HU190449B - Process for production of derivatives of acetid acid substituated by phosphorus - Google Patents

Abstract

Phosphorus containing acetic acid derivatives have the general formula (I> <IMAGE> wherein R<3> and R<4> are the same or different and represent hydrogen, halogen, hydroxy, amino, sulphonic acid group or a specified organic group or R<3> and R<4> together represent oxo-, hydroxyimino, O-alkylimino or substituted alkylhydroxyimino, R<5> represents phenyl, substituted phenyl, 1-methyl-tetrazol-5-yl, 2-methyl-1,3,4-thiadiazol-5-yl, 1,3,4-thiadazol-2-yl, 1,2,3-triazol-4-yl, 1-substituted-tetrazol-5-yl, pyrrolidin-2,5-dion-1-yl, sacharyl, 1- phenyl-3-methyl-pyrazol-4-in-5yl, 8-quinolyl or substituted 8-quinolyl or Q<4>R<5> can optionally represent halogen and R<5> can further represent N,N'-optionally substituted amidine in which the carbon atom of the amidine group is attached to Q<4> atom, and R<5> can further represent alkoxycarbonyl, aryloxycarbonyl or aralkyloxycarbonyl, R<6> and R<7> are the same or different and represent hydrogen, an optionally substituted straight or branched chained C1-6 alkyl group C3-6 cycloalkyl, phenyl or an optionally substituted phenyl group Q<1>, Q<2> and Q<3> are the same or different and typically represent O or S, Q<4> stands for O or S, k, m and n individually represent 0 or 1. The compounds of the general formula (I) can be used for the preparation of phosphorus-containing penicillanic/cephalosporin derivatives as acylating agent. Some of the compounds of the general formula (I) have potential use as antibacterial, antiviral, antifungal and herbicidal agents.

Description

The present invention relates to novel phosphorus substituted acetic acid derivatives of formula (I) and processes for their preparation.

In the formula (I), the substituents have the following meanings:

R ³ is phenyl, substituted phenyl such as trichlorophenyl, pentachlorophenyl, pentafluorophenyl, pyrrolidin-2,5-dion-1-yl, phthalimido or 8-quinolyl,

Q ¹ is oxygen or sulfur, n can be 0 or 1.

The compounds of formula (I) are the novel biologically active penicillin derivatives of formula (IV) (Hungarian Patent Application Publication No. 1714/83, Publication No. T / 34 034), and the semisynthetic cephalosporin derivatives of formula (V) U.S. Patent No. 17,502, No. 34,502, may be used as an acylating agent.

Further, some of the compounds of the formula I have valuable antibacterial, antiviral, antifungal and herbicidal activity in themselves.

Compounds of formula (I) may be prepared by reacting a compound of formula (II) wherein Q ¹ and n are as defined herein and R is hydrogen, metal, C ₁₆ alkyl or C _3-6 cycloalkyl. With a compound of general formula (III) - in which

R ³ is phenyl, substituted phenyl such as trichlorophenyl, pentachlorophenyl, pentafluorophenyl, pyrrolidin-2,5-dion-1-yl, phthalimido or 8-quinolyl.

The reaction of the compounds of formula (II) and (III) according to the invention is preferably carried out in an inert solvent which does not convert under the other conditions and components of the reaction or in a binary, temeric or other mixture of such solvents.

Preferred solvents are hydrocarbons such as benzene, toluene, hexane, chlorinated hydrocarbons such as chloroform, dichloromethane, ethers such as diethyl ether, diisopropyl ether, ketones such as acetone, acetates such as ethyl acetate, amides such as dimethylformamide, dimethylacetamide, dimethylacetamide, dimethylacetamide, dimethylacetamide, or dioxane or tetrahydrofuran.

When the free acid is used as the starting material, the reaction is preferably carried out in the presence of a dehydrating agent.

Preferably, the dehydrating agent is a symmetric or asymmetric carbodiimide such as dicyclohexylcarbodiimide, diisopropylcarbodiimide. The reaction of the compounds of formula (II) and (III) is preferably carried out at room temperature.

Further details of the invention are set forth in the Examples, without limiting the invention to the Examples.

EXAMPLES

Example 1

Preparation of diphenylphosphinoacetic acid (starting material) [K. Issleib, G. Thomas, Chem. Beer 93, 803 (1960)].

Dissolve 2 equivalents of sodium in liquid ammonia (70-80 m ³ / 0.1 M PPh 3) and add 1 equivalent of triphenylphosphine. The mixture then changes color from dark blue to dark brown. One equivalent of ammonium chloride is added very slowly. A white precipitate forms and an orange slurry is formed. At this time, 1 equivalent of freshly distilled ethyl acetate in chloroform was mixed with an equal volume of ether and added dropwise. The completion of the reaction is indicated by the pale yellow color of the mixture. The ammonia was allowed to evaporate while the slurry was diluted with ether (40-50 m ³ / 0.1 M PPh 3) and stirred to dissolve the product from sodium chloride. The salt is then filtered off, preferably under N ₂ atmosphere.

Hydrolysis of ethyl diphenylphosphinoacetic acid ester can be carried out in water and in organic solvents:

(a) To an ethereal solution of the ester (80-90 m ³ ether or petroleum ether / 0.1 M ester) is poured an equivalent amount of hot potassium hydroxide solution in concentrated ethanol. Upon cooling, the sodium salt of the acid precipitates, and the crystals are collected and washed with chloroform. Yield: 60%. Mp: 117-120 ° C.

b) From the ethereal solution of the ester, the solvent is evaporated off, an equivalent of an aqueous solution of potassium or sodium hydroxide is added to the resulting syrup and the mixture is heated briefly in a stream of N ₂ . We find out with charcoal and give birth. The filtrate is acidified with stirring until a precipitate forms. The precipitated acid is filtered off and washed with cold water. Yield: 90%. Op: 120-121 ° C.

Rf: 0.55 (Benzene-Ethyl acetate-Acetic acid = 7: 3: 1)

IR spectrum: (KBr) 1695 cm ^-1 (vCO acid)

Nuclear Magnetic Resonance Spectrum (CDCl3) δ ppm: 3.04 (s, 2Η) 7.24-7.50 (mm 10H) 10.68 (s, 1H)

Analysis: C, _4H, good ₂ P (244.215) Calculated: C% = 68.90% Found: C = 68.80; 69.06

H, 5.36; H, 5.43; 5.49

Example 2

Preparation of diphenylcarboxymethylphosphine oxide (starting material)

Diphenylphosphinoacetic acid (1.22 g, 5 mmol) was dissolved in glacial acetic acid (15 mL), heated to 50-55 ° C and hydrogen peroxide (0.53 g, 33%) dissolved in glacial acetic acid (2 mL) was added dropwise. Meanwhile, cooling is maintained at about 55 ° C. After stirring for a further half hour, the reaction mixture was poured into ice-water (200 ml) and extracted with ethyl acetate. After drying, the ethyl acetate phase is evaporated and the resulting syrup is crystallized by trituration with absolute ether or n-hexane.

Yield: 0.98 g (74.35%). Mp: 138-140 ° C.

Rf: 0.13 (Benzene-Ethyl acetate-Glacial acetic acid = 7: 3: 1)

IR: 1730 cm ^-1

190,449

Analysis: C _J4 H ₁₃ O ₃ P (260.21)

NMR Spectrum: (DMSO-d _e, 100MHz)? Ppm:

3.92 (s, 1H); 4.04 (s, 1H); 7.8-8.3 (m, 10H) (δ)

Example 3

Preparation of diphenylcarboxymethylphosphine sulfide (starting material)

3.66 g (15 mmol) of diphenylphosphinoacetic acid and 0.53 g of sulfur powder are refluxed in 30 ml of benzene for 1 hour and then evaporated in vacuo. If chromatographically uniform, it may be used as such for ester formation, otherwise it may be crystallized from acetone.

Yield: 3.2 g (76.55%).

Rf: 0.4 (Benzene-Ethyl acetate-Glacial acetic acid = 7: 3: 1)

Mp: 183-185'C

IR spectrum (KBr) 1705 cm ^-1 (vCO acid)

Analysis: Calculated for C ₁₄ H ₃ O ₂ PS (276.21): C, 60.87 Found: C, 60.61 60.92.

H, 4.70; H, 4.61; 4.87

NMR Spectrum: _(DMSO-d6, 100 MHz) (δ) ppm: 4.18 (s, lH), 4.32 (s, lH) 7.8-8.4 (m, I0H)

Example 4

Preparation of diphenylphosphinoacetic acid pentachlorophenyl ester

2.44 g (10 mmol) of diphenylphosphinoacetic acid and

Dissolve pentachlorophenol (2.66 g, 10 mmol) in dichloromethane (30 mL) and add a solution of dicyclohexylcarbodiimide (2.06 g, 10 mmol) in dichloromethane (20 mL) at room temperature. After stirring for 2 hours, the reaction mixture was filtered from the precipitated urea and evaporated. The oily syrup-like residue is evaporated to ca. It is taken up in 20 ml of acetone and placed in a refrigerator to give a white crystalline solid.

Yield: almost quantitative.

Mp: 110-114 ° C

IR spectrum: 1765 cm ^-1 (vCO ester)

NMR: (CDC1 ₃ 100MHz) ppm: 3.40 (s, 2H) (5) 7.20-7.38 (m, 10H)

Analysis: Calculated for C ₂₀ H ₁₂ Cl ₅ O ₂ P (492.55): C, 48.76 Found: C, 48.66 49.06.

H, 2.45; H, 2.85 2.87

Cl% = 35.99 Cl% = 35.72 35.86

Example 5 Preparation of diphenylcarboxymethylphosphine oxide (diphenylphosphine oxide) -yl acetic acid pentachlorophenyl ester

Dissolve 2.66 g (10 mmol) of pentachlorophenol in 35 mL of dichloromethane and add 2.06 g of dicyclohexylcarbodiimide in 10 mL of dichloromethane. After stirring at room temperature for 3-4 hours, the precipitated urea was filtered off and the filtrate was evaporated. Solidify with petroleum ether.

Yield: 4.3 g (86%).

Mp: 126-130'C

Rf: 0.65 (Benzene-Ethyl acetate = 1: 1)

IR (KBr) 1780 (vCO ester)

Analysis: C ₂₀ Hi ₂ O _and Cl ₃ P (508.55) Calculated: C% = 47.19% Found: C = 47.79 47.48

H, 2.35; H, 2.57, 2.52

NMR Spectrum: _(DMSO-d6, 100MHz) ppm: 3.78 (s, 1H) 3.92 (s, lH), 7.76 to 8.20 (m, 10H)

Example 6 Preparation of (diphenylphosphine sulfide) -yl acetic acid pentachlorophenyl ester Dissolve diphenylcarboxymethylphosphine sulfide and 10 mM pentachlorophenol in 40 mL of dichloromethane and add 2.06 g of dicyclohexylcarbodiimide in 20 mL of dichloromethane. After stirring at room temperature for 5 hours, the filtrate was concentrated, and the filtrate was crystallized from acetone-petroleum ether.

Yield: 3.2 g (61%)

Mp: 168-171 ° C

Rf: 0.7 (Benzene-Ethyl acetate = 1: 1)

IR (KBr) 1775 ^cm-1 (v CO ester)

Analysis: C ₂₀ H ₁₂ Cl ₂ O _and PS (524.55) Calculated: C% = 45.79 found: C% = 47.06, 47.03;

H, 2.30; H, 2.40; 2.37

NMR Spectrum: _(DMSO-d6, 100MHz) ppm: 4.20 (s, lH), 4.36 (s, lH), 7.8 to 8.45 (m, 10H)

Example 7 Preparation of N-hydroxyphthalimide (diphenylphosphine oxide) -yl acetic acid Dissolve diphenylcarboxymethylphosphine oxide and 10 mmol N-hydroxyphthalimide in 35 mL dichloromethane and add 10 mmol dicyclohexylcarbodiimide. dissolved in dichloromethane. After stirring at room temperature for 3-4 hours, the precipitated urea is filtered off, the filtrate is evaporated and the product is crystallized from acetone.

Yield: 48%.

Mp 149-152'C.

Rf: 0.35 (Benzene-Ethyl acetate = 1: 1)

IR spectrum (KBr) 1735 cm ^-1 (vCO ester)

Analysis: C ₂₂ H ₁₆ O ₅ NP (405.24) Calculated: C% = 65.14% Found: C = 64.92 64.86

H, 3.94; H, 3.68 3.72

N, 3.45 N, 3.48, 3.49

Example 8

Preparation of diphenylphosphinoacetic acid 8-oxoquinoline ester

Diphenylphosphinoacetic acid (1.22 g) was dissolved in dichloromethane (25 ml), 8-oxoquinoline (0.78 g) in dichloromethane (10 ml) was added at room temperature, and dicyclohexylcarbodiimide (1.03 g) in dichloromethane (10 ml) was added. At this point, the reaction mixture becomes white and crystallization begins in a few minutes. Stir at room temperature for 2 hours

After -3190 449, the precipitated urea was filtered off, the filtrate was concentrated and crystallized with petroleum ether.

Yield: 0.8 g (46.92%)

Mp: 140-143 ° C

Rf: 0.65 (benzene-ethylacetate = 1: 1) IR (KBr) 1705cnT ¹ Analysis: C ₁₈ O ₂ H, _2J NP (372.15) calculated: N% = 3.76 Found: N% = 3.90 3.95

Example 9

Preparation of diphenylphosphinoacetic acid N-hydroxysuccinimide ester Dissolve diphenylphosphinoacetic acid and 10 mmol N-hydroxysuccinimide in 40 mL dichloromethane, add 10 mmol dicyclohexylcarbodiimide in 20 mL dichloromethane and stir at room temperature for 3 hours. over. The precipitated urea is filtered off and the filtrate is evaporated to give a white crystalline solid which is triturated with ether and petroleum ether. Recrystallization: from acetone petroleum ether.

Yield: 64%.

Mp: 106-108 ° C

Rf: 0.73 (Benzene-Ethyl acetate = 1: 1)

IR (KBr) 1750 cm ^-1 1785 cm ^{-1 1 10} cm ^-1

Analysis: Calculated for C ₁₈ H _le NO ₄ P (341.28): C, 63.34 Found: C, 63.96 64.50

H, 4.72; H, 4.92, 5.09

N, 4.10 N, 4.20 4.23

Claims (4)

Claims 1. A method of (I) a phosphorus-containing formula _{of 5-acetic} acid derivatives - wherein R ³ is phenyl, substituted phenyl such as trichlorophenyl, pentachlorophenyl, pentafluorophenyl, pyrrolidin-2,5-dion-1-yl, phthalimido or 8-quinolyl, 10 Q ¹ is oxygen or sulfur atom n can be 0 or 1, characterized in that a compound of formula II - in which Q ¹ and n are as defined in the preceding paragraph and R is hydrogen, metal, C ₆ 15 alkyl or C _{3 6} cycloalkyl - (III), a compound of formula - wherein R ³ is phenyl, substituted phenyl, such as trichlorophenyl, pentachlorophenyl, pentafluorophenyl group, a pyrrolidin-2,5-dione-yl, phthalimido or 8 kinolil20 group - reacted. 2. A process according to claim 1 wherein the reaction of the compounds of formula II and III, wherein Q ¹ , n, R and R ³ are as defined in claim 1, in an inert solvent or a mixture of such solvents. , optionally in the presence of a dehydrating agent at room temperature. 3. The process of claim 2, wherein the dehydrating agent is a symmetric or asymmetric metric carbodiimide. Process according to claims 1 and 2, characterized in that the solvent is chlorinated hydrocarbons, ethers, dipolar aprotic solvents.