RU2024540C1 - (22ζ)-6b- METHOXY -3a,5 -CYCLO-5a-CHOLESTANE-24-0NE-22-OL AS SEMIPRODUCT FOR SYNTHESIS OF (22R,23R)-3b- ACETOXY-22,23- ISOPROPYLINDENDIOXY-24-METHYLCHO- LEST-5-EN - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: product: (22x)-6b-methoxy-3a,5-cyclo-5a-cholestane-24-one-22-ol, yield is 90% , empirical formula is C₂₈H₄₇O₃. Reagent 1: (22ζ)-6b- methoxy -3a,5- cyclo-5a- pregnane-20-formyl. Reagent 2: methyltriphenylphosphonium bromide in the presence of butyllithium and isobutyronitrile oxide. Reagent 3: hydrogen - gas on the Raney nickel in the presence of boric acid. Synthesized compounds is used as a plant growth stimulating agent. EFFECT: yield is increased by 2.5 times, simplified method of synthesis.

Description

являющемуся промежуточным веществом для получения (22R, 23R)-3β- ацетокси-22,23-изопропилидендиокси-24-метилхолест-5- ена формулы II;

Соединение II представляет собой известный синтетический предшественник фитогормона брассинолида III, который содержится в крайне низких концентрациях в некоторых растительных объектах и является наиболее активным из нового класса природных фитогормонов - брассиностероидов, в связи с чем может найти применение в сельском хозяйстве в качестве стимулятора роста растений /1/. Его синтез из соединения II описан с выходом 15% /2/.The invention relates to a new chemical compound, specifically to (22 ζ) -6β-methoxy-3α, 5-cyclo-5α-cholestan-24-one-22-olu of the formula I,

which is an intermediate for the preparation of (22R, 23R) -3β-acetoxy-22,23-isopropylidenedioxy-24-methylcholest-5-ene of formula II;

Compound II is a well-known synthetic precursor of the phytohormone brassinolide III, which is found in extremely low concentrations in some plant objects and is the most active of the new class of natural phytohormones - brassinosteroids, and therefore can be used in agriculture as a plant growth stimulator / 1 /. Its synthesis from compound II is described with a yield of 15% / 2 /.

II
Известен /3/ ближайший аналог соединения (I) - (22R,23R)-6 β-метокси-24-метил- 5 α-холестан-22,23,26-триол (IV):

Его получают из (20S)-6β-метокси-20-формил-3 α, 5-цикло-5 α-прегнана (V) в семь стадий с выходом 21% по общей схеме /3/:

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_IV Присоединением 2-литийфурана к (20S)-22-альдегиду (V) получают фурилкарбинол в виде смеси двух изомеров (VI) и (VII), один из которых (VI) после хроматографического разделения окисляют N-бромсукцинимидом и получают лактол (VIII) в виде смеси двух изомеров, которую затем превращают в смесь α- и β -этоксиэтиловых эфиров (IX) и (Х) с выходом 96% в соотношении 3:1. Основной изомер (IX), выделенный хроматографически, обрабатывают литий- диметилкупратом, а образовавшийся при этом кетон (XI) подвергают действию литийдиизопропиламида и метилиодида, что приводит к бис-метилированному продукту (XII) с выходом 84%. Восстановлением кето-группы соединения (XII) натрийборгидридом получают спирт (XII) с выходом 92%, обработка которого 10% HCl и последующее восстановление алюмогидридом лития приводит к требуемому триолу (IV) с выходом 81%.II

II
Known / 3 / the closest analogue of the compound (I) - (22R, 23R) -6 β-methoxy-24-methyl-5 α-cholestan-22,23,26-triol (IV):

It is obtained from (20S) -6β-methoxy-20-formyl-3 α, 5-cyclo-5 α-pregnane (V) in seven stages with a yield of 21% according to the general scheme / 3 /:

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_IV By the addition of 2-lithiumfuran to (20S) -22-aldehyde (V), furylcarbinol is obtained as a mixture of two isomers (VI) and (VII), one of which (VI) is oxidized with N-bromosuccinimide after chromatographic separation to give lactol (VIII) in the form of a mixture of two isomers, which is then converted into a mixture of α- and β-ethoxyethyl esters (IX) and (X) in 96% yield in a 3: 1 ratio. The main isomer (IX), isolated by chromatography, is treated with lithium dimethyl cuprate, and the resulting ketone (XI) is exposed to lithium diisopropylamide and methyl iodide, which leads to a bis-methylated product (XII) in 84% yield. By reducing the keto group of compound (XII) with sodium borohydride, alcohol (XII) is obtained with a yield of 92%, treatment with 10% HCl and subsequent reduction with lithium aluminum hydride leads to the desired triol (IV) with a yield of 81%.

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Соединение (IV) нагревают в уксусной кислоте и получают соответствующий 3-ацетокси-5-ен (96%), который после обработки п-толуолсульфокислотой в ацетоне приводит к ацетониду (XIV) с выходом 90%. Полученный ацетонид (XIV) превращают в (22R,23R)-3β-ацетокси-22,23-изопропили- дендиокси-24-метилхолест-5-ен (II) последовательной обработкой метансульфонилхлоридом в пиридине, восстановлением образовавшегося эфира алюмогидридом лития и ацетилированием с общим выходом 80%.The use of triol (IV) for the preparation of compound (II) comprises the following steps:

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Compound (IV) is heated in acetic acid to give the corresponding 3-acetoxy-5-ene (96%), which after treatment with p-toluenesulfonic acid in acetone leads to acetonide (XIV) in 90% yield. The resulting acetonide (XIV) is converted to (22R, 23R) -3β-acetoxy-22,23-isopropyl-diodeoxy-24-methylcholest-5-ene (II) by sequential treatment with methanesulfonyl chloride in pyridine, reduction of the resulting ester with lithium aluminum hydride and acetylation with common 80% yield.

 The total number of stages in the preparation of the brassinolide (II) precursor according to this scheme from aldehyde (V) is 9 with a total yield of about 12%.

 The disadvantage of using triol (IV) as an intermediate product to obtain compound (II) is the multi-stage process, its complexity and insufficiently high yield.

 The aim of the invention is to simplify the process of obtaining (22R, 23R) -3β-acetoxy-22,23-isopropylidenedioxy-24-methylcholest-5-ene (II) from aldehyde (V) and reduce the number of stages.

Альдегид (V) подвергают действию реагента Виттига и образовавшийся стероидный олефин путем 1,3-диполярного циклоприсоединения изобутиронитрилоксида превращают в изоксазолин (XV) c выходом 90% , который восстановительным расщеплением на никеле Ренея трансформируют в заявляемое соединение β-кетол (I) с выходом 95%.This goal is achieved by the described compound (22) -6β-methoxy-3α, 5-cyclo-5α-cholestan-24-one-22-ol (I). The described compound (I) is obtained from 20-aldehyde (V) in two stages according to the scheme:

Aldehyde (V) is exposed to the Wittig reagent and the resulting steroid olefin is converted to isoxazoline (XV) by 1,3-dipolar cycloaddition of isobutyronitrile oxide in 90% yield, which is converted by Raney nickel reduction to the claimed compound β-ketol (I) in 95 yield %

II β-Кетол (I) алкилируют метиллитием, полученный вторичный спирт окисляют реактивом Саррета (CrO₃ ^. Py) и дегидратируют путем обработки п-TsOH. Получают енкетон (XVI) с общим выходом 80% . Восстановление енкетона (XVI) диизобутилалюмогидридом, эпоксидирование m-хлорнадбен- зойной кислотой и раскрытие эпоксида гидридом алюминия приводит к диолу (XVII) с выходом 60%. Последний путем кипячения в уксусной кислоте и обработкой п-толуолсульфокислотой в ацетоне превращают в целевое соединение (II) с выходом 90% . Таким образом, (22R,23R)-3β-ацетокси-22,23-изопропилидендиокси-24-метилхолест-5-ен (II) получают из альдегида (V) по данной схеме с использованием описываемого соединения (I) в 5 стадий с выходом 37%.It should be noted that the claimed compound (I) is used in the further scheme in the form of two isomers according to C-22. In the case of synthesis of its analogue (IV) at two stages, careful chromatographic separation of epimers is required. The conversion of the claimed compound (I) into a known synthetic precursor of brassinolide (II) is carried out according to the scheme:

II β-ketol (I) is alkylated with methyllithium, resulting secondary alcohol oxidized Sarreta reagent (CrO ^_3. Py) and dehydrated by treatment with p-TsOH. Get enketone (XVI) with a total yield of 80%. The reduction of enketone (XVI) with diisobutylaluminohydride, epoxidation with m-chloroperbenzoic acid and the opening of the epoxide with aluminum hydride leads to diol (XVII) in 60% yield. The latter, by boiling in acetic acid and treatment with p-toluenesulfonic acid in acetone, is converted into the target compound (II) in 90% yield. Thus, (22R, 23R) -3β-acetoxy-22,23-isopropylidenedioxy-24-methylcholest-5-ene (II) is obtained from aldehyde (V) according to this scheme using the described compound (I) in 5 steps with a yield 37%

 PRI me R 1. Obtaining (22ζ) -6β-methoxy-3 α, 5-cyclo-5 α-cholestan-24-one-22-ol.

To a suspension of 13.09 g (36.6 mmol) of methyltriphenylphosphonium bromide in dry ether (150 ml) was added in an argon atmosphere at room temperature 14.8 ml of a 2.25 M butyl lithium solution. It is stirred for 2 hours and 11.47 g (33.3 mmol) of 20-aldehyde (V) in dry THF are added. The mixture is boiled for 5 hours. Then it is filtered, dried over Na ₂ SO ₄ , evaporated and dissolved in 30 ml of chloroform. The resulting solution is added in one step to a solution of isobutyronitrile oxide obtained from 8.96 g (66.6 mmol) of N-chlorosuccinimide in 300 ml of chloroform, 0.12 ml of pyridine and 5.78 g (66.6 mmol) of isobutyric aldehyde oxime. After a few minutes, 7.12 g (56.6 mmol) of triethylamine in chloroform was added over 6 hours. The reaction mixture was stirred at room temperature for 24 hours and the solvent was evaporated. The residue is taken up in water and extracted with ether. The ethereal solution was passed through an alumina filter, and the solvent was evaporated. Received 12.78 g (90%) of (20S, 5 'ζ) -20- (3'-isopropylisoxazolin-5-yl) -6β-methoxy-3-α, 5-cyclo-5-α-pregnane (XV) .

1 H-NMR spectrum (200 MHz, δ ppm): 0.42 m (1H, cyclopr.), 0.65 m (1H, cyclopr.), 0.71 s (3H, 18-Me), 0, 87 d (3H, J = 7 Hz, 21-Me), 1.01 s (3H, 19-Me), 1.15 d (6H, J = 7 Hz, 26 and 27-Me), 2.63 dd (1H, J ₁ = 16 Hz, J ₂ = 8 Hz, C ₂₃ -H), 2.71 sept. (1H, J = 7 Hz, C ₂₅ -H), 2.78 m (1H, C ₆ -H), 2.94 dd (1H, J ₁ = 16 Hz, J ₂ = 11 Hz, C ₂₃ -H ), 3.33 s (3H, OMe), 4.67 m (1H, C ₂₂ -H); IR spectrum (film, cm ^-1 ): 1620, 1100.

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

To well-mixed Raney nickel in ethyl alcohol, 18.6 g (300 mmol) of boric acid and 12.35 g (29 mmol) of isoxazoline (XV) are added. The reaction mixture was kept at room temperature and stirred in a hydrogen atmosphere for 7 hours. Then the catalyst was separated on a filter, the solvent was evaporated. The resulting residue was dissolved in ethyl acetate, washed with water and dried over Na ₂ SO ₄ . The solvent is evaporated in 2/3 of the volume and the residue is passed through a filter with silica gel. After evaporation of the solvent, 11.84 g (95%) (22 ζ) -6 β-methoxy-3 α, 5-cyclo-5 α-cholestan-24-one-22-ol (I) are obtained. 1 H-NMR spectrum (200 MHz, δ, ppm): 0.44 m (1H, cyclopr.), 0.65 M (1H, cyclopr.), 0.74 s (3H, 18-Me), 0 95 d (3H, J = 7 Hz, 21-Me), 1.02 s (3H, 19-Me), 1.11 d (6H, J = 7 Hz, 26 and 27-Me), 2, 41 dd (1H, J ₁ = 17 Hz, J ₂ = 10 Hz, C ₂₃ -H), 2.54 dd (1H, J ₁ = 17 Hz, J ₂ = 3 Hz, C ₂₃ -H), 2, 63 sept. (1H, J = 7 Hz, C ₂₃ -H), 2.78 m (1H, C ₆ -H), 3.33 s (3H, OMe), 4.10 m (1H, C ₂₂ -H).

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

Mass spectrum (m / z), 430 / M / ⁺ , 415 / M-Me / ^+, 398 / M-MeOH / ⁺ , 397 / M-Me-H ₂ O / ⁺ , 375, 329.

 Example 2 Preparation of (22R, 23R) - 3 β-acetoxy-22,23-isopropylidenedioxy-24-methylcholest-5-ene (II).

To a solution of 11.01 g (25.5 mmol) of β-ketol (I) in 350 ml of absolute ether under argon atmosphere was added dropwise 150 ml of 1.0 N. ether solution of methyl lithium, maintaining a temperature of 0-5 ^about C. Stir the reaction mixture for 2 hours and add ammonium chloride, water and extracted with ether. It is dried over Na ₂ SO ₄ , evaporated, the residue is dissolved in 145 ml of methylene chloride and 1.2 g of Sarret's reagent are added. The solution was stirred at room temperature for 2 hours and passed through a layer of alumina, washed with ether (3x50 ml), the filtrates were dried over Na ₂ SO ₄ and evaporated. The residue is dissolved in 300 ml of anhydrous benzene, a catalytic amount of para-toluenesulfonic acid and calcium chloride are added. The reaction mixture is heated to boiling and boiled for 5-10 minutes. Then the reaction mixture is cooled and passed through a layer of alumina, evaporated. 8.67 g (80%) of 24-methyl-6 β-methoxy-3α, 5-cyclo-5α-cholest-23-en-22-one (XVI) are obtained. IR spectrum (KBr, cm ^-1 ): 1680, 1620, 1040.

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

1 H-NMR spectrum (200 MHz, δ, ppm): 0.44 m and 0.65 m (2H, cyclopr.), 0.70 s (3H, 18-Me), 1.02 s (3H , 19-Me), 1.07 d (6H, J = 7 Hz, 26 and 27-Me), 1.11 d (3H, J = 7 Hz, 21-Me), 2.08 d (3H, J = 1.5 Hz, 28-Me), 3.33 s (3H, OMe), 6.06 br. s (1H, C ₂₃ -H).

To a stirred solution of 5.112 g (0.012 mol) of ketone (XVI) in 50 ml THF under argon is added 38 grams of 86% solution of DIBAL-H in THF at -78 ^C. The reaction mixture was stirred for 30 minutes and poured carefully under cooling in an ice bath a mixture of methanol and petroleum ether. The resulting suspension was stirred for 1 h, the solvent was evaporated, 200 ml of water was added and extracted with methylene chloride, washed with a solution of NH ₄ Cl and NaHCO ₃ , dried over Na ₂ SO ₄ . A solution of 2.40 g (0.014 mol) of meta-chloroperbenzoic acid in 25 ml of methylene chloride is added to the resulting solution. The reaction mixture was kept at room temperature for 20 hours, then washed with a NaHCO ₃ solution, the organic layer was separated and filtered through a layer of alumina. The solvent was evaporated. The residue was dissolved in ether and poured onto aluminum hydride prepared from 0.34 g of LiAlH ₄ and 0.31 AlCl ₃ in ether at room temperature. Stirred for 1 h and treated with 150 ml of 50% AcOH, extracted with ethyl acetate, the extracts were washed with NaHCO ₃ solution, water, dried over Na ₂ SO ₄ , and evaporated. The residue was subjected to silica gel column chromatography (eluent-hexane-ether). 3.21 g (60%) of (22R, 23R, 24S) -22,23-dihydroxy-24-methyl-6β-methoxy-3α, 5-cyclo-5α-cholestane (XVII) are obtained.

 1 H-NMR spectrum (200 MHz, δ, ppm): 0.82 s (3H, 18-Me), 1.04 d (3H, 21-Me), 1.06 s (3H, 19-Me) , 1.11 d (3H, 28-Me), 1.16 and 1.20, 2 d (6H, 27 and 28-Me), 2.78 m (1H, 6-H), 3.33 m ( 3H, OMe), 4.91-5.41 s (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) are dissolved in 50 ml of acetic acid and boiled for 0.5 hours. After cooling, the reaction mixture is poured into a solution of sodium bicarbonate and extracted with ether, washed with water, dried over Na ₂ SO ₄ and evaporated. The residue was dissolved in acetone (50 ml), several crystals of p-toluene sulfonic acid were added and boiled for 2 hours. The reaction mixture was poured into a solution of potassium carbonate and extracted with ether, dried over Na ₂ SO ₄ , passed through an alumina filter and evaporated. 2.31 g (90%) of (22R, 23R) -3β-acetoxy-22,23-isopropyl-dienedioxy-24-methyl-cholest-5-ene (II) are obtained.

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

 1 H-NMR spectrum (200 MHz, δ, ppm): 0.80 s (3H, 18-Me), 1.03 d (3H, 21-Me), 1.06 s (3H, 19-Me) 1.13 d (3H, 28-Me), 1.17 d and 1.29 d (6H, 26 and 27-Me), 1.34 s and 1.52 s (6H, Me-acetone. Protection) 3.90-4.42 (2H, 22-H and 23-H), 4.59 m (1H, 3-H), 5.38 m (1H, 6-H).

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

 Thus, the use of the claimed substance (1) as an intermediate of the synthesis of (22R, 23R) -3β-acetoxy-22,23-isopropylidenedioxy-24-methylcholest-5-ene (II) from aldehyde (V) allows for a five-stage transition to the target the product, which is 4 stages less than the scheme using analogue (IV), increase the yield ≈ 2.5 times and simplify the scheme, eliminating the painstaking work of separating epimer mixtures in some cases.

Claims (1)

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

3 β-acetoxy-22,23-isopropylidenedioxy-24-methylcholest-5-ene as an intermediate in the synthesis of (22R, 23R).