CN107629107A - A kind of synthetic method of CDB-2914 - Google Patents
A kind of synthetic method of CDB-2914 Download PDFInfo
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- CN107629107A CN107629107A CN201711111101.6A CN201711111101A CN107629107A CN 107629107 A CN107629107 A CN 107629107A CN 201711111101 A CN201711111101 A CN 201711111101A CN 107629107 A CN107629107 A CN 107629107A
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Abstract
The invention discloses a kind of synthetic method of CDB-2914, methods described comprises the following steps：1) gestadienol generates compound VI under ethylene glycol, p-methyl benzenesulfonic acid, trimethyl orthoformate effect；2) compound VI obtains compound VII through hydrogen peroxide oxidation；3) compound VII and 4 (N, N dimethylamino) phenyl-magnesium-bromide RMgBrs react to obtain compound VIII；4) compound VIII hydrolyzes to obtain compound XI；5) compound XI and glacial acetic acid, acetic anhydride 1 (3 dimethylamino-propyl) 3 ethyl-carbodiimide hydrochlorides, 4 dimethylamino pyridines, ferric perchlorate catalytic action under react to obtain CDB-2914.In this method, the reaction condition by Ulipristal acquisition CDB-2914 is relatively mild, is not likely to produce demethylation Ulipristal or nitrogen oxidation Ulipristal, production process are more controllable.
Description
Technical field
The present invention relates to the synthetic method of Western medicine, and in particular to a kind of synthetic method of CDB-2914.
Background technology
CDB-2914 (ulipristal acetate), its molecular formula are C30H37NO4, relative molecular mass
475.62, systematic naming method is 17 α-β of acetoxyl group -11 (4-N, N- dimethylamino phenyl) -19- norpregnas -4,9- diene -3,
20- diketone, is a kind of progesterone excitomotor/antagonism, and structural formula is as follows：
The synthesis path of CDB-2914 has a plurality of at present, and more commonly used is the Dancsi methods as shown in following equation:
Using the method as row, in the CDB-2914 of synthesis, common impurity is except intermediate 8 and the (Wu Lisi of intermediate 9
He) outside, there is defined specific relevant material, such as demethylation CDB-2914 and nitrogen oxidation Ulipristal, and Wu Lisi
His isomers, is shown below:
It was found from the patent application retrieved at present, CDB-2914, usually used method are prepared by Ulipristal
It is the rapid acylation method of acetic acid-perchloric acid and aceticanhydride three compositions system, the method needs to maintain the temperature at less than -20 DEG C, to processing
Equipment requirement is high, and the molecular structure of Ulipristal is easily destroyed by perchloric acid, makes the purity of product that finally gives also not high.
For the solvent borne crystal of CDB-2914, the crystal directly obtained using solvent evaporation method, tend not to full
Foot《Pharmacopoeia of People's Republic of China》Residual solvent and bound requirements specified in versions in 2015.
The content of the invention
It is a kind of former by starting of gestadienol the invention aims to provide for overcome the deficiencies in the prior art
The synthetic method of the few CDB-2914 of material, accessory substance.In this method, by Ulipristal obtain CDB-2914 the step of
Reaction is gentle, reaction is thorough, and the related impurities content of final product is few.
The purpose of the present invention is realized using following technical scheme：
A kind of synthetic method of CDB-2914, reaction equation are as follows:
Methods described comprises the following steps：
1) gestadienol generates compound VI under ethylene glycol, p-methyl benzenesulfonic acid, trimethyl orthoformate effect；
2) compound VI obtains compound VII through hydrogen peroxide oxidation；
3) compound VII reacts to obtain compound VIII with 4- (N, N- dimethylamino) phenyl-magnesium-bromide RMgBr；
4) compound VIII hydrolyzes to obtain compound XI；
5) compound XI and glacial acetic acid, acetic anhydride are in 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides, 4-
Dimethylamino pyridine, ferric perchlorate catalytic action under react to obtain CDB-2914.
Further, in step 1), gestadienol, ethylene glycol, trimethyl orthoformate are dissolved in dichloromethane, frozen water
Bath is lower to add p-methyl benzenesulfonic acid, is warming up to 30-40 DEG C, stirring reaction to TLC shows that gestadienol reaction is complete, adds saturation
Sodium bicarbonate aqueous solution is neutralized, and separates organic phase, and aqueous phase is extracted with dichloromethane, is dried, and adds pyridine, and vacuum distillation obtains thick
Shape thing, methanol is added into thick liquid, and 0.5-1h is stirred at 0-5 DEG C, is filtered, and is dried, is produced compound VI.
Further, in step 2), compound VI, hexachloroacetone, pyridine are dissolved in dichloromethane, are added dropwise at 0-5 DEG C
Hydrogen peroxide, 0-5 DEG C of stirring is kept, disappeared to TLC monitoring compounds VI, separate organic phase, aqueous phase is extracted with dichloromethane, is merged
Organic phase, it is neutral to be quenched to aqueous phase with sodium thiosulfate solution, dries, is concentrated under reduced pressure, obtains compound VII.
Further, in step 3), magnesium, iodine are dissolved in tetrahydrofuran, the bromo- N of 4-, N- dimethyl benzenes are instilled at 0-5 DEG C
The tetrahydrofuran solution of amine, after being added dropwise, 35-40 DEG C of continuation stirring reaction is warming up to, cooling, adds stannous chloride, cooling
To 20-25 DEG C, compound VII tetrachloro tetrahydrofuran solution is added dropwise at 5-10 DEG C, after being added dropwise, continues to react 0.5- at room temperature
2h, the ammonium chloride solution of saturation is added, separate organic phase, aqueous phase is extracted with dichloromethane, merges organic phase, is dried, is changed
Compound VIII.
Further, in step 4), 2M KHSO is added dropwise into compound VIII at 0-5 DEG C4Solution, it is added dropwise complete
Afterwards, continue to stir at room temperature, monitor to compound VIII and disappear to TLC, extracted with dichloromethane, organic phase unsaturated carbonate hydrogen
Sodium solution washs, and dries, and concentration, obtains compound IX.
Further, in step 5), glacial acetic acid and acid anhydrides are pressed into 0.1-0.2:1 mol ratio is dissolved in dichloromethane,
The ferric perchlorate of catalytic amount is added, is kept for 0-5 DEG C, is added dropwise to dissolved with 1- (3- dimethylamino-propyls) -3- ethyl carbodiimide salt
The dichloromethane solution of hydrochlorate, 4- dimethylamino pyridines and compound IX, after reaction completely, the frozen water of 5-8 times of volume is poured into, point
From organic phase, aqueous phase is extracted with dichloromethane, merges organic phase, and organic phase uses 4-5wt% citric acid and saturation successively
NaHCO3Washing, dry, be evaporated under reduced pressure, obtain CDB-2914.
Further, after step 5), in addition to step 6)：The acetic acid Wu Liesita that step 5) obtains is added using isopropanol
Heat of solution, filtering while hot, the n-hexane of 2-3 times of volume, filtering is added dropwise into filtrate while stirring, filter residue is washed with ice methanol,
Dry, obtain CDB-2914 highly finished product.
Further, by CDB-2914 plus the ethyl acetate-hexane of 1-2 times of weight, it is ground, filters, does
It is dry, obtain CDB-2914 highly finished product.
Compared with prior art, the beneficial effects of the present invention are：
1) present invention is using the gestadienol that is commercially easy to get as initiation material, and course of reaction is relatively short, each step
Product largely needs not move through and further handles the reaction that can enters next step, and final product yield is high, purity
It is high；
2) synthetic method provided by the invention, the esterification reaction process of Ulipristal, using temperate condition, make as the tertiary alcohol
Ulipristal can effectively be esterified, process does not need too low temperature so that reaction condition is more suitable for industrialized production；
3) synthetic method provided by the invention, Ulipristal esterification process are not likely to produce nitrogen oxidation and demethylation Wu Lisi
He, the purity of product is higher.
Embodiment
Below, with reference to embodiment, the present invention is described further：
The present invention provides a kind of synthetic method of CDB-2914, and the gestadienol to be commercially easy to get is used as starting original
Material, protect, aoxidize by ketone group successively, grignard addition, hydrolysis and esterification, finally give CDB-2914.In this method, by
The reaction condition that Ulipristal obtains CDB-2914 is relatively mild, is not likely to produce demethylation Ulipristal or nitrogen oxidation crow profit
Him is taken charge of, the purity of final Ulipristal is high.
A kind of synthetic method of CDB-2914, it is characterised in that reaction equation is as follows:
Methods described comprises the following steps：
1) gestadienol generates compound VI under ethylene glycol, p-methyl benzenesulfonic acid, trimethyl orthoformate effect；
The step is that two ketone groups are protected, with avoid in next step aoxidize when, destroy ketone group；
2) compound VI obtains compound VII through hydrogen peroxide oxidation；
The protection structure that diene body is transformed into α-oxirane with easy open loop in the step, so as to be easy to
RMgBr carries out addition；
3) compound VII reacts to obtain compound VIII with 4- (N, N- dimethylamino) phenyl-magnesium-bromide RMgBr；
4) compound VIII hydrolyzes to obtain compound XI；
In this method, in KHSO4In the presence of, generation synchronous with elimination reaction is hydrolyzed, to form diene ketoboidies；
5) compound XI and glacial acetic acid, acetic anhydride are in 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides
(EDCl), CDB-2914 is reacted to obtain under 4- dimethylamino pyridines (DAMP) catalytic action；
In the step, compound XI and glacial acetic acid, acetic anhydride, EDCl, DAMP, ferric perchlorate mol ratio are 1:(0.2-
0.5):(2-3):(1.05-1.2):(1.05-1.2):(0.1-0.3) step be make the tertiary alcohol compound XI in catalyst
In the presence of with glacial acetic acid carry out esterification, reaction condition milder, can be with by the way of glacial acetic acid, acetic anhydride coordinate
The generation of water is reduced, makes the reaction more complete.
Embodiment 1：Compound VI preparation
Take 62.8g (0.20mol) gestadienol, 80mL (1.44mol) ethylene glycol, 55mL (0.5mol) orthoformic acid front three
Ester is dissolved in 500mL dichloromethane, and 7.6g (0.04mol) water p-methyl benzenesulfonic acid is added under ice-water bath, 35 DEG C is warming up to, stirs
Mix reaction and show that gestadienol reaction is complete to TLC, add saturated sodium bicarbonate aqueous solution and neutralize, separate organic phase, aqueous phase
Extracted, dried with 300mL dichloromethane every time, add 0.5mL pyridines, vacuum distillation obtains thick liquid, added into thick liquid
300mL methanol, 45min is stirred at 0-5 DEG C, filtered, filter cake is washed with the methanol of ice, is dried in vacuo, is produced 66.3g compounds
VI (0.167mol), yield 83%.
Embodiment 2：Compound VII preparation
Take 60.3g (0.15mol) compound VI, 7.6mL (0.05mol) hexachloroacetone, 1.5mL (0.019mol) pyridine molten
In 200mL dichloromethane, 90mL (1.5mol) 50% hydrogen peroxide is added dropwise at 0-5 DEG C, 0-5 DEG C of stirring is kept, to TLC monitoringizations
Compound VI is disappeared, and separates organic phase, and aqueous phase is extracted with 100mL dichloromethane, is merged organic phase, is quenched with sodium thiosulfate solution
It is neutrality to go out to aqueous phase, dries, is concentrated under reduced pressure, obtains compound VII, is directly used in and reacts in next step.
Embodiment 3：Compound VIII preparation
3.6g (0.15mol) magnesium, 1.27g (0.01mol) iodine is taken to be dissolved in 200mL tetrahydrofurans, after 30 DEG C of initiation reactions,
The 200mL tetrahydrofuran solutions of the bromo- DMAs of 30g (0.15mol) 4- are instilled at 0-5 DEG C, after being added dropwise, are risen
Temperature cooling, adds 2g (0.02mol) stannous chloride, is cooled to 20-25 DEG C to 35-40 DEG C of continuation stirring reaction；By embodiment 2
Obtained compound VII is dissolved in 200mL tetrahydrofuran, and above-mentioned mixed liquor, after being added dropwise, room are added dropwise at 5-10 DEG C
Continuing to react 0.5-2h under temperature, add the ammonium chloride solution of isometric saturation, separate organic phase, aqueous phase is extracted with dichloromethane,
Merge organic phase, dry, obtain 43.7g (0.081mol) compound VIII, the total recovery of embodiment 2 and embodiment 3 is 54%.
Embodiment 4：Compound IX preparation
100mL (0.2mol) 2M KHSO is added dropwise into 27.0g (0.05mol) compounds VIII at 0-5 DEG C4Solution,
After being added dropwise, continue to stir at room temperature, monitor to compound VIII and disappear to TLC, extracted every time with 100mL dichloromethane,
Extraction 3 times, organic phase is washed with saturated sodium bicarbonate solution, is dried, and concentration, is obtained compound IX, is directly used in esterification.
Embodiment 5：The preparation of CDB-2914
0.3mL (0.005mol) glacial acetic acids and 18mL (0.19mol) acetic anhydride are taken, is dissolved in 50mL dichloromethane, keeps 0-5
DEG C, it is added dropwise to dissolved with 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides, 4- dimethylamino pyridines and compound IX
Dichloromethane solution, after reaction completely, add in the frozen water of 5-8 times of volume, separate organic phase, aqueous phase extracts with dichloromethane
Take, merge organic phase, organic phase uses 5%wt citric acid and saturation NaHCO successively3Washing, organic phase are done with anhydrous sodium sulfate
It is dry, it is evaporated under reduced pressure, obtains CDB-2914.
Effect detection and performance evaluation
The CDB-2914 that embodiment 5 obtains is analyzed on U.S.'s Waters high performance liquid chromatographs.Liquid phase
Chromatographic condition is as follows：
Chromatographic column：Water Nova-Pak C18Reversed-phase column；
Detection wavelength：303nm；
Column parameter：150 × 4.6i.d.mm, 5 μm；
Mobile phase：V (0.02mmol/L ammonium acetates):V (acetonitrile)=40:60
Flow velocity：1mL/min.
Appearance time：12.6min
The purity that the acetic acid Wu Liesita that embodiment 5 obtains detects through HPLC is 99.890%：
It will be apparent to those skilled in the art that technical scheme that can be as described above and design, make other various
Corresponding change and deformation, and all these changes and deformation should all belong to the protection domain of the claims in the present invention
Within.
Claims (8)
1. a kind of synthetic method of CDB-2914, it is characterised in that reaction equation is as follows:
Methods described comprises the following steps：
1) gestadienol generates compound VI under ethylene glycol, p-methyl benzenesulfonic acid, trimethyl orthoformate effect；
2) compound VI obtains compound VII through hydrogen peroxide oxidation；
3) compound VII reacts to obtain compound VIII with 4- (N, N- dimethylamino) phenyl-magnesium-bromide RMgBr；
4) compound VIII hydrolyzes to obtain compound XI；
5) compound XI and glacial acetic acid, acetic anhydride are in 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides, 4- diformazans
Amido pyridine, ferric perchlorate catalytic action under react to obtain CDB-2914.
2. the method as described in claim 1, it is characterised in that in step 1), gestadienol, ethylene glycol, orthoformic acid front three
Ester is dissolved in dichloromethane, and p-methyl benzenesulfonic acid is added under ice-water bath, is warming up to 30-40 DEG C, stirring reaction to TLC shows pregnant promise
Dienol reaction is complete, adds saturated sodium bicarbonate aqueous solution and neutralizes, separates organic phase, and aqueous phase is extracted with dichloromethane, is dried,
Pyridine is added, vacuum distillation obtains thick liquid, methanol is added into thick liquid, 0.5-1h is stirred at 0-5 DEG C, filters, and dries,
Produce compound VI.
3. method as claimed in claim 2, it is characterised in that in step 2), compound VI, hexachloroacetone, pyridine are dissolved in
In dichloromethane, hydrogen peroxide is added dropwise at 0-5 DEG C, keeps 0-5 DEG C of stirring, is disappeared to TLC monitoring compounds VI, separates organic phase,
Aqueous phase is extracted with dichloromethane, merges organic phase, and it is neutral to be quenched to aqueous phase with sodium thiosulfate solution, is dried, decompression is dense
Contracting, obtains compound VII.
4. the method as described in claim 1, it is characterised in that in step 3), magnesium, iodine are dissolved in tetrahydrofuran, at 0-5 DEG C
The tetrahydrofuran solution of the bromo- DMAs of 4- is instilled, after being added dropwise, is warming up to 35-40 DEG C of continuation stirring reaction, it is cold
But, stannous chloride is added, is cooled to 20-25 DEG C, compound VII tetrachloro tetrahydrofuran solution is added dropwise at 5-10 DEG C, is added dropwise
Afterwards, continue to react 0.5-2h at room temperature, add the ammonium chloride solution of saturation, separate organic phase, aqueous phase is extracted with dichloromethane, is closed
And organic phase, dry, obtain compound VIII.
5. the method as described in claim 1, it is characterised in that in step 4), 2M is added dropwise into compound VIII at 0-5 DEG C
KHSO4Solution, after being added dropwise completely, continue to stir at room temperature, monitor to compound VIII and disappear to TLC, extracted with dichloromethane
Take, organic phase is washed with saturated sodium bicarbonate solution, is dried, and concentration, obtains compound IX.
6. the method as described in claim 1, it is characterised in that in step 5), glacial acetic acid and acid anhydrides are pressed into 0.1-0.2:1 rubs
You are dissolved in dichloromethane ratio, add the ferric perchlorate of catalytic amount, are kept for 0-5 DEG C, are added dropwise to dissolved with 1- (3- dimethylaminos third
Base) -3- ethyl-carbodiimide hydrochlorides, 4- dimethylamino pyridines and compound IX dichloromethane solution, reaction completely after, fall
Enter the frozen water of 5-8 times of volume, separate organic phase, aqueous phase is extracted with dichloromethane, merges organic phase, and organic phase uses 4- successively
5wt% citric acid and saturation NaHCO3Washing, dry, be evaporated under reduced pressure, obtain CDB-2914.
7. the method as described in claim 1, it is characterised in that after step 5), in addition to step 6)：The vinegar that step 5) is obtained
Sour Wu Liesita is dissolved by heating using isopropanol, is filtered while hot, and the n-hexane of 2-3 times of volume is added dropwise into filtrate while stirring,
Filtering, filter residue are washed with ice methanol, are dried, are obtained CDB-2914 highly finished product.
8. the method as described in claim 1, it is characterised in that by CDB-2914 plus the ethyl acetate of 1-2 times of weight-just
Hexane, it is ground, filters, dries, obtain CDB-2914 highly finished product.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110256519A (en) * | 2019-05-23 | 2019-09-20 | 江苏联环药业股份有限公司 | The method of one kettle way preparation uliprista acetate |
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