DE2104871A1 - - Google Patents

Description

PATENT ADVOCATE .. ρ 7 1

DR.-ING. BY KREISLER DR.-ING. SCHÖNWALD 2lU4o / l .le.MEYER DR.FUES DIPL.-CHEM. ALEK VON KREISLER OIPL.-CHEM. CAROLA KELLER DR.-ING. KLDPSCH

COLOGNE 1, DEICHMANNHAUS

Cologne, February 1st, 1971 Kl / Ax

Takeda Chemical Industries, Ltd ,,

27, Doshomachi 2-chome, Higashi-ku, Osaka (Japan).

New (j5-methyl-5-carboxy-2- pentenyl) quinones and Process for their manufacture

The invention relates to new (3-methyl-5-carboxy-2-pentene nyl) quinones “The quinone derivatives according to the invention have the general formula

in which X and X ¹ each represent a methyl radical or methoxy radical or together represent -CH = CH-CH = CH-, as well as the corresponding lower allyl esters and pharmaceutically acceptable salts of these derivatives ₀

It has surprisingly been found that the new quinone derivatives have a strong anti-inflammatory effect to have. The invention thus includes the use of the new compounds as active ingredients in pharmaceutical preparations.

The invention also relates to a technically feasible process for the preparation of the quinone derivatives according to the invention, which is characterized in that in a first stage ny'roch tnonverbindnri; ^ n the all-

109835/1680.
BATH ORIGINAL

common formula

OH

(II)

in which X and X ^{1 have} the meanings given above, with a 4-hexenoic acid compound of the general Porroel

OH,

I ³

ZCH ₂ CH = CCH ₂ OH ₂ COOy ' ¹ (IHa)

in Z a hydroxyl group, an acetoxy radical or a

ρ
Halogen atom and Y is a hydrogen atom or a lower alkyl radical, or with an S-hexenoic acid compound of the general formula

CH,

CH ₂ = CH-G-OH ₂ Ch ₂ COOY ² (Illb) 2 ·

in which Z ^{f is} a hydroxyl group or a halogenated and

2
Y has the abovementioned meaning, and in a second stage the condensate formed as a product is condensed

OH

^Σ lY ^CH 3 ^CH 3

2 ₂₂ (lv ^r ) -

OH

1 in which X and X ^{1 had} the meanings given above and Y is a water atom or a lower alkyl radical, oxidizes,

The lower alkyl radical, for which Y ~ and Y stand, or the alkyl radical in -Ic-: m noniodic alkyl ester formed as a Sndpt'-jdukt contains vcr-au. , s'.eise 1 Ii s 7 C-Atoine. In Fvni.fz · \: o: \ vnen beispieisv-vi "c Kettc / X, iithyl, n-Fropyl, Iaopropy.1, li-butyl, η.

10S835 / 1690

Isobutyl, sec-butyl, ter-t-butyl, n-pentyl, n-hexyl and Cy c1ohexy1me thy1.

The halogen atom represented by Z and Z 'is, for example, a bromine atom or a chlorine atom.

The invention also includes the hexenoic acid compounds of general formulas (purple) and (IHb), all of which represent new compounds and as starting products for the Synthesis of the quinone derivatives according to the invention as well as other medicaments, e.g. mycophenolic acid, are suitable. The connections the formulas (IHa) and (HIb) can easily be found in. methods known per se are produced, for example, as follows will be provided:

Compounds of the general formula

CH ₃
Z ¹ CH ₂ CH = C-CH ₂ CH ₂ CHO (V)

in which Z is a hydroxyl group or an acetoxy group are produced from geranyl acetate by methods known per se (e.g. by ozonization) and then with an oxidizing agent (e.g. air and silver oxide) in a suitable solvent (e.g. ether, petroleum ether, hexane and methanol) Oxidized at room temperature. Optionally, the oxidation, for example with diazomethane comparable i esterified, wherein a 4-hexenoic acid compound of the general formula

CH ₃
Z ² -CH ₂ CH = C-CH ₂ CH ₂ COOY ² (Vl)

in which Z is a hydroxyl group or an acetoxy radical and

ρ
Y has the meaning given above is obtained.

Compounds of the general formula

CH ₃

CHhC-C-CH ₀ CH ₉ COOY ² (VIl) OH

109835/1690

in animal Y are as defined above, with a palladium catalyst (eg, Pd / CaCO,), for example by catalytic reduction using reduced at a temperature 15 to 30 ⁰ C to give the corresponding 5-hexenoic acid compounds of the general formula

CH ₅

CH ₂ = CH-C-CH ₂ CH ₂ COOY ²
OH

in which Y has the meaning given above, are obtained,

Of course, the compound (VIII), in which Y is a V / water-

is material atom, for example, by esterification with a

Converted alkyl iodide into the corresponding lower alkyl ester will.

The compounds (purple) uride (HIb), in which Z or Z ^{1 is} a halogen atom, are prepared by processes known per se, for example by halogenating the compound (VI) in

2 2

Z is a hydroxyl group and Y is a lower alkyl radical

is, or the compound (VIII) in which Y is a lower alkyl radical, with a halogenating agent (e.g. phosphorus tribromide and phosphorus trichloride).

According to the process according to the invention, the new compounds of formula (I) are represented by the following scheme sequence of reactions shown:

ZCH ₀ Ch = CCH ₀ CH ₀ COOY ² (III)

or

CH ₂ CH ₂ COOY ² Z ¹

condensation

109835/1690

IH

CH, CH, CH ₂ CH = CCH,

(IV)

oxidation

CH ₅ CH ₃ CH ₂ Ch = C-CH ₂ CH ₂ COOY

Herein, Y is a hydrogen atom or a lower alkyl radical.

The condensation reaction is carried out by reacting the hydroquinone compounds (II) with an olefin compound (purple) or (IHb) in the presence of a condensing agent. The "previously known condensing agent for this reaction is advantageously used, which are used for the condensation of phenol compounds. Eineai alcohol ■. When Z öine in the general formula (IIIa) hydroxyl group or an acetoxy radical, or if Z ^f In the general formula (IIIb) is a hydroxyl group / ground i as the condensing agent preferably an acid catalyst (eg, boron trifluoride and zinc chloride), and a sulfinyl compound (z _0, p-Nitrosulfinylanilin and N-SuIfijyl-p-aminobenzoesaureäthylester) used "If Z in the general formula (purple) or Z ¹ in the general formula (IHb) is a halogen atom, a metal catalyst (e.g. copper, tin and palladium) or an amalgamated metal (where copper, tin, palladium, zinc, etc. is the metal component to be amalgamated) is expedient. The condensation reaction is usually carried out in a suitable inert solvent ( _β . ether, tetrahydrofuran and dioxane) at one temperature carried out at -10 to 70 C and is usually in 2 "to 10 hours", if necessary, the reaction time can be as long as the heating

109635/1690

Reaction mixture can be shortened. After the reaction, the condensate (IV) formed can be used in a manner known per se (e.g. by extraction), however, it is generally used as a starting material without isolation from the Reaction mixture used for the subsequent oxidation reaction.

> The oxidation reaction is usually carried out by treating the compound (IV) with an oxidizing agent. "All known oxidizing agents which are used for the oxidation of hydroquinone to benzoquinone are suitable for this reaction, e.g. iron (III) chloride, manganese dioxide, silver oxide , Air and other mild oxidizing agents. The reaction is generally performed in a suitable inert solvent, for example ether, petroleum ether, hexane _s, methanol and ethanol, conveniently carried out at room temperature. After the reaction, the desired compound can easily be isolated from the reaction equipment in a manner known per se (eg by concentration, extraction, chromatography and crystallization).

If Y in the formulas (purple) or (IHb) or Y in the formula (IV) is a hydrogen atom, the carboxyl group can after the condensation reaction or after the oxidation reaction by methods known per se, for example with an "alkylating agent (e.g. _e diazomethane)

ρ can be converted into a lower alkyl ester. If Y in the formulas (HIa) and (HIb) or Y in the formula (IV) is a lower alkyl radical, the lower alkoxycarbonyl radical can be hydrolyzed in a known manner using alkali metal (e.g. sodium hydroxide and potassium hydroxide) after the condensation or oxidation reaction can be converted into the carboxyl group. If Y in the compound (I ¹ ) thus obtained is a hydrogen atom, the compound can be converted in a manner known per se into pharmaceutically acceptable salts, 2, B, metal salts (e.g. into the KaliüiasTilsi, Natr.imoaalz, magnesium salt and calcium salt)

! 0S835 / 169Q

or converted into amine salts (see 3 _a 3as dirathylamine salt and methylamine salt).

These compounds usually fall as a mixture of the trans isomars and cis isomers. The mixture can be in can be broken down into the individual isomers in a known manner (e.g. by recrystallization or chromatography). These individual isomers and their mixtures fall within the scope of the invention.

If the compounds prepared according to the invention as When anti-inflammatory agents are used, they are usually taken orally in an amount of 25 to 800 mg / day for Administered to adults.

It should also be noted that 2,3,5-trimethyl-6- (5-carboxy-3-methyl-2-pentenyl) -1,4-benzoquinone, its lower alkyl esters and its salts have the effect of cc-tocopherol (Vitamin E) and 2-methyl-3- (5-carboxy-3-methyl-2-pentenyl) -1,4-naphthoquinone, its corresponding lower alkyl esters and its salts exercise the puncture of Vitarain K, so that these new compounds for the treatment of the respective vitamin deficiency diseases instead of natural ones Vitamins can-be used. Also practice 2,3-dimethoxy-5-methyl-6- (5-earboxy-3-methyl-2-pentenyl) -1,4-benzoquinone, its lower alkyl esters and its salts perform the function of coenzyme Q.

It was also found that the compounds according to the invention have a stabilizing effect on the lysosomal membrane, and that this biological activity is particularly strong in the compounds in which X and X ^{1 are} methyl radicals or together are a group of the formula -CH = CH- Form CH = CH-.

The invention is illustrated by the following examples. In these examples, parts by weight are related to parts by volume how grams to cubic centimeters.

109835/1690

example 1

1) 40 parts by weight of geranyl acetate are dissolved in 300 parts by volume of methanol. Through the solution for one equivalent of ozone to produce the corresponding ozonide is conducted at -78 ⁰ C. This ozonide is created by adding 20 room dividers! Dimethyl sulfide decomposes. The methanol is evaporated off under reduced pressure and the residue is distilled under reduced pressure, 19 parts by weight of 6-acetoxy-4-methyl-4-hexenal having a boiling point of 80 to 85 ° C./0.4 mm kg being obtained as a pale yellow oil .

^IR ^ Ztl ™ ^cm ~ ^1: 2720, 1730 (CHO), 1730, 1235 (OCOCH,),

1670 (c = c).

2) 0.1 part by weight of 6-acetoxy-4-methyl-4-hexenal are in 5 parts by weight of 90% aqueous tetrahydrofuran dissolved. 0.4 parts by weight of silver hydroxyä (AgO) are added to the solution. The mixture is stirred for 6 hours. The excess silver oxide and the precipitated silver metal are filtered off and washed with boiling water. The filtrate and the washing liquid are combined and acidified with hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried with anhydrous sodium sulfate and concentrated by evaporating the solvent, 0.083 part by weight of 6-acetoxy-4-methyl-4-hexenoic acid being colorless Oil can be obtained.

IR)> lil ^m cm ^"1: ₂ 650 ^shoulder, 1710 (COOH);

NMR (in CCl ₄ ) T _T value: 8.28 (CCH ₃ , singlet), 8.04 (COCH ₃ , singlet) 7.62 (COCH ₂ , = CCH ₂ , broad), 5.53 (OCH ₂ , Doublet), 4.69 (= CH, triplet), -0.71 (COOH, broad) Elemental analysis: jC H

Calculated for C ₉ H ₁₄ O ₄ : 58.05 7.58

Found: 57.76 7.69

109835/1690

_ 9 -

3) 0.2 part by weight of 6-acetoxy-4-methyl-4-hexenoic acid dissolved in 2 parts by volume of ethanol. 0.18 parts by weight are added to the solution Potassium hydroxide is added to 1 part by volume of 90% aqueous ethanol while stirring and cooling with ice. The reaction mixture is stirred for a further hour and then mixed with water and then by adding more dilute. Acidified hydrochloric acid. The acidic mixture is extracted with ethyl acetate. The extract is washed with water, dried with anhydrous sodium sulfate and concentrated by evaporating the solvent, whereby 0 ^ 15 parts by weight of 6-hydroxy-4-methyl-4-hexenoic acid can be obtained as a pale yellow oil. The yield is $ 97.

IR V ^ i ^m cm " ¹ : 3350 (OH), ₂ 65O ^shoulder , 1710 (COOH),

1680 (c = c)

KMR (in CDCl ₃ ) T value: 8.32 "(^ CCH ₃ , singlet), 7.61 (CH ₂ COO, SCCH ₂ , multiplet), 5.87 (OCH ₂ , doublet), 4 _t 60 ( = CH, triplet), 3s37 (COOH, OH, broad).

4} 0.192 parts by weight 6-hydroxy-4 - niei;: iyl ™ ^ "L · '·: θ ---:" λ * 3 are esterified with diazomethane, where 0 _} 207 Οών «·, parts methyl -6-hydroxy-4-methyl-4-hexenoate can be obtained as a colorless oil. The yield is $ 98.

-R ^v foi ^m cm " ¹ x. 3400 (0H), 1740, 1165 (COOCH.), 1675 (c = c) max j

HMR (in CCl ₄ ) mv'erti S, 38 (= CCH ^, singlet), 7.70 (GH ₂ COO, = 00H _2> multiplet), 6.6? (OH, singlet), 6.43 (COOCH ₃ , singlet), 6.04 (OCH ₂ , doublet), 4.71 (= CH,

Triplet).

Blemental analysis t Calculated for CgH _-14 O ₃ : Found:

C. H 60.74 8.92 60.55 9.05

09835/1830

Example 2

1) 2.2 parts by weight of silver oxide are added to 5 parts by weight of a 10% (weight / volume) aqueous sodium hydroxide solution. The reaction mixture is added a solution of 1.6 parts by weight ₀ 6-acetoxy-4-methyl-4-hexenal in 10 parts by weight

■ Methanol was added with stirring, whereupon the mixture was ^{stirred at 20 °} C. for a further hour. In the manner described in Example 1 (2), 0.99 part by weight of 6-hydroxy-4-methyl-4-hexenoic acid is obtained from the reaction mixture. The yield is $ 76.

2) 0.1 part by weight of methyl 6-hydroxy-4-methyl-4-hexanoate is dissolved in a mixture of 0.1 parts by volume of petroleum ether, 0.15 parts by volume of ether and 0.05 parts by volume of pyridine , 05 parts by volume of phosphorous tribromide _s dissolved in petroleum ether, the mixture is stirred for 2 hours at 0 C. The reaction mixture was poured into water and extracted with ether. The ether extract is washed with water, dried over anhydrous sodium sulfate and concentrated by evaporation of the ether, methyl 6-bromo-4-methyl-4-hexenoate being obtained as a pale yellow oil «

KMR (in CDGl ₃ ) T value 8.27 (= COH _3> singlet),

7.60 (= CCH ₂ , GH ₂ GOO, singlet), 6.36 (COOCH ₃ , stiletto), δ, 80 (BrOH ₂ , doublet, V 4.50 (= CH, triplet).

Cash spectrum (m / e) i 191 (molecular peak -OCH ₃ +2) ₃ 189 (molecular peak -OGH ₃ ), 14t (molecular peak -Br), 140 (molecular peak -HBr).

Example 3

0.02 parts by weight of iron (IIl) nitrate are added to 43 parts by volume of liquid ammonia, whereupon 3.3 parts by weight of metallic sodium are added. Then, acetylene gas is passed through the reading at -50 ⁰ G until the gray black mixture viirä>', -. Crauf 8.3 wt, parts by levulinic acid are added. JDas "un ions ^ emiach is at room temperature

0 9836/1690

left to stand so that the ammonia evaporates. The residue is diluted with water.

The mixture is acidified with dilute hydrochloric acid. the γ-ethynyl-Y-hydroxyvaleric acid formed here is extracted with ether and mixed with diazomethane, the methyl y-ethynyl-y-hydroxyvalerate being obtained will. The ether is evaporated and the residue is dissolved in 30 $ aqueous methanol solution. Becomes the solution one of 0.5 parts by weight of 5% palladium barium sulfate, Given 0.5 parts by weight of quinoline and 20 parts by volume of methanol produced suspension. Through the mixture obtained hydrogen is passed in with shaking until an equivalent amount of hydrogen is consumed. The catalyst is filtered off and the methanol is removed under reduced pressure. The residue is dissolved in ether, for Removal of the remaining quinoline, washed with dilute hydrochloric acid and dried over anhydrous sodium sulfate. The ether solution is concentrated by evaporation of the ether, with 7.8 parts by weight of methyl y-vinyl-Y-hydroxyvalerate can be obtained.

^ max ™ ^cm "" ¹ 'x 3500 (OH), 1730, 1200 (COOCH ₃ ), 164O (c = c). NMR (in CCl ₄ ) T value: 8.75 (CH ₃ -CO), 8.20 (CH ₂ -CO), 7.67 (CH ₂ COO), 7.36 (OH), 6.40 ( COOCH ₃ ), 5.00, 4.90 (CH ₂ =), 4.17 (CH =).

Example 4

To 1 part by weight of Y-vinyl-Y-hydroxyvalerolactone 4 parts by volume of a 10% aqueous sodium hydroxide solution given while chilling with ice. The resulting mixture is stirred for 1 hour under the same conditions. The mixture is acidified with dilute hydrochloric acid while cooling and then extracted with ether. The ether extract is washed with water. The γ-vinyl-Y-hydroxyvaleric acid methyl ester is formed by adding diazomethane to the solution educated.

1098 3 5/1690

Example 5

1) 0.1 part by weight of 2,3-dimethoxy-5-methyl-1,4-benzohydroquinone and 0.087 part by weight of methyl 6-hydroxy-4-methyl-4-hexanoate are dissolved in 5 parts by volume of dioxane. 0.3 parts by volume of 47% boron trifluoride etherate are added to the solution while the mixture is stirred in flowing nitrogen. Then, further 6 hours at 2O ⁰ C is stirred. The reaction mixture is poured into 10 parts by volume of water and the mixture is extracted three times with 30 parts by volume of ether each time. The ether extracts are washed with water, whereupon a solution of 1 part by weight of iron (III) chloride in 15 parts by volume of methanol is added. The resulting mixture is shaken. The ether layer is separated off, washed with water and dried with anhydrous sodium sulfate. The solvent is evaporated under reduced pressure to give 0.15 part by weight of a red oil. The oil is separated into two substances by column chromatography on silica gel. First, 0.015 part by weight of the 2,3-dirnethoxy-5-methyl-1,4-benzoquinone used as the starting material is recovered, whereupon 0.067 part by weight of trans, cis-2,3-dimethoxy-5-methyl-6- (3-methyl-5-methoxycarbonyl-2-pentenyl) -1,4-benzoquinone can be obtained.

T ^(E 1cm ^): oxidation form 275 (449), reduction form 292 (121)

^IR ^ 111 ** ^cm ~ ^{1s 1} ? 50, 1270, 1200 (COOCH,), 1660, 1650

1615 (quinone)

NIiR (in CCl ₄ ) T value: 8.34 (CiS = CCH ₃ , singlet), 8.28 (trans = CCH ₃ , singlet), 8.08 (CH ₅ on the benzene ring, singlet), 8.04 ( CH ₅ on the benzene ring, singlet), 7.70 (trans = CH ₂ , CH ₂ COO, broad), 7.61 (cis = CCH ₂ , broad), 6.90 (CH ₂ on the benzene ring, doublet), 6, 48 (trans COOCH ₃ , singlet), 6.38 (CiS-COOCH ₃ , singlet), 6.08 (2 H ₃ CO, singlet), 5.08 (= CH, triplet).

109835/1690

Mass spectrum (m / e) i 322 (molecular peak), 307 (molecular peak-CH ₃ ), 291 (molecular peak-OCH ^), 275, 247, 235, 197 "

Elemental analysis; _C H

Calculated for C ₁₇ H ₂₂ O ₆ : 63.34 6.88

Found: 63.41 6.75

2) 0.02 part by weight of trans, cis-2,3-dimethoxy-5-methyl-6- (3-methyl-5-methoxycarbonyl-2-pentenyl) -1,4-benzoquinone and 0.2 wt. Parts of pyrogallol are dissolved in 2 parts by volume of methanol. 2 parts by volume of a 10% methanolic potassium hydroxide solution are added to the solution. The mixture is kept in flowing nitrogen for one hour at 70 ^° C. After ice water has been added to the reaction mixture, it is acidified with dilute hydrochloric acid and extracted with ether. The ether extract is washed with water, whereupon a solution of 1 part by weight of iron ( III) chloride is added in 10 parts by volume of 30% aqueous methanol and the mixture is shaken. The ether layer is separated off, washed with water and dried over anhydrous sodium sulfate. The ether is evaporated and the residue is purified by column chromatography on silica gel as an adsorbent and one Solvent mixture of chloroform and ethanol (9: 1) purified as eluent, with 0.01 part by weight of trans, cis-2,3-dimethoxy-5-methyl-6- (carboxy-3-methyl-2-pentenyl) - 1,4-benzoquinone can be obtained as a red oil.

W> oxidation form 275, reduction form 290

^IR ^ 2? I4 cm " ¹ : 2650 ^shoulder , 1700 (COOH), 1660, 1650,

Max

1610 (quinone)

NMR (in CCl ₄ ) T value 8.35 (CiS = CCH ₅ , singlet), 8.27 (trans = CCH ,, singlet), 8.09 (CH, on the benzene ring, singlet), 7.72 (CiS = CCH ₂ CH ₂ CQO, broad), 7.60 (trans = CCH ₂ CH ₂ COO, broad), 6.92 (OHj, ara benzene ring, Dublect), 6.12 (CH ^ O ₅ singlet), 5, 06 C = CH. Triplet), 0.06 (COOH, broad).

109835/1690

Mass scale (m / e): 308 (molecular peak), 293, 247, 235. The trans, cis-2,3-dimethoxy-5-methyl-6- (5-carboxy-3-methyl-2-pentenyl) -1,4-benzoquinone prepared in this way is recrystallized from ether-hexane, whereby trans-2,3-dimethoxy-5-methyl-6- (5-carboxy-3-methyl-2-pentenyl) -1,4-benzoquinone is obtained in the form of orange crystals with a melting point of 60 to 65 ° C.

NMR (in CDCl ₅ ) T value: 8.24 (= CCH ₅ , singlet), 8.00 (CH ₅ on the benzene ring, singlet), 7.64 (= CCH ₂ , CH ₂ COO, broad), 6, 80 (CH ₂ on benzene ring, doublet), 6.03 (OCH ₅ , singlet), 5.00 (= CH, triplet), 0.24 (COOH, broad).

Elemental analysis;

Calculated for ^ Λ ^ ρθ ° β '' Found:

3) 0.1 part by weight of 2,3-dimethoxy-5-methyl-6- (5-carboxy-3-methyl-2-pentenyl) -1,4-benzoquinone in 10 parts by volume of ethanolic 1,5N hydrochloric acid solved. The solution is allowed to stand for 15 hours at 2O ⁰ C. The reaction mixture is poured into water and extracted with ether. The ether extract is washed with water, dried over anhydrous sodium sulfate and concentrated by evaporating the solvent. The residue is purified by column chromatography on silica gel, 2,3-Dimeihoxy-5-fliethyl-6- (5-ethoxycarbonyl-3-methyl-2-pentenyl) -1,4-benzoquinone being obtained as a red oil.

C. 32 6th H 62, 21st 6th , 54 62, , 61

IR V max ³ " ^{5 cm} "" ^{1: 175} O, 1275 (COOC ₂ H ₅ ), 1660, 1650, 1615

(Quinone)

NMR (in CCl ₄ ) r value 8.82 (CH ₅ , triplet), 8.27 (trans = CCH ₅ , singlet), 8.08 (CH ₅ on benzene ring, singlet), 7.78 (= CCH ₂ , GH ₂ COO, broad), 6.94 (CH ₂ on benzene ring, doublet), 6 _f -it- (2 E ₃ OO, singlet), 6.04 (CH ₂ OCO, quartet).

109835/16 9 0

Mass spectrum (m / e): 336 (molecular peak).

Example 6 -

1) 0.174 parts by weight of 2-methyl-1,4-naphthohydroquinone will be reacted with 0.158 parts by weight of methyl 6-hydroxy-4-methyl-4-hexanoate in the manner described in Example 5 (1). The yellow oil obtained is purified by column chromatography on silica gel as the adsorbent using a Purified solvent mixture of benzene and hexane (95: 5) as eluent, with 0.106 parts by weight of trans, cis-2-methyl-3- (3-methyl-5-niethoxycarbonyl-2-pentenyl) -1,4-naphthoquinone as a pale yellow oil.

mu (E] *): Oxydati ο ns form 244 (562),

248 (574), 262 (473), 270 (508), 330 (89); Redultion form 245 (1114), 271 (19o), 325 (90), 334 (90) ₀ ^cni ~ ¹ⁱ 1740, 1290 (COOCH,), 1660, 1620 (quinone).

C. H 73.06 6.45 72.93 6.37

HMR (in CCL ₄ ) T value: 8.36 (CiS = CCH ₃ , singlet), 8.24 (trans = CCH ,, singlet), 7.92 (CH ₅ on benzene ring, singlet), 7.75 (CiS = CH ₂ CH ₂ COO, singlet), 7.60 (trans = CCH ₂ CH ₂ C00, broad), 6.75 (CH ₂ on the benzene ring, doublet), 6.51 (transForm, COOCH ₅ , singlet) , 6.40 (cis form, COOCH ,, singlet), 5.01 (= CH, triplet).

Elemental analysis:
Calculated for C.qH ₂₀ 0 .:
Found:

2) 0.1 part by weight of trans, cis -2-methyl-3- (3-methyl-5-methoxycarbonyl-2-pentenyl) -1,4-naphthoquinone are with 30% aqueous potassium hydroxide solution in the presence of hydrosulfite hydrolyzed and then oxidized with ferrous chloride to give yellow crystals. By recrystallization ether becomes trans-2-methyl-3- (5-carboxy-3-methyl-2-pentenyl-1,4-naphthoquinone obtained in the form of yellow needles with a melting point of 130-131.5 ° C.

109835/1690

C. 46 6th H 72, 54 6th , 08 72, , 00

- 10 -

NMR (in CDCl ₃ ) T value: 8.23 (= CCH ₃ , singlet), 7 * 89 (CH ₃ on the benzene ring, singlet), 7.70 (= CCH ₂ , CH ₂ COO, broad), 6, 70 (CH ₂ on benzene ring, doublet), 4.96 C = CH ₁ triplet), 0.20 (COOH, broad).

Elemental analysis: Calculated for C ₁₈ H ₁ QO.ί Found:

The recrystallization mother liquor is concentrated to give crystals. The crystals are recrystallized from ether to give cis-2-methyl-3- (5-carboxy-3-N-ethyl-2-pentenyl) -1,4-naphthoquinone in the form of yellow crystals of melting point 118-119 ⁰ C is obtained.

NMR (in CDCl ₃ ) r value: 8.30 (= CCH _3> singlet), 7.30 (CH ₃ arn benzene ring, singlet), 7.45 (= CCH ₂ , CH ₂ COOH, singlet), 6, 61 (CH ₂ - on benzene ring, doublet), 4.92 (= CH, triplet). -

Elemental analysis: C_ H

For C ₁₈ H ₁₈ O: 72.46 6.08

Found: 72.21-6.00

Example 7

1) 0.304 parts by weight 2,3,5-trimethyl-1,4-benzohydroquinone with 0.158 parts by weight of methyl 6-hydroxy-4-methyl-4-hexenoate reacted in the manner described in Example 5 (1), 0.217 parts by weight of trans, cis ~ 2,3,5-triraethyl-6- (3-methyl-5-methoxycarbonyl-2-pentenyl) -1,4- benzoquinone as a pale yellow oil.

VY Af * ° ^H ταμ (E ] ^ J ι oxidation form 260 (612), 267 (624);

Reduction form 288 (97).

IR ^ ltl ^m cm " ¹ : 1740, 1300 (CCOCH,), 1640, 1620 (quinone).

NMR (in CCl ₄ ) T value: 8.36 (cis = CCH _3> singlet), 8.26 (trans = CCH ₃ , singlet), 8.04 (CH ₃ on the benzene ring, singlet), 7.74 ( cis = CH ₂ CH ₂ COO, broad), 7.60 (trans =

109835/1690

OCH ₂ CH ₂ COO, broad), 6.91 (CH ₂ on benzene ring, doublet), 6.45 (trans form COOCH ₅ , singlet), 6.58 (cis form COOCH ₅ , singlet), 5.06 (= CH, triplet).

Elemental analysis:

Calculated Found:

Calculated for C ₄₁₇ H ₀₀ O ,:

1 (έέ 4

C. 7th H 70 , 32 7th .64 * 70 , 36 , 59

2) 0.063 part by weight of 2,3,5-trimethyl-6- (3-methyl-5-methoxycarbonyl-2- pentenyl) -1,4-benzoquinone and 0.5 part by weight of pyrogallol are dissolved in 1 part by volume of methanol dissolved, whereupon 3 Raurnteile 10 $ strength methanolic potassium hydroxide solution are added and the mixture is refluxed for 5 hours in flowing nitrogen. The reaction mixture is acidified with dilute hydrochloric acid and extracted with ether. The ether extract is washed with water and mixed with a solution of 1 part by weight of iron (III) chloride in 10 parts by volume of 30% aqueous methanol. The resulting mixture is shaken. The precipitate is separated off, washed with water and dried over anhydrous sodium sulfate. The ether is evaporated off and the residue is purified by column chromatography on silica gel as the adsorbent and a solvent mixture of chloroform and ethanol (95: 5) as the eluent, crystals of trans, cis-2,3,5-triethyl-6- (5th -carboxy-3-methyl-2-pentenyl) -1,4-benzoquinone. The crystals are recrystallized from ether-petroleum ether, 0.032 part by weight of the desired compound being obtained. The crystals are recrystallized again from ether-petroleum ether, trans-2,3,5-trimethyl-6- (5-carboxy-3-methyl-2-pentenyl) -1,4-benzoquinone as yellow needles with a melting point of 103-104 ⁰ C can be obtained. IR V ^ ^m cm " ¹ : ₂ 65O ^shoulder , 1710 (COOH), I64O, 1630

(Quinone)

KMR (in CDCl ₅ ) Γ value: 8.20 C = CCH ₃ , singlet), 8.00 ^ H ₅ on the Scnzolring, single ti;), 7 ^ 2 C = CCH ₀ , OH ₉ OOO, broad ^ c78 CCHp £ ffi B -'- iiSolring, Dubiet-i), 4.99 fr <f, '": i:.: Ip] 3 H),

109835/1690
BAD ORlQlNAi-

C. H 69.54 7.30 69.65 7.18

- 18 -

0.75 (COOH, broad).

Elemental analysis;
Calculated for C ^ g
Found:

The mother liquor obtained in the above-described recrystallization is concentrated, crystals being obtained which are recrystallized from ether-petroleum ether, cis-2,3,5-trimethyl-6- (5-carboxy-3-methyl-2-pentenyl) -1,4-benzoquinone as yellow platelets with a melting point 102-104 ⁰ C is obtained.

IR >> ^F i ^lm cm- ¹ : 2650 ^shoulder , (1710 COOH), 1640,

1620 (quinone).

NMR (in CDCl ₅ ) T value: 8.30 (sCCH *, singlet), 8.00 (CH ₃ on benzene ring, singlet), 7.46 (= CCH ₂ , CH ₂ COO, singlet), 6.76 (CH ₂ on benzene ring, doublet), 4.96 (= CH, triplet), 0.60 (COOK, broad).

Elemental analysis: ) ° 4 ^: example 8th 69 C. - 7th H Calculated for C .., -Hp, 69 , 54 7th , 30 Found: , 73 , 62

1 part by weight of 2,3,5-triraethyl-1,4-benzohydroquinone and 0.8 part by weight of methyl 4-hydroxy-4-methyl-5-hexenoate are dissolved in 30 parts by volume of dioxane. To the mixture, 2 space parts of 47% boron trifluoride etherate are added to 5 parts by volume of dioxane, while the mixture is stirred under flowing nitrogen. The mixture is stirred for a further 3 hours at 2O ⁰ G. The reaction mixture is poured into 50 parts by volume of water and then extracted three times with 50 parts by volume of Xther each time. The ether extracts are washed with water, whereupon a solution of 10 parts by weight of iron (III) chloride in 100 parts by volume of aqueous methanol is added. The Estonian received is shaken. The ethereal layer works i-t'iietre'it, washed with water and with

193 335/169 0

dried anhydrous sodium sulfate. The solvent is evaporated to give 1.6 parts by weight of a red oil. The oil is column chromatographed Subjected to 30 parts by volume of silica. By eluting with 400 parts of a mixture of ether and hexane (3:97) are 0.475 parts by weight of 2,3,5-trimethylbenzoquinone won. A further elution with 500 parts by volume of a mixture of ether and hexane (8s92) gives 0.709 parts by weight trans, cis -2,3,5-trimethyl-6- (3-methyl-5-methoxycarbonyl-2-pentenyl) -1,4-benzoquinone as yellow oil.

Example 9

1.8 parts by weight of 2,3-bimethoxy-5-methyl-1,4-benzohydroquinone and 1.6 parts by weight of methyl 4-hydroxy-4-methyl-5-hexenoate v / earth dissolved in 30 parts by volume of dioxane. Become a mixture

2 parts by volume of 47% boron trifluoride etherate under flowing Given nitrogen. The mixture is stirred at 20 ° C. for 5 hours. The reaction mixture is dissolved in 50 parts by volume of water poured and extracted three times with 50 parts of ether each time. The ether extracts are washed with water and. under concentrated under reduced pressure. The residue is dissolved in 10 parts by volume of ether. A 56 $ will be the solution given aqueous sodium hydrosulfite solution. The mixture will treated with 30 $ aqueous potassium hydroxide solution while cooling with ice. The resulting mixture is

Stirred for 3 hours. "The reaction mixture is dissolved in water / water poured and extracted with ether. The ether extract is washed with water and then one with 10 parts by volume Solution of iron (III) chloride in 50% aqueous methanol offset. The mixture is shaken. The ether extract is separated, washed with ether and with anhydrous Dried sodium sulfate. The solvent is evaporated, 1.4 parts by weight of trans, cis-2,3-dimethoxy-5-methyl-6- (5-carboxy-3-methyl-2-peritenyl) -1,4-benzoquinone can be obtained as red oil.

109835/1 690

Claims (15)

Claims Ühinonderivate of the general formula O in which X and X ^{1 are} each a methyl radical or methoxy radical or stand for -CH = CH-CH = CH-, their corresponding lower alkyl esters and their pharmaceutically acceptable salts. 2) 2,3 »5-trimethyl-6- (3-methyl-5-methoxycarbonyl-2-pentenyl) -1,4-benzoquinone. 3) 2,3t5-trimethyl-6- (5-carboxy-3-methyl-2-pentenyl) -1,4-benzoquinone. 4) 2,3-Dimethoxy-5-methyl-6- (3-methyl-5-niethoxycarbonyl-2-pentenyl) -1,4-benzoquinone. 5) 2,3-dimethoxy-5-methyl-6- (5-carboxy-3-methyl-2-pentenyl) 1,4-benzoquinone. 6) 2-methyl-3- (3-methyl-5-methoxycarbonyl-2-pentenyl) -1,4-naphthoquinone, 7) 2-methyl-3- (5-carboxy-3-methyl-2-pentenyl) -1,4-naphthoohinone. 8) 2,3-Dimethoxy-5-methyl-6- (5-ethoxycarbonyl-3-methyl-2-pentenyl) -1,4-benzoquinone. 9) Process for the preparation of quinone derivatives according to claim 1 to 8, characterized in that in in a first stage the hydroquinone compounds 109835/1 690 -Pl- general formula in which X and X 'have the meanings given above, with a 4-hexenoic acid compound of the general formula CH, • ⁵ 2 ZCH ₂ CH = C - CH ₂ CH ₂ COOY ^ in which Z is a hydroxyl group, an acetoxy radical or a Halogen atom and Y is a hydrogen atom or a lower alkyl radical, or with a 5-hexenoic acid compound of the general formula OH ₀ -CHO-UiI ₀ UiU ₀ COOY '" Z 'is a Hyärcxvlg ;:; ppe your a halogen atom and Y has the above-mentioned definition, a condensate ion reaction and in a second stage the formed condensate of the general formula OH _{5 3}
EH ^^ a-CH CH OH in which X and X 'have the meanings given above ussd Y ^{1 is} a hydrogen atom or a lower alkyl radical, oxidizes, 10} 4-coacenic acid of the general formula ZCH ₀ CH-G- OH ₉ CH ₀ COOY ² in egg Z a hydroxyl group, an acetor-.yrect o-.Ur · 1.1 r. Halogenate ^ r. '. mv-i "l ~ a hydrogen atom or a 1Ü9835 / 1690 whose alkyl radical is, and 5-hexenoic acids of the general formula CH ₂ = CH-C CH ₂ CH ₂ COOY ² Z ¹ in which Z ^{1 is} a hydroxyl group or a halogen atom ο and Υ has the meaning given above. 11) 6 ~ acetoxy-4-methyl-4-hexenoic acid 12) 6-hydroxy-4-methyl-4-hexenoic acid 13) methyl 6-hydroxy-4-methyl-6-hexenoate 14) Methyl 4-hydroxy-4-methyl-5-hexenoate 15) Methyl 6-bromo-4-keylethyl 4-hexenoate 109835/1690