(22)-6b-methoxy-3a,5-cyclo-5a-cholestan-24-one-22-ol as an intermediate in the synthesis of (22r,23r)-3b-acetoxy-22,23 - isopropylidenedioxy-24-metalholic-5-ene


(57) Abstract:

Use: as an intermediate product in the synthesis of rototiller plants - brassinolide). The inventive product (22 x )-6 b-methoxy-3 a , 5-cyclo-5 a-cholestan-24-one-22-ol, yield 90%. BF C28H47O3. Reagent 1: (22 )-6 b-methoxy-3 a , 5-cyclo-5 a-pregnan-20-formyl. Reagent 2: methyltriphenylphosphonium in the presence of utility and isobutyronitrile. Reagent 3: hydrogen gas on the Raney Nickel in the presence of boric acid. Output increased 2.5 times since the simplified schema of the target product.

The invention relates to new chemical compound, specifically to (22 )-6-methoxy-3,5-cyclo-5-cholestan-24-one-22-Olu formula I,

which is an intermediate substance to obtain (22R, 23R)-3 - acetoxy-22,23-isopropylidenedioxy-24-metalholic-5 - ene of formula II;

Compound II is a well-known synthetic precursor hormone brassinolide) III, which is found in very low concentrations in some plants and is the most active of the new class of natural hormones - steroids, and therefore can be used in agriculture as a growth promoter, plant /1/. His synthesis of the methoxy-24-methyl - 5-cholestan-22,23,26-triol (IV):

It is obtained from (20S)-6-methoxy-20-formyl-3 , 5-cyclo-5-pregnane (V) in seven stages with the release of 21% in the General scheme /3/:

____< / BR>
____ ____< / BR>
IVAttach 2-liliputana to (20S)-22-aldehyde (V) receive fullcarbon in the form of a mixture of two isomers (VI) and (VII), one of which (VI) after chromatographic separation oxidized with N-bromosuccinimide and get lactol (VIII) as a mixture of two isomers, which is then transformed into a mix - and-ethoxyethyl esters (IX) and (X) with the release of 96% in the ratio of 3:1. Main isomer (IX), the selected chromatographic process lithium dimethylcarbinol, and the resulting ketone (XI) is subjected to the action of sitedisability and under the conditions that leads to bis-methylated product (XII) with a yield of 84%. The restoration of the keto group of compound (XII) detribalized get the alcohol (XII) with a yield of 92%, the treatment of which 10% HCl and subsequent recovery of lithium aluminum hydride leads to the desired triol (IV) yield 81%.

The use of triol (IV) to obtain the compound (II) includes the following stages:

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_____ The compound (IV) is heated in acetic acid and obtain the corresponding 3-acetoxy-5-ene (96%), which after processing p-toluensulfonate in acetone leads to and is cholest-5-ene (II) sequential processing methanesulfonamido in pyridine, recovering the resulting ester with lithium aluminum hydride and acetylation with a total yield of 80%.

The total number of stages in obtaining predecessor brassinolide) (II) under the scheme of the aldehyde (V) is equal to 9, with a total yield of about 12%.

The disadvantage of using triol (IV) as an intermediate product to obtain the compound (II) is a multi-stage process, its complexity, and not a high yield.

The aim of the invention is to simplify the process of obtaining (22R,23R)-3-acetoxy-22,23-isopropylidenedioxy-24-IU-TileList-5-ene (II) of the aldehyde (V) and the reduction in the number of stages.

This goal is achieved by the described compound (22 )-6-methoxy-3 , 5-cyclo-5-cholestan-24-one-22-I (I). The described compound (I) is obtained from the 20-aldehyde (V) in two stages according to the scheme:

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The aldehyde (V) is subjected to the action of the Wittig reagent and the resulting steroid olefin by 1,3-dipolar cycloaddition of isobutyronitrile turn in isoxazolin (XV) c output 90% recovery splitting on the Raney Nickel transform in the inventive connection-within (I) with the release of 95%.

It should be noted that the inventive compound (I) is used on the aspects of chromatographic separation epimeres. The transformation of the claimed compound (I) in the well-known synthetic precursor of brassinolide) (II) is carried out according to the scheme:

II-Within (I) the alkylate methyllithium, the resulting secondary alcohol is oxidized by the reagent Carreta (CrO3.Py) and dehydration by treatment with p-TsOH. Get inceton (XVI) with a total yield of 80% . Restoring eketone (XVI) diisobutylaluminium, epoxidation m-chloramben - sainoi acid and disclosure of epoxide aluminum hydride leads to diolo (XVII) with a yield of 60%. Last by boiling in acetic acid and treatment p-toluensulfonate in acetone converted into the target compound (II) with a yield of 90% . Thus, (22R,23R)-3-acetoxy-22,23-isopropylidenedioxy-24-metalholic-5-ene (II) receive from the aldehyde (V) under this scheme using the described compounds (I) in 5 stages with the release of 37%.

P R I m e R 1. Obtaining (22)-6-methoxy-3 ,5-cyclo-5-cholestan-24-one-22-ol.

To the suspension to 13.09 g (36.6 mmol) of methyltriphenylphosphonium in dry ether (150 ml) is added in an argon atmosphere at room temperature of 14.8 ml of a 2.25 M solution of utility. Stirred for 2 h and add 11,47 g (33.3 mmol) of the 20-aldehyde (V) in dry THF. The mixture is boiled for 5 hours Then filtered, dried over Na2SO4, the sid, obtained from 8,96 g (66,6 mmol) N-chlorosuccinimide in 300 ml of chloroform, to 0.12 ml of pyridine and 5,78 g (66,6 mmol) of oxime samalanga aldehyde. After a few minutes add 7,12 g (a 56.6 mmol) of triethylamine in chloroform for 6 hours, the Reaction mixture was stirred at room temperature for 24 h and the solvent evaporated. The residue is treated with water and extracted with ether. The ether solution is passed through a filter with alumina, the solvent is evaporated. Received 12,78 g (90%) of (20S,5' )-20-(3'-isopropylthiazole-5-yl)-6-meth - oxy-3 ,5-cyclo-5-pregnane (XV).

PMR-spectrum (200 MHz, M. D.): 0,42 m (1H, cyclop.), 0.65 m (1H, Cyclops. ), of 0.71 (3H,18-Me), of 0.87 (3H, J = 7 Hz, 21-Me), a 1.01 (3H, 19-Me), 1,15 d (6N, J = 7 Hz, 26-and 27-IU), 2,63 DD (1H, J1= 16 Hz, J2=8 Hz, C23-N), 2,71 Sept. (1H, J = 7 Hz, C25-N), 2,78 m (1H, C6-N), 2,94 DD (1H, J1= 16 Hz, J2= 11 Hz, C23-N) to 3.33 (3H, OMe), 4,67 m (1H, C22-H); IR spectrum (film, cm-1): 1620, 1100.

Mass spectrum (m/z): 427 /M/+, 412/M-Me)+, 395/M-MeOH)+, 372.

To a well stirred in ethyl alcohol the Raney Nickel type of 18.6 g (300 mmol) of boric acid and 12,35 g (29 mmol) of isoxazoline (XV). The reaction mixture was kept at room temperature and stirring in an atmosphere of hydrogen for 7 hours Then provide water and dried over Na2SO4. The solvent is evaporated to 2/3 of its volume and the residue is passed through a filter with silica gel. After evaporation of the solvent receive 11,84 g (95% ) (22 )-6-methoxy-3 ,5-cyclo-5-cholestan-24-one-22-ol (I). PMR-spectrum (200 MHz , M. D.): 0,44 m (1H, cyclop.), 0.65 M (1H, cyclop.), to 0.74 (3H, 18-Me), 0.95 (3H, J = =7 Hz, 21-Me), of 1.02 (3H, 19-Me), 1,11 d (6N, J = 7 Hz, 26-and 27-IU), 2,41 DD (1H, J1= 17 Hz, J2= 10 Hz, C23-N), 2,54 DD (1H, J1= 17 Hz, J2= 3 Hz, C23-H), 2.63 in Sept. (1H, J = 7 Hz, C23-N), 2,78 m (1H, C6-N) to 3.33 (3H, OMe), 4.10 m (1H, C22-N).

IR spectrum (film, cm-1): 3510, 1710, 1100.

Mass spectrum (m/z) 430/M/+, 415/M-Me/+,398/M-MeOH/+, 397/M-Me-H2O/+, 375, 329.

P R I m m e R 2. Receipt of (22R,23R)- 3-acetoxy-22,23-isopropylidenedioxy - 24-metalholic-5-ene (II).

To a solution of br11.01 g (25.5 mmol) is within (I) in 350 ml of absolute ether in an argon atmosphere is added dropwise 150 ml of 1.0 N. the ether solution metallice, maintaining a temperature of 0-5aboutC. Stirred the reaction mixture for 2 hours and add ammonium chloride, water, and extracted with ether. Dried over Na2SO4, evaporated, the residue is dissolved in 145 ml of methylene chloride and add 1.2 g of reagent Carreta. The solution was stirred at room temperature and evaporated. The residue is dissolved in 300 ml of anhydrous benzene, add a catalytic amount of para-toluenesulfonic acid and calcium chloride. The reaction mixture is heated to boiling and boil for 5-10 minutes Then the reaction mixture is cooled and passed through a layer of aluminum oxide evaporated. Get 8,67 g (80% ) 24-methyl-6-methoxy-3 ,5-cyclo-5-cholesterol-23-ene-22-she (XVI). IR spectrum (KBr, cm-1): 1680, 1620, 1040.

Mass spectrum (m/z): 426/M/+, 384/M-MeOH/+.

PMR-spectrum (200, MHz , M. D.): 0,44 m and 0.65 m (2N, cyclop.), 0,70 (3H, 18-Me), of 1.02 (3H, 19-Me), 1.07 (6N, J = 7 Hz, 26-and 27-IU), 1,11 d (3H, J = 7 Hz, 21-Me), 2,08 D. (3H, J = =1.5 Hz, 28-Me), to 3.33 (3H, OMe), 6,06 Shire. (1H, C23-N).

To mix the solution 5,112 g (0.012 mol) of the ketone (XVI) in 50 ml of THF in a stream of argon add 38 g of 86% of DIBAH in THF at -78aboutC. the Reaction mixture is stirred for 30 min and gently poured upon cooling in an ice bath in a mixture of methanol and petroleum ether. The resulting suspension is stirred for 1 h, evaporated the solvent, add 200 ml of water and extracted with methylene chloride, washed with a solution of NH4Cl and NaHCO3, dried over Na2SO4. To the resulting solution was poured a solution of 2.40 g (0.014 mol) of meta-chlormadinone acid in 25 ml of methylene chloride. The reaction dare and filtered through a layer of aluminum oxide. The solvent is evaporated. The residue is dissolved in ether and poured to aluminum hydride prepared from 0.34 g LiAlH4and 0.31 AlCl3in ether at room temperature. Stirred for 1 h and treated with 150 ml of 50% AcOH, extracted with ethyl acetate, the extracts washed with a solution of NaHCO3, water, dried over Na2SO4, evaporated. The residue is subjected to column chromatography on silica gel (eluent-hexane-ether). Get 3,21 g (60%) of (22R,23R,24S)-22,23-dihydroxy-24-methyl-6-methoxy-3 ,5-cyclo-5-cholestan (XVII).

PMR-spectrum (200 MHz , M. D.): 0,82 (3H, 18-Me), was 1.04 (3H, 21-Me), was 1.06 (3H, 19-Me), 1,11 d (3H, 28-Me), 1.16 and 1.20 of, 2 d (6N, 27 and 28 IU), 2,78 m (1H, 6-H), 3.33 and m (3H, OMe), 4,91-5,41 (2H, 22-H and 23-H).

IR spectrum (film, cm-1): 3450. Mass spectrum (m/z): 446/M/+, 431/M-Me/+, 414/M-MeOH/+.

2.37 g (5 mmol) of diol (XVII) is dissolved in 50 ml of acetic acid and boiled for 0.5 hours After cooling, the reaction mixture was poured into sodium hydrogen carbonate solution and extracted with ether, washed with water, dried over Na2SO4and evaporated. The residue is dissolved in acetone (50 ml), add a few crystals of p-toluene - sulfonic acids and boil for 2 hours, the Reaction mixture was poured into a solution of potassium carbonate and extracted with ether, dried over Na2SO4

IR spectrum (KBr, cm-1): 1735, 1250.

PMR-spectrum (200 MHz , M. D.): 0,80 (3H, 18-Me), of 1.03 (3H, 21-Me), was 1.06 (3H, 19-Me), 1.13 (3H, 28-Me), 1,17 l and 1.29 d (6N, 26 and 27 IU), 1,34 with and 1.52m (6N, IU-acetone. protection), 3,90 was 4.42 (2H, 22-H and 23-H), 4.59 (1H, 3-H), 5,38 m (1H, 6-H).

Mass spectrum (m/z): 514/M/+, 454/M-AcOH/+.

Thus, the use of the inventive substances (1) as an intermediate of synthesis of (22R, 23R)-3-acetoxy-22,23 - isopropylidenedioxy-24-metalholic-5-ene (II) of the aldehyde (V) allows platitudinal the transition to the target product, which is stage 4 less, compared with the scheme using analog (IV) to increase output by 2.5 times and to simplify the scheme, excluding the hard work of separating mixtures of epimeres in some cases.

(22 )-6-methoxy-3 ,5-cyclo-5-cholestan-24-one-22-ol of the formula

< / BR>
as an intermediate in the synthesis of (22R,23R)- 3-acetoxy-22,23-isopropylidenedioxy-24-metalholic-5-ene.


Same patents:

The invention relates to bio-organic chemistry, namely to new chemical compounds - N-hydroxyl-containing phosphonates steroids of General formula I XO-H where X is the residue of the hydroxyl-containing steroid,

for example:

cholesterol (Chs)< / BR>
testosterone (TS)which can be used as source reagents for solid-phase synthesis of steroid derivatives of oligonucleotides and their analogues

FIELD: organic chemistry, steroids, medicine, pharmacy.

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38 cl, 1 tbl, 18 ex

FIELD: organic chemistry, medicine, pharmacy.

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22 cl, 7 tbl, 41 ex

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2 cl, 3 ex

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27 cl, 31 ex, 1 tbl, 2 dwg

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19 cl, 38 ex, 12 tbl

FIELD: chemistry.

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2 cl, 1 ex

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31 cl, 127 ex, 5 tbl

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6 cl, 4 ex, 3 dwg

FIELD: medicine.

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