CN104119414B

CN104119414B - The preparation method of high quality progesterone

Info

Publication number: CN104119414B
Application number: CN201410287916.XA
Authority: CN
Inventors: 蒋澄宇; 顾向忠; 林林
Original assignee: JIANGSU JIAERKE PHARMACEUTICALS GROUP CORP Ltd
Current assignee: Jiangsu Jiaerke Pharmaceutical Group Co., Ltd.
Priority date: 2014-06-25
Filing date: 2014-06-25
Publication date: 2018-06-22
Anticipated expiration: 2034-06-25
Also published as: CN104119414A

Abstract

The invention discloses a kind of preparation methods of high quality progesterone; it is using gravidity pregnenolone as raw material; it passes sequentially through ketal protection, walsh oxidation and hydrolysis and obtains progesterone crude product, then the high quality progesterone by being recrystallized to give content >=99.7%, single miscellaneous content ＜ 0.1%.Wherein ketal protection is in the presence of organic solvent, triethyl orthoformate and catalyst; it is made by gravidity pregnenolone and glycol reaction; walsh oxidation is then in the presence of dry toluene and aluminium isopropoxide, is made under reflux conditions by the Betamethasone Ketal structures that ketal is protected and cyclohexanone.Progesterone content >=99.7% made from the method for the present invention, single miscellaneous content ﹤ 0.1%, weight total recovery >=82%, so as to be suitble to industrialized production.

Description

The preparation method of high quality progesterone

Technical field

The present invention relates to a kind of preparation methods of steroidal compounds, and in particular to a kind of preparation side of high quality progesterone Method.

Background technology

Progesterone（Also known as progesterone, pregnendione or gestogen）Chemical name be：4- pregnene -3,20- diketone is made Clinically there is highly important purposes for drug, mainly have and promote and the uterus of first half period of gestation is maintained to change, for controlling Treat the threatened abortion caused by luteal phase defect, habitual abortion, irregular menstruation, functional uterine bleeding etc..In recent years The study found that progesterone be not only intended to singly treatment gynemetrics disease, it may also be used for treatment department of medicine and surgery in it is certain Disease.In addition, progesterone can also synthesize other steroid drugs as intermediate, such as cortisone, hydrocortisone, Finasteride Deng.

The method for preparing progesterone at present mainly has following a few major class：

（1）With natural plant extracts（Such as diosgenin, ergosterol, stigmasterol, cholesterine）It is prepared for raw material Progesterone：This kind of method period is long, yield is low, so as to be not suitable for industrialized production.

（2）Progesterone is prepared by raw material of androstenedione：With hero as disclosed in Chinese patent literature CN103524588A Steroid alkene diketone is raw material, through hydroxyl cyanogenation, dehydration, ketal protection reaction, catalytic hydrogenation reaction, addition hydrolysis system The method for obtaining progesterone；This method synthetic route is longer（Need five steps）, yield is relatively low（With androstenedione weight calculation amount total recovery Only 28%）.For another example Chinese patent literature CN103087136 is disclosed using 17 Alpha-hydroxy progesterone as raw material, through elimination reaction, The method of reduction reaction and refined obtained progesterone；Since 17 Alpha-hydroxy progesterone are through three-step reaction system by androstenedione , thus this method also five steps react, even and if in terms of 17 Alpha-hydroxy progesterone, weight yield highest also less than 77%, and HPLC highests are also less than 99.3%.For another example Chinese patent literature CN103848879A is disclosed using androstenedione as original Material, the method for progesterone is obtained through two-step reaction；Although this method synthetic route is very short, have the following disadvantages：a、 Wittig reagents prepare more difficult and expensive；B, wittig reactions need to carry out in a low temperature of -50 DEG C, will to equipment Ask higher；C, severe reaction conditions need to react under anaerobic；For d weight yields less than 80%, purity is even more less than 98%.

（3）Progesterone is prepared by raw material of diene alcohol ketone acetic ester, this is also presently the most universal method：It is by double Alkene alcohol ketone acetic ester obtains pregnenolone through catalytic hydrogenation and hydrolysis of ester group（Gravidity pregnenolone）, then through walsh oxidation and It is refining to obtain progesterone（Such as Chinese patent literature CN102060901A, Chinese patent literature CN102911232A and gold are bright, Chemical Manufacture and technology, the 2nd phase 10-11 of volume 20 in 2013, progesterone improvement in synthesis disclosed in page 36）.

Existing literature is shown is oxidized to progesterone by the direct walsh of gravidity pregnenolone, and obtained progesterone content is relatively low, Single miscellaneous content is higher, and yield is relatively low.

The method weight total recovery as disclosed in gold bright grade only has 63.2%, and purity only has 94.1%.

The progesterone content that for another example method disclosed in Chinese patent literature CN102060901A obtains also only has 99.3%, master For miscellaneous content close to 0.3%, weight total recovery also only has 69%.

And Chinese patent literature CN102911232A improves weight total recovery in the case where increasing step pretreatment To more than 72%（Highest 81.7%）, main miscellaneous content is then reduced to close to 0.2%, although its purity is up to more than 99.5%（Highest 99.7%）, but the purity that detects of efficient liquid phase and the content concept that be two different：The former is using area normalization method Measure subject matter area percentage, refer in a kind of substance remove impurity amount after account for total amount number；And the latter is then It is measured using external standard method or internal standard method, refers to the amount containing subject matter in a kind of substance.Therefore purity reaches 99.7% content 99.7% must be less than.

Invention content

It is an object of the invention to solve the above problems, a kind of content >=99.7%, single miscellaneous content ＜ 0.1%, weight are provided The preparation method of the high quality progesterone for being suitable for industrialized production of total recovery >=82%.

The technical concept of the present invention is as follows：Applicant is had found by a large number of experiments, leads to the prior art by gravidity pregnenolone The main reason for content that direct walsh is oxidized to progesterone is relatively low, single miscellaneous content is higher and yield is relatively low is due to pregnant alkene The back reaction of walsh oxidation reaction can occur in the reaction process for 20 carbonyls of alcohol ketone（Meerwein-Ponndorf-Verley Reduction reaction）, so as to be partially reduced to 20 hydroxyls, and then introduce 20 hydroxy by-products（Chiral carbon, shape are formed at 20 Into two chipal compounds impurity）.

Realizing the technical solution of the object of the invention is：A kind of preparation method of high quality progesterone, it is with pregnant enol Ketone is raw material, passes sequentially through ketal protection, walsh oxidation and hydrolysis and obtains progesterone crude product, then by being recrystallized to give content >=99.7%, the high quality progesterone of single miscellaneous ＜ 0.1%.Reaction route is as follows：

。

Above-mentioned ketal protection is in the presence of organic solvent, triethyl orthoformate and catalyst, by gravidity pregnenolone It is made with glycol reaction.

The organic solvent is dichloromethane, chloroform or tetrahydrofuran, preferably dichloromethane.

The catalyst is p-methyl benzenesulfonic acid, pyridine hydrochloride or pyridine hydrogen bromide salt, preferably p-methyl benzenesulfonic acid.

Above-mentioned walsh oxidation is the Betamethasone Ketal structures and ring protected by ketal in the presence of dry toluene and aluminium isopropoxide Hexanone is made under reflux conditions.

The Betamethasone Ketal structures are 1: 1.5~5: 0.1~0.5, preferably 1: 2 with the weight ratio of cyclohexanone and aluminium isopropoxide: 0.2。

The good effect that the present invention has：The method of the present invention is first passed through carries out ketal protection, then carry out to 20 carbonyls Walsh aoxidizes, and the side reaction occurred when walsh can be avoided to aoxidize in this way avoids the introducing of by-product, finally obtain content >= 99.7%（Reach as high as 99.9%）, single miscellaneous content ＜ 0.1% high quality progesterone, and weight total recovery >=82%（Highest can Up to 87%）, so as to be suitble to industrialized production.

Specific embodiment

（Embodiment 1）

The preparation method of the high quality progesterone of the present embodiment has steps of：

1. ketal is protected：

The gravidity pregnenolone of the dichloromethane of 30.0kg and 10.0kg is added in reaction unit simultaneously stirring and dissolving, then Add in the triethyl orthoformate of 15.0kg and the ethylene glycol of 10.0kg, room temperature（15~25 DEG C, similarly hereinafter）5min is stirred, is subsequently added into The p-methyl benzenesulfonic acid of 0.2kg reacts to raw material disappearance at a temperature of 24 ± 2 DEG C, adds the triethylamine of 0.12kg, stirring 0.5h。

After reaction, it is concentrated under reduced pressure and removes all solvents, add water stirring and elutriation, be cooled to 5 DEG C, centrifuge, washing filter Cake to neutrality, drying obtains the Betamethasone Ketal structures of 11.3kg.

2. walsh aoxidizes：

The Betamethasone Ketal structures of the toluene of 160kg, the cyclohexanone of 22.6kg and step 1. 11.3kg obtained are added to reaction In device, stirring is warming up to 110 DEG C of progress distillation dehydrations, moisture is controlled to 0.1% hereinafter, be then cooled to 90 DEG C, added in The aluminium isopropoxide of 2.26kg, then be warming up to 115 DEG C and carry out 1~2h of back flow reaction.

After reaction, 70 DEG C are cooled to hereinafter, add in the sodium hydrate aqueous solution of 23kg a concentration of 10wt%, stirs 1h, Stratification after organic layer is washed with water to neutrality, is evaporated off solvent and filters while hot, after filter cake washs 10min with hot water, from The heart dries, and drying obtains the walsh object of 11.3kg.

3. it hydrolyzes：

The walsh object of the methanol of 113kg and step 2. 11.3kg obtained are added in reaction unit, are added with stirring Then reaction 6h is hydrolyzed in the hydrochloric acid of a concentration of 10wt% of 226kg at a temperature of 25 ± 2 DEG C.

After reaction, it adds in sodium bicarbonate solution and adjusts pH value to neutrality, be concentrated under reduced pressure and remove solvent, add water stirring simultaneously Elutriation, centrifugation, washing filter cake to neutrality, drying obtain progesterone crude product.

4. it refines：

By the ethyl alcohol of 29.5kg and step, 3. progesterone crude product obtained is added in reaction unit, and it is molten to be warming up to reflux Solution, slightly cold addition activated carbon 1.0kg, then it is warming up to reflux 1h.

After reaction, it filters while hot, and is concentrated under reduced pressure into a large amount of solids and is precipitated, be cooled to 0~5 DEG C, centrifuge, drying, In 70~75 DEG C of drying, the high quality progesterone of 8.7kg, content 99.9% are obtained（HPLC）, single miscellaneous content ﹤ 0.1%, with starting The weight total recovery of raw material gravidity pregnenolone meter is 87%.

（2~embodiment of embodiment 5）

Each embodiment is substantially the same manner as Example 1, and the difference lies in the ketal protection of step 1., are specifically shown in Table 1.

Table 1

	Embodiment 1	Embodiment 2	Embodiment 3	Embodiment 4	Embodiment 5
						Solvent	Dichloromethane	Chloroform	Tetrahydrofuran	Dichloromethane	Dichloromethane
Catalyst	P-methyl benzenesulfonic acid	P-methyl benzenesulfonic acid	P-methyl benzenesulfonic acid	Pyridine hydrochloride	Pyridine hydrogen bromide salt
						High quality progesterone	8.7kg	8.5kg	8.3kg	8.4kg	8.2kg
Content	99.9%	99.7%	99.8%	99.7%	99.8%
						Single miscellaneous content	﹤ 0.1%	﹤ 0.1%	﹤ 0.1%	﹤ 0.1%	﹤ 0.1%
Weight total recovery	87%	85%	83%	84%	82%

As can be seen from Table 1：In the case where other conditions are all identical, using dichloromethane as solvent and use pair Toluenesulfonic acid is as catalyst, the content of obtained progesterone and the equal highest of weight total recovery.

（Comparative example 1）

Using the gravidity pregnenolone of the 10.0kg in embodiment 1 as raw material, using Chinese patent literature CN102060901A realities The similar approach for applying step b~c of example 1 prepares progesterone, as a result obtains the progesterone of 7.9kg, content 99.3%, list is miscellaneous to be contained Amount up to 0.27%.

（Comparative example 2）

Using the gravidity pregnenolone of the 10.0kg in embodiment 1 as raw material, using Chinese patent literature CN102911232A realities Apply 3 step of example（3）~（5）Method prepare progesterone, as a result obtain the progesterone of 7.8kg, content 99.5%, single miscellaneous content Up to 0.18%.

Claims

1. a kind of preparation method of high quality progesterone, it is characterised in that：Using gravidity pregnenolone as raw material, ketal guarantor is passed sequentially through Shield, walsh oxidation and hydrolysis obtain progesterone crude product, then by being recrystallized to give content >=99.7%, single miscellaneous content ＜ 0.1% High quality progesterone；

Described ketal protection be in the presence of organic solvent, triethyl orthoformate and catalyst, by gravidity pregnenolone with Glycol reaction is made；The organic solvent is dichloromethane, chloroform or tetrahydrofuran；The catalyst is pair Toluenesulfonic acid, pyridine hydrochloride or pyridine hydrogen bromide salt；

The walsh oxidation is the Betamethasone Ketal structures and hexamethylene protected by ketal in the presence of dry toluene and aluminium isopropoxide Ketone is made under reflux conditions；The Betamethasone Ketal structures and the weight ratio of cyclohexanone and aluminium isopropoxide for 1: 1.5~5: 0.1~ 0.5；

Reaction route is as follows：

。

2. the preparation method of high quality progesterone according to claim 1, it is characterised in that：The organic solvent is two Chloromethanes；The catalyst is p-methyl benzenesulfonic acid.

3. the preparation method of high quality progesterone according to claim 1, it is characterised in that：The Betamethasone Ketal structures and hexamethylene The weight ratio of ketone and aluminium isopropoxide is 1: 2: 0.2.