DE2051496A1 - - Google Patents

Description

"Furopyran compounds, process for their production and their use for the production of pharmaceuticals"

Priority: October 20, 1969, Japan, Wr. 83 708/69

October 1, 1970, Japan, ITr. not yet known

The invention relates to furopyran compounds in general
Partial formula

/ V 0 ^ ~ \ ^ 0

in which R- ^ and Rp are identical or different and are hydrogen atoms or optionally substituted hydrocarbon radicals
mean. The compounds can also be referred to as 4,5-dihydro-7H-fur'o- / 2,3-q7-pyrans. Preferred compounds of the invention are 6 ', 6'-dimethyl ~ 5β, 14β-6 · H- androstano / 16,17-2', 3'7-furo- / 3 ", 2» -4 ', 5 ^l -7 -pyran ~ 3ß, 14-diol, its 3-acetate and 3-tridigitoxoside, as well as 6 -Methy1-6 ^! H-5Ö, 14ß-androstano / l6,17-2, 3 ¹ J-

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furo-Z3 ", 2" -4 ^f , 5'_7-pyran-3ß, 14-diol _and 6'-phenyl-5ß, 14ß-6 ^f H-androstano / 16,17-2 ', 3 ' Jtuxo- ß " , 2" -4 ·, 5'7-pyran-3ß, 14-diol> .ODiCeß The aforementioned compounds have a cytotoxic effect on Heia cells and can be used, for example, for the treatment of viral infections or neoplastic diseases in human or veterinary medicine.

The invention also relates to a new process for the preparation of 4,5-dihydro-7H-furo- / 2,3-c / -pyrans and its derivatives, which is characterized in that an optionally substituted ß- (3-furyl) ethanol with a GarV, -yl compound in Bringing the presence of a dehydrating agent to the implementation.

The method of the invention runs schematically according to the following reaction equation:

Mk,

(D

(H)

- ^H 2 ° y

R-i and Rp have the meanings given above.

The compounds used according to the process of the general Formula I are known or are derived from known compounds · Palis positions 4 and 5 or ei and ß are substituted,

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these substituents can be derived from a wide variety of radicals, for example alkyl, alkenyl, alkynyl, alkylidene, alkylene, aryl, aralkyl, alkoxycarbonyl, carboxyl or acyl radicals, nitrogen functions, oxygen functions, sulfur functions or halogen atoms Carbon atoms in positions 4 and 5 or o ( and ß can also be part of a ring system.

The radicals R and Rp in the carbonyl compound of the general formula II can be aliphatic hydrocarbon radicals, for example alkyl radicals such as the methyl, ethyl, propyl, butyl, isobutyl, amyl, hexyl, octyl or isooctyl group, Alkenyl radicals, such as the vinyl, crotonyl or hexenyl group, alkynyl radicals, such as the ethynyl or propynyl group, cycloalkyl radicals, such as the cyclopentyl, cyclohexyl or cycloheptyl group, or monocyclic or polycyclic homocyclic or heterocyclic aromatic hydrocarbon radicals, such as the phenyl groups, Uaphthyl, pyridyl-pyrimidyl, thienyl or furyl group, the two radicals R ^ and R ₂ can also be linked to one another to form a cyclic ketone. The radicals R- and Rp can also be substituted. Examples of substituents are hydrocarbon radicals such as methyl, ethyl, propyl, butyl, isobutyl, amyl, heptyl, octyl, decyl, vinyl, crotonyl, hexenyl, ethynyl, propynyl, Cyclopentyl, cyclohexyl, cycloheptyl, phenyl, naphthyl, pyridyl, pyrimidyl, thienyl or furyl group. Alkoxycarbonyl radicals, such as the methoxycarbonyl, ethoxycarbonyl or phenoxycarbonyl group, carboxyl groups, acyl radicals, such as the acetyl, propionyl, capryl, methanesulphonyl, propanesulphonyl, or phenylsulphonyl, carboxylic acid acyl groups, phosphoric acid acyl groups, such as nitro, nitrogen,

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substituted amino groups, oxygen functions such as hydroxyl groups, Alkoxy or acyloxy radicals, sulfur functions, such as the mercapto, sulfide, sulfonyl or sulfoxide group, or halogen atoms, such as fluorine, chlorine or bromine atoms.

The carbonyl compound is preferably at least equimolar Amount used for ß- (5-furyl) ethanol or its derivative.

The reaction can be carried out in a solvent. The reactants can also serve as solvents. The reaction is preferably carried out at temperatures below 150 ° C. in order to avoid splitting of the furan ring.

As a dehydrating agent in the process of the invention, for. B. Lewis acids such as boron trifluoride, zinc chloride, calcium chloride, copper sulfate, tin tetrachloride, phosphorus pentoxide, inorganic acids such as nitric acid, sulfuric acid, hydrochloric acid or phosphoric acid, organic acids such as benzenesulfonic acid, .p-toluenesulfonic acid, methanesulfonic acid, acetic acid, trichloroacetic acid, Oxalic acid or formic acid, or other dehydrating agents can be used. The reaction medium preferably contains at most about 15 % of the dehydrating agent in order to avoid splitting of the furan ring.

The reaction can be carried out under anhydrous conditions or in the presence carried out by water.

The process products can be isolated and purified by customary methods, for example by separating off the dehydrating agent or non-unset starting compounds, extraction, washing, drying, chromatography, distillation and recrystallization

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sation.

The examples illustrate the invention.

example 1

A solution of 300 ml of freshly distilled β- (3-furyl) ethanol in 6 ml of acetone, which contains 3 ^c /> p-toluenesulfonic acid, is left to stand for 2 hours and 30 minutes at room temperature. The reaction mixture is then mixed with 5 percent aqueous sodium bicarbonate solution neutralized and extracted with ether. The ether extract is dried over sodium sulfate and evaporated. The crude product is purified by thin-layer chromatography on silica gel and distillation. 203 mg of 7,7-dimethyl-4,5-dihydro-7H-furo / 2,3 are obtained -c / -pyran obtained as a colorless oil.

Bp. 60 to 80 ⁰ C / 3 Torr. A ° 2 ^Η 5 ^ΟΗ 217 ταμ U = 6050).

Max
NMR (CDCl ₃ , r): 8.55 (6H, s); 7.47 (2H, t, J = 5.5 cps);

6.12 (2H, t, J = 5.5 cps); 3.79 (IH, d, J = 2 cps); 2.76 (IH, d, J = 2 .cps).

Example 2

A solution of 600 mg of ß- (3-puryl) ethanol and 0.1 ml of acetaldehyde in 10 ml of benzene, which contains 3 ^c ß> trichloroacetic acid, is left to stand for 5 hours at room temperature. The reaction mixture is then diluted with ether and washed first with 5 percent aqueous sodium carbonate solution, then with 10 percent aqueous sodium hydrogen sulfite solution, 5 percent aqueous sodium bicarbonate solution and finally with water, dried over sodium sulfate and evaporated. The residue is purified by thin layer chromatography and distillation. The 7-methyl-4,5-dihydro-7H-furo- / 2,3-c7-pyran is obtained as colorless

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Oil with a bp of 150 to 165 ° C / 3 Torr. NMR (CDCl ₅ , γ) ι 8.67 (3H, d, J = 5.5 cps); 7.33 (2H, m); 6.33 (2H, m); 5.20 (IH, g, J = 5.5 cps); 3.68 (IH, d, J = 2 cps); 2.68 (IH, d, J = 2 cps).

Example 3

A solution of 600 mg of β- (3-furyl) -ethanol and 250 mg of benzaldehyde in 5 ml of benzene, which contains 5 · $ trichloroacetic acid, is left to stand for 3 hours at room temperature. The reaction mixture is then washed, dried and evaporated according to Example 3. The residue is purified by thin layer chromatography. 7-PhenyJ-4,5-dihydro-7H-furo- / ~ 2,3-c / -pyran is obtained as a colorless oil. NMR (CDCl ₃ ,?): 7.33 (2H, m); 6.05 (2H, m); 4.32 (IH, broad singlet); 3.68 (IH, d, J = 2 cps); 2.70 (IH, s); 2.66 (5H, s).

Example 4

A mixture of 200 mg ß- (3-furyl) ethanol and 300 mg acetophenone in 5 ml benzene is mixed with 200 mg anhydrous copper sulfate and left to stand for 2 days at 0 ° C. The reaction mixture is then filtered and the piltrate evaporated under reduced pressure. The residue is purified by thin layer chromatography. The 7-methyl-7-phenyl-4,5-dihydro-7H-furo- [ 2,3-o / pyran] is obtained as a colorless oil.

Example 5

A solution of 200 mg .beta. (5-methyl-3-furyl) ethanol in 4 ml acetone containing 3 i> p-toluenesulfonic acid contains, is allowed to stand for 5 hours at ⁰ ° C. The reaction mixture is then neutralized with 5 percent aqueous sodium bicarbonate solution and extracted with ether. The ether extract is dried and evaporated. Of the

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The residue is distilled under reduced pressure. The 2,77-trimethyl-4,5-dihydro-7H-furo- / 2,3-c / -pyran is obtained as colorless Oil with a bp of 100 to 120 ° C / 3 Torr.

Example 6

A solution of 100 mg of 17β- (3-furyl) -5β, 14β-androstane-3β, 14, 16β triol in 30 ml of anhydrous acetone is stirred for 90 minutes at room temperature in the presence of 1.25 g of anhydrous copper sulfate. The reaction mixture is then filtered and the filter residue is washed out with acetone. The filtrate and the washing solution are combined and evaporated under reduced pressure. The residue is recrystallized from acetone. 96 mg of 6 ', 6'-dimethyl-6 ^f H -5β, 14β-androstano- / 16,17-2 ·, 3' / -for 0- / 3 ", 2" -. 4 ¹ , 5'_7-pyran-3β, 14-diol with a melting point of 192 to 195 ° C were obtained. λ ^σ 2 ^Η 5 ^ΟΗ 213 mu (£ = 6100). ν 3450, 1603 cm " ^1. £ Vj ?, ⁸ =

max _ ^majc

+ 28.4 (c = 0.162 in CHCl ₃ ).

By acetylation of the product with acetic anhydride in pyridine at room temperature gives the monoacetate mp 192-194 ⁰ C.

Example 7

A solution of 100 mg of 17β- (3-furyl) ~ 5β, 14β-androstane-3β, 14,16β triol in 2 ml of anhydrous acetone, which contains 1 ° β> p-toluenesulfonic acid, is stirred for 45 minutes at room temperature. The reaction mixture is then neutralized with 5 percent aqueous sodium bicarbonate solution and extracted with chloroform. The chloroform extract is washed with water, dried and evaporated under reduced pressure. The residue is recrystallized from a mixture of acetone and η-hexane. It becomes 92 mg

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of the compound obtained in Example 6.

Example 8

A solution of 100 mg of 17ß- (3-furyl) -5ß, 14ß-androstane-3ß, 14, 16ßtriol in 30 ml of benzene, which contains 1 $ acetic acid, is mixed with 1 ml of acetaldehyde, which is obtained from paraldehyde by distillation at 50 to 55 C was obtained in the presence of a small amount of concentrated sulfuric acid. The reaction mixture is left to stand at room temperature for 16 to 18 hours, then washed with 10 percent strength aqueous sodium bisulfite solution and water, dried and evaporated. The residue is purified by thin layer chromatography. There are 45 mg 6'-methyl-6'H ~ 5ß, 14ßandrostano / l6,17-2 ', 3 • y-furo / 3 ", 2" -4 ^l, 5 ^ 7-pyran-3.beta., 14 diol obtained from P. 197-200 ⁰ C. {«J ^ ² = + 7.2 ° (c = 0.929 in methanol), λ- £ f ^ 5 ^0H 217 ψ. (£ = 5910).

Example 9

A solution of 100 mg 17ß- (3-i ^l uryl) -5ß, 14ss-androstan-3.beta., 14,16ßtriol in 20 ml of benzene, which is saturated in the cold with p-toluenesulfonic acid, 1 ml of benzaldehyde. The mixture is left to stand at room temperature for 16 to 18 hours, then washed with 10 percent aqueous sodium bisulfite solution and water, dried and evaporated. The residue is purified by thin layer chromatography and recrystallized from a mixture of acetone and η-hexane. Yield 54 mg of pure 6'-phenyl-5β, 14β-6 Ή-androstano- / l6,17-2.3 ^! 7 ~ furo- / 3 "2» -4 ', 5 ¹ J- pyran-3β, 14-diol from P. 195 to 196 ⁰ C. f (Xj ^ ^Q = -40.0 ° (c = 0.430 in CHCl ,).

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Example 10

A solution of 200 mg of 17ß- (3-furyl) -5ß , 148 ~ andTos-taji-3ß, 1A-, 16ß triol-3-tridigitoxosid in 65 ml of anhydrous acetone is mixed with 2.5 g of anhydrous copper sulfate and 2 hours at Room temperature stirred. The reaction mixture is then filtered and the filter residue is washed out with acetone. The filtrate and the washing solution are combined and evaporated. The residue is purified by thin layer chromatography and recrystallization. There are 92 mg of 3-Tridigitoxosid the product of Example 6, mp 236-240 ⁰ C obtained.

213 mji (f = 686o). v ^ ⁰¹ 3450, 16O ₅ cm " ¹ .

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Claims (13)

-ίο- 205U96 Claims 1. Furopyranverbindungen the general partial formula J-U H, in which R ₁ and B _{2 are} identical or different and denote hydrogen atoms or optionally substituted hydrocarbon radicals. 2. 6 ^l , 6'-dimethyl-6 ^I H-5β, 14β-androstano- / 16,17-2 ', 3'7-furo- / 3 ", 2» -4 ·, 5' 7-pyran- 3β, 14-diol. 3. 6 ^{I, 6-dimethyl-t} 6 ^l H-5ß, 14ss-androstano - / i6,17-2 ^1, 3'7-furo l3 "ß" -4 ", 5 '7-pyran-3.beta., 14-diol-3-acetate. 4. 6 ·, 6 ^l -Dimeth _y l-6 ^l H-5ß, 14ß-androstano- / 16,17-2 ', 3' 7-furo-V "-4 ', 5 • 7-pyran-3ß, 14 ^fc- diol-3-tridigitoxoside. 5. 6 ^l -Methyl-6 ¹ H-5 [beta], 14 [beta] -androstano- / l6,17-2 ^f 3 '/ -furok / 0 ", 2" -4 ·, 5' 7-pyran-3 [beta], 14-diol . 6. 6'-Phenyl-6'H-5β, 14β-androstano- / 16,17-2 ', 3 ^! 7-furo- / 3 ", 2" -4 ', 5' 7-Py ^ran -3 ß. 14-diol. 7. Process for the preparation of 4,5-Mhydro-7H-furo- / 2,3-c7-pyrans or their derivatives, characterized in that an optionally substituted ß- (3-furyl) ethanol with a Carbonyl compound in the presence of a dehydrating agent brings to implementation. 109818/2262 205U96 8. The method according to claim 7, characterized in that a compound of the general formula is used as the carbonyl compound R ₁ -CO-R ₂ used in which R ₁ and R _{2 are} identical or different and denote hydrogen atoms or optionally substituted hydrocarbon radicals. 9. The method according to claim 7 and 8, characterized in that the carbonyl compound in at least an equimolar amount used. 10. The method of claim 7 to 9, characterized in that one carries out the reaction at temperatures below about 150 ⁰ C. 11. The method according to claim 7 to 10, characterized in that the reaction is carried out in the presence of the dehydrating agent carried out at a concentration of below about 15 percent by weight. 12. The method according to claim 7 to 11, characterized in that the ß- (3-furyl) ethanol compound is 3ß, 14, 16ß-trihydroxy-17ß-3-furyl) -5ß, 14ß-androstane or its 3-tridigitoxoside * is used. 13. Use of the compounds according to claim 2 to 6 for the preparation of medicines. 109818 / ^ 262