IE43162B1 - Novel 5-oxo-alkanoic acid derivatives - Google Patents

Description

This invention relates to novel 5-oxo-alkanoic acid derivatives.

Patent Specification No. 43161 describes and claims a process for producing tetrahydro-a-pyrones of the formula \ .Λ „ i-Cl / 3 ciL 'R.

R. 6 z R5 c-=o wherein R^, R^, Rg, R^, Rg and R^, which may be the same or different each represents a hydrogen atom or .i substituted or unsubstituted alkyl, aryl or aralkyl group, which comprises reacting a nitrile of the formula R3- CH—CN wherein R„ and R, are ns defined above, with an 3 4 alkenone of the formula R,-C=CH-CO-R_ 1 ι n to form a 4-oxo alkane nitrile of the formula - 3 R -C-CN i R. -C-CH-.CO.Rc 1 z □ »2 and converting tha so-formed 4-oxo alkane nitrile to the required compound of formula I by the following steps, performed in any appropriate order or if desired, with one or more of the steps being performed simultaneou sly: (i) solvolysis to convert the nitrile group to a free or esterified carboxyl group, (ii) conversion of the oxo group to a group of the structure ->CR..OH by a method known per se, and b (iii) cyclisation.

The present invention concerns intermediates in said process for the production of compounds in which R3 is phenyl.

According to the present invention there are provided compounds of the formula R3 R.-C-COO Aik 44· .

II R -C-CH2.2.Rg R2 wherein Z represents a keto group or a group feCR-.OH, Aik represents an alkyl group or an alkali metal atom, R,, R„, R., R_ and R. are as defined above and 2 4 5 6 - 4 Kg represent;! phenyl.

Tlie compounds of the present invention may be prepared by forming a 4-oxo alkane nitrile in accordance with the first step of the process of the aforementioned copending application, followed by one or both of the following steps: (i) solvolysis to convert the nitrile group to a free or esterified carbonyl group, and (ii) conversion of the oxo group to a group of the structure i>CRg.OH by a known method.

Wherein R_ is hydrogen, the conversion of the o oxo group to the group />CRg.OH may be effected by hydrogenation. Alternatively, where Rg is other than hydrogen, the conversion of the oxo group to the group 3>CRg.0H may be effected by known methods of nucleophilic addition, for example using a Grignard reagent of formula R^.M .X where X is halogen, particularly Hr or I. By a known method as used herein is meant • ι mnl.lind hitherto used or described in the literature.

In carrying out Lhe process of the invention to prepare compounds of formula II in which Rg is phenyl and R^ and Rg are hydrogen, the alkyl ester of a 5-oxo alkanoic acid may be prepared from a 4-oxo alkane earbonitrile obtained in the course of a first stage of the process by the action o.f benzyl cyanide upon the corresponding alkenone, the obtained ester being saponified in an appropriate medium and hydrogenated.

Preferably, the reaction of the benzyl cyanide upon the alkenones for the obtaining of 4-oxo alkane carbonitrile, which constitutes the first stage of Lhe process, is effected in a solvent constituted advantageously by an ethanol-hexane mixture and in the presence of a catalyst advantageously constituted by potash .

According to another preferred manner of operation, the preparation of the ethyl ester of 5-oxo alkanoic acid from the corresponding 4-oxo alkane carbonitrile, which constitutes the second stage of the process, takes place in the presence of an acid.

According to an advantageous manner of execution of the third stage of the process the hydrogenation of the ester is effected before its saponification. Alternatively, the saponification and the hydrogenation may be carried out simultaneously in a hydrogenation cylinder.

According to yet a further advantageous manner of execution of the third stage of the process according to the present invention, when the saponification and/or the hydrogenation take place in alcoholic medium, the latter is eliminated by distillation.

According to one of its particularly advantageous manners of realisation, the hydrogenation effected in the cour.se of the third stage of the process according to the present invention is carried out under pressure, preferably using a hydrogenation catalyst constituted by the nickel obtained from Raney nickel alloy.

The intermediate products obtained respectively in the course of the first and second stages of the process may be purified by recrystallisation in absolute alcohol containing up to 2% of H^SO^.

The preparation of compounds of formula XI in accordance with the invention and their conversion to α-pyrones is illustrated by the following examples:43162 - 6 Example 1 Preparation of 6-Mcthyl 3,4-Diphenyl 3,4,5,6Tetruhydro 2-Pyrone 1st Stage Preparation of the 1,2-diphenyl· 4-oxo pentane carbonitrile:CH -CH-CN 6 5 I (II) C.H -CH-CH--C-CH 2 3 g (0.5 mol) of trans-4-phenyl-3-buten-2-one are dissolved in 60 g (0.51 mol) of benzyl cyanide, 200 ccs of the mixture of hexane and absolute alcohol (70:30) are added. The solution is agitated and cooled in a cooling bath at about -5°C. Then the catalyst is added: 20 ccs. of 2N ethanol KOH. The addition must bo slow (about 1 hour) and the temperature must not exceed 0°C.

In the reaction vessel a crystallisation is observed which develops with time. 4 hours after the beginning of the addition, the reaction vessel is placed in the refrigerator for the night. At the end of this time the content of the vessel, which is partly sot in a lump, is filtered. The crystals are washed twice with 100 cc., then once with 200 cc. of cold hexane, then twice with 100 ecu. of cold methanol in order to eliminate the potash. The yield is of the order of 90%.

The vapour phase chromatographic (VPC) analysis indicates a content of 98% of threo product and 2% of erythro product. There is no more starting product. - 7 4 316-2 c H N 82.10 6.51 5.32 82.04 6.53 5.39 in a solution of absolute Analysis C H ON J.O 2./ Calculated % Found % Recrystallisation alcohol containing 1% by weight of sulphuric acid gives a product having a content of 100% of threo isomer.

Yield 80% Melting point 100°C. 2nd Stage Preparation of the ethyl ester of 2,3-diphenyl -oxo 2-hexanoic acid:0 C H_-CH-C-O-C H 6 5 j 2 5 CX-CH-CH,-C-CH 6 5 2 || 3 g of 1,2-diphenyl 4-oxo pentane carbonitrile obtained in the course of the first stage are dissolved in the hot state in 270 ccs. of alcohol at 95° GL.

Then 90 ccs. of concentrated sulphuric acid are added. The reaction mixture is heated under reflux for 6 hours. After cooling it is extracted 4 times with 200-100-100-100 ccs. of CH2C12-ether (50:50 vol/vol), until almost complete decolorisation of the aqueous phase.

The recovered rich organic phase is washed twice with 100 ccs. of a 10% solution of Na2C0 , then 3 times with 100 cc. of brine and then dried over sodium sulphate.

After evaporation of the solvents, the product is distilled in vacuo: it passes at 166-167°C at 0.6 mm of mercury. - 8 Yield of the stage: 80% approximately - melting I >o i n t.: 'J 5°C. ' Analysis C II Calculated % 77.39 7.14 Found % 77.14 7.12 3rd Stage Preparation of 6-methyl 3,4-diphenyl 3,4,5,6tetrahydro 2-pyrone. g (0.064 mol) of ethyl ester of 2,3-diphenyl 5-one hexanoic acid are placed in suspension in 20 ccs. of 10 N NaOII and 130 ccs. of water and placed in the hydrogenation cylinder. The neutral nickel obtained fror· 8 q of Raney alloy is added with 50 ccs. of water. Neutral nickel is used in order that the exact quantity of NaOII utilised may be known.

The procedure of saponification and hydrogenation lasts 12 hours at 100°C under 10 bars. The unsaponifiable substances are extracted with ether (100 ccs.), the ethyl alcohol is eliminated by evaporation.

After filtration of the nickel, the alkaline solution is acidified with 20 ccs. of concentrated HCl and brought to boiling during 1 hour.

After cooling and saturation with NaCl, extraction is effected'3 times with 200-100-100 ccs. of '’ther-CH2Cl2 mixture (50-50 vol/vol).

The organic phase is twice washed with 100 ccs. nf a saturated solution of NallCO^, 3 times with 100 ccs. of brine and dried over sodium sulphate.

After evaporation of the solvent, the solid white residue is taken up hot in 80 ccs. of absolute alcohol, then hot filtered. - 9 of the third stage H 6.81 6.92 Crystallisation gives very white crystals: 12.3 g. Yield: 73% Melting point: 135°C.

A single recrystallisation brings the melting point to 140°C, which melting point is then constant.

Recrystallisation yield 80%. Yiel is pure product = 73 x 80:58%.

Analysis 0^0., c Calculated % 81.17 Found % 81.19 Spectroscopic Analysis The infrared spectra obtained on a Perkin-Elmer (Registered Trade Mark) 257 apparatus (KBr disc).

The NMR spectra were recorded at 60 MHz on a Varian (Registered Trade Meirk) A-60 spectrometer. (1) C,H_-CH-CN .

(II) CrH -CH-CH -C-CH 6 5 2 3 ί- 0 M.P. = 100°C. (2) (3) (4) (5) -1 -1 IR: vC=N:2220 cm : -jC=O: 1705 cm NMR: 5=7.17 signal for 10 protons (phenyl) (cdci3 ) 6=4.10 doubletfOr H(1)JH(1)H(2)=7 HZ 6=3.72 multiplet for h(2) 6=3.01 multiplet for =2.0 singlet for CH , . (5) C H -CH-C-O-CH -CH (ΠΙ) ί (3) Μ·Ρ· = 110°CC.H-CH-CH -C-CH a 5 2 ,, 3 (5) (6) (7) (8) 162 - 10 IR: vC=0 very great between 1700 and 1740 cm '0=0 and -C-OCgHg NMR (CDCl ) •=7.30 signal for 10 aromatic protons 0=3.80 solid for 4 protons 6=2.45 solid for 2 protons Λ =1.69 singlet for CH^ θ j 6=0.85 triplet for CH , . J 3(1; CH CH. = 7Hz C6H5 / CO M.P.: 140 C (I) CH.

IR: \'C=0: 1725 cm NMR: 2 spectra, in deuterated acetone and in deliberated chloroform:In deuterated acetone: 6— 7.10 signal for 10 aromatic protons, 4.85 solid poorly resolved for H (6) = 4.20 doublet for H^j ^=11.1 Hz for one isomer 6= 3. 90 doublet for g - 11.6 Hz for the other isomer = 3.50 solid poorly resolved for H (4) 2.18 superposed triplets (2 isomers) for CH, ,,, coupled to H,.> and H,,. 2(5) (4) (6) 1.42 doublet for CH,,,. one isomer (6) CH. . II, Hz '3' ‘ (6) 1.40 doublet for CII isomer J CII, (6) 3(6) = 6 Hz tho other - 11 Following the preparations one obtains 35-45% for the minority diasterioisomer. The proportion of the two isomers can be determined from the doublets δ=4.2Ο and 3.90. The couplings H,3j H j = 11 indicated a trans5 axial position, which permits of attributing the threo configuration of the products II and III.

The spectrum in deuterated chloroform shows only one doublet for CH.^^ (5=1.49) and a single doublet for H{3) (5=3.85).

Example 2 Preparation of 3,4,6-triphenyl 3,4,5,6-tetrahydro 2-pyrone. 1st Stage Ch -CH-CN 6 5 2 (IV) + 117 C,H -CH=CH-C-C Hc 6 5 , 6 5 II 208 0 KOH EtOH Yield = 95% .8 q (0.1 mole) of chalcone (x OH -CH-CN 6 5 , i C H -CH-CH -C-CrKc 6 5 2 || 6 5 325 0 ,3-diphenyl 1propenone) are dissolved hot in 12.0 g (0.102 mol) of benzyl cyanide, 60 ccs. of hexane-absolute alcohol mixture (20-80) are added; the reaction medium is cooled to 0°C in an ice-salt mixture. The catalyst 20 (8 ccs of 2N ethanol KOJl) is then added slowly.

Crystallisation intervenes very quickly in the vessel, about 1 hour after the commencement of pouring which lasts 3/4 of an hour. The vessel is then placed in the refrigor·itor for tho night. 162 - 12 The crystals contained in the vessel are filtered and washed with 3 times 30 ccs of cold hexane then once with 30 ccs of cold methanol.

Mass = 30.8 g. Yield: 95% M.P. : 112°C.

VPS analysis shows only one single peak (no more starting product).

Two recrystallisations in absolute alcohol (the first in the presence of 1% Η,ΞΟ^) bring the melting point to 116°C., which melting point then remains constant (no difference in IR) . Analysis C H ON 2 j ±y C H N Calculated% 84.89 5.89 4.30 Pound% 84.98 5.94 4.39 2nd Stage (V) C H -CH-CN 6 5 | C H -CH-CII -C-C H 6 5 2 6 5 II 325 0 H2S°4 + C_II_0H —-— H2° C6H5-fH-CO2-C2H5 C,H -CH-CH_-C-C,H 2 j, 6 5 372 0 Yield of crude product: 80% Yield of pure product: 65% g (0.134 mol) of 1,2,3-triphenyl 4-oxo butane carbonitrile are dissolved hot in 500 ccs. of alcohol at 95° GL. After dissolving, 200 ccs. of concentrated sulphuric acid are added.

The solution, under vigorous mechanical agitation, is heated under reflux for 7 hours. At the end of 3 hours, crystals appear in the vessel and the solution thickens. Cooling accentuates the setting. In order to dissolve the whole, 150 ccs. of C^Cl are added and heating is effected under reflux; nothing - 13 10 reprecipitates by cooling. The mixture is poured into 300 ccs. of brine. The decanted aqueous phase is again extracted with 3 times 100 ccs. of ether-CH^Cl^ mixture (50-50 vol/vol). The reassembled organic phases are washed with TOO ccs. of a 10% solution of Na2CO3 then with 3 times 200 ccs. of brine and dried over sodium sulphate. After evaporation the solid residue is taken up with 300 ccs. of alcohol, hot-filtered and crystallised.

After filtration and drying, 45.9 g. of light white product are recovered, M.P. : 147°C, yield: 80%.

Yield of the recrystallisation: 80% M.P. : 150°C (absolute alcohol) Analysis C25H24°3 Calculated % Found % C H 80.62 6.50 80.46 6.40 3rd Stage C6H5-CH-C°2-CH2-CH3 I C.H_-CH-CH,-C-CH (i 5 2 6 5 372 0 NaOH (h2°) C,H—CH-CO Na 6 5 , 2 CH -CH-CH -C-CH 6 5 2 ,, 6~5 386 C,Hr , 6 5 C,Hr 6 5 HCl +H_ I c ο Λ 328 (VI) (not isolated) Raney nickel P = 10 bars t = 100°C C,H -CH-CO -Na | 2 C,H -CH-CH -CH-CH 6 5 2 6 5 368 I OH (not isolated) 1162 - 14 Crude yield: 82% Yield of purified product: 62% g (0.048 mol) of ethyl ester of 2,3,5-triphenyl 5-oxo pcntanoic acid (pure by VPC) are saponified by heating under reflux for 4 hours in a sodium hydroalcoholic solution (18 ccs. of 10 N NaOH, 100 ccs. of alcohol at 95° GL and 50 ccs. of water) . Then the hot solution is filtered in the hydrogenation cylinder. Neutral nickel· prepared from 5 g of Raney alloy with 50 ccs. of water is added.

The hydrogenation lasts 14 hours, p:10 bars, t:l00°C. After filtration of the nickel, 100 ccs. of water are added to the filtrate and the ethyl alcohol is eliminated by distillation. After cooling, acidification is effected with agitation with 18 ccs. of concentrated HCl, then heating is effected under reflux for 1 hour, still with agitation. After cooling, the product is filtered with a Buchner funnel. 13.0 g yellowish crystals are collected, M.P. = 198°Cj Yield = 82%.

Re-crystallisation is the benzene-butanone mixture (50-50) M.P. = 25O°C.

Analysis C^H^ Calculated % Found % Spectroscopic Analysis (KBr disc for the I.R.) C H 84.12 6.24 83.74 6.40 - 15 IV (1) C H —CH-CN ί '4) C H —CH-CH —C-C Η M.P.: 116 C (absolute 6 5 2 ij alcohol) (IV) (2) (3) 0 IR: vC“N:22O5 cm vC=O: 1670 cm NMR: in deuterated chloroform. 6 = 8 to 7 ppm spread solid for 15 aromatic protons = 4.5 ppm doublet for IH in (1), JH(1)H(2) = 5 Hz = from 4 to 3.5 ppm solid poorly resolved 10 for IH in (2) and 2H in (3).

(V) (4) j (1) C H -CII-C-O-CH -CII • (3) M.P.: 150 C (absolute alcohol) CrH -Cli—CH -C-C H 6 5 2 , b s (5) (6) 0 IR: 2 bands C=0, CO in a of a phenyl at -1 -1 1570 cm CO ester at 1710 cm NMR: ύ= 7.30 signal for 15 aromatic protons (CDCl3) δ= 3.82 solid for 4 protons = 3.07 solids for 2 protons = 0.89 one triplet for CH3(1) = Hz - 16 43162 C6H5 S Crnr 6 5 VI CO M.P. = 205 C (butanone benzene 50-50) C6H5 IR: (KBr): ^C=0:1700 cnf Example 3 Preparation ol 4,4,6-trimetliyl 3-phenyl, 2tetrahydropyrone. 1st Stage C,H -CH?CN (VII) 5 5 117 +(CH-)_C=CH-C-CH 3 2 l|! 0 KOH EtOH CH -CH-CN j (CH ) C-CH -C-CH 3 2 2 j 3 215 0 Yield: 87% 29.4 g (0.30 mole) of 4-methyl 3-pentene 2-one are dissolved in 36 g (0.31 mol) of benzyl cyanide. ccs. of the mixture of hexane and absolute alcohol (80-20) are added. The agitated solution is cooled to 0°C in an ice-salt mixture. When the temperature is of the order of -2°C, the ethanol potash is added, firstly until neutralisation of the acid impurities contained in the mesityl oxide (checked with pH paper), then 5 ccs. to catalyse the reaction. One hour after the end of the addition a commencement of crystallisation is noted. Two hours later the vessel is placed in a refrigerator. 4316 2 The contents of the vessel, totally solidified, are filtered over fritted glass. The crystals are washed with twice 100 ccs. of cold hexane then 100 ccs. of cold methanol. MP -- 90°C, Yield = 87%.

MP - 93°C (ethyl alcohol); the first crystallisation takes place in the presence of traces of sulphuric aci d. 2nd Stage (VIII) C-H -CH-CN 6 5 ι (CH)-C-CH -C-CH + C H OH 3 2 2 , 3 2 5 215 O (CH ) C-CH -C-CH 2 2 || 3 262 0 Yield = 70% g (0.116 mole) of 2,2-dimethyl. 4-oxo 1-phenyl pontane carbonitrile arc dissolved hot in 240 ccs. of alcohol at 95% GL. Then 90 ccs. of concentrated HgSO^ are added and heating is effected under reflux for 6 hours.

After cooling the solution is diluted with 200 ccs. of brine, then extracted with 200-100-100-100 ccs. of CH2C1q-ether mixture (50-50 vol/vol).

The recovered organic phase is washed with 100 ccs. of a 10% solution of Na^O^ then with three times 100 ccs. of brine and finally dried over sodium sulphate.

After evaporation of the solvents, the product is distilled in vacuo. It passes at 145-150°C (p=1.5 mm of Hg). Yield: 70% Colourless slightly viscous liquid product. 3162 Analysis Calculated % Found % C H 73.25 8.45 73.28 8.22 3rd Stage C II -CII-CO -C II 0 5 2 2 I (CII ) C-CH -C-CH ii 262 0 + NaOH C.H -CH-CO.Na 0 5' 2 i (CH ) C-CH,-C-CH 3 2 2 j, 3 256 0 (not isolated) Raney nickel p = 20 bars t = 1OO°C 218 \k C.H -CH-C0„Na 6 5 j 2 (CI^^C-CI^CII-CH OH (not isolated) 258 Crude yield: 50% Yield of purified product: 38% g (0.057 mol) of ethyl ester of 3,3-dimethyl 5-oxo 2-phenyl hexanoic acid are saponified for 3 hours by heating under reflux in a solution containing 20 ccs. of 10 N soda, 50 ccs. of alcohol at 95° GL and 50 ccs. of water. The solution is filtered and placed in the hydrogenation cylinder and the neutral Raney nickel is added (prepared from 6 g of Raney alloy) with 50 ccs. of water. - 19 Hydrogenation lasts 14 hours at 100°C (under a pressure of 1.0 bars) .

After filtration of the nickel and addition of 200 ccs. of water, the ethyl alcohol is evaporated then acidification is effected with 20 ccs. of concentrated HCl and heating is effected for 1 hour under reflux.

After cooling and saturation by NaCl, extraction is effected with three times 100 ccs. of ether CH^Cl^ mixture (50-50 vol/vol).

The recovered organic phases are washed with 100 ccs. of an 8% solution of NaHCO^, twice 100 ccs. of brine, then dried over sodium sulphate.

After evaporation of the solvents, the white residue is redissolved hot in 20 ccs. of hcxaneiibsolutc alcohol mixture (G0-40 vol/vol).

Crystallisation gives very white crystals: 6.4 g.

Yield: 50% M.P. 77° (hexane-absolute alcohol).

A recr/stallisation in 25 ccs. of hexane-absolute alcohol mixture (20-30 vol/vol) brings the melting point to 80°C. Yield: 75%. Pure product by VPC. Reerystallisation to constant melting point MP = 81°C.

Analysis Calculated % Pound % Spectroscopic analysis (1) C.IL-CH-CH vii () 3 ; (CII ).,C-CH -C-CH J .. Z y J (2) (3) 0 (4) C 77.03 76.82 H 8.31 8.36 MP: 93 C (absolute alcohol) 3162 IR: NMR: vC_N:2210 cm vC=0: 1690 cm (solvent: CDClg): ύ= 7.28 one signal for five aromatic protons <5— 4.47 one singlet for 2.67 and 2.25 two doublets for 2H(3)' JH.H=17 H2 δ- 2.10 one singlet for 6= 1.05 and 1.20 two singlets for 6H (2) This spectrum is in accordance with the asymmetry of the molecule. (3) (2) (1) (VIII) C H -CH-CO -CII -CII 6 5 | 2 2 3 (0Η3)20-αΐ2-0-0Η3 b.p. 0.3 116-118 C (4) (5) (6) IR: NMR: vC=O between 1710 and 1740 cm (CDC1 ): 0= 7.25 one protons 6= 4.10 and ‘ 2H,„. J (2) H.l ύ= 3.95 one fi= 2.73 and : 2H.e, > J, (5) H 6 = 2.02 one : 0 = 1.18 one ; = 5.5 Hz and J _= 5.5 Hz inglet for Hz ±eL J_U£ on, , (6) ,d for 6H,„. and 3H,_ . (4) (1) This spectrum is in accordance with the asymmetry ol the molecule. - 21 10 43163 -'CfA MP: 81°C (hexane-absolute alcohol 70-30)' IR: NMR: vC=0: 1700 cm spectrum in deuterated acetone δ = 7.25 signal for 5 aromatic protons δ = 4.75 solid poorly resolved for H (6) δ = 3.75 and 3.61 two singlets for H (3), each corresponding to a diasterioisomer of 5. & = 1.75 one solid for the methylene in 5. δ = J.4 one doublet for the methyl in 6 of a diasterioisomer (JCH Η = 6 Hz) δ = 1.37 one doublet for the methyl in 6 of the other diasterioisomer (J-,, „ = 6Hz) w tl tl = 1.11 and 0.8 two singlets for the methyls in 4 of one of the diasterioisomers δ = 1.0 and 0.91 two singlets for the methvls in four of the other isomer The signals caused by isomers are in an approximate the presence of two diasterioratio of 55-45.

Claims (4)

CLAIMS:

1. A compound of the formula R. '3 R — C-COO .Aik 4 , R^C-C^.Z.Rg R. '2 wherein Z represents a keto group or a group ?>CR .OH b Aik represents an alkyl group or an alkali metal atom R l' R 2’ R 4' R 5 ant ^ R 6' ma y be the same or different each represents a hydrogen atom or substituted or unsubstituted alkyl, aryl or aralkyl groups and R^ represents phenyl.

2. A compound as claimed in claim 1 wherein 2 represents a keto group.

3. A compound as claimed in claim 1 or claim 2 wherein Aik represents an alkyl group.

4. A compound as claimed in claim 1 wherein Aik represents an alkyl group and 2 represents CHOH.