CN105693808B - A kind of acetic acid crow founds appropriate bulk drug impurity and preparation method thereof and the purposes as standard items - Google Patents
A kind of acetic acid crow founds appropriate bulk drug impurity and preparation method thereof and the purposes as standard items Download PDFInfo
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- CN105693808B CN105693808B CN201510745121.3A CN201510745121A CN105693808B CN 105693808 B CN105693808 B CN 105693808B CN 201510745121 A CN201510745121 A CN 201510745121A CN 105693808 B CN105693808 B CN 105693808B
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- acetic acid
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- acid crow
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of only two carbon atoms, e.g. pregnane derivatives
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to acetic acid crow to found caused a kind of new impurity and its production and use in appropriate synthesis technique.The impurity is that the diketone its preparation method of the α of 17 α acetoxyl groups 11 (4 N methyl Ns Fonnylphenyl) 19 norpregna, 4,9 diene 3,20 is：Acetic acid crow founds appropriate demethyl；Then N formoxyls are introduced to obtain, it is this method economy, simple.The compound of the present invention can found the standard items of Control of Impurities in appropriate production technology as acetic acid crow.
Description
Technical field
The present invention relates to acetic acid crow to found a kind of new relevant material and its preparation method and use in appropriate production technology, belongs to
Medicinal chemistry art.
Background technology
It is a kind of sex hormone that acetic acid crow, which founds appropriate (Ulipristal acetate), there is antagonism and partial agonist to PgR
Effect.It prevents progesterone from occupying its acceptor, and beginning and dimension can not be synthesized so as to block by the genetic transcription that progesterone normally starts
Albumen necessary to holding gestation, interference ovulation, while endometrium can be caused to change.
Drug containing 30mg tablet is emergency contraception of new generation, 120 hours after unprotected sexual intercourse or contraceptive failure
Used in (five days), terminal pregnancy.Drug containing 5mg acetic acid crow is vertical appropriate for treating fibroid.
It is the progesterone receptor modulator synthesized that acetic acid crow, which stands appropriate, is not gone public also in China.Do not have yet in pharmacopoeia of each country
Recorded, reported in disclosed document and singly go first acetic acid crow vertical appropriate, it is double to go vertical appropriate and 11 α of first acetic acid crow-acetic acid crow vertical appropriate miscellaneous
Matter and preparation, other related impurity and preparation technology report are also less.
The content of the invention
The present invention provides a kind of a kind of new relevant material found in acetic acid crow founds appropriate production technology, and provides one
Bar economy, the simple preparation method about material, as well as acetic acid crow found the mark about material in appropriate production technology
Quasi- product, for controlling acetic acid crow to found the purposes of appropriate quality.
The relevant material of the present invention goes first pregnant for 17 α-α of acetoxyl group-11-(4-N- methyl-N- Fonnylphenyls) 19-
Steroid -4,9- diene -3,20- diketone, structural formula are as follows：
Relevant 17 α of material-α of acetoxyl group-11-(4-N- methyl-N- Fonnylphenyls) 19- norpregnas of the present invention-
4,9- diene -3,20- diketone do not have any document report mistake, are a kind of brand-new materials.
The present invention also provides 17 α-α of acetoxyl group-11-(4-N- methyl-N- Fonnylphenyls) 19- norpregnas-4,9-
The preparation method of diene -3,20- diketone, comprises the following steps：Acetic acid crow is vertical appropriate to react under the conditions of calcium oxide and iodine
It is appropriate to singly going first acetic acid crow to stand；Singly go first acetic acid crow is vertical appropriate to react to obtain 17 α of target impurity-acetyl in formic acid and formic acid salt system
The α of Oxy-1 1-(4-N- methyl-N- Fonnylphenyls) 19- norpregna-4,9- diene-3,20- diketone, its process route are：
Present invention also offers 17 α-α of acetoxyl group-11-(4-N- methyl-N- Fonnylphenyls) 19- norpregna-4,
The purposes of 9- diene -3,20- diketone, i.e., a kind of standard items application of defects inspecting in appropriate production technology is stood as acetic acid crow.
Beneficial effects of the present invention are：
Prepare vertical appropriate 17 α of impurity-α of acetoxyl group-11-(4-N- methyl-N- Fonnylphenyls) 19- of acetic acid crow of high-purity
Norpregna -4,9- diene -3,20- diketone, the standard items of the impurity in being analyzed as the vertical appropriate finished product detection of acetic acid crow, so as to
The vertical appropriate finished product detection analysis of acetic acid crow is improved to remove 17 α of impurity-α of acetoxyl group-11-(4-N- methyl-N- Fonnylphenyls) 19-
Pregnant steroid -4,9- diene -3, the 20- diketone of first be accurately positioned with it is qualitative, be advantageous to strengthen control to the impurity, so as to improve vinegar
Sour crow founds appropriate final product quality.
Brief description of the drawings
Fig. 1 is the vertical appropriate HPLC-UV detection of acetic acid crow
Fig. 2 is 17 α-α of acetoxyl group-11-(4-N- methyl-N- Fonnylphenyls) 19- norpregnas-4,9- diene-3,
The HPLC-UV detection of 20- diketone
Brief description of the drawings：A is 17 α-α of acetoxyl group-11-(4-N- methyl-N- Fonnylphenyls) 19- norpregnas-4,9-
Diene -3,20- diketone, B are that acetic acid crow is vertical appropriate
Embodiment
Embodiment 1
Under nitrogen protection, acetic acid crow is added in the 3L four-hole bottles equipped with thermometer and constant pressure funnel and founds appropriate 30g, nothing
Water methanol and the common 750ml of tetrahydrofuran, stirring is opened, add calcium oxide 33g, be cooled to -10 DEG C, the methanol four of 90g iodine is added dropwise
Hydrogen tetrahydrofuran solution, after being added dropwise, stirring 1.5h adds saturated aqueous sodium thiosulfate terminating reaction, warp to reacting complete
Ethyl acetate is extracted, and dries, concentration, and yellow solid list is obtained after refined and goes first acetic acid crow to found appropriate 26g.
Embodiment 2
Addition 5g is mono- in the 250ml there-necked flasks equipped with thermometer goes first acetic acid crow to found appropriate, 10ml formic acid, 0.7g formic acid
Ammonium, stirring are warming up to 40-45 DEG C, insulation reaction 3-4h, are disappeared to raw material spot.Room temperature is cooled to, adds 40ml dichloromethane,
100ml saturated sodium bicarbonate aqueous solutions regulation pH to 7-8, dichloromethane extraction organic phase, through dry are added after making reaction solution dissolved clarification
Dry, concentration, column chromatography obtains faint yellow solid lg, as 17 α of the target impurity-α of acetoxyl group-11-(4-N- methyl-N- after purification
Fonnylphenyl) 19- norpregna -4,9- diene -3,20- diketone.
High resolution mass spectrum ESI (+)：490.26 (M+1), 512.24 (M+23), 528.22 (M+39)
Table one and table two be respectively 17 α-α of acetoxyl group-11-(4-N- methyl-N- Fonnylphenyls) 19- norpregnas-
The hydrogen modal data and carbon modal data of 4,9- diene -3,20- diketone.
Table one：17 α-the α of acetoxyl group-11-(4-N- methyl-N- Fonnylphenyls) 19- norpregnas-4,9- diene-3,
20- diketone hydrogen nuclear magnetic resonance modal datas (CDCl3)
Table two：17 α-the α of acetoxyl group-11-(4-N- methyl-N- Fonnylphenyls) 19- norpregnas-4,9- diene-3,
20- diketone carbon-13 nmr spectra data (CDCl3)
Claims (3)
1. a kind of compound, its is entitled：17 α-the α of acetoxyl group-11-(4-N- methyl-N- Fonnylphenyls) 19- goes first pregnant
Steroid -4,9- diene -3,20- diketone, structural formula are as follows：
2. the preparation method of compound described in claim 1, it is characterized in that comprising the following steps：Acetic acid crow it is vertical it is appropriate in calcium oxide and
Reaction is singly gone first acetic acid crow vertical appropriate under the conditions of iodine；Singly go first acetic acid crow is vertical appropriate to be reacted in formic acid and formic acid salt system
To 17 α of target impurity-α of acetoxyl group-11-(4-N- methyl-N- Fonnylphenyls) 19- norpregna-4,9- diene-3,20-
Diketone, specific route are as follows：
A kind of 3. the answering as standard items of defects inspecting in acetic acid crow founds appropriate production technology of compound described in claim 1
With.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510745121.3A CN105693808B (en) | 2015-11-05 | 2015-11-05 | A kind of acetic acid crow founds appropriate bulk drug impurity and preparation method thereof and the purposes as standard items |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510745121.3A CN105693808B (en) | 2015-11-05 | 2015-11-05 | A kind of acetic acid crow founds appropriate bulk drug impurity and preparation method thereof and the purposes as standard items |
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| Publication Number | Publication Date |
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| CN105693808A CN105693808A (en) | 2016-06-22 |
| CN105693808B true CN105693808B (en) | 2018-03-16 |
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| CN106279326A (en) * | 2016-08-09 | 2017-01-04 | 南京臣功制药股份有限公司 | A kind of medroxyprogesterone acetate capsule have related substance and analyzing detecting method thereof |
| CN106366149B (en) * | 2016-08-09 | 2018-01-23 | 南京臣功制药股份有限公司 | The relevant material and its analyzing detecting method of a kind of medroxyprogesterone acetate dispersible tablet |
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