CN105693803A - Method for preparing progesterone - Google Patents
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- CN105693803A CN105693803A CN201610136574.0A CN201610136574A CN105693803A CN 105693803 A CN105693803 A CN 105693803A CN 201610136574 A CN201610136574 A CN 201610136574A CN 105693803 A CN105693803 A CN 105693803A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
- C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
- C07J7/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa
- C07J7/002—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa not substituted in position 16
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Abstract
The invention discloses a method for preparing progesterone. 4-androstenedione (I) is taken as a raw material, a 17-position branch chain is introduced through cyanation and other reactions, and progesterone (VI) is prepared. The reaction formula is shown in the specification. The invention discloses a novel process for preparing progesterone. 4-androstenedione (I) with low price is initially taken as a starting raw material, progesterone with the total yield as high as 80% or higher by weight is obtained after five steps of reactions, the cost is low, and the method is suitable for industrial production.
Description
Technical field
The preparation method that the present invention relates to a kind of chemicals, particularly relates to a kind of method preparing Progesterone。
Background technology
Progesterone is a very important progestogens medicine of class, and the endometrium in vivo estrogen excited has notable Morphology Effects, required for maintaining gestation。It is mainly used in the amenorrhea such as threatened abortion, habitual abortion or the reactive diagnosis etc. of amenorrhea reason。The structural formula of Progesterone is:
About several the routes preparing Progesterone in prior art:
1. the technique being widely used most in current Progesterone production technology is exactly with diene alcohol ketone acetic ester for initiation material, prepare through over hydrogenation, hydrolysis, oxidation three-step reaction, " whole nation crude drug technique compilation " and patent (CN102911232A) etc. just report this process route, and its reaction equation is as follows:
The initiation material diene alcohol ketone acetic ester price in recent years of this conventional processing routes constantly increases, and causes that this route cost rises steadily。The walsh oxidation of this route not only operation inconvenience there is also potential safety hazard。
2. with various sterols for initiation material, carrying out transformation through multistep reaction to 17 and prepare Progesterone, patent (JP2014076066) and (PCT2010079594) etc. just report this type of synthetic route。
This type of synthesis route is long, and step is many, causes that its production cycle is long。By-product is many, and yield is low, limits its large-scale industrial production。
3. with 17 Alpha-hydroxy Progesterone for initiation material, preparing through elimination and reduction two-step reaction, patent (CN103087136A) just reports this process route, and its reaction equation is as follows:
The reduction step poor selectivity of this technique, two double bonds of intermediate, all easily by catalytic hydrogenation, cause that its yield is low, also limit its large-scale production simultaneously and use。
Summary of the invention
It is an object of the invention to the cost of material for solving to be currently used for preparing Progesterone high, synthetic route is long, and step is many, and the production cycle is long, and by-product is many, and yield is low, limits the technical problem of its large-scale industrial production。
In order to solve above-mentioned technical problem, the present invention provides a kind of method preparing Progesterone, comprises the steps:
(1) cyanalation reaction: be sequentially added into 4-AD (I), sodium carbonate, water and methanol in reaction bulb, it is warming up to 35 DEG C～40 DEG C, adds .alpha.-hydroxyisobutyronitrile. reagent, after reacting 4 hours at this temperature, dropping water continues reaction 5 hours, react 20 hours after being cooled to 15 DEG C～20 DEG C, stopped reaction when TLC detection is without raw material point, add concentrated hydrochloric acid aqueous solution cancellation reaction, add water elutriation, sucking filtration is to dry, and vacuum drying oven is dried and obtained cyanalation product (II), and reaction equation is
；
(2) ketal protection reaction: add described cyanalation product (II), alcohol reagent and catalyst in reaction bulb, add triethyl orthoformate；Heat to uniform temperature reaction certain time；Stopped reaction when TLC detection is without raw material point, cools to less than 20 DEG C, adds triethylamine cancellation reaction, is poured into water elutriation, and sucking filtration is to dry, and oven for drying obtains ketal protection product (III), and reaction equation is
；
(3) reaction is eliminated: in reaction bulb, add described ketal protection (III), pyridine and elimination reagent; it is warming up to 40 DEG C; after insulation reaction 2 hours; it is warming up to 45 DEG C to react 5 hours, stopped reaction when TLC detection is without raw material point, cooling; pour in frozen water; filtering, the dry thing (IV) that is eliminated, reaction equation is
；
(4) hydrogenation: add described elimination thing (IV), ethyl acetate and catalyst in reaction bulb, pass into hydrogen, be warming up to 40 DEG C, insulation reaction 2 hours, Filtration of catalyst, filtrate concentrates, elutriation, filtering, dry and obtain hydride (V), reaction equation is
；
(5) grignard hydrolysis: add described hydride (V), oxolane and methylating reagent in reaction bulb, is warming up to backflow, back flow reaction 12 hours, stopped reaction when TLC detection is without raw material point, is cooled to 0 DEG C, and the cancellation that adds water is reacted, add methanol and hydrochloric acid, 40 DEG C are reacted 3 hours, add sodium bicarbonate and adjust pH value to neutral, concentration, elutriation, filtering, dry and obtain end product Progesterone crude product (VI), reaction equation is
。
Further, described in step (1), the ratio of 4-AD (I), sodium carbonate, water and .alpha.-hydroxyisobutyronitrile. reagent is 1W:0.02W:0.2V:1.0V～1W:0.04W:0.4V:1.2V。
Further, described in step (1), the reaction density of 4-AD (I) is 0.3～0.8mol/L。
Further, alcohol reagent described in step (2) is the one in ethylene glycol, 1,3-PD and neopentyl glycol。
Further, catalyst described in step (2) is the one in p-methyl benzenesulfonic acid, boron trifluoride diethyl etherate and pyridine hydrochloride。
Further, ketal protection (III) described in step (3) is 1W:0.8W～1W:1.2W with the ratio of described elimination reagent。
Further, described in step (3), the reaction density of ketal protection (III) is 0.1～0.5mol/L。
Further, eliminating reagent described in step (3) is the one in phosphorus oxychloride and phosphorus pentachloride。
Further, the ratio eliminating thing (IV) and described catalyst described in step (4) is 1W:0.1W～1W:0.2W。
Further, the reaction density eliminating thing (IV) described in step (4) is 0.2～0.5mol/L。
Further, catalyst described in step (4) is the one in active nickel and palladium carbon。
Further, described in step (5), the ratio of hydride (V) and described methylating reagent is 1W:0.8V～1W:1.5V。
Further, methylating reagent described in step (5) is the one in methyl-magnesium-halide and lithium methide。
It is different from traditional Progesterone preparation technology; the present invention is first with 4-AD for raw material; Progesterone is obtained by cyanalation reaction, ketal protection reaction, elimination reaction, hydrogenation and grignard hydrolysis; not only reduce the production cost of Progesterone; and processing step is ripe, it is easy to large-scale industrial production。The present invention altogether five steps reaction, the weight yield often walked all between 80%～110%, the plurality of advantages such as weight total recovery, more than 80%, has feed stock conversion height, and process route is ripe, with low cost。
Detailed description of the invention
Presently in connection with embodiment, the present invention is further detailed explanation, and the application of the present invention is not limited to the following examples, and any pro forma accommodation that the present invention is done falls within protection scope of the present invention。
In following embodiment, the reaction equation of the cyanalation reaction of the first step is:
；
The reaction equation of the ketal protection reaction of second step is:
；
The reaction equation eliminating reaction of the 3rd step is:
；
The reaction equation of the hydrogenation of the 4th step is:
；
The reaction equation of the grignard hydrolysis of the 5th step is:
。
Embodiment 1
The first step, cyanalation reaction: 4-AD 50g, sodium carbonate 2g and water 20ml are added reaction bulb, add methanol 250ml stirring, be warming up to about 40 DEG C, add .alpha.-hydroxyisobutyronitrile. 55ml, survey PH=8～9;After reacting 4 hours at about 40 DEG C, dropping water 80ml continues reaction 5 hours, cools to about 17 DEG C and stirs 20 hours, stopped reaction when thin layer chromatography (TLC) detection is without raw material point。Add hydrochloric acid 5ml and water 250ml elutriation, filter, dry 12 hours in 75 DEG C to 80 DEG C, obtain off-white color solid cyanalation product II 50g, weight yield 100%, HPLC(HighPerformanceLiquidChromatography, high performance liquid chromatography) content 98%。
Second step, ketal protection reaction: cyano group compound 50g, ethylene glycol 100ml are put in reaction bulb, stirring, put into p-methyl benzenesulfonic acid 1.25g, triethyl orthoformate 45ml；It is warming up to 40 DEG C, reacts 16 hours in about 40 DEG C；Solution is become purple from yellow, stopped reaction when TLC detection is without raw material point。Cool to less than 20 DEG C, add triethylamine 30ml cancellation reaction, pour elutriation in water 250ml into, filter, in 75 DEG C of dry 12 hours, obtain off-white color solid ketal protection product III 55g。Weight yield 110%, HPLC about 95%。
3rd step, eliminates reaction: joined by ketal protection 55g in pyridine 400ml, and stirring puts into phosphorus oxychloride 50g。Being warming up to 40 DEG C to react 2 hours, post-heating reacts 5 hours to 45 DEG C, stopped reaction when TLC detection is without raw material point。Being cooled to 0 DEG C, pour elutriation in frozen water 500ml into, filter, 75 DEG C dry 10 hours, obtain off-white color solid and eliminate thing IV 45g, and weight yield 82%, HPLC is about 92%。
4th step, hydrogenation: thing 45g will be eliminated and add in ethyl acetate 450ml, stirring, put into active nickel 9g, pass into hydrogen。Being warming up to 40 DEG C to react 2 hours, be filtered to remove active nickel, filtrate is concentrated into dry, adds water 100ml elutriation discharging, filters, and 70 DEG C dry obtains solid hydrides V about 44g for 10 hours, and weight yield 98%, HPLC is about 90%。
5th step, grignard hydrolysis: magnesium sheet 20g is put in the reaction bulb added with oxolane 50ml, pass into monochloro methane, to magnesium sheet molten clear after ventilate again 6 hours。Standby；Grignard hydrolysis bottle adds hydride 44g, oxolane 200ml, adds the methylating reagent prepared, be warmed up to backflow, back flow reaction 12 hours, stopped reaction when TLC detection is without raw material point。It is cooled to 0 DEG C, adds 40ml shrend and go out reaction, rear addition methanol 440ml, hydrochloric acid 75ml, 40 DEG C are reacted 3 hours, stopped reaction when TLC detection is without raw material point, add sodium bicarbonate and regulate pH value to neutral, are evaporated near dry, adding 1000ml water elutriation, filter, washing, 70 DEG C dry 10 hours。Obtaining off-white color solid Progesterone VI about 39.6g, weight yield 90%, HPLC about 92%, namely crude product refining obtains Progesterone fine work。
Embodiment 2
The first step, cyanalation reaction: 4-AD 50g, sodium carbonate 1g and water 10ml are added reaction bulb, add methanol 580ml stirring, be warming up to about 40 DEG C, add .alpha.-hydroxyisobutyronitrile. 50ml, survey PH=8～9;After reacting 4 hours at about 40 DEG C, dropping water 80ml continues reaction 5 hours, cools to about 17 DEG C and stirs 20 hours, stopped reaction when TLC detection is without raw material point。Add hydrochloric acid 5ml and water 250ml elutriation, filter, dry 12 hours in 75 to 80 DEG C, obtain off-white color solid cyanalation product II 49g, weight yield 98%, HPLC content 95%；
Subsequent step is with embodiment 1。
Embodiment 3
The first step, with embodiment 1；
Second step, ketal protection reaction: cyano group compound 50g, 1,3-PD 100ml are put in reaction bulb, stirring, put into pyridine hydrochloride 1.25g, triethyl orthoformate 45ml；It is warming up to 40 DEG C, reacts 16 hours in about 40 DEG C；Solution is become purple from yellow, stopped reaction when TLC detection is without raw material point。Cool to less than 20 DEG C, add triethylamine 30ml cancellation reaction, pour elutriation in water 250ml into, filter, in 75 DEG C of dry 12 hours, obtain off-white color solid ketal protection product III 56g。Weight yield 112%, HPLC about 92%；
Subsequent step is with embodiment 1。
Embodiment 4
The first step, with embodiment 1；
Second step, ketal protection reaction: cyano group compound 50g, neopentyl glycol 100ml are put in reaction bulb, stirring, put into boron trifluoride diethyl etherate 1.25g, triethyl orthoformate 45ml；It is warming up to 40 DEG C, reacts 16 hours in about 40 DEG C；Solution is become purple from yellow, stopped reaction when TLC detection is without raw material point。Cool to less than 20 DEG C, add triethylamine 30ml cancellation reaction, pour elutriation in water 250ml into, filter, in 75 DEG C of dry 12 hours, obtain off-white color solid ketal protection product III 57.5g。Weight yield 115%, HPLC about 93%；
Subsequent step is with embodiment 1。
Embodiment 5
The first step and second step, with embodiment 1；
3rd step, eliminates reaction: is added by ketal protection 55g in pyridine 1.5L, stirring, puts into phosphorus pentachloride 44g。Be warming up to 40 DEG C react 2 hours, after heat to 45 DEG C react 5 hours, TLC detection without raw material point time stopped reaction。Being cooled to 0 DEG C, pour elutriation in frozen water 500ml into, filter, 75 DEG C dry 10 hours, obtain off-white color solid and eliminate thing IV 38.5g, and weight yield 70%, HPLC is about 87%；
Subsequent step is with embodiment 1。
Embodiment 6
The first step is with embodiment 1；Second step is with embodiment 3；
3rd step, eliminates reaction: is added by ketal protection 55g in pyridine 300ml, stirring, puts into phosphorus oxychloride 66g。Being warming up to 40 DEG C to react 2 hours, post-heating reacts 5 hours to 45 DEG C, stopped reaction when TLC detection is without raw material point。Being cooled to 0 DEG C, pour elutriation in frozen water 500ml into, filter, 75 DEG C dry 10 hours, obtain off-white color solid and eliminate thing IV 44g, and weight yield 79%, HPLC is about 90%；
Subsequent step is with embodiment 1。
Embodiment 7
The first step is with embodiment 1；Second step is with embodiment 4；3rd step with embodiment 5,
4th step, hydrogenation: thing 45g will be eliminated and add in ethyl acetate 660ml, stirring, put into palladium carbon 4.5g, pass into hydrogen。Being warming up to 40 DEG C to react 2 hours, be filtered to remove palladium carbon, filtrate is concentrated into dry, adds water 100ml elutriation discharging, filters, and 70 DEG C dry obtains solid hydrides V about 42.8g for 10 hours, and weight yield 95%, HPLC is about 85%；
Subsequent step is with embodiment 1。
Embodiment 8
The first step is with embodiment 1；Second step is with embodiment 4；3rd step with embodiment 6,
4th step, hydrogenation: thing 45g will be eliminated and add in ethyl acetate 260ml, stirring, put into palladium carbon 9g, pass into hydrogen。Being warming up to 40 DEG C to react 2 hours, be filtered to remove palladium carbon, filtrate is concentrated into dry, adds water 100ml elutriation discharging, filters, and 70 DEG C dry obtains solid hydrides V about 43.2g for 10 hours, and weight yield 96%, HPLC is about 90%；
Subsequent step is with embodiment 1。
Embodiment 9
The first step is with embodiment 1；Second step is with embodiment 4；3rd step is with embodiment 6；4th step is with embodiment 7；
5th step, grignard hydrolysis: lithium bar 4.11g is put in the reaction bulb added with oxolane 35ml, passes into monochloro methane, to lithium bar molten clear after ventilate again 6 hours, standby；Grignard hydrolysis bottle adds hydride 44g, oxolane 200ml, adds the lithium reagent prepared, be warming up to backflow, back flow reaction 12 hours, stopped reaction when TLC detection is without raw material point。It is cooled to 0 DEG C, adds 40ml shrend and go out reaction, rear addition methanol 440ml, hydrochloric acid 75ml, 40 DEG C are reacted 3 hours, stopped reaction when TLC detection is without raw material point, add sodium bicarbonate and adjust pH value to neutral, are evaporated near dry, adding water 1000ml elutriation, filter, washing, 70 DEG C dry 10 hours。Obtaining off-white color solid Progesterone VI about 40g, weight yield 90%, HPLC about 91%, namely crude product refining obtains Progesterone fine work。
Embodiment 10
The first step is with embodiment 1；Second step is with embodiment 4；3rd step is with embodiment 6；4th step is with embodiment 8；
5th step, grignard hydrolysis: magnesium sheet 26.5g is put in the reaction bulb added with oxolane 66ml, pass into monochloro methane, to magnesium sheet molten clear after ventilate again 6 hours, standby；Grignard hydrolysis bottle adds hydride 44g, oxolane 200ml, adds the grignard reagent prepared, be warming up to backflow, back flow reaction 12 hours, stopped reaction when TLC detection is without raw material point。It is cooled to 0 DEG C, adds 40ml shrend and go out reaction, rear addition methanol 440ml, hydrochloric acid 75ml, 40 DEG C are reacted 3 hours, stopped reaction when TLC detection is without raw material point, add sodium bicarbonate and adjust pH value to neutral, are evaporated near dry, adding water 1000ml elutriation, filter, washing, 70 DEG C dry 10 hours。Obtaining off-white color solid Progesterone VI about 38.7g, weight yield 88%, HPLC about 92%, namely crude product refining obtains Progesterone fine work。
The Progesterone fine work prepared in various embodiments above is detected, mass spectrum: m/z315 (M+H+), compare with Progesterone reference material, comply fully with the characteristic of Progesterone。
With the above-mentioned desirable embodiment according to the present invention for enlightenment, by above-mentioned description, relevant staff in the scope not necessarily departing from this invention technological thought, can carry out various change and amendment completely。The technical scope of this invention is not limited to the content in description, it is necessary to determine its technical scope according to right。
Claims (13)
1. the method preparing Progesterone, it is characterised in that comprise the steps:
(1) cyanalation reaction: be sequentially added into 4-AD (I), sodium carbonate, water and methanol in reaction bulb, it is warming up to 35 DEG C～40 DEG C, adds .alpha.-hydroxyisobutyronitrile. reagent, after reacting 4 hours at this temperature, dropping water continues reaction 5 hours, react 20 hours after being cooled to 15 DEG C～20 DEG C, stopped reaction when TLC detection is without raw material point, add concentrated hydrochloric acid aqueous solution cancellation reaction, add water elutriation, sucking filtration is to dry, and vacuum drying oven is dried and obtained cyanalation product (II), and reaction equation is
；
(2) ketal protection reaction: add described cyanalation product (II), alcohol reagent and catalyst in reaction bulb, add triethyl orthoformate；Heat to uniform temperature reaction certain time；Stopped reaction when TLC detection is without raw material point, cools to less than 20 DEG C, adds triethylamine cancellation reaction, is poured into water elutriation, and sucking filtration is to dry, and oven for drying obtains ketal protection product (III), and reaction equation is
；
(3) reaction is eliminated: in reaction bulb, add described ketal protection (III), pyridine and elimination reagent; it is warming up to 40 DEG C; after insulation reaction 2 hours; it is warming up to 45 DEG C to react 5 hours, stopped reaction when TLC detection is without raw material point, cooling; pour in frozen water; filtering, the dry thing (IV) that is eliminated, reaction equation is
；
(4) hydrogenation: add described elimination thing (IV), ethyl acetate and catalyst in reaction bulb, pass into hydrogen, be warming up to 40 DEG C, insulation reaction 2 hours, Filtration of catalyst, filtrate concentrates, elutriation, filtering, dry and obtain hydride (V), reaction equation is
；
(5) grignard hydrolysis: add described hydride (V), oxolane and methylating reagent in reaction bulb, is warming up to backflow, back flow reaction 12 hours, stopped reaction when TLC detection is without raw material point, is cooled to 0 DEG C, and the cancellation that adds water is reacted, add methanol and hydrochloric acid, 40 DEG C are reacted 3 hours, add sodium bicarbonate and adjust pH value to neutral, concentration, elutriation, filtering, dry and obtain end product Progesterone crude product (VI), reaction equation is
。
2. method according to claim 1, it is characterised in that described in step (1), the ratio of 4-AD (I), sodium carbonate, water and .alpha.-hydroxyisobutyronitrile. reagent is 1W:0.02W:0.2V:1.0V～1W:0.04W:0.4V:1.2V。
3. method according to claim 1, it is characterised in that described in step (1), the reaction density of 4-AD (I) is 0.3～0.8mol/L。
4. method according to claim 1, it is characterised in that alcohol reagent described in step (2) is the one in ethylene glycol, 1,3-PD and neopentyl glycol。
5. method according to claim 1, it is characterised in that catalyst described in step (2) is the one in p-methyl benzenesulfonic acid, boron trifluoride diethyl etherate and pyridine hydrochloride。
6. method according to claim 1, it is characterised in that the ratio of ketal protection (III) described in step (3) and described elimination reagent is 1W:0.8W～1W:1.2W。
7. method according to claim 1, it is characterised in that described in step (3), the reaction density of ketal protection (III) is 0.1～0.5mol/L。
8. method according to claim 1, it is characterised in that eliminating reagent described in step (3) is the one in phosphorus oxychloride and phosphorus pentachloride。
9. method according to claim 1, it is characterised in that the ratio eliminating thing (IV) and described catalyst described in step (4) is 1W:0.1W～1W:0.2W。
10. method according to claim 1, it is characterised in that the reaction density eliminating thing (IV) described in step (4) is 0.2～0.5mol/L。
11. method according to claim 1, it is characterised in that catalyst described in step (4) is the one in active nickel and palladium carbon。
12. method according to claim 1, it is characterised in that described in step (5), the ratio of hydride (V) and described methylating reagent is 1W:0.8V～1W:1.5V。
13. method according to claim 1, it is characterised in that methylating reagent described in step (5) is the one in methyl-magnesium-halide and lithium methide。
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| Publication number | Priority date | Publication date | Assignee | Title |
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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 |
| CN107892708A (en) * | 2017-12-27 | 2018-04-10 | 浙江仙居君业药业有限公司 | The synthetic method of the β itrile group steroidal compounds of 17 α hydroxyls 17 |
| CN109988210A (en) * | 2017-12-30 | 2019-07-09 | 天津药业研究院有限公司 | A kind of preparation method of progesterone and progesterone intermediate |
| CN117257775A (en) * | 2023-11-01 | 2023-12-22 | 南京羚诺生物医药技术研究院有限公司 | Oral soluble film preparation for endometriosis and preparation method thereof |
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| CN103910775A (en) * | 2014-03-31 | 2014-07-09 | 仙居县圃瑞药业有限公司 | Synthesis method of 17alpha-hydroxyl progesterone |
| CN104945459A (en) * | 2015-06-17 | 2015-09-30 | 湖北葛店人福药业有限责任公司 | Method for preparing finasteride intermediate |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN107892708A (en) * | 2017-12-27 | 2018-04-10 | 浙江仙居君业药业有限公司 | The synthetic method of the β itrile group steroidal compounds of 17 α hydroxyls 17 |
| CN109988210A (en) * | 2017-12-30 | 2019-07-09 | 天津药业研究院有限公司 | A kind of preparation method of progesterone and progesterone intermediate |
| CN117257775A (en) * | 2023-11-01 | 2023-12-22 | 南京羚诺生物医药技术研究院有限公司 | Oral soluble film preparation for endometriosis and preparation method thereof |
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Application publication date: 20160622 |