CN105017377B - The preparation method of cortex hormone of aadrenaline pharmaceutical intermediate - Google Patents

The preparation method of cortex hormone of aadrenaline pharmaceutical intermediate Download PDF

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CN105017377B
CN105017377B CN201510390485.4A CN201510390485A CN105017377B CN 105017377 B CN105017377 B CN 105017377B CN 201510390485 A CN201510390485 A CN 201510390485A CN 105017377 B CN105017377 B CN 105017377B
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刘喜荣
曾春玲
唐杰
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Hunan Xinhexin Biological Medicine Co ltd
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    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0005—Oxygen-containing hetero ring
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Abstract

The invention discloses a kind of preparation method of cortex hormone of aadrenaline pharmaceutical intermediate, comprise the following steps：Using chemical compounds I as raw material, add cyanating reagent progress cyano group substitution reaction and obtain compound ii；Compound ii and silane epoxide reagent are subjected to siloxy group protection reaction under alkaline environment and obtain compound III；Compound III and alkali amide reagent are subjected to intramolecular nucleophilic substitution reaction under alkaline environment and obtain compounds Ⅳ；Compounds Ⅳ and organic carboxylate are subjected to substitution reaction under alkaline environment and obtain compound V；Compound V and brominated reagent are subjected to bromine reaction under sour environment and obtain compound VI；Compound VI is subjected to epoxy reaction under alkaline environment and obtains cortex hormone of aadrenaline pharmaceutical intermediate, the cortex hormone of aadrenaline medicine is betamethasone or dexamethasone.The preparation method of the present invention is simple, raw material is easy to get, cortex hormone of aadrenaline pharmaceutical intermediate high income and stably.

Description

The preparation method of cortex hormone of aadrenaline pharmaceutical intermediate
Technical field
The present invention relates to chemosynthesis technical field, more particularly to a kind of preparation of cortex hormone of aadrenaline pharmaceutical intermediate Method.
Background technology
Betamethasone and dexamethasone belong to cortex hormone of aadrenaline medicine, and both chemical structural formulas are similar：
Betamethasone is a kind of Adrenal Glucocorticoid medicine, is the isomer of dexamethasone, and effect is filled in ground Rice pine is identical, but antiinflammatory action is strong compared with dexamethasone, fluoxyprednisolone etc..It is mainly used in anaphylaxis and diseases associated with inflammation.It is clinical It is mainly used in organ transplant to prevent rejection；Also the first aid using medicine as critical illness, as encephaledema, shock, serious allergy are anti- Should, collagenosis, rheumatism, leukaemia, polyneuritis, endocrinopathy and Atomizing inhalation etc..
Dexamethasone is a kind of Adrenal Glucocorticoid medicine, and because its antiinflammatory action is powerful, dosage is less, and sodium storage is stayed Effect is slight, can mitigate body tissue to pathological reaction caused by infringement sexual stimulus, be widely used in clinic.Now into For treatment encephaledema, shock, anaphylactia, the fiest-tire medication for reducing inflammation etc..Conventional dexamethasone series in addition Medicine also has dexamethasone acetate, dexamethasone sodium phosphate etc., and clinical injection injection, oral can be made in their bulk drug Tablet and external preparation etc..
CN101397319, CN101397320 report betamethasone, dexamethasone typically with It is prepared for key intermediate, the long yield of syntheti c route is low, and the preparation method cost of the intermediate is also high.
The content of the invention
The technical problem to be solved in the present invention is overcome the deficiencies in the prior art, there is provided a kind of preparation method is simple, raw material It is easy to get, the preparation method of high income and stable cortex hormone of aadrenaline pharmaceutical intermediate.
In order to solve the above technical problems, the technical solution adopted by the present invention there is provided a kind of cortex hormone of aadrenaline medicine The preparation method of intermediate, the preparation method comprise the following steps：
(1) cyano group substitution reaction：Using chemical compounds I as raw material, add cyanating reagent progress cyano group substitution reaction and obtain chemical combination Thing II；
(2) silane epoxide protection reaction：The compound ii and silane epoxide reagent are subjected to silica under alkaline environment Alkyl protection reaction obtains compound III；
(3) intramolecular nucleophilic substitution reaction：The compound III and alkali amide reagent are carried out under alkaline environment Intramolecular nucleophilic substitution reaction obtains compounds Ⅳ；
(4) substitution reaction：The compounds Ⅳ and organic carboxylate are subjected to substitution reaction under alkaline environment Compound V；
(5) bromine reaction on：The compound V and brominated reagent are subjected to bromine reaction under sour environment and obtain chemical combination Thing VI；
(6) epoxy reaction：Compound VI is subjected to epoxy reaction under alkaline environment and obtains cortex hormone of aadrenaline medicine Intermediate；The cortex hormone of aadrenaline pharmaceutical intermediate is the betamethasone intermediate or Dexamethasone Intermediate；
The structural formula of the chemical compounds I is：
The structural formula of the compound ii is：
The structural formula of the compound III is：
The structural formula of the compounds Ⅳ is：
The structural formula of the compound V is：
The structural formula of the compound VI is：
The structural formula of the betamethasone intermediate is：Among the dexamethasone The structural formula of body is：
Above-mentioned preparation method, it is preferred that the cyano group substitution reaction is specially：By the chemical compounds I and the cyaniding Reagent is dissolved in organic solvent according to mass ratio for 1: 0.3~1；Compound ii is obtained in -10 DEG C~100 DEG C reactions；The cyanogen Change reagent is acetone cyanohydrin, Cymag or potassium cyanide.It is further preferred that reaction temperature is 30~35 DEG C.Organic solvent is preferred For the one or more in lower aliphatic alcohols, lower aliphatic acids and ethers, further preferably methanol.
Above-mentioned preparation method, it is preferred that added in the cyano group substitution reaction and account for chemical compounds I weight 0.04~2.0 Catalyst again, the catalyst is lower aliphatic acids, potassium carbonate or sodium carbonate.
Above-mentioned preparation method, it is preferred that silane epoxide protection reaction is specially：Alkali is added in organic solvent, Then the compound ii and the silane epoxide reagent are dissolved in the organic solvent according to mass ratio for 1: 0.5~2.0, The compound III is obtained in -10 DEG C~20 DEG C reactions.Further preferable, reaction temperature is 0~5 DEG C.
Above-mentioned preparation method, it is preferred that silane epoxide reagent is chloromethyl described in the silane epoxide protection reaction Dimethylchlorosilane or bromomethyl dimethylchlorosilane；The organic solvent be halogenated hydrocarbon organic solvent, ether organic solvent, One or more in amide-type organic solvent or pyridine.Further preferable, organic solvent is tetrahydrofuran.Alkali is preferably Imidazoles, triethylamine or DMAP.
Above-mentioned preparation method, it is preferred that the intramolecular nucleophilic substitution reaction is specially：By compound III and alkali soluble in In organic solvent, in -80 DEG C~-10 DEG C reactions, the amino bases gold for accounting for 3.0~5.0 times of compound III molar equivalent is then added Belong to reagent, separation obtains compounds Ⅳ after drying.Further preferable, reaction temperature is -40~-30 DEG C.
Above-mentioned preparation method, it is preferred that the intramolecular nucleophilic substitution reaction is carried out under nitrogen protection, the amino Alkali metal reagent is lithium diisopropyl amido or HMDS lithium；The organic solvent is that organic solvent is that ethers is organic Solvent.
Above-mentioned preparation method, it is preferred that the substitution reaction is specially：By compounds Ⅳ and organic carboxylate according to matter Amount is dissolved in organic solvent than 1: 1.0~3.0, and in 0 DEG C~100 DEG C reactions, then separation obtains compound V after drying；It is described Organic carboxylate is potassium acetate or sodium acetate.
Above-mentioned preparation method, it is preferred that the upper bromine reaction is specially：By compound V, bromide reagent and acid according to matter Amount is reacted at -10 DEG C~50 DEG C than being added to for 1: 0.5~1: 1.0~3.0 in organic solvent and obtains compound VI, described Acid is perchloric acid, fluoboric acid or the concentrated sulfuric acid；The brominated reagent is C5H6Br2N2O2 or N- bromo-succinimides.Organic solvent is One or more in organic solvent of ketone, amide-type organic solvent.
Above-mentioned preparation method, it is preferred that the epoxy reaction is specially：According to mass ratio it is 1 by compound VI and alkali: 0.1~2 is dissolved in organic solvent, is reacted at -10 DEG C~50 DEG C and obtains cortex hormone of aadrenaline pharmaceutical intermediate, the alkali is Sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.Organic solvent is alcohol organic solvent, organic solvent of ketone, amide-type One or more in organic solvent.
In the present invention, when cortex hormone of aadrenaline pharmaceutical intermediate is betamethasone intermediate, its reaction scheme is：
When cortex hormone of aadrenaline pharmaceutical intermediate is Dexamethasone Intermediate, its reaction scheme is：
Compared with prior art, the advantage of the invention is that：
The present invention is used with phytosterol intermediate cheap and easy to getTo rise Beginning raw material, 17- positions hydroxyl is protected by cyaniding, silane epoxide reagent, is reacted at low temperature with lithium diisopropyl amido LDA through dividing Migrated in sub, build chloromethyl ketone, with soap through nucleophilic substitution reaction, then after upper brominated eopxy, obtain betamethasone, Sai meter Song important intermediateAmong this key Body only needs three steps to be obtained with betamethasone, dexamethasone, and high income, cost is low, environment-friendly.
Embodiment
Below in conjunction with specific preferred embodiment, the invention will be further described, but not thereby limiting the invention Protection domain.
Material and instrument employed in following examples are commercially available.
Embodiment 1：
The preparation method of betamethasone intermediate, specifically includes following steps：
(1) with 16 β methyl-pregnant steroid -4,9 (11)-diene -3,17- diketone (chemical compounds I) for raw material, acetone cyanohydrin is added Progress cyano group substitution reaction 16 β methyl-17 β cyano group of preparation, 17a- monohydric pregnants -4,9 (11)-diene -3- ketone (compound ii), Specifically preparation method is：
1.1 reaction：Room temperature, under nitrogen protection, be equipped with thermometer, reflux condensing tube, machinery toward a clean dried stir Mix sequentially added in the 250ml four round flask of bar 30ml methanol, 8ml concentration be 99% acetone cyanohydrin, 20.0g chemical compounds Is, After stirring, the wet chemical that 10ml mass concentrations are 10% is added.By four round flask at 40~45 DEG C it is anti- After answering 20 hours, no longer reduced with TLC detection raw materials, stop reaction.
1.2 filter：Reaction system in four round flask is added dropwise in 400ml water, stirred 2 hours.Suction filtration takes filter Cake, filter cake is washed to neutrality, drains the compound ii crude product for after 50 DEG C of drying, obtaining 19.0g.Calculate crude compound II Yield is 95%, use HPLC (HPLC mobile phase for：Methanol: water=55: it is 93.8% 45) to detect purity.
1.3 purification：Compound ii crude product, which is dissolved in 20ml methanol, to be beaten, and suction filtration takes filter cake.17.6g is obtained after filter cake is dried Compound ii sterling.The yield of compound ii sterling be 92.6%, use HPLC (HPLC mobile phase for：Methanol: water=55: 45) it is 97.1% to detect purity.
In step (1), the structural formula of chemical compounds I is：
The structural formula of compound ii is：
(2) by 16 β methyl-17 β cyano group, 17a- monohydric pregnants -4,9 (11)-diene -3- ketone (compound ii) and chloromethyl Dimethylchlorosilane carries out the protection reaction of silane epoxide and prepares (11)-two of 16 β methyl-17 β cyano group -17a- monohydric pregnants -4,9 Alkene -3- ketone -17- (chloromethyl) dimethyl-silicon ethers (compound III), its specific preparation method are：
2.1 reaction：Room temperature, under nitrogen protection, toward fitting temperature meter, tetra- mouthfuls of circles of 250ml of puddler of a clean dried 50ml tetrahydrofurans, 15.0g compound iis, 5.2g imidazoles are sequentially added in the flask of bottom, after stirring, ice bath is cooled to -5 DEG C ~0 DEG C, -5 DEG C of temperature control~5 DEG C, 10g CMDMCS chloromethyl dimethyl chlorosilane (CH is then slowly added dropwise3Cl(CH3)2SiCl), about 20min is added dropwise, then insulation reaction 1 hour at -5 DEG C~5 DEG C, and TLC is detected without starting material left.
2.2 filter：Reaction system in four round flask is added dropwise in 200ml water, stirring obtains mixing molten for 2 hours Liquid.Mixed solution is filtered and takes filter cake, washing filter cake to neutrality, filter cake is drained to the compound for after 50 DEG C of drying, obtaining 18.3g Ⅲ.Be computed, the yield of compound III is 122%, use HPLC (HPLC mobile phase for：Methanol: water=55: 45) detect pure Spend for 96.1%.
The structural formula of compound III is：
(3) by 16 β methyl-17 β cyano group -17a- monohydric pregnants -4,9 (11)-diene -3- ketone -17- (chloromethyl) dimethyl Silicon ether (compound III) and lithium diisopropyl amido carry out intramolecular nucleophilic substitution reaction and prepare the 16 chloro- 17a- hydroxyls of β methyl -21- The pregnant steroid -4,9 of base (11)-diene -3,20- diketone (compounds Ⅳ), specific reactions steps are：
3.1：Room temperature, under nitrogen protection, toward fitting temperature meter, reflux condensing tube, the 250ml of puddler of a clean dried 100ml tetrahydrofurans, 10.0g compound IIIs are sequentially added in four round flask, after stirring, reaction system is cooled To -40 DEG C~-35 DEG C, it is -30 DEG C then to control to system temperature, and it is 2mol/L that 45.8ml concentration is slowly added dropwise into reaction system Lithium diisopropyl amido (LiN (C3H7)2), about 30min is added dropwise, then insulation reaction 0.5 hour, and TLC is detected without raw material It is remaining.
3.2：The temperature of reaction system is controlled to be less than 20 DEG C, reaction system then is added dropwise into 20ml mass fractions is In 36.5% hydrochloric acid, stir 5 hours.Then it is that 7 (pH value is 6~7 to adjust the pH value of reaction system with 20% sodium hydrate aqueous solution Can implement), temperature control T≤40 DEG C, and be concentrated into without obvious cut, 100ml water is then added dropwise into the remaining system after concentration, Stirring 1 hour, suction filtration take filter cake, washing filter cake to neutrality, then filter cake are dried in 50 DEG C, obtains 7.6g compounds Ⅳ.Meter Calculate compounds Ⅳ yield be 72.0%, use HPLC (HPLC mobile phase for：Methanol: water=55: 45) detecting purity is 90.9%.
IV structural formula of compounds Ⅳ is：
(4) by the 16 chloro- 17a- monohydric pregnants -4,9 (11) of β methyl -21--diene -3,20- diketone (compounds Ⅳ) and vinegar Sour potassium carries out substitution reaction and prepares 16 β methyl-17s a, 21- dimonohydric pregnants -4,9 (11)-diene -3,20- diketone -21- acetic acid Ester (compound V), specific reactions steps are：
4.1：Room temperature, under nitrogen protection, toward fitting temperature meter, reflux condensing tube, the 250ml of puddler of a clean dried 35ml dimethylformamides (DMF), 7.0g compounds Ⅳs, 1.4ml glacial acetic acid, 10.8g vinegar are sequentially added in four round flask Sour potassium, 1.4ml water.After reaction system is stirred, reaction system is warming up to 55 DEG C~60 DEG C insulation reactions 8 hours, TLC Detection is without starting material left.
4.2：Reaction system after 4.1 steps is down to room temperature, 70ml water is added dropwise into reaction system, is added dropwise After continue stirring 1 hour, filter, then filter cake is drained after 50 DEG C of drying, obtain 7.0g compounds V to neutrality by washing filter cake Crude product.Calculate the crude product of compound V yield be 100.0%, use HPLC (HPLC mobile phase for：Methanol: water=55: 45) Detect purity and be more than 95.0%.
4.3：By the crude product chloroform of compound V and acetone recrystallization, 6.2g off-white powders, the i.e. sterling of compound V are obtained. The yield for calculating the sterling of compound V is 88.6%；Use HPLC (HPLC mobile phase for：Methanol: water=55: 45) detect pure Spend for 98.8%.
The structural formula of compound V is：
Compound V is prepared into two Duplicate Samples, the fusing point of detection compound V is respectively 210~212 DEG C, and 209~213 DEG C, it is respectively 138.6 °, 140.2 ° that optical activity is detected at 20 DEG C.
Compound V is subjected to magnetic resonance detection, testing result is as follows：
1H NMR(400MHz,CDCl3):5.73(1H,4-H),5.54(1H,11-H),4.94(2H,dd,21-CH2-), 2.17(3H,s,-OCCH3),1.32(3H,19-CH3), 1.16 (3H, d, J=6.8,16 β-CH3)and 0.77(3H,s,18- CH3)。
Disclosed in magnetic resonance detection result and J.Chem.Soc., Perkin Trans.1,1992,1995-1196 documents 16 β methyl-17s a, 21- dimonohydric pregnants -4,9 (11)-diene -3,20- diketone -21- acetic acid esters nuclear magnetic resonance result phase Seemingly.
(5) by 16 β methyl-17s a, 21- dimonohydric pregnants -4,9 (11)-diene -3,20- diketone -21- acetic acid esters (chemical combination Thing V) with C5H6Br2N2O2 carry out bromine reaction prepare the 16 pregnant Gona-4-ene-3s of β methyl-17s a, 11 β, 21- trihydroxy -9- bromines, 20- Diketone -21- acetic acid esters (compound VI), specific reactions steps are：
5.1：Room temperature, nitrogen protection under, toward one cleaning fitting temperature meter, puddler 500ml four round flask in Sequentially add 250ml dimethylformamides (DMF), 50.0g compounds V, 1.4ml perchloric acid.Reaction system is stirred Afterwards, 10 DEG C~20 DEG C of temperature control, 25.6g C5H6Br2N2O2s are then added, adds rear system and stir 1 hour, TLC detections remain without raw material It is remaining.
5.2：It will be poured into by the reacted reaction system of step 5.1 in 2L water, and continue stirring 1 hour, filtered Cake, filter cake is washed to neutrality, drains the compound VI for after 50 DEG C of drying, obtaining 49.5g.Calculate compound VI yield be 99.0%, use HPLC (HPLC mobile phase for：Methanol: water=55: 45) detect purity and be more than 95.0%.
The structural formula of compound VI is：
(6) by 16 β methyl-17s a, 21- dimonohydric pregnants -4,9 (11)-diene -3,20- diketone -21- acetic acid esters (chemical combination Thing V) the progress epoxy reaction 16 β methyl of preparation under alkaline environment, 17a, 21- dimonohydric pregnants-(9,11) epoxy -4- alkene -3, 20- diketone -21- acetic acid esters (betamethasone intermediate), specific reactions steps are；
6.1：Under N2 protective atmospheres, toward a clean fitting temperature meter, puddler 500ml four round flask A in 100ml dichloromethane is sequentially added, 100ml methanol, 20.0g compounds VI, 2ml mass fractions are that 20% sodium hydroxide is water-soluble Liquid, stir 1 hour, TLC is detected without starting material left.
6.2：Into reaction system with appropriate glacial acetic acid tune pH to neutrality, 40~50 DEG C of temperature control, be concentrated under reduced pressure out solvent, point 2 addition water displacements, add 50ml every time.Then it is cooled to 5~10 DEG C to stir 2 hours, filters, washing filter cake is taken out to neutrality It is dry to be dried after 50 DEG C, obtain 16.3g betamethasone intermediates, yield：81.5%, use HPLC (HPLC mobile phase for：Methanol : water=55: it is 98.5% 45) to detect purity.
Betamethasone intermediate is subjected to magnetic resonance detection, testing result is as follows：
1H NMR(400MHz,CDCl3):5.73(s,1H,4-H),4.94(dd,2H,21-CH2-),3.19(br s, 1H),2.17(s,3H,-OCH3),1.32(s,3H,19-CH3), 1.16 (d, J=6.8Hz, 3H, 16 β-CH3)and 0.77(s, 3H,19-CH3)。
It was found from nuclear magnetic resonance result：The intermediate that method according to embodiment 1 is prepared is betamethasone intermediate.
Meanwhile the structural formula of betamethasone intermediate is：
Embodiment 2：
The preparation method of Dexamethasone Intermediate, specifically includes following steps：
(1) with 16 α methyl-pregnant steroid -4,9 (11)-diene -3,17- diketone (chemical compounds I) for raw material, acetone cyanohydrin is added Progress cyano group substitution reaction 16 α methyl-17 β cyano group of preparation, 17a- monohydric pregnants -4,9 (11)-diene -3- ketone (compound ii), Specifically preparation method is：
1.1 reaction：Room temperature, under nitrogen protection, thermometer, reflux condensing tube, puddler are equipped with toward a clean dried 250ml four round flask in sequentially add 40ml methanol, the acetone cyanohydrins of 10ml 99%, 20.0g chemical compounds Is, stir Afterwards, the wet chemical that 15ml mass concentrations are 10% is added.Four round flask is reacted 20 hours at 40~45 DEG C Afterwards, no longer reduced with TLC detection raw materials, stop reaction.
1.2 filter：Reaction system in four round flask is added dropwise in 400ml water, stirred 2 hours.Suction filtration takes filter Cake, filter cake is washed to neutrality, drains the compound ii crude product for after 50 DEG C of drying, obtaining 19.7g.Calculate crude compound II Yield is 98.5%, use HPLC (HPLC mobile phase for：Methanol: water=55: it is 95.8% 45) to detect purity.
1.3 purification：Compound ii crude product, which is dissolved in 20ml methanol, to be beaten, and suction filtration takes filter cake.18.8g is obtained after filter cake is dried Compound ii sterling.The yield of compound ii sterling be 94.0%, use HPLC (HPLC mobile phase for：Methanol: water=55: 45) it is 99.1% to detect purity.
In step (1), the structural formula of chemical compounds I is：
The structural formula of compound ii is：
(2) by 16 α methyl-17 β cyano group, 17a- monohydric pregnants -4,9 (11)-diene -3- ketone (compound ii) and chloromethyl Dimethylchlorosilane carries out the protection reaction of silane epoxide and prepares (11)-two of 16 α methyl-17 β cyano group -17a- monohydric pregnants -4,9 Alkene -3- ketone -17- (chloromethyl) dimethyl-silicon ethers (compound III), its specific preparation method are：
2.1 reaction：Room temperature, under nitrogen protection, toward fitting temperature meter, tetra- mouthfuls of circles of 250ml of puddler of a clean dried 50ml tetrahydrofurans, 10.0g compound iis, 5.2g imidazoles are sequentially added in the flask of bottom, after stirring, ice bath is cooled to -5 DEG C ~0 DEG C, -5 DEG C of temperature control~5 DEG C, 18g CMDMCS chloromethyl dimethyl chlorosilane (CH is then slowly added dropwise3Cl(CH3)2SiCl), about 40min is added dropwise, then insulation reaction 2 hours at -5 DEG C~5 DEG C, and TLC is detected without starting material left.
2.2 filter：Reaction system in four mouthfuls of original place flasks is added dropwise in 200ml water, stirring obtains mixing molten for 2 hours Liquid.Mixed solution is filtered and takes filter cake, washing filter cake to neutrality, filter cake is drained to the compound for after 50 DEG C of drying, obtaining 12.6g Ⅲ.Be computed, the weight yield of compound III is 126%, use HPLC (HPLC mobile phase for：Methanol: water=55: 45) examine It is 97.1% to survey purity.
The structural formula of compound III is：
(3) by 16 α methyl-17 β cyano group -17a- monohydric pregnants -4,9 (11)-diene -3- ketone -17- (chloromethyl) dimethyl Silicon ether (compound III) and lithium diisopropyl amido carry out intramolecular nucleophilic substitution reaction and prepare the 16 chloro- 17a- hydroxyls of α methyl -21- The pregnant steroid -4,9 of base (11)-diene -3,20- diketone (compounds Ⅳ), specific reactions steps are：
3.1：Room temperature, under nitrogen protection, toward fitting temperature meter, reflux condensing tube, the 250ml of puddler of a clean dried 60ml tetrahydrofurans, 10.0g compound IIIs are sequentially added in four round flask, after stirring, reaction system is cooled to- 40 DEG C~-35 DEG C, it is -30 DEG C then to control to system temperature, and it is 2mol/L's that 45.8ml concentration is slowly added dropwise into reaction system Lithium diisopropyl amido (LiN (C3H7)2), about 30min is added dropwise, then insulation reaction 0.5 hour, and TLC detections remain without raw material It is remaining.
3.2：The temperature of reaction system is controlled to be less than 20 DEG C, it is 30% salt that 20ml mass fractions then, which are added dropwise, to reaction system Acid, stir 5 hours.Then with 20% sodium hydrate aqueous solution adjust the pH value of reaction system be 7 (pH value be 6~7 can implement), Temperature control T≤40 DEG C, and be concentrated into without obvious cut, 100ml water is then added dropwise into the remaining system after concentration, stirs 1 hour, Suction filtration takes filter cake, washing filter cake to neutrality, then filter cake is dried in 50 DEG C, obtains 7.2g compounds Ⅳ.Calculate compounds Ⅳ Yield be 72.0%, use HPLC (HPLC mobile phase for：Methanol: water=55: it is 90.9% 45) to detect purity.
IV structural formula of compounds Ⅳ is：
(4) by the 16 chloro- 17a- monohydric pregnants -4,9 (11) of α methyl -21--diene -3,20- diketone (compounds Ⅳ) and vinegar Sour potassium carries out substitution reaction and prepares 16 α methyl-17s a, 21- dimonohydric pregnants -4,9 (11)-diene -3,20- diketone -21- acetic acid Ester (compound V), specific reactions steps are：
4.1：Room temperature, under nitrogen protection, toward fitting temperature meter, reflux condensing tube, the 250ml of agitator of a clean dried 35ml dimethylformamides (DMF), 7.0g compounds Ⅳs, 1.4ml glacial acetic acid, 10.8g vinegar are sequentially added in four round flask Sour potassium, 1.4ml water.After reaction system is stirred, reaction system is warming up to 55 DEG C~60 DEG C insulation reactions 8 hours, TLC Detection is without starting material left.
4.2：Reaction system after 4.1 steps is down to room temperature, 70ml water is added dropwise into reaction system, is added dropwise After continue stirring 1 hour, filter, then filter cake is drained after 50 DEG C of drying, obtain 7.0g compounds V to neutrality by washing filter cake Crude product.Calculate the crude product of compound V yield be 100.0%, use HPLC (HPLC mobile phase for：Methanol: water=55: 45) Detect purity and be more than 95.0%.
4.3：By the crude product chloroform of compound V and acetone recrystallization, 6.2g off-white powders, the i.e. sterling of compound V are obtained. The yield for calculating the sterling of compound V is 88.6%；Use HPLC (HPLC mobile phase for：Methanol: water=55: 45) detect pure Spend for 98.8%.
The structural formula of compound V is：
Compound V is prepared into two Duplicate Samples, the fusing point of detection compound V is respectively 203~205 DEG C, and 202~204 DEG C, it is respectively 99.7 °, 99.3 ° that optical activity is detected at 20 DEG C.
Compound V is subjected to magnetic resonance detection, testing result is as follows：
1H NMR(400MHz,CDCl3):5.72(1H,4-H),5.51(1H,11-H),4.91(2H,dd,21-CH2-), 2.15(3H,s,-OCCH3),1.31(3H,19-CH3), 0.92 (3H, d, J=6.8,16 α-CH3)and 0.70(3H,s,18- CH3)。
Magnetic resonance detection result and 16 α methyl-17s a, 21- dihydroxy disclosed in US4990612 (Upjohn) document The nuclear magnetic resonance result of pregnant steroid -4,9 (11)-diene -3,20- diketone -21- acetic acid esters is similar.
(5) by 16 α methyl-17s a, 21- dimonohydric pregnants -4,9 (11)-diene -3,20- diketone -21- acetic acid esters (chemical combination Thing V) with C5H6Br2N2O2 carry out bromine reaction prepare the 16 pregnant Gona-4-ene-3s of α methyl-17s a, 11 β, 21- trihydroxy -9- bromines, 20- Diketone -21- acetic acid esters (compound VI), specific reactions steps are：
5.1：Room temperature, nitrogen protection under, toward one cleaning fitting temperature meter, puddler 500ml four round flask in Sequentially add 250ml dimethylformamides (DMF), 50.0g compounds V, 1.4ml perchloric acid.Reaction system is stirred Afterwards, 10 DEG C~20 DEG C of temperature control, 25.6g C5H6Br2N2O2s are then added, adds rear system and stir 1 hour, TLC detections remain without raw material It is remaining.
5.2：It will be poured into by the reacted reaction system of step 5.1 in 2L water, and continue stirring 1 hour, filtered Cake, filter cake is washed to neutrality, drains the compound VI for after 50 DEG C of drying, obtaining 49.5g.Calculate compound VI yield be 99.0%, use HPLC (HPLC mobile phase for：Methanol: water=55: 45) detect HPLC purity and be more than 95.0%.
The structural formula of compound VI is：
(6) by the 16 pregnant Gona-4-ene-3s of α methyl-17s a, 11 β, 21- trihydroxy -9- bromines, 20- diketone -21- acetic acid esters (chemical combination Thing V) the progress epoxy reaction 16 α methyl of preparation under alkaline environment, 17a, 21- dimonohydric pregnants-(9,11) epoxy -4- alkene -3, 20- diketone -21- acetic acid esters (Dexamethasone Intermediate), specific reactions steps are；
6.1：Under N2 protective atmospheres, toward a clean fitting temperature meter, puddler 500ml four round flask A in 100ml dichloromethane is sequentially added, 100ml methanol, 20.0g compounds VI, 2ml mass fractions are that 20% sodium hydroxide is water-soluble Liquid, stir 1 hour, TLC is detected without starting material left.
6.2：Into reaction system with appropriate glacial acetic acid tune PH to neutrality, 40~50 DEG C of temperature control, be concentrated under reduced pressure out solvent, point 2 addition water displacements, add 50ml every time.Then it is cooled to 5~10 DEG C to stir 2 hours, filters, washing filter cake is taken out to neutrality It is dry to be dried after 50 DEG C, obtain 16.5g Dexamethasone Intermediates, yield：82.5%, use HPLC (HPLC mobile phase for：Methanol : water=55: 45) detect purity and be more than 98.0%.
Dexamethasone Intermediate is subjected to magnetic resonance detection, testing result is as follows：
1H NMR(400MHz,CDCl3):5.72(s,1H,4-H),4.91(dd,2H,21-CH2-),3.19(br s, 1H),2.15(s,3H,-OCH3),1.31(s,3H,19-CH3), 0.92 (d, J=6.8Hz, 3H, 16 β-CH3)and 0.70(s, 3H,19-CH3)。
It was found from nuclear magnetic resonance result：The intermediate that method according to embodiment 2 is prepared is Dexamethasone Intermediate.
Meanwhile the structural formula of Dexamethasone Intermediate is：
The above described is only a preferred embodiment of the present invention, any formal limitation not is made to the present invention.Though So the present invention is disclosed as above with preferred embodiment, but is not limited to the present invention.It is any to be familiar with those skilled in the art Member, in the case where not departing from the Spirit Essence of the present invention and technical scheme, all using in the methods and techniques of the disclosure above Appearance makes many possible changes and modifications to technical solution of the present invention, or is revised as the equivalent embodiment of equivalent variations.Therefore, Every content without departing from technical solution of the present invention, the technical spirit according to the present invention is to made for any of the above embodiments any simple Modification, equivalent substitution, equivalence changes and modification, still fall within technical solution of the present invention protection in the range of.

Claims (1)

  1. A kind of 1. preparation method of cortex hormone of aadrenaline pharmaceutical intermediate, it is characterised in that the preparation method include with Lower step：
    (1) cyano group substitution reaction：Using chemical compounds I as raw material, add cyanating reagent progress cyano group substitution reaction and obtain compound ii；
    (2) silane epoxide protection reaction：The compound ii and silane epoxide reagent are subjected to siloxy group under alkaline environment Protection reaction obtains compound III；
    (3) intramolecular nucleophilic substitution reaction：The compound III and alkali amide reagent are subjected to molecule under alkaline environment Interior nucleophilic substitution obtains compounds Ⅳ；
    (4) substitution reaction：The compounds Ⅳ and organic carboxylate are subjected to substitution reaction under alkaline environment and obtain compound Ⅴ；
    (5) bromine reaction on：The compound V and brominated reagent are subjected to bromine reaction under sour environment and obtain compound VI； The brominated reagent is C5H6Br2N2O2 or N- bromo-succinimides；
    (6) epoxy reaction：Compound VI is carried out into epoxy reaction under alkaline environment to obtain among cortex hormone of aadrenaline medicine Body；The alkali is sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate；
    The cortex hormone of aadrenaline pharmaceutical intermediate is betamethasone intermediate or Dexamethasone Intermediate；
    The structural formula of the chemical compounds I is：
    The structural formula of the compound ii is：
    The structural formula of the compound III is：
    The structural formula of the compounds Ⅳ is：
    The structural formula of the compound V is：
    The structural formula of the compound VI is：
    The structural formula of the betamethasone intermediate is：The knot of the Dexamethasone Intermediate Structure formula is：
    The cyano group substitution reaction is specially：The chemical compounds I and the cyanating reagent is molten for 1: 0.3~1 according to mass ratio In organic solvent, compound ii is obtained in 40 DEG C~45 DEG C reactions；The cyanating reagent is acetone cyanohydrin, Cymag or cyaniding Potassium；
    Silane epoxide protection reaction is specially：Alkali is added in organic solvent, then by the compound ii and the silicon Alkoxy reagent is dissolved in the organic solvent according to mass ratio for 1: 0.5~2.0, is obtained in -10 DEG C~20 DEG C reactions described Compound III；
    The intramolecular nucleophilic substitution reaction is specially：By compound III and alkali soluble in organic solvent, in -80 DEG C~-10 DEG C Reaction, then adds the alkali amide reagent for accounting for 3.0~5.0 times of compound III molar equivalent, and separation obtains chemical combination after drying Thing IV；
    The intramolecular nucleophilic substitution reaction is carried out under nitrogen protection, and the alkali amide reagent is lithium diisopropyl amido Or HMDS lithium；The organic solvent is ether organic solvent；
    The substitution reaction is specially：Compounds Ⅳ and organic carboxylate are dissolved in organic solvent according to mass ratio 1: 1.0~3.0 In, in 0 DEG C~100 DEG C reactions, then separation obtains compound V after drying；The organic carboxylate is potassium acetate or acetic acid Sodium；
    The upper bromine reaction is specially：Compound V, bromide reagent and acid are added according to mass ratio for 1: 0.5~1: 1.0~3.0 Into organic solvent, reacted at -10 DEG C~50 DEG C and obtain compound VI, the acid is perchloric acid, fluoboric acid or the concentrated sulfuric acid；
    The epoxy reaction is specially：Compound VI and alkali are dissolved in organic solvent according to mass ratio for 1: 0.1~2, in -10 DEG C~50 DEG C at reaction obtain cortex hormone of aadrenaline pharmaceutical intermediate；
    The catalyst for accounting for 0.04~2.0 times of chemical compounds I weight is added in the cyano group substitution reaction, the catalyst is rudimentary Fatty acid, potassium carbonate or sodium carbonate；
    The silane epoxide reagent is CMDMCS chloromethyl dimethyl chlorosilane or bromomethyl dimethylchlorosilane；The organic solvent is halogen For the one or more in hydrocarbon organic solvent, ether organic solvent, amide-type organic solvent or pyridine.
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CN107619424A (en) * 2016-07-15 2018-01-23 天津金耀集团有限公司 A kind of preparation method of 17 hydroxyl nitrile steroid derivative
CN107400153B (en) * 2017-04-23 2019-08-27 浙江仙琚制药股份有限公司 A kind of preparation method of hydrocortisone acetate
CN108033990A (en) * 2017-12-29 2018-05-15 广西万德药业有限公司 The preparation method of Dexamethasone Intermediate
CN112578032A (en) * 2019-09-30 2021-03-30 天津药业研究院股份有限公司 Method for detecting content of betamethasone precursor epoxy material and related substances
CN113512085B (en) * 2021-04-21 2024-04-09 河南利华制药有限公司 Preparation method of mometasone furoate

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