CN104119414A

CN104119414A - Preparation method of high-quality progesterone

Info

Publication number: CN104119414A
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: 2014-10-29
Anticipated expiration: 2034-06-25
Also published as: CN104119414B

Abstract

The invention discloses a preparation method of high-quality progesterone, which comprises the following steps: by using pregnenolone as the raw material, sequentially carrying out ketal protection, Oppenauer oxidation and hydrolysis to obtain a progesterone crude product, and recrystalizing to obtain the high-quality progesterone of which the purity is greater than or equal to 99.7% and the single impurity content is less than 0.1%. In the ketal protection process, the pregnenolone and ethylene glycol react in the presence of an organic solvent, triethyl orthoformate and a catalyst; and in the Oppenauer oxidation process, the ketal product obtained by ketal protection reacts with cyclohexanone under reflux conditions in the presence of anhydrous toluene and aluminum isopropoxide. The purity of the prepared progesterone is greater than or equal to 99.7%, the single impurity content is less than 0.1%, and the total weight yield is greater than or equal to 82%, so the method is suitable for industrialized mass production.

Description

The preparation method of high quality Progesterone

Technical field

The present invention relates to a kind of preparation method of steroidal compounds, be specifically related to a kind of preparation method of high quality Progesterone.

Background technology

The chemical name of Progesterone (having another name called progesterone, pregnendione or gestogen) is: 4-pregnene-3,20-diketone, there is clinically very important purposes as medicine, mainly having the uterus that promotes and maintain first half period of gestation changes, be used for the treatment of threatened abortion, habitual abortion because luteal phase defect causes, menoxenia, dysfunctional uterine hemorrhage etc.Research discovery in recent years, Progesterone is not singly just used for the treatment of the disease of Obstetric and Gynecologic Department, also can be used for treating some disease in department of medicine and surgery.In addition, Progesterone can also synthesize other steroid drugs as intermediate, as cortisone, hydrocortisone, Finasteride etc.

The method of preparing at present Progesterone mainly contains following several large class:

(1) prepare Progesterone taking natural plant extracts (as diosgenin, ergosterol, Stigmasterol, cholesterol etc.) as raw material: this class methods cycle is long, yield is low, thereby is not suitable for industrialized production.

(2) prepare Progesterone taking rotex as raw material: as disclosed in Chinese patent literature CN103524588A taking rotex as raw material, make the method for Progesterone through hydroxyl cyanogenation, dehydration reaction, ketal protective reaction, catalytic hydrogenation reaction, addition hydrolysis reaction; The method synthetic route long (needing five steps), yield lower (only having 28% in rotex weight total recovery).And for example Chinese patent literature CN103087136 is disclosed taking 17 Alpha-hydroxy Progesterone as raw material, through elimination reaction, reduction reaction and make the method for Progesterone; Because 17 Alpha-hydroxy Progesterone are to be made through three-step reaction by rotex, therefore the method is equally also five steps reactions, even and if in 17 Alpha-hydroxy Progesterone, weight yield is the highest also less than 77%, and HPLC is the highest also less than 99.3%.For another example Chinese patent literature CN103848879A is disclosed taking rotex as raw material, obtains the method for Progesterone through two-step reaction; Although the method synthetic route is very short, there is following shortcoming: a, comparatively difficulty and expensive of wittig reagent preparation; B, wittig reaction needed are carried out under the low temperature of-50 DEG C, higher to equipment requirements; C, severe reaction conditions need to be reacted under oxygen free condition; D weight yield is less than 80%, and purity is especially less than 98%.

(3) prepare Progesterone taking diene alcohol ketone acetic ester as raw material, this is also current the most general method: it is to obtain Vitarrine (gravidity pregnenolone) by diene alcohol ketone acetic ester through shortening and hydrolysis of ester group, then be oxidized and refine through Wo Shi and obtain Progesterone (as Chinese patent literature CN102060901A, Chinese patent literature CN102911232A and Jin Can etc., Chemical Manufacture and technology, the 20th volume the 2nd phase 10-11 in 2013,36 pages of disclosed Progesterone improvement in synthesis).

Existing document all shows direct gravidity pregnenolone Wo Shi is oxidized to Progesterone, and the Progesterone content obtaining is on the low side, and single assorted content is higher, and yield is on the low side.

Only have 63.2% as disclosed method weight total recoverys such as Jin Can, purity only has 94.1%.

The Progesterone content that and for example the disclosed method of Chinese patent literature CN102060901A obtains also only has 99.3%, and main assorted content approaches 0.3%, and weight total recovery also only has 69%.

And Chinese patent literature CN102911232A is increasing in the pretreated situation of a step, weight total recovery has been brought up to more than 72% (the highest by 81.7%), main assorted content is reduced to and approaches 0.2%, although its purity more than 99.5% (the highest by 99.7%), but it is two different concepts that high performance liquid phase detects the purity that obtains and content: the former adopts area normalization method to record subject matter area percentage, refer to account for after the amount of removing impurity in a kind of material total amount number; The latter adopts external standard method or marker method to record, and refers to the amount that contains subject matter in a kind of material.Therefore purity reach 99.7% content must be lower than 99.7%.

Summary of the invention

The object of the invention is to address the above problem, the preparation method of the high quality Progesterone that is suitable for industrialized production of a kind of content >=99.7%, single assorted content < 0.1%, weight total recovery >=82% is provided.

Technical conceive of the present invention is as follows: applicant finds by lot of experiments, the content assorted content major cause higher and that yield is on the low side on the low side, single that causes prior art that direct gravidity pregnenolone Wo Shi is oxidized to Progesterone is the reversed reaction (Meerwein-Ponndorf-Verley reduction reaction) that Wo Shi oxidizing reaction can occur due to 20 carbonyls of gravidity pregnenolone in this reaction process, thereby be 20 hydroxyls by partial reduction, and then 20 hydroxyl by products of introducing (form chiral carbon at 20, form two chipal compounds impurity).

The technical scheme that realizes the object of the invention is: a kind of preparation method of high quality Progesterone; it is taking gravidity pregnenolone as raw material; successively by ketal protect, Wo Shi oxidation and hydrolysis obtain Progesterone crude product, then obtain the high quality Progesterone of content >=99.7%, single assorted < 0.1% by recrystallization.Reaction scheme is as follows:

。

Above-mentioned ketal protection is under the existence of organic solvent, triethyl orthoformate and catalyzer, is made by gravidity pregnenolone and glycol reaction.

Described organic solvent is methylene dichloride, trichloromethane or tetrahydrofuran (THF), preferably methylene dichloride.

Described catalyzer is tosic acid, pyridine hydrochloride or pyridine hydrogen bromide salt, preferably tosic acid.

Above-mentioned Wo Shi oxidation is under the existence of dry toluene and aluminum isopropylate, and the Betamethasone Ketal structures and the pimelinketone that are obtained by ketal protection under reflux conditions make.

The weight ratio of described Betamethasone Ketal structures and pimelinketone and aluminum isopropylate is 1: 1.5～5: 0.1～0.5, preferably 1: 2: 0.2.

The positively effect that the present invention has: method of the present invention is first by carrying out ketal protection to 20 carbonyls; carry out again Wo Shi oxidation; the side reaction occurring can avoid like this Wo Shi oxidation time; avoid the introducing of by product; finally obtain content >=99.7%(and reach as high as 99.9%), the high quality Progesterone of single assorted content < 0.1%; and weight total recovery >=82%(reaches as high as 87%), thus be applicable to industrialized production.

Embodiment

(embodiment 1)

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

1. ketal protection:

The gravidity pregnenolone of the methylene dichloride of 30.0kg and 10.0kg is joined in reaction unit and stirring and dissolving, then add the triethyl orthoformate of 15.0kg and the ethylene glycol of 10.0kg, (15～25 DEG C of room temperatures, lower same) stirring 5min, then add the tosic acid of 0.2kg, at the temperature of 24 ± 2 DEG C, react to raw material disappearance, then add the triethylamine of 0.12kg, stir 0.5h.

After reaction finishes, concentrating under reduced pressure is removed all solvents, adds water and stirs and elutriation, is cooled to 5 DEG C, centrifugal, and washing filter cake, to neutral, is dried, and obtains the Betamethasone Ketal structures of 11.3kg.

2. Wo Shi oxidation:

The Betamethasone Ketal structures of the 11.3kg that 1. pimelinketone of the toluene of 160kg, 22.6kg and step made joins in reaction unit, stirring is warming up to 110 DEG C and carries out distillation dehydration, below moisture controlled to 0.1%, then be cooled to 90 DEG C, add the aluminum isopropylate of 2.26kg, then be warming up to 115 DEG C and carry out back flow reaction 1～2h.

After reaction finishes, be cooled to below 70 DEG C, adding 23kg concentration is the aqueous sodium hydroxide solution of 10wt%, stirs 1h, stratification, organic layer is washed with water to after neutrality, steams and desolventizes and filtered while hot, and filter cake is with after hot wash 10min, centrifugal, dry, dry, obtain the Wo Shi thing of 11.3kg.

3. hydrolysis:

The Wo Shi thing of the 11.3kg that 2. methyl alcohol of 113kg and step made joins in reaction unit, and under stirring, adding 226kg concentration is the hydrochloric acid of 10wt%, and reaction 6h is then hydrolyzed at the temperature of 25 ± 2 DEG C.

After reaction finishes, add sodium hydrogen carbonate solution to regulate pH value to neutral, concentrating under reduced pressure, except desolventizing, adds water and stirs and elutriation, centrifugal, and washing filter cake, to neutral, is dried, and obtains Progesterone crude product.

4. refining:

The Progesterone crude product that 3. ethanol of 29.5kg and step made joins in reaction unit, and being warming up to refluxes dissolves, and slightly coldly adds gac 1.0kg, then is warming up to backflow 1h.

After reaction finishes, filtered while hot, and be evaporated to a large amount of solids and separate out, be cooled to 0～5 DEG C, centrifugal, dry, 70～75 DEG C of oven dry, obtain the high quality Progesterone of 8.7kg, content is 99.9%(HPLC), single assorted content ﹤ 0.1%, taking the weight total recovery of starting raw material gravidity pregnenolone as 87%.

(embodiment 2～embodiment 5)

Each embodiment is substantially the same manner as Example 1, and difference is step ketal protection 1., specifically in table 1.

Table 1

?	Embodiment 1	Embodiment 2	Embodiment 3	Embodiment 4	Embodiment 5
						Solvent	Methylene dichloride	Trichloromethane	Tetrahydrofuran (THF)	Methylene dichloride	Methylene dichloride
Catalyzer	Tosic acid	Tosic acid	Tosic 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 assorted 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 situation that other conditions are all identical, adopt methylene dichloride as solvent and adopt tosic acid as catalyzer, the content of prepared Progesterone and weight total recovery are all the highest.

(comparative example 1)

Taking the gravidity pregnenolone of the 10.0kg in embodiment 1 as raw material, adopt the similar approach of step b～c of Chinese patent literature CN102060901A embodiment 1 to prepare Progesterone, result obtains the Progesterone of 7.9kg, and content is 99.3%, and single assorted content is up to 0.27%.

(comparative example 2)

Taking the gravidity pregnenolone of the 10.0kg in embodiment 1 as raw material, adopt the method for Chinese patent literature CN102911232A embodiment 3 steps (3)～(5) to prepare Progesterone, result obtains the Progesterone of 7.8kg, and content is 99.5%, and single assorted content is up to 0.18%.

Claims

1. the preparation method of a high quality Progesterone, it is characterized in that: taking gravidity pregnenolone as raw material, successively by ketal protect, Wo Shi oxidation and hydrolysis obtain Progesterone crude product, then obtain the high quality Progesterone of content >=99.7%, single assorted content < 0.1% by recrystallization; Reaction scheme is as follows:

。

2. the preparation method of high quality Progesterone according to claim 1, is characterized in that: described ketal protection is under the existence of organic solvent, triethyl orthoformate and catalyzer, is made by gravidity pregnenolone and glycol reaction.

3. the preparation method of high quality Progesterone according to claim 2, is characterized in that: described organic solvent is methylene dichloride, trichloromethane or tetrahydrofuran (THF); Described catalyzer is tosic acid, pyridine hydrochloride or pyridine hydrogen bromide salt.

4. the preparation method of high quality Progesterone according to claim 3, is characterized in that: described organic solvent is methylene dichloride; Described catalyzer is tosic acid.

5. the preparation method of high quality Progesterone according to claim 1, is characterized in that: described Wo Shi oxidation is under the existence of dry toluene and aluminum isopropylate, and the Betamethasone Ketal structures and the pimelinketone that are obtained by ketal protection under reflux conditions make.

6. the preparation method of high quality Progesterone according to claim 5, is characterized in that: the weight ratio of described Betamethasone Ketal structures and pimelinketone and aluminum isopropylate is 1: 1.5～5: 0.1～0.5.

7. the preparation method of high quality Progesterone according to claim 6, is characterized in that: the weight ratio of described Betamethasone Ketal structures and pimelinketone and aluminum isopropylate is 1: 2: 0.2.