KR100911357B1 - PROCESS OF PREPARING alpha;-KETO CYANOPHOSPHORANES FROM CARBONYL COMPOUNDS - Google Patents

Abstract

A method for producing an alpha-keto cyanophosphorane which is a core intermediate for making alpha-keto acid, imide, ester compound using a carbonyl compound is provided to reduce the production price and improve the yield of alpha-keto cyanophosphorane compound. A method for producing a beta,gamma-saturation alpha-keto cyanophosphorane compound of the chemical formula IV comprises: a step of performing Horner-Wadsworth-Emmons olefination of diethyl[3-cyano-2-oxo-3-(triphenylphosphoranyliden)propyl]phosphonate with a carbonyl compound of the chemical formula II; and a step of performing catalyst hydrogenation of beta,gamma-unsaturation alpha-keto cyanophosphorane compound.

Description

Process for preparing α-keto cyanophosphoranes from carbonyl compounds

The present invention relates to a method for preparing α-keto cyanophosphorane, which is a key intermediate for preparing physiologically active alpha-keto acids, amides and ester compounds. More specifically, the present invention relates to a method for easily preparing a variety of α-keto cyanophosphorane compounds in high yield using a commercially available carbonyl compound which is readily available at low cost.

α-keto acid, amide and esters structural units are found in many biologically active natural substances and are also introduced into the synthetic peptide compounds in relation to pharmacological action. Has attracted a lot of attention in organic chemistry and pharmacy. [References: Otto, HH; Schirmeister, T. Chem. Rev. 1997 , 97 , 133; Babine, RE; Bender, SL Chem . Rev. 1997 , 97 , 1359; Cooper, AJE; Ginos, JZ; Meister, A. Chem . Rev. 1983 , 83 , 321]. Thus, a number of methods for synthesizing α-keto acids, amides and ester functionalities have been reported in the literature, and in particular US Pat. No. 5,834,588 discloses (triphenylphosphoranylidene) acetonitrile ( A method for synthesizing α-keto acid, amide and ester compound ( 6 ) using 1 ) has been reported [Wasserman, HH; Ho, W.-B. J. Org . Chem . 1994 , 59 , 4364-4366.

 Scheme 1

The method is a very excellent method for synthesizing α-keto acid, amide and ester compounds in view of the mildness of the reaction conditions, the convergence of the reaction process, and the wide range of application of the reaction. Has been widely used in [Ref .: Wasserman, HH; Chen, J.-H .; Xia, M. J. Am . Chem . Soc . 1999 , 121 , 1401; Wasserman, HH; Zhang, R. Tetrahedron 2002 , 58 , 6277; Lee, K. Bull . Korean Chem . Soc . 2002 , 23 , 351; Price, WS; Fletcher, S .; Jorgensen, MR; Miller, AD Synlett 2006 , 1933. However, the method to a key intermediate, α- cyano-keto-established Lane Spokane (α-keto cyanophosphoranes, 3) as a starting material for the synthesis of the carboxylic acid or the required acid chloride (2) in the course of the reaction, these Compounds often have difficulties in synthesizing various α-keto cyanophosphorane ( 3 ) because they are often difficult to obtain or require strong reagents for synthesis, and are easily hydrolyzed, and therefore, various α-keto acids There are limitations to the use in the commercial preparation of, amide and ester compounds.

Accordingly, the present inventors have studied diligently to overcome the above problems, and found that various α-keto cyanophosphorane can be easily produced in high yield from a carbonyl compound which can be easily purchased at low cost. This invention was completed.

Accordingly, it is an object of the present invention to provide a method for preparing various α-keto cyanophosphorines using a carbonyl compound as a starting material.

Before describing the present invention, the following several important terms used throughout the specification and claims are defined.

As used herein, an alkyl group of C ₁ -C ₁₅ refers to a straight or branched hydrocarbon having 1 to 15 carbon atoms, and includes, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, and the like. It is not.

As used herein, a C ₃ -C ₁₀ cycloalkyl group means a cyclic hydrocarbon composed of 3 to 10 carbon atoms, and examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. .

As used herein, the aryl group includes both aromatic groups and heteroaromatic groups and their partially reduced derivatives. The aromatic group is a simple or fused cyclic consisting of 5 to 15 pentagons, heteroaromatic group refers to an aromatic group containing one or more oxygen, sulfur or nitrogen. Examples of representative aryl groups are phenyl, naphthyl, pyridyl, indolyl, quinolinyl, imidazolinyl, oxazolyl, thiazolyl, thiazolyl, tetrahydronaph And the like, but are not limited thereto.

The C ₁ -C ₁₅ alkyl group, C ₃ -C ₁₀ cycloalkyl group and aryl group is one or more hydrogen is C ₁ -C ₅ alkyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ Alkynyl group, C ₃ -C ₁₀ cycloalkyl group, C ₁ -C ₅ alkoxy group, C ₁ -C ₅ thioalkoxy group, aryl group, acyl group, hydroxy, thio, halo, amino, alkoxy Carbonyl, carboxy, carbamoyl, cyano, nitro and the like.

Carbonyl compound as used herein refers to aldehyde and ketone compounds.

Hereinafter, the present invention will be described in more detail. The present invention relates to a method for preparing α-keto cyanophosphorane using a carbonyl compound as a starting material. The manufacturing method of the present invention

(i) diethyl [3-cyano-2-oxo-3- (triphenylphosphoranylidene) propyl] phosphonate of formula (I) with Hornyl-Worthworth-Emons (Horner-Wadsworth-Emmons) olefination to obtain a β, γ-unsaturated α-keto cyanophosphorane compound of formula III; And

(ii) optionally subjecting the β, γ-unsaturated α-keto cyanophosphorane compound of formula III to catalytic hydrogenation to obtain a β, γ-saturated α-keto cyanophosphorane compound of formula IV Include.

[Formula I]

[Formula II]

[Formula III]

[Formula IV]

In the above formula, R ₁ and R ₂ are each independently hydrogen, an alkyl group of C ₁ -C ₁₅ , a cycloalkyl group of C ₃ -C ₁₀ , or an aryl group.

The C ₁ -C ₁₅ alkyl group may be preferably substituted with an amino group protected or unprotected by a phenyl group or t-butyloxycarbonyl (BOC) or the like. Examples of the C ₁ -C ₁₅ alkyl group include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, benzyl, 2-phenylethyl, aminomethyl, t-butyloxycarbonylaminomethyl, and the like. It doesn't happen.

On the other hand, the aryl group may be substituted by one or more C ₁ -C ₅ alkyl group. Examples of the aryl group include, but are not limited to, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 2,6-dimethylphenyl, and the like.

Hereinafter, the preparation method of the present invention will be described in more detail with reference to Scheme 2 below. The method described in Scheme 2 below merely illustrates the method used as a representative, the order of the unit operation, the reaction reagent, the reaction conditions and the like may be changed in some cases.

Scheme 2

β, γ-unsaturated α-keto cyanophosphorane compound ( 9 ) carbonyl diethyl [3-cyano-2-oxo-3- (triphenylphosphoranylidene) propyl] phosphonate ( 7 ) Prepared by subjecting compound ( 8 ) to a Horner-Worthworth-Emonth olefination reaction (step (i)). Specifically, when a new Horner-Worthworth-Emons reagent ( 7 ) is first treated with a base and then reacted with a carbonyl compound ( 8 ), a condensation reaction takes place, resulting in a β, γ-unsaturated α-keto cyanophosphorane compound ( 9 ) Is obtained with excellent yield. Representative bases used here include sodium hydride (NaH), lithium hydroxide (LiOH), 1,8-diazabicyclo [5.4.0] undec-7-ene (1,8-Diazabicyclo [5.4.0] undec -7-ene: DBU), but is not limited thereto.

β, γ-saturated α-keto cyanophosphorane compound ( 10 ) is prepared by catalytic hydrogenation of β, γ-unsaturated α-keto cyanophosphorane compound ( 9 ) (step (ii)). Catalysts such as platinum, nickel and palladium may be used in the hydrogenation process, but most preferably, it is carried out using a hydrogen gas of 1 atm in a palladium catalyst (Pd-C).

The diethyl [3-cyano-2-oxo-3- (triphenylphosphoranylidene) propyl] phosphonate ( 7 ) is (triphenylphosphoranylidene) acetonitrile, as shown in Scheme 3 below. Neyl ( 1 ) is reacted with acetic acid chloride ( 11 ) to give 4-chloro-3-oxo-2- (triphenylphosphoranylidene) butannitrile ( 12 ), which is then reacted with triethyl phosphite Can be prepared.

Scheme 3

As used herein, the α-keto cyanophosphorane compound may be a β, γ-unsaturated α-keto cyanophosphorane compound of Formula III and a β, γ-saturated α-keto cyanophosphorane compound of Formula IV. All are included and can be used to prepare α-keto acid, amide and ester compounds by oxidative reaction as shown in Scheme 1 and then reacted with nucleophilic compounds such as water, amine and alcohol.

According to the preparation method of the present invention, as a starting material, a carbonyl compound which can be easily and cheaply commercially purchased various α-keto cyanophosphorane compounds which are key intermediates in the preparation of various alpha-keto acid, amide and ester compounds It can be easily produced in high yield .

Hereinafter, the present invention will be described in more detail with reference to Examples. It is apparent to those skilled in the art that these examples are only for illustrating the present invention, and the scope of the present invention is not limited to these examples.

Production Example  1: 4- Chloro -3-oxo-2- ( Triphenylphosphoranylidene ) Butanenitrile  (4- Chloro -3- oxo -2-( triphenylphosphoranylidene ) butanenitrile )

Anhydrous methylene chloride (30 mL) solution containing (triphenylphosphoranylidene) acetonitrile (2.59 g, 8.60 mmol) was cooled to 0 ^° C. and N , O -bis (trimethylsilyl) acetamide (2.55 mL , 1.2 equivalents), and stirred in argon gas for 30 minutes, followed by addition of acetic acid chloride (0.69 mL, 1.0 equivalents), stirred at 0 ^° C. for 1 hour, and then stirred at room temperature for 10 hours. Water (20 mL) was then added to the reaction solution to stop the reaction. The two layers were separated with a separatory funnel, and the aqueous layer was extracted twice with methylene chloride (10 mL). After all the separated methylene chloride layers were combined, anhydrous magnesium sulfate (5 g) was added to remove water, filtered and the solvent was removed under reduced pressure. The resulting residue was separated using chromatography (silica gel column; 20 cm x 2 cm, Merck 70-230, solvent was methylene chloride: ethyl acetate = 20: 1) to give 4-chloro-3-oxo-2 as a pure compound. -(Triphenylphosphoranilidene) butanenitrile was obtained. Yield: 2.66 g (82%).

Light brown solid; mp 185-187 ^o C; IR (KBr) 3064, 3027, 2956, 2180, 1594 cm ^-1 ; ¹ H NMR (CDCl ₃ , 400 MHz) 4.44 (s, 2 H), 7.49-7.72 (m, 15 H).

Production Example  2: Diethyl  [3- Cyano -2-oxo-3- ( Triphenylphosphoranylidene )profile] Phosphonates ( Diethyl  [3- cyano -2- oxo -3- ( triphenylphosphoranylidene ) propyl ] phosphonate )

Triethyl phosphite (10 mL) was added to 4-chloro-3-oxo-2- (triphenylphosphoranylidene) butannitrile (2.20 g, 5.83 mmol) obtained in Example 1, and in argon gas Heated to 110 ^° C. for 24 hours, cooled and triethyl phosphite was removed by vacuum distillation. The solid residue was recrystallized with ethyl acetate (60 mL) to give the title compound (2.50 g) in crystalline form, followed by removal of the solvent from the filtrate and repeating the recrystallization process to give extra product (0.15 g). . Total yield: 2.65 g (95%).

White solid; mp 180.0-182.0 ^o C; IR (KBr) 3057, 2982, 2916, 2173, 1586 cm ⁻¹ ; ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.31 (t, 6H, J = 7.1 Hz), 3.37 (d, 2H, J _HP = 22.0 Hz), 4.16 (m, 4H), 7.49-7.71 (m, 15H ) .; ¹³ C NMR (CDCl ₃ , 100 MHz) δ 16.3 (d, J _{C -P} = 5.8 Hz), 38.4 (dd, J _{1 , CP} = 129.9 Hz, J ₂ , _CP = 7.4 Hz), 51.0 (dd, J _{1 , CP} = 126.7 Hz, J ₂ , _CP = 5.0 Hz), 62.2 (d, J _{C -P} = 5.8 Hz), 121.9 (d, J _{C -P} = 15.7 Hz), 122.8 (d, J _{C -P} = 93.5 Hz), 129.1 (d, J _{C -P} = 13.2 Hz), 133.1 (d, J _{C -P} = 3.3 Hz), 133.6 (d, J _{C -P} = 10.8 Hz), 186.9 (dd, J _{1 , CP} = 6.6 Hz, J ₂ , _CP = 5.0 Hz); HRMS calcd for C ₂₆ H ₂₇ NO ₄ P ₂ 479.1415, found 479.1412; Anal. calcd for C ₂₆ H ₂₇ NO ₄ P ₂ : C, 65.13; H, 5.68; N, 2.92. found: C, 65.36; H, 5.67; N, 2.96.

Example  1: 3-oxo-5- Phenyl -2-( Triphenylphosphoranylidene ) Pent -4- Ennitrile  (3- Oxo -5- phenyl -2-( triphenylphosphoranylidene ) pent -4- enenitrile )

NaH in anhydrous tetrahydrofuran (THF) (15 mL) containing diethyl [3-cyano-2-oxo-3- (triphenylphosphoranylidene) propyl] phosphonate (240.0 mg, 0.50 mmol) (26.1 mg, 60% in oil, 1.3 equiv) was added and stirred in argon gas for 20 minutes at room temperature and 0 ° C. for 20 minutes to give a light tan solution. Benzaldehyde (50.8 mL, 1 equiv) was added to the solution, stirred at 0 ° C. for 30 minutes at room temperature for 1 hour, and then water (15 mL) was added to stop the reaction. The product was purified by CH ₂ Cl ₂ (20 mL). Extracted three times. All the separated organic layers were combined, anhydrous magnesium sulfate (5 g) was added to remove water, and then filtered and concentrated. The residue obtained is separated by chromatography (silica gel column; 20 cm × 2 cm, Merck 70-230, solvent; dichloromethane: hexane = 15: 1) to give 201.0 mg (93%) of the title compound as a pale yellow solid. It was.

mp 232.0-234.0 ° C .; IR (KBr) 2172, 1636 cm ⁻¹ ; ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.30-7.70 (m, 22H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 50.9 (d, J _{C -P} = 128.3 Hz), 122.1 (d, J _{C -P} = 15.7 Hz), 123.2 (d, J _{C -P} = 93.5 Hz), 123.7 (d, J _{C -P} = 9.1 Hz), 128.1, 128.6, 129.2 (d, J _{C -P} = 12.4 Hz ), 129.3, 133.1 (d, J _{C -P} = 3.3 Hz), 133.6 (d, J _{C -P} = 9.9 Hz), 135.4, 138.9 (d, J _{C -P} = 1.7 Hz), 185.8 (d, J _{C -P} = 3.3 Hz); HRMS calcd for C ₂₉ H ₂₂ NOP 431.1439, found 431.1430.

Example  2: 3-oxo-5- o - Tolyl -2-( Triphenylphosphoranylidene ) Pent -4- Ennitrile  (3- Oxo -5- o - tolyl -2-( triphenylphosphoranylidene ) pent -4- enenitrile )

NaH (21.9 mg, 60 in anhydrous THF (10 mL) containing diethyl [3-cyano-2-oxo-3- (triphenylphosphoranylidene) propyl] phosphonate (202.0 mg, 0.42 mmol) % in oil, 1.3 equivalents) was added and stirred in argon gas at room temperature for 20 minutes and at 0 ° C. for 20 minutes to give a light tan solution. To this solution was added o -tolualdehyde (50.3 mL, 1 equiv), stirred at 0 ° C. for 30 minutes at room temperature for 3 hours, and then water (10 mL) was added to stop the reaction and the product was CH ₂ Cl ₂ ( 15 mL). All the separated organic layers were combined, anhydrous magnesium sulfate (5 g) was added to remove water, and then filtered and concentrated. The residue obtained was separated by chromatography (silica gel column; 20 cm × 2 cm, Merck 70-230, solvent; hexanes: ethyl acetate = 2: 3) to give 176.7 mg (91%) of the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) δ 2.42 (s, 3H), 7.13-7.25 (m, 4H), 7.39 (d, 1H, J = 15.6 Hz), 7.52-7.75 (m, 15H), 7.92 ( d, 1H, J = 15.6 Hz).

Example  3: 5- (2,6- Dimethylphenyl ) -3-oxo-2- ( Triphenylphosphoranylidene ) Pent -4- Ennitrile  (5- (2,6- Dimethylphenyl ) -3- oxo -2-( triphenylphosphoranylidene ) pent -4- enenitrile )

NaH (28.6 mg, 60 in anhydrous THF (15 mL) containing diethyl [3-cyano-2-oxo-3- (triphenylphosphoranylidene) propyl] phosphonate (228.5 mg, 0.48 mmol) % in oil, 1.3 equivalents) was added and stirred in argon gas at room temperature for 20 minutes and at 0 ° C. for 20 minutes to give a light tan solution. 2,6-dimethylbenzaldehyde (64.0 mg, 1 equiv) was added to the solution, the mixture was stirred at 0 ° C. for 30 minutes at room temperature for 22 hours, and then water (15 mL) was added to stop the reaction. The product was changed to CH ₂ Cl _2. Extracted with 3 times (20 mL). All the separated organic layers were combined, anhydrous magnesium sulfate (5 g) was added to remove water, and then filtered and concentrated. The residue obtained was separated by chromatography (silica gel column; 20 cm x 2 cm, Merck 70-230, solvent; CH ₂ Cl ₂ : ethyl acetate = 20: 1) to give 191.0 mg (87%) of the title compound. .

¹ H NMR (CDCl ₃ , 400 MHz) δ 2.38 (s. 6H), 7.02-7.13 (m, 4H), 7.52-7.75 (m, 16H).

Example  4: 3-oxo-7- Phenyl -2-( Triphenylphosphoranylidene ) Hept -4- Ennitrile  (3- Oxo -7- phenyl -2-( triphenylphosphoranylidene ) hept -4- enenitrile )

NaH (37.2 mg, 60 in anhydrous THF (20 mL) containing diethyl [3-cyano-2-oxo-3- (triphenylphosphoranylidene) propyl] phosphonate (342.0 mg, 0.71 mmol) % in oil, 1.3 equivalents) was added and stirred in argon gas at room temperature for 20 minutes and at 0 ° C. for 20 minutes to give a light tan solution. 30 minutes at 0 ℃ was added phenyl propionaldehyde (94.2 mL, 1 eq.) 3 to the solution, and the mixture was stirred at room temperature for 1 hour, the reaction was stopped by addition of water (15 mL) the product CH ₂ Cl ₂ Extracted with 3 times (20 mL). All the separated organic layers were combined, anhydrous magnesium sulfate (5 g) was added to remove water, and then filtered and concentrated. The residue obtained was separated by chromatography (silica gel column; 20 cm x 2 cm, Merck 70-230, solvent; CH ₂ Cl ₂ : ethyl acetate = 20: 1) to give 292.2 mg (89%) of the title compound. .

¹ H NMR (CDCl ₃ , 400 MHz) δ 2.50-2.60 (m, 2H), 2.78 (t, 2H, J = 7.8 Hz), 6.86 (d, 1H, J = 15.4 Hz), 7.00 (dt, 1H, J ₁ = 15.4 Hz, J ₁ = 6.7 Hz), 7.15-7.31 (m, 5H), 7.51-7.71 (m, 15H).

Example  5: 3-oxo-2- ( Triphenylphosphoranylidene ) Dodec -4- Ennitrile  (3- Oxo -2-( triphenylphosphoranylidene ) dodec -4- enenitrile )

NaH (22.0 mg, 60 in anhydrous THF (10 mL) containing diethyl [3-cyano-2-oxo-3- (triphenylphosphoranylidene) propyl] phosphonate (202.8 mg, 0.42 mmol) % in oil, 1.3 equivalents) was added and stirred in argon gas at room temperature for 20 minutes and at 0 ° C. for 20 minutes to give a light tan solution. 30 minutes at 0 ℃ octane was added to Al (66.0 mL, 1 eq.) To the solution, and the mixture was stirred at room temperature for 1 hour, the reaction was stopped by addition of water (10 mL) the product CH ₂ Cl ₂ Extracted with (15 mL) three times. All the separated organic layers were combined, anhydrous magnesium sulfate (5 g) was added to remove water, and then filtered and concentrated. The residue obtained was separated by chromatography (silica gel column; 20 cm × 2 cm, Merck 70-230, solvent; hexanes: ethyl acetate = 1: 1) to give 168.9 mg (88%) of the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) δ 0.88 (t, 3H, J = 6.8 Hz), 1.20-1.34 (m, 8H), 1.41-1.47 (m, 2H), 2.20 (br q, 2H, J = 7.3 Hz), 6.74 (dt, 1H, J ₁ = 15.1 Hz, J ₂ = 6.9 Hz), 6.81 (d, 1H, J = 15.1 Hz), 7.49-7.54 (m, 5H), 7.60-7.66 (m, 10H).

Example  6: [5- Cyano -4-oxo-5- ( Triphenylphosphoranylidene ) Pent -2-yen] Carbamic  mountain t -Butyl ester ([5- Cyano -4- oxo -5- ( triphenylphosphoranylidene ) pent -2- enyl ] carbamic acid t -butyl ester )

NaH (19.8 mg, 60 in anhydrous THF (10 mL) containing diethyl [3-cyano-2-oxo-3- (triphenylphosphoranylidene) propyl] phosphonate (183.0 mg, 0.38 mmol) % in oil, 1.3 equivalents) was added and stirred in argon gas at room temperature for 20 minutes and at 0 ° C. for 20 minutes to give a light tan solution. N- BOC-2-aminoacetaldehyde (64.0 mg, 1 equiv) was added to the solution, stirred at 0 ° C. for 30 minutes at room temperature for 1 hour, and then water (10 mL) was added to stop the reaction. ₂ Cl ₂ Extracted with (15 mL) three times. All the separated organic layers were combined, anhydrous magnesium sulfate (5 g) was added to remove water, and then filtered and concentrated. The residue obtained was separated by chromatography (silica gel column; 20 cm x 2 cm, Merck 70-230, solvent; hexanes: ethyl acetate = 1: 4) to give 164.6 mg (89%) of the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.44 (s, 9H), 3.90 (br s, 2H), 4.81 (br s, 1H), 6.68 (d, 1H, J = 15.4 Hz), 6.89 (d, 1H, J = 15.4 Hz), 7.45-7.70 (m, 15H).

Example  7: 3-oxo-5- Phenyl -2-( Triphenylphosphoranylidene ) Hex -4- Ennitrile  (3- Oxo -5-  phenyl -2-( triphenylphosphoranylidene )] hex -4- enenitrile )

NaH (24.4 mg, 60 in anhydrous THF (15 mL) containing diethyl [3-cyano-2-oxo-3- (triphenylphosphoranylidene) propyl] phosphonate (224.0 mg, 0.47 mmol) % in oil, 1.3 equivalents) was added and stirred in argon gas at room temperature for 20 minutes and at 0 ° C. for 20 minutes to give a light tan solution. Acetophenone (54.6 mL, 1 equiv) was added to the solution, stirred at 0 ° C. for 30 minutes at room temperature for 24 hours, and then water (15 mL) was added to stop the reaction and the product was CH ₂ Cl _2. Extracted with 3 times (20 mL). All the separated organic layers were combined, anhydrous magnesium sulfate (5 g) was added to remove water, and then filtered and concentrated. The residue obtained was separated by chromatography (silica gel column; 20 cm x 2 cm, Merck 70-230, solvent; CH ₂ Cl ₂ : ethyl acetate = 20: 1) to give 143.7 mg (69%, E- / Z -isomer Proportion: The title compound of ca. 4/6) was obtained.

E -isomers:

¹ H NMR (CDCl ₃ , 400 MHz) δ 2.45 (br d, 3H, J = 1.5 Hz), 7.04 (br d, 1H, J = 1.5 Hz), 7.28-7.72 (m, 20H).

Z -isomers:

¹ H NMR (CDCl ₃ , 400 MHz) δ 2.17 (br d, 3H, J = 1.0 Hz), 6.60 (br d, 1H, J = 1.0 Hz), 7.24-7.70 (m, 20H).

Example  8: 3-oxo-5,5- Diphenyl -2-( Triphenylphosphoranylidene ) Pent -4- Ennitrile  (3- Oxo -5,5- diphenyl -2-( triphenylphosphoranylidene ) pent -4- enenitrile )

NaH (25.0 mg, 60 in anhydrous THF (15 mL) containing diethyl [3-cyano-2-oxo-3- (triphenylphosphoranylidene) propyl] phosphonate (230.0 mg, 0.48 mmol) % in oil, 1.3 equivalents) was added and stirred in argon gas at room temperature for 20 minutes and at 0 ° C. for 20 minutes to give a light tan solution. To this solution, benzophenone (87.5 mg, 1 equiv) was added, stirred at 0 ° C. for 30 minutes at room temperature for 22 hours, and then water (15 mL) was added to stop the reaction and the product was CH ₂ Cl _2. Extracted with 3 times (20 mL). All the separated organic layers were combined, anhydrous magnesium sulfate (5 g) was added to remove water, and then filtered and concentrated. The residue obtained was separated by chromatography (silica gel column; 20 cm x 2 cm, Merck 70-230, solvent; CH ₂ Cl ₂ : ethyl acetate = 20: 1) to give 141.4 mg (58%) of the title compound. .

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.04 (s, 1H), 7.28-7.62 (m, 25H).

Example  9: 3-oxo-5- Phenyl -2-( Triphenylphosphoranylidene ) Pentanenitrile  (3- Oxo -5- phenyl -2-( triphenylphosphoranylidene ) pentanenitrile )

3-oxo-5-phenyl-2- (triphenylphosphoranylidene) pent-4-ennitrile (216.0 mg, 0.50 mmol) and Pd-C (10%) obtained in Example 1 (21.6 mg, 10 Mixed solvent (5 mL, THF / MeOH, 1/1) slurry was stirred at room temperature for 1 hour in a hydrogen gas at room temperature. The reaction was filtered and the residue was washed again with 15 mL of THF and MeOH, the solvent was removed under reduced pressure and then dried in vacuo to give 212.6 mg (98%) of the title compound as a white solid.

mp 172.0-174.0 ° C; IR (KBr) 2172, 1584 cm ⁻¹ ; ¹ H NMR (CDCl ₃ , 400 MHz) δ 3.06 (t, 2H, J = 7.1 Hz), 3.16 (t, 2H, J = 7.1 Hz), 7.18-7.32 (m, 5H), 7.45-7.70 (m, 15H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 31.2, 40.4 (d, J _{C -P} = 7.4 Hz), 48.7 (d, J _{C -P} = 126.6 Hz), 122.6 (d, J _{C -P} = 16.6 Hz ), 123.2 (d, J _{C -P} = 93.5 Hz), 125.8, 128.2, 128.7, 129.1 (d, J _{C -P} = 13.2 Hz), 133.0 (d, J _{C -P} = 3.3 Hz), 133.5 (d , J _{C -P} = 9.9 Hz), 141.5, 195.9 (d, J _{C -P} = 3.3 Hz); HRMS calcd for C ₂₉ H ₂₄ NOP 433.1596, found 433.1596.

Example  10: 3-oxo-5- o - Tolyl -2-( Triphenylphosphoranylidene ) Pentanenitrile  (3- Oxo -5-o- tolyl -2-( triphenylphosphoranylidene ) pentanenitrile )

3-oxo-5- o -tolyl-2- (triphenylphosphoranilidene) pent-4-ennitrile (148.0 mg, 0.33 mmol) and Pd-C (10%) obtained in Example 2 (14.8 mg) , 10 wt%) mixed solvent (4 mL, THF / MeOH, 1/1) slurry was stirred for 10 hours in a hydrogen gas of 1 atm at room temperature. The reaction was filtered and the residue was washed again with 8 mL of THF and MeOH, the solvent was removed under reduced pressure and then dried in vacuo to give 144.0 mg (97%) of the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) δ 2.35 (s, 3H), 2.98 (br s, 4H), 7.10-7.25 (m, 4H), 7.47-7.73 (m, 15H).

Example  11: 5- (2,6- Dimethylphenyl ) -3-oxo-2- ( Triphenylphosphoranylidene ) Pentanenitrile  (5- (2,6- Dimethylphenyl ) -3- oxo -2-( triphenylphosphoranylidene ) pentanenitrile )

5- (2,6-dimethylphenyl) -3-oxo-2- (triphenylphosphoranylidene) pent-4-ennitrile (105.0 mg, 0.23 mmol) and Pd-C obtained in Example 3 A mixed solvent (4 mL, THF / MeOH, 1/1) slurry containing (10%) (31.5 mg, 30% by weight) was stirred for 24 hours at 1 atmosphere of hydrogen gas at room temperature. The reaction was filtered and the residue was washed again with 8 mL of THF and MeOH, the solvent was removed under reduced pressure and then dried in vacuo to yield 100.2 mg (95%) of the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) δ 2.37 (s, 6H), 2.83 (t, 2H, J = 8.3 Hz), 2.99 (t, 2H, J = 8.3 Hz), 7.00 (br s, 3H), 7.49-7.69 (m, 15 H).

Example  12: 3-oxo-7- Phenyl -2-( Triphenylphosphoranylidene ) Heptanenitrile  (3- Oxo -7- phenyl -2-( triphenylphosphoranylidene ) heptanenitrile )

3-oxo-7-phenyl-2- (triphenylphosphoranylidene) hept-4-ennitrile (100.0 mg, 0.22 mmol) and Pd-C (10%) (10.0 mg, 10 obtained in Example 4 A mixed solvent (4 mL, THF / MeOH, 1/1) slurry containing a wt%) was stirred for 3 hours at 1 atmosphere of hydrogen gas at room temperature. The reaction was filtered and the residue was washed again with 8 mL of THF and MeOH, the solvent was removed under reduced pressure and dried in vacuo to give 98.5 mg (98%) of the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.63-1.83 (m, 4H), 2.64 (t, 2H, J = 7.6 Hz), 2.82 (t, 2H, J = 7.3 Hz), 7.13-7.32 (m, 5H), 7.48-7.70 (m, 15H).

Example  13: 3-oxo-2- ( Triphenylphosphoranylidene ) Dodecanenitrile  (3- Oxo -2-( triphenylphosphoranylidene ) dodecanenitrile )

3-oxo-2- (triphenylphosphoranylidene) dodec-4-enenitrile (155.9 mg, 0.34 mmol) and Pd-C (10%) (16.0 mg, 10% by weight) obtained in Example 5 Mixed solvent containing (4 mL, THF / MeOH, 1/1) slurry was stirred for 3 hours in a hydrogen gas of 1 atm at room temperature. The reaction was filtered and the residue was washed again with 8 mL of THF and MeOH, the solvent was removed under reduced pressure and dried in vacuo to afford 152.0 mg (97%) of the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) δ 0.88 (t, 3H, J = 6.8 Hz), 1.20-1.42 (m, 12H), 1.65-1.75 (m, 2H), 2.76 (t, 2H, J = 7.6 Hz), 7.49-7.71 (m, 15 H).

Example  14: [5- Cyano -4-oxo-5- ( Triphenylphosphoranylidene ) Pentyl } Carbamic  mountain t -Butyl ester ([5- Cyano -4- oxo -5- ( triphenylphosphoranylidene ) pentyl ] carbamic acid tert -butyl ester )

[5-cyano-4-oxo-5- (triphenylphosphoranylidene) pent-2-enyl] carbamic acid t -butyl ester (178.0 mg, 0.37 mmol) and Pd-C obtained in Example 6 A mixed solvent (4 mL, THF / MeOH, 1/1) slurry containing (10%) (17.8 mg, 10% by weight) was stirred for 3 hours at 1 atmosphere in a hydrogen gas. The reaction was filtered and the residue was washed again with 8 mL of THF and MeOH, the solvent was removed under reduced pressure and dried in vacuo to yield 162.6 mg (91%) of the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.43 (s, 9H), 1.78-1.88 (m, 2H), 2.74 (t, 2H, J = 7.3 Hz), 3.15 (br q, 2H), 4.77 (br s, 1 H), 7.49-7.69 (m, 15 H).

Example  15: 3-oxo-5- Phenyl -2-( Triphenylphosphoranylidene ) Hexanenitrile  (3- Oxo -5- phenyl -2-( triphenylphosphoranylidene ) hexanenitrile )

3-oxo-5-phenyl-2- (triphenylphosphoranylidene) hex-4-enenitrile (116.0 mg, 0.26 mmol) and Pd-C (10%) obtained in Example 7 (34.8 mg, 30 A mixed solvent (4 mL, THF / MeOH, 1/1) slurry containing a weight percent) was stirred for 10 hours in a hydrogen gas at 1 atmosphere at room temperature. The reaction was filtered and the residue was washed again with 8 mL of THF and MeOH, the solvent was removed under reduced pressure and dried in vacuo to afford 115.2 mg (99%) of the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.29 (d, 3H, J = 6.8 Hz), 2.81 (dd, 1H, J ₁ = 14.6 Hz, J ₂ = 6.8 Hz), 3.21 (dd, 1H, J ₁ = 14.6 Hz, J ₂ = 8.8 Hz), 3.38-3.44 (m, 1H), 7.20-7.65 (m, 20H).

Example  16: 3-oxo-5,5- Diphenyl -2-( Triphenylphosphoranylidene ) Pentanenitrile  (3- Oxo -5,5- diphenyl -2-( triphenylphosphoranylidene ) pentanenitrile )

3-oxo-5,5-diphenyl-2- (triphenylphosphoranylidene) pent-4-ennitrile (125.0 mg, 0.25 mmol) and Pd-C (10%) obtained in Example 8 (37.5) mg, 30% by weight) mixed solvent (4 mL, THF / MeOH, 1/1) slurry was stirred for 6 hours in a hydrogen gas of 1 atm at room temperature. The reaction was filtered and the residue was washed again with 8 mL of THF and MeOH, the solvent was removed under reduced pressure and dried in vacuo to afford 124.1 mg (99%) of the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) δ 3.45 (d, 2H, J = 7.8 Hz), 4.70 (t, 1H, J = 7.8 Hz), 7.18-7.64 (m, 25H).

Claims (11)

(i) diethyl [3-cyano-2-oxo-3- (triphenylphosphoranylidene) propyl] phosphonate of formula (I) with Hornyl-Worthworth-Emons Olefining to obtain a β, γ-unsaturated α-keto cyanophosphorane compound of formula III; And (ii) a process for preparing the β, γ-saturated α-keto cyanophosphorane compound of formula (IV) comprising the step of subjecting the β, γ-unsaturated α-keto cyanophosphorane compound of formula (III) to a catalytic hydrogenation reaction : [Formula I]

[Formula II]

[Formula III]

[Formula IV]

In the above formula, R ₁ and R ₂ are each independently hydrogen; C ₁ -C ₁₅ alkyl groups unsubstituted or substituted by a phenyl group or a protected or unprotected amino group; Or an aryl group unsubstituted or substituted by one or more C ₁ -C ₅ alkyl groups. The compound of claim 1, wherein R ₁ and R ₂ are each independently hydrogen; C ₁ -C ₁₅ alkyl groups unsubstituted or substituted by a phenyl group or a protected or unprotected amino group; Or a phenyl group unsubstituted or substituted by one or more C ₁ -C ₅ alkyl groups. The compound of claim 1, wherein R ₁ and R ₂ are each independently hydrogen; An alkyl group selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, benzyl, 2-phenylethyl, aminomethyl and t-butyloxycarbonylaminomethyl; Or an aryl group selected from the group consisting of phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl and 2,6-dimethylphenyl. The process according to claim 1, wherein in step (i) the Horner-Worthworth-Emonth olefination reaction is carried out in the presence of a base group. 5. A process according to claim 4 wherein the base is sodium hydride (NaH). The process according to claim 1, wherein the hydrogenation reaction in step (ii) is carried out using hydrogen gas in the presence of a palladium catalyst (Pd-C). The diethyl [3-cyano-2-oxo-3- (triphenylphosphoranylidene) propyl] phosphonate of formula (I) is reacted with a carbonyl compound of formula (II) with Horner-Worthworth-Emons olefination Method for preparing a β, γ-unsaturated α-keto cyanophosphorane compound of formula III: [Formula I]

[Formula II]

[Formula III]

In the above formula, R ₁ and R ₂ are each independently hydrogen; C ₁ -C ₁₅ alkyl groups unsubstituted or substituted by a phenyl group or a protected or unprotected amino group; Or an aryl group unsubstituted or substituted by one or more C ₁ -C ₅ alkyl groups. The compound of claim 7, wherein R ₁ and R ₂ are each independently hydrogen; C ₁ -C ₁₅ alkyl groups unsubstituted or substituted by a phenyl group or a protected or unprotected amino group; Or a phenyl group unsubstituted or substituted by one or more C ₁ -C ₅ alkyl groups. The compound of claim 7, wherein R ₁ and R ₂ are each independently hydrogen; An alkyl group selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, benzyl, 2-phenylethyl, aminomethyl and t-butyloxycarbonylaminomethyl; Or an aryl group selected from the group consisting of phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl and 2,6-dimethylphenyl. 8. A process according to claim 7, wherein the Horner-Worthworth-Emons olefination reaction is carried out in the presence of a base. The process according to claim 10, wherein the base is sodium hydride (NaH).