CN102617691A - Improved preparation method for mifepristone intermediate - Google Patents
Improved preparation method for mifepristone intermediate Download PDFInfo
- Publication number
- CN102617691A CN102617691A CN2012100151996A CN201210015199A CN102617691A CN 102617691 A CN102617691 A CN 102617691A CN 2012100151996 A CN2012100151996 A CN 2012100151996A CN 201210015199 A CN201210015199 A CN 201210015199A CN 102617691 A CN102617691 A CN 102617691A
- Authority
- CN
- China
- Prior art keywords
- mifepristone
- reaction
- diene
- compound
- magnesium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- DMAAXHKUEWOVEJ-KLZFTYBFSA-N CCO[C@@](CC1)(CC(CCC2C3CC4)=C1C2=CCC3(C)C4C#CC)N Chemical compound CCO[C@@](CC1)(CC(CCC2C3CC4)=C1C2=CCC3(C)C4C#CC)N DMAAXHKUEWOVEJ-KLZFTYBFSA-N 0.000 description 1
Landscapes
- Steroid Compounds (AREA)
Abstract
The present invention discloses an improved preparation method for a mifepristone intermediate. The method comprises the following steps: (a) in the presence of tetrahydrofuran, adopting magnesium sheets and bromoethane as raw materials, and carrying out a reaction at a temperature of 25-39 DEG C to obtain ethyl magnesium bromide; (b), introducing propyne gas to the ethyl magnesium bromide to carry out a reaction to obtain propynyl magnesium bromide; (c), in the presence of tetrahydrofuran, adding a compound 3alpha,3beta-ethylenedioxy-estra-5(10),9(11)-dien-17-one to the propynyl magnesium bromide to obtain a compound 3alpha,3beta-ethylenedioxy-17beta-hydroxyl-(1-propynyl)-estra-5(10),9(11)-diene; and (d), collecting the compound 3alpha,3beta-ethylenedioxy-17beta-hydroxyl-(1-propynyl)-estra-5(10),9(11)-diene. With the preparation method for the mifepristone intermediate, the purity of the intermediate 3alpha,3beta-ethylenedioxy-17beta-hydroxyl-(1-propynyl)-estra-5(10),9(11)-diene of the propynyl magnesium bromide and the mifepristone is improved, the production cost is reduced, and the environment protection is provided.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, be specifically related to a kind of improved mifepristone intermediate preparation method.
Background technology
In the building-up process of gestation mifepristone and analogue prior art thereof, its proyl magnesium bromide is at first by monobromethane and the synthetic ethylmagnesium bromide (CH of MAGNESIUM METAL 99
3CH
2MgBr), produce proyl magnesium bromide (CH with the propine solid/liquid/gas reactions again
3C ≡ CMgBr).Use the proyl magnesium bromide to compound 3 α then; Introduce proyl in 3 β-ethylene two oxy-female steroid-5 (10), 9 (11)-diene-17-ketone (I) and prepare mifepristone midbody 3 α, 3 β-ethylene two oxy-17 beta-hydroxy-(1-proyl)-female steroid-5 (10); 9 (11)-diene (II) (" Chinese Medicine industry " magazine 1999; 30, (7) " mifepristone and analogue thereof are at synthesis progress of China "), its reaction process is following:
In above-mentioned reaction; The preparation of proyl magnesium bromide is under the low-temperature atmosphere-pressure condition, to feed propine gas, and Yin Wendu is low to make ethylmagnesium bromide be prone to crystallization, causes ethylmagnesium bromide to feed the back at propine gas and forms the gas-solid two phase reaction; Be difficult to carry out thoroughly; And, need to feed excessive propine gas, cause the luxus consumption and the environmental pollution of propine gas.Simultaneously, the ethylmagnesium bromide of solid phase is because reaction not exclusively can reduce the purity of product (II) with (I) reaction.Therefore, be necessary to provide a kind of improved mifepristone intermediate preparation method, to improve productive rate and purity, to cut down the consumption of raw materials, reduce environmental pollution.
Summary of the invention
The object of the present invention is to provide a kind of improved mifepristone intermediate preparation method.
For reaching the foregoing invention purpose, the present invention has adopted following technical scheme:
A kind of improved mifepristone intermediate preparation method may further comprise the steps:
(a), in the presence of THF, be raw material with magnesium sheet and haloalkane, 25～39 ℃ down reaction obtain the alkyl halide magnesium;
(b), in said alkyl halide magnesium, feed propine solid/liquid/gas reactions, acquisition proyl magnesium halide;
(c), in the presence of THF, in said proyl magnesium halide, add compound 3 α, 3 β-ethylene two oxy-female steroid-5 (10); 9 (11)-diene-17-reactive ketone; Obtain compound 3 α, 3 β-ethylene two oxy-17 beta-hydroxy-(1-proyl)-female steroid-5 (10), 9 (11)-diene;
(d), collect said compound 3 α, 3 β-ethylene two oxy-17 beta-hydroxy-(1-proyl)-female steroid-5 (10), 9 (11)-diene.
According to a preferred embodiment of the invention, in the step (a), said haloalkane is selected from methyl chloride, monobromethane, monochloroethane, monobromethane.
According to a preferred embodiment of the invention, in the step (a), the mass volume ratio of said magnesium sheet and said monobromethane is 3: 10, and the mass volume ratio of said magnesium sheet and said THF is 1: 6, and the volume ratio of said monobromethane and said THF is 3: 10.
According to a preferred embodiment of the invention, in the step (b), the temperature of reaction of said reaction is 15～60 ℃, and reaction pressure is 0.01～0.3MPa.
According to a preferred embodiment of the invention, in the step (b), also comprise the collection discharging of light gas.
According to a preferred embodiment of the invention, said light gas is an ethane.
According to a preferred embodiment of the invention, in the step (c), said compound 3 α, the mass volume ratio of 3 β-ethylene two oxy-female steroid-5 (10), 9 (11)-diene-17-ketone and said THF is 1: 6.
Compared with prior art, the present invention has following advantage:
(1) under the condition that THF exists, monobromethane and MAGNESIUM METAL 99 are prepared into ethylmagnesium bromide, do not reduce temperature and can keep ethylmagnesium bromide and be in dissolved state, direct feeding propine gas generates the proyl magnesium bromide immediately under pressurized conditions.Because reaction at normal temperatures; Avoided the ethylmagnesium bromide shortcoming of crystallization at low temperatures, with emitting after the enrichment of by product ethane gas process light gas collection device, propine gas carries out homogeneous reaction with ethylmagnesium bromide after THF absorbs simultaneously; Reaction is carried out more fully with more thorough; Proyl magnesium bromide and mifepristone midbody 3 α have been improved, 3 β-ethylene two oxy-17 beta-hydroxy-(1-proyl)-female steroid-5 (10), 9 (11)-diene degree of purity of production.
(2) since reaction carry out fully with thoroughly, thereby avoid the consumption of excessive propine gas, reduced production cost, more friendly to environment simultaneously.
Therefore, no matter the disclosed technical scheme of the present invention is technically or from economically, all has favorable industrial application prospect.
Embodiment
Below in conjunction with specific embodiment, the present invention is described further.Should be understood that following examples only are used to the present invention is described but not are used to limit scope of the present invention.
The compound that relates in following examples (I) is 3 α, and 3 β-ethylene two oxy-female steroid-5 (10), 9 (11)-diene-17-ketone have following structural formula:
The compound that relates in following examples (II) is 3 α, and 3 β-ethylene two oxy-17 beta-hydroxy-(1-proyl)-female-5 (10), 9 (11)-diene has following structural formula:
Table 1 is the composition of raw materials of each embodiment.
Table 1, composition of raw materials
Embodiment 1:
(a), in autoclave, add THF and magnesium sheet according to the prescription shown in the table 1; Stir and under 30～39 ℃; Slowly drip 16ml monobromethane/tetrahydrofuran solution, behind the initiation grignard reaction, under the same conditions; Continue to drip residue monobromethane/tetrahydrofuran solution, then 35～39 ℃ of following stirring reactions 1 hour;
(b) after reaction finished, at 25～35 ℃, pressure was to feed propine gas under the condition of 0.08MPa, then under the same conditions, continues stirring reaction 1 hour.In this process, the ethane gas of generation is collected the back by the light gas enriching apparatus and is discharged autoclave, to keep constant pressure.After reaction finished, proyl magnesium bromide content was 99.4% in the detecting reactant;
(c) above-mentioned reactant is cooled to 20 ± 2 ℃, under normal pressure, drips the solution that compound (I) and THF are made into, then stirring reaction 2 hours under the same conditions.Sampling detects raw material (I)＜1% through HPLC, and product (II) content is 94.5%, and reaction finishes;
(d) above-mentioned reactant is cooled to 0 ℃; Regulate pH to 6～6.5 with 28% aqueous ammonium chloride solution, be warmed up to 30 ℃, leave standstill layering in 30 minutes; Organic layer is behind the reclaim under reduced pressure THF; Gained midbody 3 α, 3 β-ethylene two oxy-17 beta-hydroxy-(1-proyl)-female steroid-5 (10), 9 (11)-diene (II) can directly change next step reaction over to.
Embodiment 2:
(a), in autoclave, add THF and magnesium sheet according to the prescription shown in the table 1; Stir and under 25～39 ℃; Slowly drip 10ml monobromethane/tetrahydrofuran solution, behind the initiation grignard reaction, under the same conditions; Continue to drip residue monobromethane/tetrahydrofuran solution, then 35～39 ℃ of following stirring reactions 1 hour;
(b) after reaction finished, at 30～50 ℃, pressure was to feed propine gas under the condition of 0.2MPa, then under the same conditions, continues stirring reaction 1 hour.In this process, the ethane gas of generation is collected the back by the light gas enriching apparatus and is discharged autoclave, to keep constant pressure.After reaction finished, proyl magnesium bromide content was 99.3% in the detecting reactant;
(c) above-mentioned reactant is cooled to 30 ± 2 ℃, under normal pressure, drips the solution that compound (I) and THF are made into, then stirring reaction 1 hour under the same conditions.Sampling detects raw material (I)＜1% through HPLC, and product (II) content is 94.3%, and reaction finishes;
(d) above-mentioned reactant is cooled to 0 ℃; Regulate pH to 6～6.5 with 28% aqueous ammonium chloride solution, be warmed up to 30 ℃, leave standstill layering in 30 minutes; Organic layer is behind the reclaim under reduced pressure THF; Gained midbody 3 α, 3 β-ethylene two oxy-17 beta-hydroxy-(1-proyl)-female steroid-5 (10), 9 (11)-diene (II) can directly change next step reaction over to.
Embodiment 3:
(a), in autoclave, add THF and magnesium sheet according to the prescription shown in the table 1; Stir and under 30～39 ℃; Slowly drip 10ml monobromethane/tetrahydrofuran solution, behind the initiation grignard reaction, under 35～39 ℃; Continue to drip residue monobromethane/tetrahydrofuran solution, then 35～39 ℃ of following stirring reactions 1 hour;
(b) after reaction finished, at 30～40 ℃, pressure was to feed propine gas under the condition of 0.15MPa, then under the same conditions, continues stirring reaction 1 hour.In this process, the ethane gas of generation is collected the back by the light gas enriching apparatus and is discharged autoclave, to keep constant pressure.After reaction finished, proyl magnesium bromide content was 99.2% in the detecting reactant;
(c) above-mentioned reactant is cooled to 25 ± 2 ℃, under normal pressure, drips the solution that compound (I) and THF are made into, then 25～30 ℃ of following stirring reactions 1 hour.Sampling detects raw material (I)＜1% through HPLC, and product (II) content is 94.4%, and reaction finishes;
(d) above-mentioned reactant is cooled to 0 ℃; Regulate pH to 6～6.5 with 28% aqueous ammonium chloride solution, be warmed up to 30 ℃, leave standstill layering in 30 minutes; Organic layer is behind the reclaim under reduced pressure THF; Gained midbody 3 α, 3 β-ethylene two oxy-17 beta-hydroxy-(1-proyl)-female steroid-5 (10), 9 (11)-diene (II) can directly change next step reaction over to.
Embodiment 4:
Improved mifepristone intermediate preparation technology of the present invention and preparation technology of the prior art are compared.Operation steps is with embodiment 1, wherein, step (b) and (c) in actual conditions as shown in table 2.1# and 2# prepare the proyl magnesium bromide under the condition of low-temperature atmosphere-pressure in the prior art, 3#～7# is an improved mifepristone intermediate preparation technology of the present invention.
The mifepristone intermediate preparation technology of table 2, the present invention and prior art test condition relatively
The test result that improved mifepristone intermediate preparation technology of the present invention and preparation technology of the prior art compare is as shown in table 3.
The mifepristone intermediate preparation technology of table 3, the present invention and prior art test result relatively
| Numbering | Proyl magnesium bromide content | Compound (II) content |
| 1 | 94.5％ | 89.5％ |
| 2 | 94.1％ | 88.7％ |
| 3 | 99.3％ | 94.2％ |
| 4 | 99.2％ | 94.5％ |
| 5 | 99.3％ | 94.1％ |
| 6 | 99.4％ | 94.5％ |
| 7 | 99.3％ | 94.3％ |
Result by table 3 is visible, and improved mifepristone intermediate preparation technology of the present invention is compared with prior art, on the basis that has reduced the consumption of raw material propine gas, has further improved the product purity of proyl magnesium bromide and compound (II).Wherein, the content of proyl magnesium bromide is brought up to more than 99% from about 94% of original technology, and the content of compound (II) is brought up to more than 94% from about 89% of original technology.Therefore, use improved mifepristone intermediate preparation technology of the present invention to reduce production costs, improve product purity, more friendly to environment simultaneously.
Should be pointed out that the present invention has only carried out concrete introduction to certain preferred embodiment, protection scope of the present invention includes, but are not limited to cited numerical range and preferred version.The modification of any compound aim of the present invention and variation all allow.
Claims (10)
1. improved mifepristone intermediate preparation method is characterized in that may further comprise the steps:
(a), in the presence of THF, be raw material with magnesium sheet and haloalkane, 25～39 ℃ down reaction obtain the alkyl halide magnesium;
(b), in said alkyl halide magnesium, feed propine solid/liquid/gas reactions, acquisition proyl magnesium halide;
(c), in the presence of THF, in said proyl magnesium halide, add compound 3 α, 3 β-ethylene two oxy-female steroid-5 (10); 9 (11)-diene-17-reactive ketone; Obtain compound 3 α, 3 β-ethylene two oxy-17 beta-hydroxy-(1-proyl)-female steroid-5 (10), 9 (11)-diene;
(d), collect said compound 3 α, 3 β-ethylene two oxy-17 beta-hydroxy-(1-proyl)-female steroid-5 (10), 9 (11)-diene.
2. mifepristone intermediates preparation as claimed in claim 1 is characterized in that: in the step (a), said haloalkane is selected from methyl chloride, monobromethane, monochloroethane, monobromethane.
3. mifepristone intermediates preparation as claimed in claim 1 is characterized in that: in the step (a), the mass volume ratio of said magnesium sheet and said monobromethane is 3: 10.
4. mifepristone intermediates preparation as claimed in claim 1 is characterized in that: in the step (a), the mass volume ratio of said magnesium sheet and said THF is 1: 6.
5. mifepristone intermediates preparation as claimed in claim 1 is characterized in that: in the step (a), the volume ratio of said monobromethane and said THF is 3: 10.
6. mifepristone intermediates preparation as claimed in claim 1 is characterized in that: in the step (b), the temperature of reaction of said reaction is 15～60 ℃.
7. mifepristone intermediates preparation as claimed in claim 1 is characterized in that: in the step (b), the reaction pressure of said reaction is 0.01～0.3MPa.
8. mifepristone intermediates preparation as claimed in claim 1 is characterized in that: in the step (b), also comprise the collection discharging of light gas.
9. mifepristone intermediates preparation as claimed in claim 8 is characterized in that: said light gas is an ethane.
10. mifepristone intermediates preparation as claimed in claim 1 is characterized in that: in the step (c), and said compound 3 α, the mass volume ratio of 3 β-ethylene two oxy-female steroid-5 (10), 9 (11)-diene-17-ketone and said THF is 1: 6.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210015199.6A CN102617691B (en) | 2012-01-18 | 2012-01-18 | Improved preparation method for mifepristone intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210015199.6A CN102617691B (en) | 2012-01-18 | 2012-01-18 | Improved preparation method for mifepristone intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102617691A true CN102617691A (en) | 2012-08-01 |
| CN102617691B CN102617691B (en) | 2014-05-14 |
Family
ID=46557942
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210015199.6A Active CN102617691B (en) | 2012-01-18 | 2012-01-18 | Improved preparation method for mifepristone intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102617691B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1087090A (en) * | 1992-11-19 | 1994-05-25 | 北京第三制药厂 | 17 replace 11 beta substitution aromatic bases-4, the complete synthesizing process of 9-estradiene compounds |
| WO2007098382A2 (en) * | 2006-02-17 | 2007-08-30 | Janssen Pharmaceutica N.V. | 17-phosphorous steroid derivatives useful as progesterone receptor modulators |
| CN101415720A (en) * | 2006-02-17 | 2009-04-22 | 詹森药业有限公司 | 11-phosphorous steroid derivatives useful as progesterone receptor modulators |
-
2012
- 2012-01-18 CN CN201210015199.6A patent/CN102617691B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1087090A (en) * | 1992-11-19 | 1994-05-25 | 北京第三制药厂 | 17 replace 11 beta substitution aromatic bases-4, the complete synthesizing process of 9-estradiene compounds |
| WO2007098382A2 (en) * | 2006-02-17 | 2007-08-30 | Janssen Pharmaceutica N.V. | 17-phosphorous steroid derivatives useful as progesterone receptor modulators |
| CN101415720A (en) * | 2006-02-17 | 2009-04-22 | 詹森药业有限公司 | 11-phosphorous steroid derivatives useful as progesterone receptor modulators |
Non-Patent Citations (4)
| Title |
|---|
| PONCINI, LAURENCE: "Preparation of Acetylenic Diethyl Acetals from the Ortho Ester HC(OC2H5)2OC6H5", 《JOURNAL OF ORGANIC CHEMISTRY》 * |
| W. JIANG 等: "Discovery of novel phosphorus-containing steroids as selective glucocorticoid receptor antagonist", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| 刘云 等: "米非司酮及其类似物在我国的合成进展", 《中国医药工业杂志》 * |
| 陈连喜: "3,4-双三甲硅基呋喃的合成", 《武汉理工大学学报》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102617691B (en) | 2014-05-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102617359B (en) | Method for preparing bromhexine hydrochloride | |
| CN102432590B (en) | Method for synthesizing thiophene ethylamine | |
| CN106866503A (en) | A kind of method that low temperature liquid phase reaction fixed bed continuously synthesizes triacetonamine | |
| CN107805206A (en) | The method that the coupling of micro-pipe reactive distillation is continuously synthesizing to monoethanolamine and its derivative | |
| CN106588758A (en) | Synthetic process for 2-hydrazinylpyridine derivative | |
| CN102633653A (en) | Method for preparing o-phenylenediamine by catalytic hydrogenation of o-nitrophenylamine | |
| CN105085282B (en) | Preparation method for alkyl alcohol amine | |
| CN102617691B (en) | Improved preparation method for mifepristone intermediate | |
| CN101857537A (en) | Method for preparing ferric acetyl acetonade | |
| CN103524305B (en) | Preparation method of 1,3-propanediol derivatives and intermediates | |
| CN100503540C (en) | Method for preparing alkyl orthoacetate | |
| CN110590569A (en) | Method for synthesizing tulobuterol | |
| CN103848768B (en) | The application method of a kind of Methylaminoformyl chloride decomposed tail gas hydrogenchloride in cartap synthesis | |
| CN1053450C (en) | Total synthesis method of 17-substituted 11 beta-substituted aromatic group-4, 9-estradiene compound | |
| CN104447576A (en) | Method for preparing 5-fluorouracil | |
| CN104926665B (en) | Method for synthesizing cinacalcet | |
| CN103880575A (en) | Method for preparing beta-amino amide derivatives | |
| CN104761457A (en) | Preparation method of isopropanolamine | |
| CN102731556A (en) | Process for preparing tetramethyldivinyldisilazane by conversion of divinyl tetramethyl disiloxane | |
| CN103131481A (en) | Biosynthetic fuel | |
| CN102070513A (en) | Synthesis method of 1-teriary butoxy carbonyl-4-piperidone | |
| CN102060778B (en) | Method for synthesizing 4-(1-hydroxyl-1-methylethyl)-2-propyl iminazole-5-carboxylic ethyl ester | |
| CN103896903A (en) | Method for preparing and purifying 2,3-O-isopropylidene threitol | |
| CN104557947B (en) | A kind of method of 2 methylol triethylene diamines of continuous production | |
| CN104059094B (en) | The dimeric synthetic method of 9-borabi cyclo [3.3.1] nonane |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |