DE2120223A1 - C ycloheptoxaphosphole compounds and processes for making the same - Google Patents

Description

The invention relates to new Oycloheptoxaphospho! Compounds the formula

(D

wherein R ^ represents hydrogen atom; a halogen atom, such as Chlorine, bromine, iodine and fluorine; a straight or branched chain alkyl group having 1 to 4 carbon atoms, such as Methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl; an alkoxy group having 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy; Nitro group; or

103845/1964

Cyano group; wherein E2 represents hydrogen atom; one Alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl; an aralkyloxycarbonyl group such as benzyloxycarbonyl; a straight or branched chain alkyl group with 1 Ms 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, η-butyl, sec-butyl and t-butyl; an aryl group, which may have substituents such as an alkyl group or (and) an alkoxy group, for example phenyl, ο-, ρ- or m-tolyl, ο-, ρ- or m-methoxyphenyl and naphthyl; or cyano group; and where R represents * a straight or branched chain alkyl group having 1 to carbon atoms, such as methyl, ethyl, propyl, isopropyl and η-butyl; or an aryl group such as phenyl and tolyl; and wherein the substituent IL on the seven-membered ring can be in any of the 4- to 7-position.

The present invention also relates to a new process for the preparation of cycloheptoxaphospho ! connections (I).

All of the cycloheptoxaphosphole compounds (I) obtained according to the invention are new and useful as an intermediate in drug synthesis. For example, the known azulene compounds, useful as an anti-inflammatory agent are prepared by reacting the compound (I) with an acetylene compound.

According to the present invention, the cycloheptoxaphosphole compound of the formula (I) can be prepared by reacting a tropone compound of the formula

(II)

_ 3 _ 109845/1964

where R * has the meaning described above and an is any one of positions 3 to 6 of the seven-membered ring, and wherein X represents a halogen atom, such as Chlorine, bromine and iodine; an alkanoyloxy group such as acetoxy and propionyloxy; an arylsulfonyloxy group such as benzene sulf onyloxy or toluenesulfonyloxy, with a phosphorane compound of formula

E ₂ -CH- ¹ ^) * (III)

wherein R ₂ and R, have the meanings described above.

The process of the present invention can be easily carried out by bringing the compound (II) into contact with the compound (III), preferably in the presence of a suitable solvent. As the solvent usable in the reaction, any inert organic solvent which does not adversely affect the reaction can be satisfactorily used. "Preferred examples of such a solvent include hydrocarbons such as benzene, toluene, xylene and cyclohexane, and ethers such as diethyl ether, tetrahydrofuran, and dioxane. The reaction temperature is not limited and is expediently from ⁰ ° C. to a reflux temperature of the solvent used. However, the reaction can also be carried out at a lower or higher temperature. The reaction time can vary mainly depending on the nature of the starting material, the reagent and the solvent as well as the reaction temperature. It is expediently from about 10 minutes to several days.

When the phosphorane (III), which is used in the reaction ve ^-> is proportionate unstable, then it is preferable to use the Hiosphoranverbindung directly which is formed in the reaction solvent in situ. The phosphorane compound can be prepared, for example, by the reaction of a phosphonium salt,

10 9 8 4 5/1964

like a phosphoniuia halide, with a strong base, like butyllithium. The phosphorane compound (III) is expediently used in an excess amount over the Tropone compound (II) is used, preferably in one molar ratio of approximately 2: 1.

If the substituent E ,, is in the 7-position of the tropone compound, then different reactions occur instead of the desired reaction. If the bubstituent Ή.Λ is in one of the positions 3 to 6 of the * tropone compound, then the desired reaction proceeds without any hindrances.

After completion of the reaction, the desired Product © with the formula (I) isolated from the reaction mixture. For example, the reaction mixture is filtered and the solvent is distilled off from the ITiitrate. The residue is purified, "for example by recrystallization from a suitable solvent, by column chromato- ■ graphi® or by extraction with. a suitable solvent after acid or alkali treatment.

The invention is illustrated by the following examples explained in more detail ο

(1) In 90 ml of benzene τ? · 3τάβη '1, ^ g of 2-chlorotropon and 3.2 g of gyanomethyleiitriph-enylphosphora ». iSrhitaen dissolved, and the resulting solution is heated 30 hours aiii ftücte- flnL · ο The EealciionsgeEiach is cooled, and the crystal formed thereby are © a'bxilbriart .. Eas solvent is from the i ^{T 'il:} ra' =. - turner reduced egg DrucV: distilled "and a crystalline residue yields ■>

109843/1934

The residue is recrystallized from a mixture of cyclohexane and benzene to give 1.6 g of the desired product is obtained which melts "at 217" ⁰ to 218 G. 0.7 g of 2-chlorotropone can be recovered from the mother liquor from the recrystallization by distillation of the solvent.

UV spectrum: A _max * Ai (D \ 267 (26000), 273 (27600)

390 (13300), 467 (16500) in ethyl alcohol.

Analysis values:

Calculated for C ₂₇ H ₂₀ ONP »1/2 G ₅ H ₁₂ :

C = 80.51%; H = 5.87%; N-3.13%; P = 6.92% Found: C = 80.83 #; H = 5.67%; N = 3.08 % \ .P = 7.39 %

(2) 2.77 g are dissolved in 120 ml ± enzol with heating 2-tosyloxytropon and 6.03 g of cyanomethylene triphenylphosphorane, and the resulting solution is refluxed for 3 days. The reaction mixture is cooled and the thereby crystals formed are filtered off. The solvent is distilled off from the filtrate and the residue in Dissolved chloroform and poured onto 280 g of silica gel in a column | adsorbed. Elution is carried out by use by chloroform and then by a mixture of ethyl acetate and chloroform (1: 2). The Bluate with the latter Solvents are collected and the solvent is distilled off. The residue is dissolved in 100 ml of benzene solved. The benzene solution is made with 10% hydrochloric acid (4 × 40 ml) extracted. The combined extracts become alkaline by adding 10% sodium hydroxide made, extracted with benzene (3 x 100 ml), washed with a small amount of water and dried over anhydrous Dried sodium sulfate. After the solvent is distilled off under reduced pressure, the

- 6 109845/1964

Recrystallized residue from a mixture of benzene and cyclohexane, 1.5 g of the desired product receives.

(3) In 60 ml of benzene, 0.5 g of 2-acetoxytropone and .2.02 g of gyanomethylene triphenylphosphorane under .heat dissolved, and the resulting solution is refluxed for 8 days. The reaction mixture is cooled and activated charcoal added. The mixture is filtered and the solvent removed from the filtrate under reduced pressure distilled off. The residue is in a small amount Dissolved chloroform and put on 100 g of silica gel in a column adsorbed. The elution is carried out using chloroform and then a mixture of ethyl acetate and chloroform (1: 2).

The eluates with the latter solvent are collected and the solvent is distilled off. The residue is dissolved in a small amount of chloroform and thin-layer chromatographed (silica gel E 254-, a product of Merck & Co., 20 cm × 20 cm). Developing is carried out by using a mixture of ethyl acetate and chloroform (1: 2). The presence of the desired product on the plate is confirmed by an ultraviolet quartz lamp. The fractions which contain the desired product are eluted with ethyl acetate. The solvent is distilled off from the juluate and the residue is recrystallized from a mixture of benzene and cyclohexane, 0.1 g of the desired product being obtained.

- 7 -

1098 4 5/1964

Example 2 2,2,2-triphenyl-3-ethoxycarbonyl-1,2-cycloheptoxaphosphole

1.41 g of 2-chlorotropone and 6.96 g of ethoxycarbonylmethylene triphenylphosphorane are dissolved in 60 ml of benzene while being heated, and the resulting solution is refluxed for 24 hours. The reaction mixture is cooled and filtered. The 'filtrate is concentrated under reduced pressure and ether is added to the crystalline residue. The crystals are isolated by filtration and recrystallized from isopropyl ether, 2.1 g of the desired product which ^{melts at 182 to 183 °} C. being obtained.

UV spectrum: \ _max -sau. (£): 266 (18500), 2? 2 (18500),

403 (9800), 463 (9200)

in ethyl alcohol.

Analysis values:
Calculated for C

C-76.97%; H »5.58 " M P = 6.84%; Found: 0 = 77.05 / o \ Η = 5 «5 ^λ " · % \ P =? , 25%.

Example 3 2, 2,2-tripheny 1-1 ^ -cycloheptoxaphosp iiol

(1) In 1100 ml of tetrahydrofuran 5918 S TriphenylmethyIphosphonjumbromid are suspended, and to the resulting suspension troOfenweise 10 are ^z '-, 1 ml of a 1 ¹ V, 2% η-butyl] ithiusilösung η hexane osi atmosphere 20 ° G in nitrogen out £ Uf? ef \ lgt. After stirring

- 8 1088 ^ 5/196 "

for 30 minutes at this temperature the reaction mixture is cooled to 5 tis 10 ⁰ C and 11.9 S 2-Chlortropon in 100 ml of tetrahydrofuran was added dropwise. The resulting mixture is stirred at this temperature for 1 hour and stirred at room temperature for a further 2 hours. The reaction mixture is filtered by using Gelite (trade name of a diatomaceous earth product, available from Johns Manville Sales Corp., USA) as a filter medium , and the solvent is distilled off from the filtrate. 2 l of water are added to the residue, and the mixture is extracted with ether (3 × 600 ml). The ether extract is extracted again with 10% hydrochloric acid (3 × 300 ml). The aqueous layer is deposited and made alkaline with 10% sodium hydroxide while cooling. The crystals formed in the solution are separated by filtration, air dried and recrystallized from η-hexane to give 18.1 g of the desired product is obtained which melts at 167 G ^0.

UV spectrum; λ _max mM (E) ί 267 (24400), 272 (25900),

277 (24700), 390 (9300),

410 (1240G), 442 (7900),

466 (7400), 492 (52ΟΟ)

in ethyl alcohol.

Analysis values .;
Calculated for Ο ^ Β ^ ΟΡ:

C "82.08 % \ fl" 5 ₅ 85%; P = 8.14% · Found % 0 = 82.56 % \ H = 5.82% · P = 8.53 %.

(2) In 280 ml of tetrahydrofuran, 143 g of Triphenylphosphoniumbroiaid su ^ peiiciisr *; and to the received

h ö 4 5/1 9 6 h

Suspension added dropwise 25.2 ml of a 14.9% n-butyllithium solution in hexane "at 20 ⁰ O in a nitrogen atmosphere. After stirring for 50 minutes at this temperature, the reaction mixture is ^{cooled to 0 to 5 0} C, and 5, 54 g of 2-tosyloxytropone are added. The resulting mixture is stirred at this temperature for 1 hour and stirred at room temperature for a further 2 hours. The reaction mixture is filtered using Celite as a filter medium, and the solvent is distilled off from the J filtrate. 500 ml are added to the residue Water is added and the mixture is extracted with ether (3 x 200 ml). The ether extract is re-extracted with 10% hydrochloric acid (3 x 100 ml). The aqueous layer is separated and made alkaline with 10% sodium hydroxide while cooling. The crystals formed in the solution are separated off by filtration, air-dried and recrystallized from η-hexane, giving 0.83 g of the desired product elder

■ Example 4 2,2,2-triphenyl-5-chloro-1,2-cycloheptoxaphosphole

3 »13 g of triphenylmethylphosphonium bromide are suspended in 60 ml of tetrahydrofuran, and 5» 53 ml of a 14.9% strength n-butyllithium solution in hexane at 20 ° 0 in a nitrogen atmosphere are added dropwise to the suspension obtained. After stirring for 30 minutes at this temperature, the reaction mixture is cooled to 0 to 5 ⁰ O, and there will be 0.768 g of 2,5-Dichlortropon in 10 ml of tetrahydrofuran was added dropwise. The resulting mixture is stirred at this temperature for 1 hour and at room temperature for a further 2 hours

- 10 1098A5 / 196A

touched. The reaction mixture is filtered using gelite as a filter medium and the solvent is distilled off from the filtrate. 200 ml of water are added to the residue, and the mixture is extracted with ether (4 × 100 ml). The ether extract is extracted again with 10% hydrochloric acid (3 × 100 ml). The aqueous "layer is deposited and made alkaline with 10% sodium hydroxide while cooling. The crystals formed in the solution are separated by filtration, air-dried and recrystallized from η-hexane to give 0.54 g of the desired product, which at 129 to 130 ⁰ G melts.

UV spectrum: A _max m ^ ( % ): 267 (17800), 274 (19300),

281 (20300), 366 (5800),

393 (8800), 413 (11400),

442 (7200), 466 (5400),

4-93 (2900)

in ethyl alcohol.

Analysis values:

Calculated for G ₂₆ H ₂₀ OPCl «1/2 G ₆ H ^:

0 = 76.05%; H = 5.95 % \ Cl-7.74%; P = 6.76%; Found: G-76.18 % \ H = 5.9O%; Gl-7.76 y &; P = 6.76%.

Example 5 2,2>, 2,3-ffetraphenyl-1 ^ -cycloheptoxaphosphole

(1) In 240 ml of tetrahydrofuran, 12.24 g of benzyltriphenylphosphonium bromide are added suspended, and 17.6 ml of a suspension are added dropwise to the suspension obtained

- 11 -

109845/1964

% n-butyllithium solution in hexane "added at 20 ^° C. in a nitrogen atmosphere.

After stirring for 30 minutes at this temperature the heating mixture is cooled to 0 to 5 0, and 2 g of 2-chlorotropon in 10 ml of tetrahydrofuran are added dropwise. After the dropwise addition is complete the resulting mixture is stirred for 2 hours at room temperature. The reaction mixture is made by using filtered by Celite as a filter medium and the solvent was distilled off from the filtrate. Become the residue 500 ml of water are added and the mixture is extracted with ether (3 x 300 ml). The ether extract is again with 10% hydrochloric acid (3 x 100 ml) extracted. The aqueous layer is separated and washed with 10% sodium hydroxide made alkaline with cooling. The crystals formed in the solution are separated out by filtration, air-dried and recrystallized from cyclohexane to give 1.05% of the desired product, which at 244 melts up to 245 ° C.

UV spectrum: A _mDV m / O (£): 267 (26400), 274 (28800),

IucLjC y

280 (30100), 392 (13200),

412 (16900), 460 (7600),

482 (7600), 515 (4400), in ethyl alcohol.

Analysis values:
Calculated for C, _o Hoc0P;

0 = 84.18 % -, H = 5.53%; P = 6.78%; Found: 0 = 83.69%; H = 5.60%; P = 7.05%

(2) In 866 ml of tetrahydrofuran, 43.3 g of benzyltriphenylphosphonium bromia are added suspended, and to the received

1G3845 /

Suspension dropwise 63.3 ml of a 14x.9% n-butyllithium solution in hexane at 20 G in a nitrogen atmosphere. The reaction mixture is 30 minutes stirred at this temperature, and 13.85 g of 2-tosyloxytropone are added. The received The mixture is stirred at room temperature for 4 hours and filtered using Gelite as a filter medium. The solvent is distilled off from the filtrate and added 1 1 water was added to the residue. The mixture is extracted again with ither (3 x 300 ml) and the ither extract extracted with 10% maltic acid (3 x 100 ml). The watery one ■ Layer is separated and treated with 10% sodium hydroxide made alkaline with cooling. The crystals formed in the solution are separated out by filtration, air-dried and recrystallized from cyclohexane, 1.0 g of the desired product being obtained,

Claims

/ 1964

Claims (7)

Patent claims: η. φι . JJine compound of formula ^E 2 where E _x . represents a hydrogen atom, a halogen atom, a straight or branched chain alkyl group with 1 "to 4 carbon atoms, an alkoxy group with 1 to 4 carbon atoms, nitro group or gyano group, in which Ep represents hydrogen atom, an alkoxycarbonyl group, an aralkyloxycarbonyl group, a straight or branched chain alkyl group with 1 to 4 carbon atoms, an aryl group or cyano group, and where E ^ represents a straight or branched chain alkyl group having 1 to 4 carbon atoms or an aryl group, and where E ^ can be in any of the positions 4 to 7 on the seven-membered ring. 2.2.2-0? Riphenyl-3-cyano-1 ^ -cycloheptoxaphosphole. 3. 2,2 ^ -Triphenyl-J-ethoxycarbonyl-1,2-cycloheptoxaphosphole. 4. 2,2,2-tripheny1-1 ^ -cycloheptoxaphosphole. 5. 2,2,2-triphenyl-5-chloro-1 ^ -cycloheptoxaphosphole. 6. 2,2,2,3-tetraphenyl-1 ^ -cycloheptoxaphosphole. 7. Process for the preparation of a compound of the formula - 14 - 109845/1984 wherein R ,. represents hydrogen atom, a halogen atom, a straight or branched chain alkyl group with 1 to 4 carbon atoms, an alkoxy group with 1 to 4 carbon atoms, nitro group or cyano group, in which R represents hydrogen atom, an alkoxycarbonyl group, an aralkyloxycarbonyl group, a straight or branched chain An alkyl group having 1 to 4 carbon atoms, an aryl group or cyano group, and where R 1 represents a straight or branched chain alkyl group having 1 to 4 carbon atoms or an aryl group, and where R _x . is on the seven-membered ring in any one of the positions 4 to 7, characterized in that a compound of the formula wherein R, - has the meaning described above and in any one of the positions 3 to 6 of the seven-membered ring and wherein X is a halogen atom, an alkanoyloxy group or represents an arylsulfοnyloxy group, for Reacts with a compound of the formula R ₂ -CH- j ₅
wherein Ro and R, have the meanings described above. 109845/1964