphite complex include dimethylbis (triphenylphosphine) palladium, dimethylbis (diphenylmethylphosphine) palladium, dimethylbis (dimethylphenylphosphine) palladium, dimethylbis (triethylphosphine) palladium, (ethylene) bis ( Triphenylphosphine) palladium, tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium and the like.
Examples of a palladium catalyst that does not contain tertiary phosphine or tertiary phosphite as a coordination used in combination with this include, but are not limited to, bis (dibenzylideneacetone) palladium, palladium acetate, and the like. .

As the catalyst containing rhodium, those having various structures can be used, but a preferable one is a so-called low valence catalyst, and in particular, monovalent having tertiary phosphine or tertiary phosphite as a ligand. Are preferred. It is also a preferred embodiment to use an appropriate precursor complex that can be easily converted to a low valence in the reaction system. Further, a complex not containing tertiary phosphine or tertiary phosphite as a ligand is mixed with tertiary phosphine or phosphite in the reaction system, and tertiary phosphine or phosphite is used as the ligand in the reaction system. Low valence complexes are also a preferred embodiment.
Examples of the ligand that exhibits advantageous performance by any of these methods include various tertiary phosphines and tertiary phosphites. Examples of ligands that can be suitably used include triphenylphosphine, diphenylmethylphosphine, phenyldimethylphosphine, 1,4-bis (diphenylphosphino) butane, 1,4-bis (diphenylphosphino) propane, 1 , 4-bis (diphenylphosphino) ethane, 1,1′-bis (diphenylphosphino) ferrocene, trimethyl phosphite, triphenyl phosphite and the like. Complexes that do not contain tertiary phosphine or tertiary phosphite used as a coordination are acetylacetonatobisethylenerhodium, chlorobisethylenerhodium dimer, dicarbonylacetylacetonatodium, hexarhodium hexadecacarbonyl. Chloro (1,5-cyclooctadiene) rhodium, chloronorbornadienerhodium, and the like, but are not limited thereto. Examples of the phosphine or phosphite complex that can be suitably used include chlorocarbonylbistriphenylphosphine rhodium, hydridocarbonyl tristriphenylphosphine rhodium, and chlorotris (triphenylphosphine) rhodium.

  These catalysts may be used in so-called catalytic amounts, and generally 20 mol% or less is sufficient with respect to the disubstituted phosphine oxide compound as the reaction substrate. The use ratio of the disubstituted phosphine oxide compound and the isocyanide compound is generally preferably 2: 1 in terms of molar ratio. However, even if it is larger or smaller than this, it does not inhibit the occurrence of the reaction. The reaction is not particularly required to use a solvent, but can be carried out in a solvent if necessary. As the solvent, a hydrocarbon-based or ether-based solvent is generally used. The reaction temperature is selected from the range of 20 ° C. to 300 ° C., preferably from room temperature to 150 ° C., because the reaction does not proceed at an advantageous rate at too low temperature and the catalyst decomposes at too high temperature. Implemented in a range.

  Although this reaction proceeds in air, it is more preferable to carry out in an inert gas atmosphere such as nitrogen, argon or methane. Separation of the product from the reaction mixture is readily accomplished by chromatography, distillation or recrystallization.

  The present invention will be described more specifically with reference to the following examples and comparative examples, but the present invention is not limited to the examples.

Example 1
To 1 ml of toluene, 1 mmol of 2,6-dimethylphenyl isocyanide and 2 mmol of diphenylphosphine oxide were added, and tris (dibenzylideneacetone) dipalladium (3 mol%) was further added as a catalyst, followed by stirring at 25 ° C. for 24 hours. However, 2,6-Me ₂ C ₆ H ₃ NHCH [P (O) Ph ₂ ] ₂ was obtained in a yield of 86%.

Example 2
When heated at 80 ° C. for 48 hours using Pd (PPh ₃ ) ₄ (3 mol%) as a catalyst under the same conditions as in Example 1, 2,6-Me ₂ C ₆ H ₃ NHCH [P (O ) Ph ₂ ] ₂ was obtained in 99% yield.

Example 3
When heated at 80 ° C. for 48 hours using Rh (PPh ₃ ) ₃ Cl (3 mol%) as a catalyst under the same conditions as in Example 2, 2,6-Me ₂ C ₆ H ₃ NHCH [P ( O) Ph ₂ ] ₂ was obtained in 87% yield.

Example 4
When the reaction was carried out using cyclohexyl isocyanide instead of 2,6-dimethylphenyl isocyanide under the same conditions as in Example 1, the yield of C ₆ H ₁₁ NHCH [P (O) Ph ₂ ] ₂ was 66%. Obtained at a rate.

Example 5
The reaction was conducted using 4-diethylaminophenyl isocyanide instead of 2,6-dimethylphenyl isocyanide under the same conditions as in Example 1. As a result, 4-Et ₂ NC ₆ H ₄ NHCH [P (O) Ph _{2 2} was obtained in 51% yield.

Example 6
When the reaction was carried out using 4-chlorophenyl isocyanide instead of 2,6-dimethylphenyl isocyanide under the same conditions as in Example 1, 4-ClC ₆ H ₄ NHCH [P (O) Ph ₂ ] ₂ was Obtained in 63% yield.

Example 7
The reaction was carried out using bis (4-methoxyphenyl) phosphine oxide instead of diphenylphosphine oxide under the same conditions as in Example 1. As a result, PhNHCH [P (O) (4-MeOC ₆ H ₄ ) ₂ ] ₂ was obtained in 78% yield.

Example 8
To 1 ml of toluene, 1 mmol of 2,6-dimethylphenyl isocyanide, 1 mmol of diphenylphosphine oxide and (dibenzylideneacetone) dipalladium (3 mol%) as a catalyst were added and heated at 80 ° C. for 20 hours under a nitrogen atmosphere. Thereafter, 1 mmol of di (4-chlorophenyl) phosphine oxide was added and the mixture was further heated at 80 ° C. for 24 hours. As a result, 2,6-Me ₂ C ₆ H ₃ NHCH [P (O) Ph ₂ ] [P (O) ( _{4-Cl-C 6 H 4} ) 2] was obtained in 91% yield.

Comparative Example In Example 1, no reaction occurred in the same manner as in Example 1 except that no catalyst was added.

Claims (2)

An isocyanide represented by the general formula (1) R ¹ NC;
Formula (2) R ² R ³ P (OH),
Or general formula (3) R ⁴ R ⁵ P (O) H
The disubstituted phosphine oxide represented by the general formula (4) R ¹ NHCH [P (O) PR ² R ³ ] [] is reacted in the presence of a catalyst containing a group 9 or group 10 transition metal. P (O) R ⁴ R ⁵ ]
(Wherein R ^{1 to} R ⁵ are an alkyl group having 1 to 18 carbon atoms, a cycloalkyl group having 5 to 18 carbon atoms, and an aryl having 1 to 14 carbon atoms) A group selected from a group or a heteroaryl group selected from a aralkyl group having 7 to 13 carbon atoms, a thienyl group having 4 to 12 carbon atoms, a furyl group, a pyridyl group, and pyrrolyl, and an alkenyl group having 2 to 18 carbon atoms. The above-mentioned groups representing R ^{1 to} R ³ may be substituted with a group selected from methoxy, cyano, dimethylamino, fluoro, chloro and hydroxy .   The method for producing bisphosphinoylaminomethanes according to claim 1, wherein the transition metal is palladium or rhodium.