Steroids, the method of obtaining steroids, a method of obtaining a 16 - meilensteine, connection

 

(57) Abstract:

Use: as intermediate products in the synthesis of steroid drugs. The inventive product - steroids of General formula I listed in the description. The product is obtained by a multi-stage process comprising a stage of trialkylamine and oxidation thioalkyl group. 4C. and 11 C.p. f-crystals.

The invention relates to the field of synthesis of steroid compounds. More specifically, the invention relates to novel steroids of General formula I:

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where is the system or the 3-keto4or 3-keto1,4or 3-OR45in which R4a hydrogen atom or a group protecting the hydroxyl radical, R is methyl, -CH2OH or-CH2OR' in which R' is a group protecting the hydroxyl radical, R1and the same or different, phenyl, peredelnyj, diazolidinyl or bezodiazepines radical, n and m are the same or different, are 0 or 1, R2and R3a hydrogen atom, or R2the fluorine atom and R3formyloxy or actinometrical, and the dotted line in position 9(11) represent the possible presence of a double bond.

Among the compounds of formula (I) include:

the compound of formula (I) meets the General is more and R1and means phenyl or peredelnyj radical,

the compounds of formula (I) complying with General formula (IIN):

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where K, R, R1, R2, R3and the dotted line have a higher value;

the compounds of formula (I) complying with General formula (IC):

< / BR>
where K, R, R1, R2, R3and the dotted line have a higher value.

Among the compounds of formula (I), especially can be called:

21-acetoxy-alpha-[bis-(phenylthio)methyl] pregna-1,4,9/11/-triene-3,20-dione;

21-acetoxy-alpha-[/phenylthio//phenylsulfanyl/methyl]pregna - 1,4,9/11/-triene-3,20-dione;

21-acetoxy-alpha-[bis-(phenylsulfinyl)methyl] pregna - 1,4,9/11/-triene-3,20-dione.

The invention relates also to a method for producing compounds of formula (I) consists in the fact that the compound of formula (II):

< / BR>
where K, R, R2, R3and the dotted line have the meanings indicated above is subjected to an alkaline medium to the action of a reagent of the formula (R):

R1S-CH2-NO2(P)

where R1has the meaning indicated above, to obtain compounds of formula (III)

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where K, R, R1, R2, R3and the dotted line have the meanings specified above, in the presence of Carla obtain compounds of General formula (IA):

< / BR>
where K, R, R1, R2, R3and the dotted line have the above values, corresponding to the compound of formula (I), where m and n is 0, compounds of formula (IA), or subjected to the action of one equivalent of oxidizing agent to obtain compounds of formula (IB):

< / BR>
where K, R, R1, R2, R3and the dotted line have the above significance, corresponding to the compound of formula (I) where one of the values of m and n is 1, and the other is 0, or the action of at least two equivalents of oxidizing agent, to obtain the compounds of formula (IC):

< / BR>
where K, R, R1, R2, R3and the dotted line have the above value of the corresponding compounds of formula (I), where m and n are equal to 1.

In particular, the method according to the invention lies in the fact that the compound of formula (II):

< / BR>
where K, R, R2, R3and the dotted line have a higher value, put in an alkaline medium to the action of a reagent of the formula (R):

R1S-CH2-NO2(P)

where R1is above a certain value, to obtain the compounds of formula (III):

< / BR>
where K, R, R1, R2, R3and the dotted line are defined above znachitelnoe higher the value, to obtain the compounds of formula (IA):

< / BR>
where K, R, R1, R2, R3and dashed lines are above a certain value, corresponding to the compound of formula (I), where m and n are equal to 0, the compound of formula (IA) is subjected to the action of at least two equivalents of oxidizing agent, to obtain the compounds of formula (Ic):

< / BR>
where K, R, R1, R2, R3and dashed lines are above a certain value, corresponding to the compound of formula (I), where m and n are equal to 1.

The action of a reagent of the formula P in the compound of formula (II) is conducted in the presence of a base, which can be, in particular, aminirovanie basis, for example, secondary or tertiary amine, such as diethylamine or triethylamine, diazabicyclo (DBU), diazabicyclo (DBN), acetate, carbonate, hydride, hydroxide or alkoxide of an alkali metal, with a strong base, preferably used in catalytic quantities.

Work in the medium of organic solvent, which may be, for example, ether such as tetrahydrofuran or dioxane, an alcohol, such as methanol or ethanol, aromatic series solvent, such as benzene or toluene, or dimethylformamide, dimethylsilane weak, which can be, in particular, formic, acetic or propionic acid, a Lewis acid such as zinc chloride or aluminum chloride, or phosphoric acid. This acid may also play the role of solvent. The solvent may be a solvent of the aromatic series such as benzene or toluene. Reaction conditions are selected so that they are compatible with the protective group of hydroxyl, which may be the compound (II), and with the structure of the molecule in General, you want to save.

The oxidant used for the conversion of compounds of formula (IAin monosulfated or desulfated may be percolate such as m-chlormadinone acid, natantia acid, naftalina acid salt of magnesium monongalia acid or hydrogen peroxide in the presence of carboxylic acids, such as acetic acid or periodate, perborate or persulfate, in particular, sodium or potassium.

The compounds of formula (III) used to obtain steroids of the formula (I) are new compounds.

The steroids of formula I can be used in the synthesis of 16-methylene-steroids of General formula (A):

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where K, R, R2, R3and punction is cnyh products in the synthesis of therapeutically active compounds.

The method of 16-methylene-steroids of the General formula:

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where R is alkyl (C1-C4CH2OR', where R' is H or a protective group for a hydroxy-group,

- - - R2, R3and K have the above values,

is that a compound of General formula IA:

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where, R, R1, R2, R3and To have the above values, is treated with at least two equivalents of an oxidant, such as nakilat or hydrogen peroxide in the presence of carboxylic acid to obtain the compounds of General formula ICas described above, which is subjected to hot action teofilina means to obtain the target compounds of formula a or a compound of formula (Ic) defined above, hot expose teofilina means to obtain the target compounds of formula (A); or heat the compound of formula (IB) above, in the presence of teofilina agent to obtain compounds of formula (IV):

< / BR>
where K, R, R2, R3and the dotted lines have the meaning indicated above the dotted line in position 16/17/ and 16/16/ " indicates the presence of a mixture of diallylsulfide and vinyl sulfide, and the wavy line means the presence of cheap modern obtain the compounds of formula (V):

< / BR>
where K, R, R2, R3, dashed lines and the wavy line have the above significance, in which hot expose teofilina agent to obtain the target compounds of formula (A).

According to this method, you can:

to allocate or not to allocate desulfated formula (Ic):

first delete only by heating the first group-S(O)RIfrom desulfated formula (Icto obtain monosulfide compounds (V), and then delete the second group-S(O)RIthrough an intermediate form sulfonate described below, hot with teofilina agent;

to allocate or not to allocate the received monosulfated formula (V);

be removed only by heating the group-S(O)RIof the compounds of formula (IB);

to allocate or not to allocate monosulfide formula (V) obtained by oxidation of compounds of formula (IV).

The oxidant used for the conversion of compounds of formula (IAin the compound of formula (Icor for the conversion of compounds of formula (IV) into the compound of the formula (V) is one of those listed above.

Teofilina agent can be, for example, triphenylphosphine, trimethyl - or triarylphosphine, triphenyl the lot, thiol, such as thiophenol or a mercaptan, or a thiosulfate or bisulfite, such as sodium. Especially preferred triphenylphosphine.

Work in the medium of organic solvent or mixture of organic solvents, preferably under reflux. You can apply solvents aromatic series such as benzene, toluene, xylene, or cyclohexane, tetrahydrofuran, dioxane, dimethoxyethane, monoglyme or diglyme, optionally in a mixture with a proton solvent, in particular with alcohol, such as methanol, ethanol or isopropanol.

If necessary, operate in the presence of an alkaline carbonate such as sodium carbonate or potassium carbonate.

For information, it can be noted that during the reaction of allyl form of the sulfoxide of formula (V) is in equilibrium with sulfonates form (Va):

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which is restored to obtain the target compound (A).

Removing the protection from the products obtained, having one or two protected hydroxide, carry out well-known specialist of ways.

The invention relates to new intermediate products of the formula (IV) defined above, as well as to the compound of formula (Vb):

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the corresponding compounds of the formula (V), in which the dotted line position 16/17/ and 16/16'/ means the second link only in the 16/17/, except for those where R is the methyl radical, R2and R3the hydrogen atom and the double bond is 9/11/.

The compounds of formula (A), where R is the methyl radical, are described in particular in U.S. patents. 3354184, 3178462, 3312692, 3359287, 3064015, 3519619 or can be obtained from the compounds described in these patents, by methods known in the art. The compounds of formula (A), where R is the radical-CH2OH, free or protected, for example described in German patent 1263765, 1263766, and in U.S. patents 3350394, 4567001, 3354184, in the French patent 1285336 or in the European patent 104054 or 174496, or can be obtained by methods known in the art, from compounds described in these patents or U.S. patents 3309272 or 3178462.

The compounds of formula (II) in which R is methyl, is described in British patent 881501, 2199325 or can be obtained from the compounds described in these patents, as well as in German patent 2207420 or U.S. patents 4113722 and 3976638, by methods known in the art. Connection form, 2773058, 2864834, Belgian patents 540478 or 789, German patent 2207420, Dutch patent 6902507 or in the Soviet patent 819119, or may be obtained from compounds described in these patents and in U.S. patents 3976638 or 2966504, European patent 123736 or canadian patent 760431, by methods known to experts.

The reagents of the formula (R), where RIthe radical is methyl or phenyl, described in J. Chem. Soc. Chem. Comm. 1983, 835, 1878, 362 or even J. Org. Chem. 1978, 43, 3101. Other reagents of the formula (R) can be prepared by methods described in the above references.

The following examples illustrate the invention but do not limit it.

Example 1. 21-Acetoxy-alpha-[bis-(phenylthio)methyl] pregna-1,4,9/11/-triene-3,20-dione.

Stage A: 21-acetoxy-alpha-[(phenylthio)nitro methyl] - 1,4,9/11/-pregnadien-3,20-dione.

2,01 g of 21-acetoxy-1,4,9/11/, 16-pregnadien-3,20-dione and 1.1 g (phenylthio)nitromethane is dissolved in an inert atmosphere and without access of light, in a mixture of dry THF (20 ml) and tert-butanol (20 ml). Add 0.8 ml DBU /1,8-diazabicyclo[5,4,0] undec-7-EN/ and the reaction mixture stirred at room temperature for 8 hours. Add 2 g of citric acid in 50 ml of water. After extraction with dichloromethane, filtrowanie get to 3.73 g of crude product. Excess (phenylthio)nitromethane removed by absorption of the crude reaction product with a mixture of pentane (75 ml) and ether (30 ml). Get 2,79 21-acetoxy-alpha[(phenylthio)nitro methyl]-1,4,9/11/-pregnadien - 3,20-dione. So pl. 92 100oC.

IR spectrum (cm-1): 1740 (s); 1720 (s); 1655 (w); 1615 (w); 1540 (s), (NO2); 885 (w) (C-sph)

NMR spectrum 1N:

2 isomer: to 0.72 and 0.73 (3H, s, Me-18); of 1.41 (3H, s, Me-19); 2,17 and of 2.20 (3H, s, COCH3); to 2.67 and of 2.97 (1H, d, J, a 9.2 Hz, C17N); of 3.60 (1H, m, W1/235 Hz, C16-H); 4,43 and of 4.75 (2H, AB system, J of 16.9 Hz and 4,58 and 4,88 (2H, AB system, J of 17.0 Hz); 5,38 (1H, d, J 8,14 Hz, C16'-H) and 5,43 (1H, d, J 5,9 Hz, C16'-H); of 5.55 (1H, array, W1/210 Hz, C11-H); between 6.08 (1H, array, W1/210 Hz, C4-H); 6,30 (1H, d-d, J 10,2 Hz, J 1.7 Hz, C2-H); 7,17 (1H, d, J 10,2 Hz, C1-H), 7,34 7,38 (5H, array).

NMR spectrum13WITH:

30 carbon 2 isomer:

even: 29,87 and 30,65 (s); 32,00 (s); 34,60 (s); 44,38 44,60 and (g); 45,91 (g); 69,01 (g); 130,58 (g); 130,98 (g); 143,21 and 143,34 (g); 166,03 (g); 170,40 (g); 186,24 (g); 201,40 and 201,65 (g).

odd: 13,64 (p, 18-Me); to 20.52 (p, COCH3); 26,61 (p, 119-Me); 36,29 (t); 40,05 and 40,17 (t); 40,97 (t); 52,21 and 52,62 (t); of 61.95 (t); 98,03 and 98,54 (t); 119,65 (t); 124,18 (t); 127,62 (t); 129,71 (t); 129,87 (t); 132,94 (t); 133,23 (t); 154,17 (t).

Mass spectrum: m/z 512 (M+); 483; 391; 314; 213.

Stage B: 21-acetoxy-alpha-[(phenylthio)methyl]-1,4,9/11/-pregnadien - 3,20-dione.

2 ml of thiophenol and 5 ml of the thio)nitro methyl] -1,4,9/11/-pregna-triene - 3,20-dione and the mixture is heated with reflux for 4 hours 30 minutes. When the mixture cools, add 25 ml of ether. After neutralization with acetic acid solution (saturated) sodium bicarbonate was added 25 ml of ether. The organic layer is collected, washed with water, and then dried and concentrated. Get 4 g of brown oil. Remove excess thiophenol is the absorption of the crude product with a mixture of ether (25 ml) and pentane (100 ml). Obtain 1.70 g of the target derived disulfide. So pl. 98 100oC after purification by chromatography on silica (eluent: ether dichloromethane 9-1).

(alpha)D-13,4o(12,7 mg/ml; chloroform).

IR spectrum (cm-1): 1750 (s); 1720 (s); 1665 (s); 1630 (m); 1610 (w); 1585 (w); 1550 (w); 1480 (w); 1440 (w); 1410 (w); 1370 (w); 1270 (m); 1120(w); 1155 (w); 1070 (m); 1050 (m); 1025 (m); 890 (m).

NMR spectrum1H: 0,61 (3H, s, Me-18); of 1.37 (3H, s, Me-19); of 2.10 (3H, s, COCH3); 2,87 (1H, d, J, a 9.2 Hz, C17-H); and 3.31 (1H, m, W1/2GC, C16-H); 4.25 in and to 4.68 (2H, AB system, J of 16.9 Hz); 4,33 (1H, d, J 4.8 Hz, C16'-H; vs. 5.47 (1H, array, W1/29 Hz, C11-H); 6,03 (1H, array, W1/25 Hz, C4-H); 6,23 (1H, d-d, J 10.1 Hz, J 1.7 Hz, C2-H); 7,10 (1H, d, J 10,2 Hz, C1-H), 7.18 in 7,41 (1OH, array).

NMR spectrum 13WITH:

even: 30,38 (s); 32,14 (s); 34,64 (s); 40,23 (s); 44,54 (g); 134,40 (g); 143,38 (g); 154,45 (g); 166,50 (g); 170,32 (g); 186,31 (g); 202,50 (g),

odd: of 13.18 (p); 20,53 (p), 26,61 (p); 36,50 (t) is KTR: m/z 489 (M+ Sph).

Example 2. 21-Acetoxy-alpha-[(phenylthio) (phenylsulfinyl)methyl] -1,4,9(11)-pregnadien-3,20-dione.

60 mg of the disulfide obtained in example 1 are dissolved in 1 ml dichloromethane and cooled to -60oC. was Added 26 mg of metallocarboranes acid. After 1 hour again add 5 ml metallocarboranes acid. The reaction mixture is left at -60oC for 1 hour. Add 2 ml of saturated solution of sodium bicarbonate; bring the mixture to room temperature and extracted with dichloromethane (2, 1.5 ml). Then the organic layer is washed with water (3 2 ml), then dried and the solvent is evaporated under reduced pressure. Obtain 56 mg of the target raw monosulfated.

This derivative is unstable and stored in the refrigerator.

Example 3. 21-Acetoxy-alpha-[bis-(phenylsulfinyl)methyl] -1,4,9(11)- pregnadien-3,20-dione.

1,09 obtained in example 1 dissolved in 10 ml dichloromethane and cooled to -78oC. Add 796 mg, 80% metallocarboranes acid and incubated the reaction mixture at -78oC 3 hours. Add 15 ml of saturated sodium bicarbonate solution; the mixture is immediately brought to room temperature and extracted with dichloromethane. The organic layer PR is to participate chromatography on silica (eluant cyclohexane ethyl ester acetic acid 1-1); get 649 mg of the target product.

IR spectrum (cm-1): 3050, 2960, 2920, 1745(s), 1720 (s), 1660 (s), 1625, 1615 (m), 1580, 1450 (m), 1375, 1320, 1270, 1240 (s), 1150 (m), 1090 (m), 1050 (m), 890.

NMR spectrum1H:

1st isomer: to 0.62 (3H, s, Me-18); of 1.40 (3H, s, Me-19); to 2.18 (3H, s, COCH3); 3,43 of 3.54 (3H, 16-H, 16'-H and 17-H); 4,29 and 4.59 (2H, AB system, J of 16.6 Hz); the 5.51 (1H, array, W1/210 Hz, C11-H); between 6.08 (1H, array, W1/25 Hz, C4-H); 6,28 (1H, d-d, J 10,2 Hz, J 1.7 Hz, C2-H); to 7.15 (1H, d, J 10.1 Hz, C1-H); 7,31 7,66 (1OH, array).

2nd isomer: to 0.68 (3H, s, Me-18); of 1.40 (3H, s, Me-19); to 2.13 (3H, s, COCH3); 3,54 3,62 (3H, 16H, 16'-H b 17-H); of 4.44 and rate 4.79 (2H, AB system, J 16.5 Hz); 5,58 (1H, array, W1/210 Hz, C11-H); between 6.08 (1H, array, W1/25 Hz, C4-H); 6,28 (1H, dd, J of 10.2 Hz, J 1.7 Hz, C2-H); to 7.18 (1H, d, J 10.1 Hz, C1-H); 7,31-7,66 (1OH, array).

Example 3'. 21-Acetoxy-alpha-[(phenylthio) (phenylsulfinyl)] and alpha-[bis-(phenylsulfinyl)methyl]-1,4,9(11)-pregnadien-3,20-dione.

0,206 obtained in example 1 disulfide diluted in 2 ml of acetic acid in an argon atmosphere. Cooled to 0oC in an ice bath. To the mixture was added 5 drops of 30% hydrogen peroxide. Add a few drops of dichloromethane and allow the temperature to rise. After aging for 21 hours at room temperature get in large quantity monocult atmosphere and at room temperature, and then stop the reaction by adding water.

After processing as described in example 3 to obtain the target desulfated, identical to the product obtained in example 3.

Example 4. 21-Acetoxy-16-methylene-alpha-hydroxypregn-1,4,9(11)-triene - 3,20-dione.

Stage A. 21-Acetoxy-alpha-[(phenylthio)methyl] -1,4,9(11) 16-pregnadien-3,20-dione and the corresponding alpha-[(phenylthio)methylene]TV derived.

Monosulfated obtained as in example 2, on the basis of 204 mg of the disulfide, absorb 3 ml of dry toluene. Give 101 mg of triphenylphosphine and the solution is heated under reflux in an argon atmosphere for 15 hours. After 6 hours of heating was added 55 mg of triphenylphosphine. Then the toluene is evaporated and the product purified by chromatography on silica [eluent: cyclohexane/ethyl ester acetic acid 9/1, and then 3/1] Get a mixture of two isomers with the double bond in position 16 (Delta 16-16' or Delta 16-17).

The spectrum of IR (cm-1): 3020, 2910, 2820, 1750 (s), 1720 (m), 1660 (s), 1620 (m), 1580, 1550, 1430, 1370, 1260, 1040, 880.

NMR spectrum 1H: 0,80 (3H, s, Me-18); 1,41 and of 1.42 (3H, s, Me-19); 2,18 and are 2.19 (3H, s, COCH3); to 3.38 (1H, m, W1/210 Hz, C17-H); 3.72 points and 4.09 to (2H, AB system, J of 13.6 Hz, C16-H); of 4.44 and of 4.67 (2H, AB system, J 16.6 Hz) and 4,71 and the 4.90 (2H, systems of 1.7 Hz, C2-H); of 6.31 and 6,27 (1H, d, J 1.9 Hz, C16'-H), 7,16 7,52 (6H, array).

NMR spectrum13WITH:

even: 32,03; 34,27; 34,66; 36,66; 37,12; 37,77; 40,41; 44,05; 45,97; 47,09; 68,08; 69,01; 134,58; 136,18; 143,06; 143,79; 144,11; 145,90; 151,58; 166,37; 170,29; 186,34; 193,57; 200,77,

odd: 14,16; 16,02; 20,53; 26,54; 28,72; 35,73; 51,19; 63,20; 117,37; 119,84; 120,23; 123,97; 126,43; 127,43; 128,54; 129,09; 131,72; 154,47.

Mass spectrum: m/z 490, 489, 488 (M+), 448, 447, 446 (M+ -COCH3), 430, 415, 387, 319, 207.

Stage B: 21-Acetoxy-alpha-[(phenylsulfinyl)methyl] -1,4,9(11) 16-pregnacare-3,20-dione and the corresponding alpha-[(phenylsulfonyl)methylene] TV derived 6.42 per g of the mixture of isomers obtained in the preceding stage, are dissolved in 100 cm3dichloromethane and cooled to -78oC in nitrogen atmosphere. Add 2,92 g 80-s metallocarboranes acid and stirred for about 2 hours.

At low temperature, treated with saturated sodium bicarbonate solution and then water, dried and evaporated to dryness. After chromatography on silica (eluant ethyl ester acetic acid, and then ethyl ester acetic acid / methanol 9-1) get 3,44 g of a mixture of target sulfoxidov.

Stage b: 21-Acetoxy-16-methylene-alpha-hydroxypregn-1,4,9(11)-triene-3,20-dione.

The product obtained in the preceding stage, dissolved the 0oC, and then cooled and the solvent is distilled off.

After chromatography on silica (eluent ether - dichloromethane-petroleum ether 4-1-5), gain of 1.97 g of the target product. So pl. 213 215oC (decomp.) after crystallization in methanol. /alpha/D-32,8o/To 10.5 mg/ml; chloroform/.

IR spectrum (cm-1): 3200; 2900; 2850; 2250; 1750 (s); 1730 (s); 1675 (s); 1625; 1605; 1440; 1410; 1370; 1235 (s); 1075; 915 (s).

NMR spectrum1H: 0,70 (3H, s, Me-18); of 1.41 (3H, s, Me-19); 2,17 (3H, s, COCH3); 4,93 and 5,07 (2H, AB system, J 17.6 Hz); 5,02 (1H, s, C=CH2); 5,15 (1H, s, C=CH2); the ceiling of 5.60 (1H, array, W1/2=12 Hz, C11-H); 6,07 (1H, array, W1/25 Hz, C4-H); of 6.29 (1H, d-d, J 10,2 Hz, J 1.4 Hz, C2-H); then 7.20 (1H, d, J 10,2 Hz, C1-H).

NMR spectrum13WITH:

even: 31,96 (s); 32,25 (s); 33,36 (s); 35,05 (s); 46,04 (g); 45,45 (g); 68,65 (g); 89,65 (g); 114,45 (s); 142,28 (g); 152,64 (g); 166,49 (g); 170,64 (g); 186,37 (g); 204,00 (g),

odd: 14,18 (R); 20,60 (R); 26,81 (R); 36,38 (t); 64,31 (t); 120,83 (t); 124,05 (t); 127,50 (t); 154,51 (t).

Example 5. 21-Acetoxy-16-methylene-alpha-hydroxypregn-1,4,9(11)-triene - 3,20-dione.

205 mg of the mixture obtained as described in stage a of example 4, dissolved in 3 ml dichloromethane and cooled to -78oC in nitrogen. Give 91 mg 80-s metallocarboranes acid. After 2 hours the reaction of the initial product has completely disappeared. is the group and replace it with dry toluene. After 2 hours and 30 minutes of heating with reflux evaporated to dryness and after purification by chromatography on silica (eluant: cyclohexane ether, 4-1 to 0-1) obtain 113 mg of the target alcohol, the same as the alcohol obtained in example 4. So pl. 213 215oC.

Example 6. 21-Acetoxy-16-methylene-alpha-hydroxypregn-1,4,9(11)-triene-3,20-dione.

648 mg desulfated obtained in example 3 in an argon atmosphere was dissolved in 10 cm3toluene and the solution is cooled to -60oC. Add 500 mg of calcium carbonate and the reaction mixture is heated for 2 hours at 80oC. Then added 540 mg of triphenylphosphine and 10 cm3of methanol. The resulting solution is heated under reflux at 80oC for 11 hours and then cooled and brought to a dry condition. After chromatography on silica (eluant: cyclohexane ethyl ester acetic acid: 7-3, and then 1-1) obtain 217 mg of the target alcohol, identical to that obtained in example 4. So pl. 213 215oC.

Example 6'. 21-Acetoxy-16-methylene-alpha-hydroxypregn-1,4,9(11)-triene - 3,20-dione.

287 mg of desulfated obtained in example 3 or 3', dissolved in 5 ml of dry toluene and is added 250 mg of calcium carbonate. The solution is heated on the eh of trimethylphosphine after 8 hours and after 24 hours. After 34 hours of heating under reflux see by chromatography in thin layer that the reaction is completely finished. After cooling, the solution was added 15 ml of dichloromethane and 15 ml of water. The resulting mixture is filtered and the organic and aqueous layer separated. The organic layer was washed with a saturated solution of bicarbonate and a saturated solution of sodium chloride. After drying and removal of solvent to obtain 256 mg of crude desired product, which chromatographic on silica (eluant: petroleum ether ethyl ester acetic acid, 7-3, and then 1-1). Get 64 mg, i.e. 36% of the desired product, identical to that obtained in example 4. So pl. 213 215oC.

Example 7. 21-Acetoxy-16-methylene-alpha-hydroxypregn-1,4,9(11)-triene - 3,20-dione.

702 mg obtained in example 1 dissolved in 10.5 cm3dichloromethane in a nitrogen atmosphere and the solution is cooled to -60oC. Give 319 mg 80-s metallocarboranes acid. After 30 minutes add 243,6 mg of metallocarboranes acid and the reaction proceeds 5 hours between -60oC and -40oC. Then add 942 mg of triphenylphosphine, dichloromethane is evaporated under reduced pressure and replace it with 11 cm3dry tol is matographic the residue on a column of silica (eluant: cyclohexane ethyl ester acetic acid: 1-0 to 1-1), obtain 115 mg of the target alcohol, which is the same as the alcohol obtained in example 4. So pl. 213 215oC.

Example 8. 16-Methylene-alpha-hydroxy-4-pregnen-3,20-dione.

Stage A: alpha-[(phenylthio)-nitro methyl]-4-pregnen-3,20-dione.

138 mg 4,16-pregnadien-3,20-dione and 110 mg (phenylthio)nitromethane dissolve in the atmosphere (inert) and in the absence of light, 2 ml of a mixture of (1-1) of tetrahydrofuran and tert-butanol, and then add 0.1 ml of DBU (1,8-diazabicyclo-5,4,0-undec-7-ene) and the reaction mixture stirred at room temperature for 48 hours. Then add a solution of 0.5 g of citric acid in 5 ml of water. After extraction with dichloromethane, drying on sodium sulfate, filtration, and evaporation of the solvent under reduced pressure, the residue chromatographic on silicon dioxide, elwira ether and get to 48.3 mg of the desired product as a mixture of 2-1 epimeres. So pl. 166 172oC.

IR-spectrum (ADHD3): 1702, 1660, 1551 cm-1< / BR>
NMR spectrum (200 MHz):

1H: 7,4 (5H, m); 5,7 (1H, s); 5,4 (1H, 2d); 3,55 (1H, m); 2,87 (1/3H, d, J 8,8 Hz); 2,64 (2/3H, d, J 8,8 Hz); 2.23 to (2/3 3H, s); 2,16 (1/3 3H, s); of 1.18 (3H, s); of 0.71 (3H, s),

13C (ppm): 14,38; 17,47; 21,04; 28,72; 29,23; 31,58; 31,58; 31,76; 32,64; 34,00; 35,39; 35,83; 38,66; 38,76; 40,67; 45,23; 53,50; 54,75; 55,24; 66,86; 98,66; 98,99; 124,26; 129,53; 129,80; 131,45; 132,94; 170,18; 199,19; 206,37.

the I of the product obtained in stage a, get the appropriate diolepoxide that turn, as indicated in example 6, to obtain 16-methylene-alpha-hydroxy-4-pregnen-3,20-dione (target), obtained as described in U.S. patent 3354184.

Example 9. Beta-acetoxy-16-methylene-alpha-hydroxy-5-pregnen-3,20-dione.

Stage A: beta-acetoxy-alpha-[(phenylthio)nitro methyl]-5-pregnen-20-he.

124,3 g beta-acetoxy 5,16-pregnadien-20-she 89,7 mg (phenylthio)-nitromethane dissolved in inert atmosphere and in the absence of light in 2 ml of a mixture of (1-1) of tetrahydrofuran and tert-butanol, and then add 0.05 ml of DBU (1,8-diazabicyclo[5,4,0] undec-7-ene) and the reaction mixture stirred at room temperature for 48 hours. Then add a solution of 0.5 g of citric acid in 5 ml of water. After extraction with dichloromethane, drying on sodium sulfate, filtration and removal of the solvent under reduced pressure, the residue chromatographic on silicon dioxide, elwira a mixture of ether petroleum ether (1-3) and obtain 66 mg of the desired product as a mixture of 2-1 epimeres. So pl. 135 159oC.

IR-spectrum (ADHD3): 1720, 1702, 1551 cm-1< / BR>
NMR spectrum (200 MHz):

1H: (Delta) to 7.4 (5H, m); to 5.35 (1H, 2d); 4,6 (1H, m); 3,55 (1H, m); 2,85 (1/3H, d, J 8,8 Hz); 2,64 (2/3H, d, J 8,8 Hz); 2.23 to (2/3 3H, s); 2,16 (1/3 3H, s5,83; 66,90; 73,74; 98,73; 99,06; 121,96; 129,43; 129,71; 132,88; 139,72; 170,56; 206,64.

Stage B: beta-acetoxy-16-methylene-alpha-hydroxy-5-pregnen-3,20-dione.

Operating as described in example 3, but on the basis of the product obtained above in stage And receive the appropriate desulfated, which transform as described in example 6, to obtain beta-acetoxy-16-methylene-alpha-hydroxy-5-pregnen-3,20 dione (described in U.S. patent 3 519 619).

Example 10. 16-Methylene-alpha-hydroxy-4-pregna-4,9(11)diene-3,20-dione.

Stage A: alpha-[(phenylthio)nitro methyl]4,9(11)-pregnadien-3,2-dione.

100 mg pregna-4,9(11),16-triene-3,20-dione and 100 mg (phenylthio)nitromethane is dissolved in an inert atmosphere and in the absence of light, in 1 ml of a mixture of (1-1) of tetrahydrofuran and tert-butanol, and then add 30 mg of DBU (1,8-diazabicyclo[5,4,0] -undec-7-ene) and the reaction mixture is stirred 16 hours at room temperature. Then add a solution of 0.5 g of citric acid in 5 ml of water. After extraction with dichloromethane, drying on sodium sulfate and evaporation of the solvent under reduced pressure, the residue chromatographic on silicon dioxide, elwira a mixture of petroleum ether ethyl ester acetic acid (2-1) and obtain 129 mg of the desired product as a mixture of 2 is (CHBr3): 1707, 1665, 1614, 1552 cm-1< / BR>
NMR spectrum (200 MHz)

1H: (Delta) to 7.4 (5H, m); of 5.75 (1H, s); of 5.55 (1H, m); 5,4 (1H, 2d); and 3.6 (1H, m); 2.95 and (1/3H, d, J 9 Hz); 2,75 (2/3H, d, J 9 Hz); 2,24 (2/3 3H, s); 2,17 (1/3 3H, s); of 1.34 (3H, s); of 0.65 (3H, s).

13C (ppm): 13,96; 26,16; 29,50; 30,08; 31,28; 31,98; 32,60; 33,90; 34,25; 36,94; 40,70; 41,07; 43,47; 51,58; 52,09; 66,50; 66,68; 98,46; 98,81; 117,84; 124,26; 129,41; 129,70; 132,81; 145,10; 198,70; 206,03.

Stage B: 16-methylene-alpha-hydroxypregn-4,9(11)diene-3,20-dione.

Operating as described in example 3, on the basis of the product obtained in the previous stage And receive the appropriate desulfated that turn, as indicated in example 6, to obtain 16-methylene-alpha-hydroxypregn 4,9(11)-diene-3,20-dione (described in U.S. patent 3 359 287).

Example 11. 21-Acetoxy-alpha-fluoro-11-beta-acetoxy-alpha-bis- (2-pyridylthio)methylpregna-1,4-diene-3,20-dione.

Stage A: 21-Acetoxy-alpha-fluoro-11-beta-acetoxy-alpha-[(2-pyridylthio) nitro methyl]pregna-1,4-diene-3,20-dione.

Suspended in the inert gas atmosphere of 0.1 g of 21-acetoxy-alpha-fluoro-11 - beta-acetoxyphenyl-1,4,16-triene-3,20-dione in a mixture of 4 cm3of tetrahydrofuran and 1 cm3tert-butanol. Add in the lack of light 0,046 g (2-dipyridyl)-nitromethane and 0.035 cm31,8-diazabicyclo[5,4,0]-undec-7-ene. Agriauto> water. Extracted with methylene chloride, the organic phase is dried and the solvent evaporated. Chromatographic on silica, elwira a mixture of ethyl acetate-heptane (7-3). Get 0,128 g of target compound. So pl. 161 - 162oC.

IR-spectrum (nujol)

The absorption at 1735, 1657 and 1556 cm-1.

Analysis: C13H35FN2O8S

Calculated With 60,57; H 5,74; N 4,56.

Found, C 60,02; H 5,61; N 4,51.

1H-NMR spectrum (250 MHz)Delta ppm 0,94 (2s, 3H, Me); 1,4 (s, 3H, Me); of 2.15 (s, 6N, COMe); 6,11 (s, 1H); 6,32 (d, 1H, J 9 Hz); is 6.78 (d, 1H, J 10.5 Hz); and 7.6 (t, 1H, J 7.5 Hz); 8.3 (l, 0,4 H, J 3 Hz); 8,46 (l, 0,6 H, J 3 Hz).

Stage b: 21-acetoxy-alpha-fluoro-11-beta-acetoxy-alpha- [bis-(2-pyridylthio)methyl]pregna-1,4-diene-3,20-dione.

Work on the technique of stage B of example 1, based on 0,128 g of the product obtained in the previous phase A, and replacing thiophenol on pyridine-2-thiol. Get the target product.

1. Steroids of General formula I

< / BR>
where is a system of 3-keto --4, or 3-keto --1,4, or 3-OR4--5,

in which R4a hydrogen atom or a group protecting the hydroxyl radical;

R is methyl, -CH2OH or CH2OR1in which R1- group protecting the hydroxyl radical;

R1and R> n and m are the same or different, is 0 or 1;

R2and R3a hydrogen atom, or R2the fluorine atom and R3formyloxy or actinometrical,

and dotted lines in the position 9/11/ symbolize the possible presence of a double bond.

2. Steroids under item 1, characterized in that they correspond to the formula IA

< / BR>
where - - -, R1, R2, R3and To have the above values and phenyl or peredelnyj radical.

3. Steroids under item 1, characterized in that they correspond to the formula IB

< / BR>
where - - -, R, R1, R2, R3and To have the above values.

4. Steroids under item 1, characterized in that they correspond to the formula IC

< / BR>
where, R, R1, R2, R3and To have the above values.

5. Steroids under item 1, characterized in that the line - - - in position 9,11

carbon-carbon bond.

6. 21-acetoxy-16- - (bis/phenylthio-methyl/pregna/-1,4,9(11)-triene-3,20-dione.

7. 21 acetoxy-16 [(phenylsulfinyl)-methyl] pregna-1,4,-9,(11) triene-3,20-dione.

8. 21 acetoxy - a [bis(phenylsulfinyl)methyl]-pregna-1,4,9(11)-triene-3,20-dione.

9. The method of obtaining steroids of General formula under item 1, characterized in that the compound of General formula II

< / BR>
NTA General formula P

R1S CH2NO2,

where R1have the above values,

in the presence of laminirovannogo the basis for obtaining the compounds of General formula III

< / BR>
where - - -, R, R1, R2, R3and To have the above values,

which in the presence of carboxylic acid is subjected to the action of thiol or thiophenol General formula

< / BR>
where has the specified values to obtain compounds of General formula IA

< / BR>
where, R, R1, R2, R3and To have the above values,

which is further subjected to the action of one equivalent of oxidizing agent, such as nakilat or hydrogen peroxide, in the presence of carboxylic acid to obtain the compounds of General formula IB

< / BR>
where, R, R1, R2, R3and To have the above values,

or the action of at least two equivalents of an oxidant, such as nakilat or hydrogen peroxide, in the presence of carboxylic acid to obtain the compounds of General formula IC

< / BR>
where - - -, R, R1, R2, R3and To have the above values.

10. The method according to p. 9, characterized in that the compound of General formula II

< / BR>
where - - -, R, R2, R3and To have videocase>< / BR>
where R1have the above values,

to obtain compounds of General formula III

< / BR>
where - - -, R, R1, R2, R3and To have the above values,

which in the presence of carboxylic acid is subjected to the action of thiol or thiophenol General formula

< / BR>
where have the above values,

to obtain compounds of General formula IA

< / BR>
where - - -, R, R1, R2, R3and To have the above values,

and the compound of formula IA is exposed to at least two equivalents of an oxidant, such as nakilat or hydrogen peroxide, in the presence of carboxylic acid to obtain the compounds of General formula IC

< / BR>
where - - -, R, R1, R2, R3and To have the above values.

11. A method of obtaining a 16-meilensteine General formula

< / BR>
where R is alkyl (C1C4CH2OR', where R' is H or a protective group for a hydroxy-group,

- - -, R2, R3and To have the above values,

characterized in that the compound of General formula IA

< / BR>
where - - -, R, R1, R2, R3and To have the above values,

treated with at least two equivalents of oxidant, tformula IC under item 10, which is subjected to hot action teofilina means for obtaining the compounds of formula A, or a compound of General formula IB under item 9, is heated in the presence of teofilina agent to obtain compounds of General formula IV

< / BR>
where - - - R, R2, R3and To have the above values,

the symbol indicates the presence of a mixture of isomers of formula IV, after which it is subjected to the action of at least one equivalent of oxidizing agent, such as nakilat or hydrogen peroxide, in the presence of carboxylic acid to obtain the compounds of General formula V

< / BR>
where - - -, R, R2, R3and To have the above values,

that hot expose teofilina means to obtain the target compounds of formula A.

12. The method according to p. 11, characterized in that teofilina agent is triphenylphosphine.

13. The compound of General formula III

< / BR>
where - - -, R, R1, R2, R3and To have the above values,

as intermediate products.

14. Compounds of General formula IV

< / BR>
where - - -, R, R1, R2, R3and To have the above values,

as intermediate products.

15. Connect the e intermediate products.

 

Same patents:

The invention relates to covered bridge in position 1417thestratriene General formula I

< / BR>
where

if OR3is set tothen

R1, R2and R3independently from each other represent a hydrogen atom, acyl groupin which R4represents an organic residue with a number of carbon atoms up to 11, or a residue -/CH2/nCOOH carboxylic acid, with n=1-4, and, in addition, R1denotes benzyl, C1-C8-alkilany or C3-C5-cycloalkenyl balance, and

if OR3is in "beta", then

R1, R2and R3independently from each other represent a hydrogen atom, acyl group with 1-12 C-atoms, and R1additionally represents C1-C8is an alkyl residue, and in both cases A-B denote ateno or ethano-bridge,

the method of production thereof, pharmaceutical preparations that contain these compounds and to the use for the preparation of Lech

The invention relates to organic chemistry, specifically to a method for producing triterpene glycopeptides derived glycyrrhizic acid (GA) using unprotected glycoside (carboxy-component) and free amino acids or dipeptides (aminoquinones AK)

The invention relates to extraction of valuable chemicals from waste wood, namely the method of obtaining betulin formula 1 from birch bark used in medicine and perfumery industry [1]

< / BR>
Known methods of obtaining betulin, namely, that the bark is then ground in aqueous alkali and extracted with isopropyl alcohol

The invention relates to chemical-pharmaceutical industry, namely to new biologically active substances on the basis of which can be created drugs that have coagulation activity

FIELD: organic chemistry, steroids, chemical technology.

SUBSTANCE: invention describes a method for preparing 3-keto-7α-alkoxycarbonyl-substituted ▵4,5-steroid of the formula (I): wherein is taken among or R3 means hydrogen atom (H), lower alkyl, lower alkoxy-group or cyano-group (CN); R21 means hydrogen atom (H) or alkyl; R26 means (C1-C4)-alkyl; R8 and R9 form in common heterocyclic ring system. Method involves interaction of an alkylating agent with 4,5-dihydro-5,7-lactone steroid of the formula (II): wherein R18 means (C1-C4)-alkyl or R18O-group taken in common form O,O-oxyalkylene bridge or keto-group and R3, R8 and R9 have above given values in the presence of a base. Compounds of the formula (I) are used as intermediate compounds in improved methods for synthesis of epoxymexerone.

EFFECT: improved preparing method.

56 cl, 42 tbl, 30 sch, 5 dwg, 89 ex

FIELD: chemistry.

SUBSTANCE: invention describes an improved method forobtaining composition of the formula (II) or its salt, , by affecting compound of the formula (III) with activated derivative of propionic acid taken in the quantity of 1.3 mol per 1 mol of the compound III, and further removal of propionyl group linked to S atom from the compound of the formula IIA by effect of organic primary or secondary amine base capable of forming a water-soluble propanamide of diethanolamine or N-methylpiperazine preferentially.

EFFECT: obtaining product free from N,N-diethylpropanamide.

11 cl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention claims an improved method for obtaining flutixasone propionate in the form of polymorphous Form 1, which involves reaction of compound of the formula (II) or its salt with compound of the formula LCH2F, where L is a leaving group, possibly in the presence of interphase transfer catalyst, organic non-solvating fluid solvent non-mixable with water, and water.

EFFECT: chances to carry out crystal polumorphous fluticasone propionate obtaining process at normal air pressure and without extraction of transition product.

11 cl, 14 dwg

FIELD: chemistry.

SUBSTANCE: there is disclosed improved method of producing connection of formula [II] , being intermediate in fluticasone propionate synthesis by etherification of C-17 hydroxyl group 6α,9α-difluoro-11β, 17α-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-thiocarboxylic acid, compound of formula [I] . Method involves processing of compound [I] with small excess of carboxylic acid chloranhydride of general formula R-COCl where R stands for -CH2CH3, -CH2CH2CH3 or -CH(CH3)2, in inert solvent, with tertiary amine added. Preferentially, method is enabled with using pyridine with acetone added at temperature 5°C to -20°C.

EFFECT: method enables to eliminate intermediate byproduct.

13 cl, 3 ex

Chemical compounds // 2462472

FIELD: chemistry.

SUBSTANCE: invention relates to certain glucocorticoids derived by unsaturated fatty acids having anticancer therapeutic action and pharmaceutical compositions containing said compounds.

EFFECT: improved properties of the compound.

26 cl, 7 ex, 3 tbl

FIELD: biotechnology.

SUBSTANCE: invention relates to racemic 2,17β-disulfomoyloxy-3-methoxy-8α-extra-1,3,5(10)-triene inhibiting tumour cell proliferation of breast cancer MCF-7.

EFFECT: improvement of properties.

1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to disulphide polycationic amphiphile 1,32-bis(cholest-5-en-3-yloxycarbonylamino)-8,25-dioxo-3,4,21,22-tetrathia-7,10,14,19,23,26-hexaasedotriacontane tetrahydrochloride:

The invention also relates to a composition for extended and short nucleic acids delivery to mammalian cells and to a method for producing the composition for extended and short nucleic acids delivery.

EFFECT: disulphide polycationic amphiphile, capable of efficient delivery of nucleic acids to cells in the presence of serum in a growth medium.

4 cl, 2 tbl, 4 ex

FIELD: organic chemistry, steroids, pharmacy.

SUBSTANCE: invention describes unsaturated 14,15-cyclopropanoandrostanes of the general formula (I):

wherein R1 means hydrogen atom (H), hydroxy-group (OH); R2 means hydroxy-group (OH), hydrogen atom (H); R3 means hydrogen atom (H), (C1-C10)-alkyl at α- or β-position; R4 means halogen atom (F, Cl, Br) or pseudohalogen group (azide, rhodanide), hydroxy-group (OH), perfluoroalkyl; R5 means (C1-C4)-alkyl; if double bond is at 1,2-position then R4 can mean hydrogen atom (H). Also, invention relates to a method for preparing these compounds and pharmaceutical compositions containing these compounds. Compounds of the formula (I) are compounds eliciting gestagenic and/or androgenic effect.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

11 cl, 1 tbl, 9 ex

FIELD: organic chemistry, steroids, pharmacy.

SUBSTANCE: invention relates to a new type of selective estrogens comprising steroid structure of the general formula (I) with nonaromatic ring A and free of bound hydroxyl group at carbon atom 3 wherein R1 means hydrogen atom (H), (C1-C3)-alkyl or (C2-C3)-acyl; R2 means hydrogen atom (H), α-(C1-C4)-alkyl, α-(C2-C4)-alkenyl or α-(C2-C4)-alkynyl; R3 means hydrogen atom (H) or (C1-C4)-alkyl at position 16 of steroid structure; R4 means ethynyl; R5 means hydrogen atom (H), (C1-C3)-alkyl or (C2-C3)-acyl; R6 means (C1-C5)-alkyl, (C2-C5)-alkenyl, (C2-C5)-alkynyl being each of that is substituted optionally with chlorine or fluorine atom; dotted line means the optional double bond. Compounds of the formula (I) elicit the selective affinity to ERα-receptors.

EFFECT: valuable properties of compounds and composition.

4 cl, 3 sch, 1 tbl, 8 ex

FIELD: chemical technology, natural materials, medicine, pharmacy.

SUBSTANCE: invention relates to the improved method for preparing betulin from betulinic acid that can be used in preparing anti-tumor and anti-HIV medicinal preparations. Method for preparing betulinic acid involves oxidation of betulin with chrome (VI) oxide in acetic acid to betulonic acid and reduction with sodium boron hydride to betulinic acid. Betulonic acid sodium salt is reduced to betulinic acid and reduction reaction is carried out at room temperature at the concentration of sodium boron hydride 1.0-6.0 wt.-%. Invention provides simplifying method for preparing betulinic acid, reducing its cost and enhancing ecological safety of the process of it producing.

EFFECT: improved preparing method.

1 cl, 4 ex

FIELD: organic chemistry, steroids, medicine, pharmacy.

SUBSTANCE: invention relates to 3-methylene-steroid derivative of the general formula (1):

wherein R1 means hydrogen atom (H), or in common with R3 it forms β-epoxide; or R1 is absent in the presence of 5-10-double bond; R2 means (C1-C5)-alkyl; R3 means βH, βCH3 or in common with R1 it forms β-epoxide; either R3 is absent in the presence of 5-10-double bond; R4 means hydrogen atom, lower alkyl; Y represents [H, H], [OH, H], [OH, (C2-C5)-alkenyl], [OH, (C2-C5)-alkynyl] or (C1-C6)-alkylidene, or =NOR5 wherein R5 means hydrogen atom (H), lower alkyl; dotted lines represent optional double bond. Compound can relate also to its prodrug used for treatment of arthritis and/or autoimmune diseases.

EFFECT: valuable medicinal properties of compounds, improved method for treatment.

38 cl, 1 tbl, 18 ex

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