Technique for synthesizing ground shepping

Technique for synthesizing ground shepping

  • CN 101,081,849 A
  • Filed: 04/28/2007
  • Published: 12/05/2007
  • Est. Priority Date: 04/28/2007
  • Status: Active Application
First Claim
Patent Images

1. , a kind of synthesis technique of deserpidine may further comprise the steps:

  • 1) preparation of β

    -vinylacrylic acid1000~

    2000ml pyridine is stirred adding 300~

    600g propanedioic acid down, heating, temperature rises to 80 ℃

    , cooling drips down 400~

    450ml propenal, and temperature maintenance is at 80 ±

    5 ℃

    , 50~

    100 minutes, be chilled to 10 ℃

    , add refrigerated 1000~

    1500ml20~

    40% sulphuric acid soln, controlled temperature is separated out a large amount of solids below 20 ℃

    , filtration press dry, the water recrystallization, the gained solid adds 250ml water, heating for dissolving, behind the ice-cold 2h, separate out solid, filter faint yellow solid, merge above filtrate, use dichloromethane extraction, use the anhydrous sodium sulfate drying extraction liquid, reclaim methylene dichloride, get red oil, the water recrystallization gets solid, vacuum-drying, product C 5H6O2=98.14, mp.73~

    75 ℃

    ;

    2) along 5,8-diketone-1,4,5,8,9, the preparation of the 10-six hydrogen bitter edible plant-β

    -carboxylic acidsStep 1 product 300~

    400g is mixed the stirring heating dissolving with 300~

    400g benzoquinones, 1500~

    1800ml Glacial acetic acid, place, separate out yellow solid, filtration under diminished pressure, after filter residue washs with 100~

    180ml Glacial acetic acid, be washed till no acetic acid flavor with ether again, vacuum-drying gets product C 11H9O4=205.2, mp;

    220~

    222 ℃

    ;

    3) along 5-hydroxyl-8-ketone group-1,4,5,8,9, the preparation of the 10-six hydrogen bitter edible plant-carboxylic acidsStep 2 product 300~

    400g is added 2.4L water, cool off with ice bath, stir the aqueous solution that adding 2.4L is dissolved with 130~

    160g sodium bicarbonate, add 300~

    400ml ethyl acetate, molten entirely, begin to add the aqueous solution 1.2L that is dissolved with the 42g sodium borohydride, reaction mixture stirred after 15 minutes, added ethyl acetate 1200ml, was acidified to acidity with 20% aqueous sulfuric acid, begin to have crystallization to separate out, stirred 30 minutes at 0 ℃

    , filter, washing, dry that crude product is 270g, add the 600ml ethyl acetate in the mother liquor, layering, upper organic phase is separated, lower floor uses the 600ml ethyl acetate extraction again, merge organic layer, use the saturated sodium-chloride water washing, anhydrous sodium sulfate drying, concentrated ethyl acetate get oily matter with ether grind wash product C 11H10O4=206.2, mp;

    180~

    182 ℃

    ;

    4) suitable-8-ketone-1,4,5,8,9, the 10-six hydrogen bitter edible plants-1,5-carboxylic acid lactone'"'"'s preparationWith step 3 product 250~

    320g and 250~

    320ml aceticanhydride, 40~

    80g sodium acetate, anhydrous, the 4200ml methylene dichloride mixes stirring down, reflux, stirred 1.5 hours, cooling adds 1400ml methylene dichloride and an amount of frozen water and separates organic phase, organic phase is washed once with ice-cold sodium bicarbonate, merge water and wash with the methylene dichloride collection, combined dichloromethane is washed twice with saturated nacl aqueous solution, use anhydrous sodium sulfate drying, be concentrated into small volume to there being crystallization to separate out, filter 60 ℃

    of vacuum-dryings, obtain product C 11H10O3=190.2, mp;

    103~

    105 ℃

    ;

    5) suitable-5-hydroxyl-1,4,5,8,9, the 10-six hydrogen bitter edible plants-1,8-carboxylic acid lactone'"'"'s preparationStep 4 product 180~

    220g is added 5000ml Virahol and the stirring of 450g aluminum isopropylate, heating makes solid molten entirely, be heated to backflow then, begin slowly to steam acetone afterwards, steam Virahol to beginning decompression after acetone no longer produces, four of simmer down to original volume/for the moment, add ethyl acetate 3000ml, dissolving is cooled to 0 ℃

    , add the aqueous solution 5000ml that is dissolved with 3000g Seignette salt and 250g sodium bicarbonate, this mixture is divided into two-phase after stirring, water ethyl acetate extraction three times, and combined ethyl acetate washs with ice-cold sodium bicarbonate aqueous solution, with the saturated sodium-chloride water solution washing once, use the anhydrous potassium sulfate drying, after the evaporated under reduced pressure yellow solid, with ether grind wash white crystals, 60 ℃

    of vacuum-dryings get product C 11H12O3=192.2, mp;

    121.5~

    123 ℃

    ;

    6) suitable-2-bromo-3,5-oxygen-1,4,5,8,9, the 10-six hydrogen bitter edible plants-1,8-carboxylic acid lactone'"'"'s preparationStep 5 product 120~

    160g is dissolved in 200~

    250ml methyl alcohol, with the methanol solution reaction that contains the 124.8g bromine, the reactant room temperature was placed 45 minutes, used in the sodium bicarbonate solid and the Hydrogen bromide that generates, reaction solution is concentrated into about 200ml, with water dissolution inorganic salt wherein, the bromo-derivative that generates then becomes oily matter separates out, with water sepn, with acetone (1;

         1), grind wash white solid, 60 ℃

    of vacuum-dryings get product C 11H11BrO3=271.1, mp;

    121~

    123 ℃

    ;

    7) suitable-2-methoxyl group-3,5-oxo bridge-1,4,5,8,9, the 10-six hydrogen bitter edible plants-1,8-carboxylic acid lactone'"'"'s preparationStep 6 product 120~

    160g is dissolved in 900~

    1200ml methyl alcohol, add the 350ml sodium methoxide solution again, 3g sodium is dissolved in the 60ml methyl alcohol, places 2.5 hours in room temperature, reaction mixture glacial acetic acid acidifying, be concentrated into driedly then, add 840ml water, shake, add the 595ml methylene dichloride, layering, water layer dichloromethane extraction twice, combined dichloromethane, respectively wash once with saturated sodium bicarbonate and water, anhydrous sodium sulfate drying, drying under reduced pressure gets faint yellow solid, and ether grinds to be washed, filter, 60 ℃

    of vacuum-dryings, white solid C12H14O4=222.2, mp;

    97~

    98 ℃

    ;

    8) suitable-2-dimethoxy-3,5-oxo bridge-6-bromo-7-hydroxyl-1,4,5,8,9, the 10-six hydrogen bitter edible plants-1,8-carboxylic acid lactone'"'"'s preparationStep 7 product 90~

    110g is added 840ml and 0.5mol/L sulphuric acid soln 175ml, stir, be heated to 80 ℃

    , stir and keep temperature of reaction, add NBS.84g at 60~

    70 ℃

    , reaction mixture was 80 ℃

    of reactions 0.5 hour, be negative with starch potassium iodide test insolubles,, use 2100ml dichloromethane extraction four times to reaction end, extraction liquid with dried over sodium sulfate after, evaporated under reduced pressure gets yellow oil C12H15BrO5=319.1;

    9) suitable-methoxyl group-3,5-oxo bridge-6-bromo-7-chloro-1,4,5,8,9, the 10-six hydrogen bitter edible plants-1,8-carboxylic acid lactone'"'"'s preparationStep 8 product 150~

    200g with hot ethanol 371ml dissolving, is cooled to room temperature again.The 70g chromic anhydride is dissolved in 42ml water and the 420ml acetic acid, add in the flask, solution begins to heat up, begin to separate out crystallization after 2 minutes, reaction continues 10 hours, filter crystallization, with acetic acid and ether washing back acetone extract, concentrate acetone, product C 13H13BrO5=317.1, mp.;

    164~

    166 ℃

    ;

    10) preparation of acetoxyl group acidStep 9 product 80~

    100g is dissolved in 900ml Glacial acetic acid and 1;

    1 the mixed solution of aceticanhydride, in 15~

    20 ℃

    temperature range, in 1 hour, add the 25g zinc powder, adding the back reacted 30 minutes between 18~

    20 ℃

    , filter out unreacted zinc powder, wash with 1;

    1 mixed solution of 100ml Glacial acetic acid-aceticanhydride, in reaction mixture, add the 100ml pyridine, placed 4 hours 50~

    60 ℃

    of insulations, evaporated under reduced pressure solvent then, add 750ml water, with sodium bicarbonate pH value 8~

    9, wash to remove nonacid material, again with the aqueous phase solution hcl acidifying with ether, pH value 3~

    4, add sodium-chlor and make saturatedly, get product C 14H18O6=289.3 with 10 hours evaporate to dryness ether of extracted with diethyl ether again, mp.;

    212~

    216 ℃

    ;

    11) preparation of acetyl carboxylic acid50~

    80g joins the diazomethane diethyl ether solution with step 10 product, when not having bubble and produce, add diazomethane diethyl ether solution to solution again and be little when yellow, till when there is no the bubble generation, concentrated ethyl ether solution, filter to such an extent that yellow solid gets white solid C15H20O6=296.3 with cold washing with alcohol, mp.;

    135~

    1366 ℃

    ;

    12) preparation of adjacent hydroxylic speciesStep 11 product 50~

    80g is dissolved in the 1500ml acetone, stirs adding sal epsom 40g down, water 300ml, cryosel is bathed and is cooled to-5 ℃

    , gradation adds potassium permanganate powder 22g, keeps temperature of reaction at-5 ℃

    , adds half an hour approximately, add entry then, make solution be suspension, centrifugal, precipitate with washed with dichloromethane, use saturated aqueous sodium chloride, use dichloromethane extraction again, merge above-mentioned dichloromethane solution at last, anhydrous sodium sulfate drying, evaporated under reduced pressure, grind with small amount of ethanol and to wash, filter white solid, ethanol is placed still can separate out solid, merge product C 15H22O8=330.3, mp.;

    167~

    170 ℃

    ;

    13) preparation of lactanStep 12 product 30~

    60g adding is contained in the 6300ml aqueous solution of 11.5g Periodic acid, room temperature was placed 20 minutes under the nitrogen protection, use the 2500ml ethyl acetate extraction, combined ethyl acetate, it is inferior to give a baby a bath on the third day after its birth with saturated aqueous common salt, with a large amount of anhydrous sodium sulfate dryings, evaporated under reduced pressure, obtain light oily matter, add diethyl ether solution 2500ml, reaction continues 3 minutes, does not have bubble to produce, add repeatedly the diazomethane diethyl ether solution when not having gas and take place till, evaporated under reduced pressure then, temperature is no more than 30 ℃

    , obtains the 24.15g methyl compound, is glassy yellow oily matter, add the 200ml tetrahydrofuran (THF), add the 21.6g tryptamines simultaneously, tetrahydrofuran solution 300ml, the reaction mixture room temperature was placed 5 minutes, 50 ℃

    of following evaporated under reduced pressure, get yellow oil, be dissolved in the 1250ml methyl alcohol, with the reduction of 12.5g solid sodium borohydride, be reflected in 10 minutes and finish, be evaporated to 250ml, drip Glacial acetic acid and destroy unreacted sodium borohydride, use the 2M hcl acidifying again to PH4, use ethyl acetate extraction, combined ethyl acetate is used anhydrous sodium sulfate drying, evaporated under reduced pressure, obtain product 61.5g, add 7750ml pyridine and 400ml aceticanhydride then, placed about 14 hours, after the evaporated under reduced pressure, add the 1000ml ethyl acetate again, the ethyl acetate solution that obtains washs with sodium hydrogen carbonate solution, with 2M hydrochloric acid and saturated salt solution washing, uses anhydrous sodium sulfate drying again, concentrating under reduced pressure, grind with ether and to wash, product C 22H30N2O6=442.5, mp.;

    216~

    218 ℃

    ;

    14) preparation of hydroxyl lactamStep 13 product 10~

    30g is suspended in the methanol solution of 0.438g sodium methylate, refluxed 3 hours under the nitrogen protection, the end back of refluxing is used in the acetic acid and sodium methylate, and crystallization is separated out in 0~

    5 ℃

    of placement, obtain product C 22H28N2O5=400.5, mp.;

    220.5~

    222 ℃

    ;

    15) 3,4, the preparation of 5-trimethoxy benzoylation lactanStep 14 product 10~

    18g is dissolved in the 120ml pyridine and dissolves in 12g 3,4, the pyridine solution reaction of 5-trimethoxy-benzoyl chloride 12 hours, then in 45 ℃

    of reactions 8 hours, add ice-cold concentrated hydrochloric acid, chloroform extraction washs respectively with sodium carbonate solution, sodium hydrogen carbonate solution and sodium chloride solution, be neutral, drying, decompression steams chloroform, the residual acetone recrystallization of using of still, this product C 32H38N2O9=594.7, mp.;

    219~

    221 ℃

    ;

    16) preparation of (±

    ) deserpidineStep 15 product 10~

    20g is dissolved in the 150ml phosphorus oxychloride;

    nitrogen protection refluxed 2 hours down;

    decompression steams phosphorus oxychloride;

    get yellow solid;

    the chloric acid 40ml that crosses of adding 70% dewaters, and the frozen water of reaction back input 4000ml filters the product acetone that obtains;

    each the 200ml heating of tetrahydrofuran (THF) and water;

    added chloric acid 50ml and 25g zinc powder reduction;

    filter concentrated mother liquor, gained solids;

    dissolve in 100ml acetone;

    splash into an amount of strong aqua;

    mixing drops into the 400ml frozen water and gets crystallization after 5 minutes, filter;

    must invention deserpidine C32H38N2O8=578.7, mp.;

    201~

    203 ℃

    .

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