CN109384824A - Desogestrel intermediate and preparation method thereof - Google Patents
Desogestrel intermediate and preparation method thereof Download PDFInfo
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- CN109384824A CN109384824A CN201710665638.0A CN201710665638A CN109384824A CN 109384824 A CN109384824 A CN 109384824A CN 201710665638 A CN201710665638 A CN 201710665638A CN 109384824 A CN109384824 A CN 109384824A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0051—Estrane derivatives
- C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
- C07J1/007—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
- C07J1/0074—Esters
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0051—Estrane derivatives
- C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
Abstract
The present invention relates to steroidal compounds Desogestrel intermediates (compound VI) and preparation method thereof.This method is starting material with 13 β-ethyl -3- methoxyl group-female steroid -1,3,5 (10), -17 β -ol of 8 (9)-tetraene, generates target product by protection, epoxidation, hydrolysis, epoxidation, hydrolysis.The route is simple and easy, and chemical reagent used is relatively inexpensive and environmental-friendly, simple process, and yield is high, is suitble to industrialized production.Wherein, R are as follows: A ,-CH3Or B ,-Cl.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology.More particularly to Desogestrel midbody compound and preparation method thereof.
Technical background
Desogestrel is to take orally potent progestational hormone, and progestin is 18 times strong compared with norethindrone, 1 times strong compared with dl-Norgestrel.And
There is no androgen and estrogenic activity.The drug is reliable for effect when practising contraception, safety is good, is clinically widely used.
There are many domestic and international synthetic method of Desogestrel, and Chinese patent CN201510995906.6 discloses a kind of Desogestrel
The preparation method of intermediate, with D-13 β-ethyl -3- methoxyl group-female steroid -1,3,5 (10), -17 β alcohol I of 8 (9)-tetraene is raw material,
Compound II is obtained by 17 hydroxyl protections；8,9- double bonds are converted 9,11- double bonds by reflux in acidic mixed solvent
Compound III, is converted into 11- hydroxy compounds IV after hydroxylating, and compound IV is aoxidized through oxidising agent
Oxygen pregnene intermediate, reaction process as shown in reaction scheme 1:
The shortcomings that above-mentioned preparation method, is main are as follows: benzyl has larger toxicity, has biggish irritation to human eye portion, is not easy to
Labor protection is carried out, and phenyl steric hindrance is relatively small, 14 H are easy isomery.
United States Patent (USP) US3927046 and US5831104 are disclosed such as next synthetic reaction route (reaction route 2):
It is 17 carbonyls of selective protection when synthesizing compound 4 from compound 3, according to document in the reaction route
Described in US5831104, the step is poor to the selectivity of 17 carbonyls, leads to higher cost, therefore is also not suitable for industrial metaplasia
It produces.
Therefore, the new intermediate being simple and efficient is invented, avoids being used for using biofermentation and the method for selective protection
Synthesis Desogestrel is particularly important.
Summary of the invention
The first purpose of invention is to provide a kind of steroidal compounds and the preparation method of the compound；
The second object of the present invention is to provide application of the steroidal compounds when preparing Desogestrel midbody compound.
The midbody compound of Desogestrel, structure are as follows:
Wherein, R are as follows:
A、-CH3, or
B、-Cl。
With 13 β-ethyl -3- methoxyl group-female steroid -1,3,5 (10), -17 β -ol (compound I) of 8 (9)-tetraene is that starting is former
Material, the protection for first passing around 17 hydroxyls generate compound II；Then using 8,9- epoxidation reactions, hydrolysis, 9,
11- epoxidation reactions and hydrolysis obtain Desogestrel pharmaceutical intermediate VI (reaction route 3).
Compound I can be commercially available on the market.
The compound of the present invention can be used for preparing Desogestrel and its midbody compound.
The present invention provides a kind of preparation method for preparing Desogestrel intermediate, and this method includes as shown in reaction route 3
Reaction.
[reaction route 3]
The present invention provides a kind of method for preparing Desogestrel intermediate, and this method includes anti-as shown in reaction route 4
It answers.
[reaction route 4]
Specifically, above-mentioned steps of the invention can be realized by following reaction:
1), the protection reaction of compound I, obtains compound II
A certain amount of compound I is dissolved in solvent appropriate, is slowly added dropwise after dissolved clarification into above-mentioned system appropriate
Protective agent and acid binding agent are warming up under the conditions of certain temperature and react, and TLC monitors reaction process, after reaction carries out completely, are added suitable
Measuring acid for adjusting pH is acidity, and drinking water is added and carries out liquid separation extracting operation, filters decompression and is spin-dried for, obtains compound II.Wherein solvent
Including ethyl acetate, tetrahydrofuran, acetone and methylene chloride, preferably methylene chloride；Acid binding agent includes triethylamine, imidazoles and pyrrole
Pyridine, preferably pyridine；Temperature can be selected in 0 DEG C -70 DEG C, preferably 40 DEG C.
2), the oxidation reaction of compound II obtains compound III
Compound II is dissolved in solvent appropriate, addition oxidant is appropriate, vacuumizes argon gas protection, is warming up to certain
Under the conditions of react, TLC monitoring reaction carry out completely after, the sodium thiosulfate solution of saturation is slowly added into above-mentioned system,
Ethyl acetate is added after stir about 30min and carries out liquid separation extraction, merges organic phase, depressurizes lower solvent evaporated, obtains compound III.
Wherein, selected solvent includes tetrahydrofuran, acetone, methylene chloride, preferably tetrahydrofuran；Oxidant includes hydrogen peroxide, m-chloro
Benzoyl hydroperoxide, peroxidating trifluoroacetic acid, preferably hydrogen peroxide；Temperature can be selected in 0-70 DEG C, preferably 60 DEG C.
3), the hydrolysis of compound III obtains compound IV
Compound III is dissolved in suitable organic solvent, it is under argon gas protection that pre-configured acid solution is slow
It is added drop-wise in above-mentioned reaction system, after being added dropwise, continuation is stirred to react at room temperature, washes out a large amount of solids, is filtered, is obtained compound
IV.Wherein, acid solution includes sulfuric acid, hydrochloric acid, acetic acid and perchloric acid, preferably sulfuric acid.
4), the oxidation reaction of compound IV obtains compound V
Compound IV is dissolved in solvent appropriate, addition oxidant is appropriate, vacuumizes argon gas protection, is warming up to certain
Under the conditions of react, TLC monitoring reaction carry out completely after, the sodium thiosulfate solution of saturation is slowly added into above-mentioned system,
Ethyl acetate is added after stir about 30min and carries out liquid separation extraction, merges organic phase, depressurizes lower solvent evaporated, obtains compound V.Its
In, selected solvent includes tetrahydrofuran, acetone, methylene chloride, preferably tetrahydrofuran；Oxidant includes hydrogen peroxide, m-chloro mistake
Oxybenzoic acid, peroxidating trifluoroacetic acid, preferably hydrogen peroxide；Temperature can be selected in 0-70 DEG C, preferably 60 DEG C.
5), the oxidation reaction of compound V obtains compound VI
Compound V is dissolved in suitable organic solvent, is slowly dripped pre-configured acid solution under argon gas protection
It is added in above-mentioned reaction system, after being added dropwise, continuation is stirred to react about 2-3h at room temperature, washes out a large amount of solids, filters；To institute
Appropriate isopropanol be added in solid carry out mashing processing, filter, obtain compound IV.Wherein, organic solvent includes methanol, second
Alcohol, tetrahydrofuran and acetone, preferably methanol；Acid includes perchloric acid, sulfuric acid, hydrochloric acid, phosphoric acid, nitric acid, acetic acid, alchlor, chlorine
Change zinc, lithium chloride, trifluoromethanesulfonic acid zinc, copper trifluoromethanesulfcomposite, preferably sulfuric acid.
6), the ketal reaction of compound VI generates compound VII
Compound VI is dissolved in appropriate solvent, a certain amount of ethylene glycol is added, a small amount of catalyst is added, it is appropriate to be increased to
Temperature is stirred to react about 2-3h, after TLC monitoring reaction carries out, appropriate ethyl acetate and water is added, liquid separation extraction subtracts
Pressure screws out solvent, obtains compound VII.Wherein the catalyst includes p-methyl benzenesulfonic acid, trifluoromethanesulfonic acid indium, pyridine hydrochloride
Salt, trifluoromethanesulfonic acid pyridiniujm, preferably p-methyl benzenesulfonic acid；Reaction temperature includes 20 DEG C -80 DEG C, preferably 50 DEG C.
7), the lithium ammonia reduction of compound VII, generates compound VIII:
By a certain amount of dissolving metal in suitable liquid ammonia solution, -40 DEG C -- compound VII is added under the conditions of 70 DEG C,
After TLC monitoring reaction carries out, the appropriate quenching reaction of dehydrated alcohol is added, catches up with ammonia, is extracted with ethyl acetate and ammonium chloride
It takes, liquid separation operation, organic phase is dry with anhydrous sodium sulfate, is spin-dried for solvent and obtains compound VIII.Wherein, the metal include lithium,
Sodium, calcium, magnesium, preferably lithium.
8), the hydrolysis of compound VIII generates compound IX
Compound VIII is dissolved in appropriate amount of acid and solvent, is stirred to react at moderate temperatures, TLC monitoring reaction
After, appropriate saturated sodium bicarbonate aqueous solution is added and is neutralized to pH=7-8, ethyl acetate is added and carries out liquid separation, extraction in right amount,
Organic phase is dry with anhydrous sodium sulfate, and decompression screws out solvent and obtains compound IX.Wherein, the acid includes hydrochloric acid (1N-12N), sulphur
Acid, acetic acid and boron trifluoride ether, preferably 12N hydrochloric acid；The solvent includes tetrahydrofuran, ethyl acetate, methylene chloride and third
Ketone, preferably tetrahydrofuran；The temperature includes 0 DEG C -80 DEG C, preferably 60 DEG C.
Desogestrel can be made according to Chinese patent CN1865276A in compound IX.
The advantage of this reaction route is:
1., chemical synthesis process it is simple, it is easily operated；
2., first carbonyl protected, reduce integrally-built electron density, be easy to carry out lithium ammonia reaction；
3., the Desogestrel intermediate total recovery of the whole reaction route of the present invention up to 90% or more, yield is higher.
Specific implementation method
Embodiment 1: the preparation (tert-butoxy) of compound II
It takes compound I (150g, 0.5mol) to be added in 3000mL there-necked flask, measures 1500mL methylene chloride and be added to three
In mouth bottle, dissolved clarification is stirred.210mL pyridine, pivaloyl chloride (120g, 1mol) and 1.5gDMAP is added, is warming up to 40 DEG C, starts back
Stream, is stirred to react about 8h；After TLC monitors fully reacting, the sodium hydroxide solution that preparation is added is appropriate, and adjusting PH is alkalinity, adds
Separatory funnel is poured into after entering the stirring of 300mL Drinking Water, separates organic saturated aqueous ammonium chloride for being added to preparation, surveys water
Phase PH is 7, separates organic saturated sodium-chloride water solution for being added to preparation, separates organic 20g anhydrous magnesium sulfate that is added to and dries
30min is filtered, and filtrate is concentrated under reduced pressure in P=-0.08Mpa, T=50 DEG C, obtains 190g yellow oil, mass yield
125%-128%.
MS (m/z): 389 [M+1]+, 1H-NMR (CDCl3), δ 7.14 (1H, dd, 1-H), δ 3.73 (3H, s, 3-OCH3), δ
1.30 (9H, t, tert-butyl on hydrogen atom), δ 0.96 (3H, t, 19-CH3)；13C-NMR (CDCl3), δ 127.5-137.5 (benzyl
Carbon atom on aromatic rings), δ 55.9 (3-OCH3 carbon atom), δ 12.2 (carbon atom on pivaloyl group).
Embodiment 2: the preparation (chloro) of compound II
It takes compound I (250g, 0.8mol) to be added in 5000mL there-necked flask, measures 2500mL methylene chloride and be added to three
In mouth bottle, dissolved clarification is stirred.350mL pyridine, trichloro-acetic chloride (288g, 1.6mol) and 2.5gDMAP is added, is warming up to 40 DEG C, opens
Begin to flow back, is stirred to react about 8h；After TLC monitors fully reacting, the sodium hydroxide solution that preparation is added is appropriate, and tune PH is alkali
Property, separatory funnel is poured into after the stirring of 400mL Drinking Water is added, it is water-soluble to separate organic saturated ammonium chloride for being added to preparation
Liquid, surveying water phase PH is 7, separates organic saturated sodium-chloride water solution for being added to preparation, separates and organic is added to 20g anhydrous slufuric acid
Magnesium dries 30min, filters, and filtrate is concentrated under reduced pressure in P=-0.08Mpa, T=50 DEG C, obtains 300g yellow oil, and quality is received
Rate 120%-125%.
MS (m/z): 389 [M+1]+, 1H-NMR (CDCl3), δ 7.14 (1H, dd, 1-H), δ 3.73 (3H, s, 3-OCH3), δ
0.96 (3H, t, 19-CH3)；13C-NMR (CDCl3), δ 127.5-137.5 (carbon atom on benzyl aromatic rings), 55.9 (3- of δ
OCH3 carbon atom).
Embodiment 3: the synthesis (tert-butoxy) of compound III
It weighs the compound (190g) prepared in embodiment 1 to be added in 3000mL there-necked flask, measures 1900mL tetrahydro furan
It mutters and is added in there-necked flask, stir dissolved clarification.Reaction flask is vacuumized three times, divides 290g hydrogen peroxide to 3-5 under protection of argon gas
It criticizes and is slowly added in there-necked flask, be to slowly warm up to 60 DEG C, be stirred to react 2-4h.After TLC monitors fully reacting, it is cooled to 25. ± 5
DEG C, the hypo solution stirring 30min of preparation is added.Reaction solution is poured into separatory funnel and is stood, 400mL is added in water phase
Ethyl acetate extraction is primary, merges organic sodium-chloride water solution extraction for being added to preparation once, merges organic phase, in P=-
0.08Mpa, T=50 DEG C of reduced pressures, obtain 200g yellow solid, yield 105%-110%.MS (m/z): 375 [M+1]+,
1H-NMR (CDCl3), δ 7.14 (1H, dd, 1-H), δ 3.73 (3H, s, 3-OCH3), δ 3.52 (2H, m, 8,9 H), δ 1.30
(9H, t, tert-butyl on hydrogen atom), δ 0.96 (3H, t, 19-CH3)；13C-NMR (CDCl3), δ 127.5-137.5 (benzyl fragrance
Carbon atom on ring), δ 60.5 (8,9 carbon atoms), δ 55.9 (3-OCH3 carbon atom), δ 12.2 (carbon atom on pivaloyl group).
Embodiment 4: the synthesis (chloro) of compound III
It weighs the compound (200g) prepared in embodiment 2 to be added in 3000mL there-necked flask, measures 1900mL tetrahydro furan
It mutters and is added in there-necked flask, stir dissolved clarification.Reaction flask is vacuumized three times, divides 310g hydrogen peroxide to 3-5 under protection of argon gas
It criticizes and is slowly added in there-necked flask, be to slowly warm up to 60 DEG C, be stirred to react 2-4h.After TLC monitors fully reacting, it is cooled to 25 ± 5
DEG C, the hypo solution stirring 30min of preparation is added.Reaction solution is poured into separatory funnel and is stood, 400mL is added in water phase
Ethyl acetate extraction is primary, merges organic sodium-chloride water solution extraction for being added to preparation once, merges organic phase, in P=-
0.08Mpa, T=50 DEG C of reduced pressures, obtain 207g yellow solid, yield 105%-110%.MS (m/z): 456 [M+1]+,
1H-NMR (CDCl3), δ 7.14 (1H, dd, 1-H), δ 3.73 (3H, s, 3-OCH3), δ 3.50 (2H, m, 8,9 H), δ 0.96
(3H, t, 19-CH3)；13C-NMR (CDCl3), δ 127.5-137.5 (carbon atom on benzyl aromatic rings), (8,9 carbon of δ 59.3
Atom), δ 55.9 (3-OCH3 carbon atom).
Embodiment 5: the preparation (tert-butoxy) of compound IV
The compound 50g prepared in Example 3 is added in 2L reaction flask, is measured 500ml acetone and is added in reaction flask
Stirring, then measure sulfuric acid 100ml and be added in reaction flask, 60 DEG C of back flow reactions are warming up to, 2-4h is stirred, stop reaction, second is added
Acetoacetic ester 200ml liquid separation extraction, organic phase are neutralized to neutrality, liquid separation with saturated sodium bicarbonate, and organic phase uses saturated salt solution again
200ml washing retains organic phase, and dries about 30min with anhydrous sodium sulfate 20g, filters, 50 DEG C of evaporated under reduced pressure solvents obtain oily
Object 45g, yield: 90%.MS (m/z): 398 [M+1]+, 1H-NMR (CDCl3), δ 7.14 (1H, dd, 1-H), δ 3.73 (3H, s,
3-OCH3), δ 3.50 (1H, 8 H), δ 1.30 (9H, t, tert-butyl on hydrogen atom), δ 0.96 (3H, t, 19-CH3)；13C-NMR
(CDCl3), δ 127.5-137.5 (carbon atom on benzyl aromatic rings), δ 105.2-111.5 (double-linked carbon), δ 60.5 (8
Carbon atom), δ 55.9 (3-OCH3 carbon atom), δ 12.2 (carbon atom on pivaloyl group).
Embodiment 6: the preparation (chloro) of compound IV
The compound 50g prepared in Example 4 is added in 2L reaction flask, is measured 500ml methanol and is added in reaction flask
Stirring, then measure sulfuric acid 100ml and be added in reaction flask, 60 DEG C of back flow reactions are warming up to, 2-4h is stirred, stop reaction, second is added
Acetoacetic ester 200ml liquid separation extraction, organic phase are neutralized to neutrality, liquid separation with saturated sodium bicarbonate, and organic phase uses saturated salt solution again
200ml washing retains organic phase, and dries about 30min with anhydrous sodium sulfate 20g, filters, 50 DEG C of evaporated under reduced pressure solvents obtain oily
Object 42g, yield: 84%.MS (m/z): 398 [M+1]+, 1H-NMR (CDCl3), δ 7.19 (5H, m, the hydrogen on benzyl aromatic ring), δ
7.14 (1H, dd, 1-H), δ 3.73 (3H, s, 3-OCH3), δ 3.50 (1H, 8 H)；13C-NMR (CDCl3), δ 127.5-137.5
(carbon atom on benzyl aromatic rings), 105.2-111.5 (double-linked carbon), δ 60.5 (8 carbon atoms), 55.9 (3-OCH3 of δ
Carbon atom).
Embodiment 7: the preparation (tert-butoxy) of compound V
It weighs the compound (100g) prepared in embodiment 5 to be added in 3000mL there-necked flask, measures 1000mL tetrahydro furan
It mutters and is added in there-necked flask, stir dissolved clarification.Reaction flask is vacuumized three times, under protection of argon gas by 250g hydrogen peroxide, divides 3-5
It criticizes and is slowly added in there-necked flask, be to slowly warm up to 60 DEG C, be stirred to react 2-4h.After TLC monitors fully reacting, it is cooled to 25 ± 5
DEG C, the hypo solution stirring 30min of preparation is added.Reaction solution is poured into separatory funnel and is stood, 300mL is added in water phase
Ethyl acetate extraction is primary, merges organic sodium-chloride water solution extraction for being added to preparation once, merges organic phase, in P=-
0.08Mpa, T=50 DEG C of reduced pressures, obtain 106g yellow solid, yield 105%-110%.MS (m/z): 414 [M+1]+,
1H-NMR (CDCl3), δ 7.14 (1H, dd, 1-H), δ 3.73 (3H, s, 3-OCH3), δ 3.47 (2H, m, 9,11 H), δ 1.30
(9H, t, tert-butyl on hydrogen atom), δ 0.96 (3H, t, 19-CH3)；13C-NMR (CDCl3), δ 127.5-137.5 (benzyl fragrance
Carbon atom on ring), δ 60.5 (9,11 carbon atoms), (carbon is former on pivaloyl group by δ 55.9 (3-OCH3 carbon atom), δ 12.2
Son).
Embodiment 8: the preparation (chloro) of compound V
It weighs the compound (100g) prepared in embodiment 6 to be added in 3000mL there-necked flask, measures 1000mL tetrahydro furan
It mutters and is added in there-necked flask, stir dissolved clarification.Reaction flask is vacuumized three times, under protection of argon gas by 250g hydrogen peroxide, divides 3-5
It criticizes and is slowly added in there-necked flask, be to slowly warm up to 60 DEG C, be stirred to react 2-4h.After TLC monitors fully reacting, it is cooled to 25 ± 5
DEG C, the hypo solution stirring 30min of preparation is added.Reaction solution is poured into separatory funnel and is stood, 300mL is added in water phase
Ethyl acetate extraction is primary, merges organic sodium-chloride water solution extraction for being added to preparation once, merges organic phase, in P=-
0.08Mpa, T=50 DEG C of reduced pressures, obtain 101g yellow solid, yield 100%-105%.MS (m/z): 474 [M+1]+,
1H-NMR (CDCl3), δ 7.14 (1H, dd, 1-H), δ 3.73 (3H, s, 3-OCH3), δ 3.51 (2H, m, 9,11 H), δ 1.30
(9H, t, tert-butyl on hydrogen atom), δ 0.96 (3H, t, 19-CH3)；13C-NMR (CDCl3), δ 127.5-137.5 (benzyl fragrance
Carbon atom on ring), δ 60.5 (9,11 carbon atoms), (carbon is former on pivaloyl group by δ 55.9 (3-OCH3 carbon atom), δ 12.2
Son).
Embodiment 9: the preparation (tert-butoxy) of compound VI
It weighs the compound 10g prepared in embodiment 7 to be added in 200mL there-necked flask, measures 45mL methanol and be added to three
In mouth bottle, reaction flask is vacuumized three times, prepared 1N sulfuric acid solution is added in there-necked flask under protection of argon gas, is added dropwise
After, room temperature continues to be stirred to react 2-3h, and a large amount of yellowish solids are precipitated, filter to obtain 9.5g yellow solid.By gained yellow
Solid is added in 450mL isopropanol, is warming up to 50 DEG C, and mashing stirring 30min is cooled to 5 ± 5 DEG C, filters to obtain light yellow solid.
It is weighed as 9g, yield 90%.MS (m/z): 396 [M+1]+1, H-NMR (CDCl3), δ 7.19 (5H, m, on benzyl aromatic ring
Hydrogen), δ 7.14 (1H, dd, 1-H), δ 3.73 (3H, s, 3-OCH3), δ 1.30 (9H, t, tert-butyl on hydrogen atom)；13C-NMR
(CDCl3), δ 199.2 (11-C), δ 127.5-137.5 (carbon atom on benzyl aromatic rings), δ 55.6 (3-OCH3), δ 12.2
(carbon atom on pivaloyl group).
Embodiment 10: the preparation (chloro) of compound VI
It weighs the compound 10g prepared in embodiment 8 to be added in 100mL there-necked flask, measures 30mL methanol and be added to three
In mouth bottle, reaction flask is vacuumized three times, prepared 1N sulfuric acid solution is added in there-necked flask under protection of argon gas, is added dropwise
After, room temperature continues to be stirred to react 2-3h, and a large amount of yellowish solids are precipitated, filter to obtain 9.5g yellow solid.By gained yellow
Solid is added in 70mL isopropanol, is warming up to 50 DEG C, and mashing stirring 30min is cooled to 5 ± 5 DEG C, filters to obtain light yellow solid.
It is weighed as 8.8g, yield 88%.MS (m/z): 396 [M+1]+1, H-NMR (CDCl3), δ 7.19 (5H, m, on benzyl aromatic ring
Hydrogen), δ 7.14 (1H, dd, 1-H), δ 3.73 (3H, s, 3-OCH3),；13C-NMR(CDCl3), δ 199.2 (11-C), δ 127.5-
137.5 (carbon atoms on benzyl aromatic rings), 55.6 (3-OCH of δ3)。
Embodiment 11: the preparation of compound IX
Compound VI (5g), 40mL ethylene glycol and 40mL trimethyl orthoformate, 0.9g are successively put into 250ml reaction flask
P-methyl benzenesulfonic acid reacts at room temperature about 8h；To after completion of the reaction, ethyl acetate (50ml) be added into reaction system, extraction divides
Liquid, organic phase is dry with anhydrous sodium sulfate (5g), filters, and filtrate obtains grease (5.5g) in 50 DEG C of evaporated under reduced pressure；By 250ml
Reaction flask is cooled to -70 DEG C, steams into liquefied ammonia about 150ml, is added portionwise lithium metal (5g), stirs 1h, and the change dissolved with DCM is added dropwise
It closes object VII (5g) to continue to be stirred to react 3h controlled at -50 DEG C or so during dropwise addition, after completion of the reaction, by 20ml second
Alcohol is slowly added dropwise as in above-mentioned reaction system, moves to system after finishing and carries out catching up with ammonia to operate to sticky, Xiang Ti under room temperature
Ethyl acetate (100ml) and purified water (100ml) stirring, standing, liquid separation are added in system, organic phase is dry with anhydrous sodium sulfate (5g)
It is dry, it filters, 45 DEG C of decompressions are spin-dried for obtaining yellow oil (5.5g)；Compound VIII (5g) is added into 250ml reaction flask, 12N
Hydrochloric acid, methanol (100ml), is warming up to reflux, is stirred to react 2h；In being neutralized to after completion of the reaction with saturated sodium bicarbonate aqueous solution
Property (pH=7-8), be added ethyl acetate (100ml), extraction, liquid separation, organic phase is dry with anhydrous sodium sulfate (10g), filters, 40
DEG C evaporated under reduced pressure solvent, obtains compound IV (4.5g) yield: 90%.
MS (m/z): 303 [M+1]+,1H-NMR(CDCl3), δ 5.85 (1H, s, 4-CH), δ 3.63 (1H, m, 17-CH), δ
0.96 (3H, t, 19-CH3)；13C-NMR(CDCl3), δ 211 (C-11), δ 199 (C-3), δ 156 (C-5), δ 127 (C-4), δ 79
(C-17)。
Claims (11)
1. a kind of steroidal compounds, structure are shown below:
Wherein, R are as follows:
A、-CH3, or
B、-Cl。
2. steroidal compounds according to claim 1, it is characterized in that R is-CH3
3. steroidal compounds according to claim 1, it is characterized in that R is-Cl.
4. the preparation method of steroidal compounds described in claim 1, it is as follows to prepare reaction route:
(1) the hydroxyl protection reaction of compound I, obtains compound II；
(2) it the epoxidation of compound II, hydrolysis, epoxidation and hydrolyzes again, obtains compound VI；
Wherein, R are as follows:
A、-CH3, or
B、-Cl。
5. the preparation method according to claim 4, it is characterised in that: molten used in the hydroxyl protection reaction from I to II
Agent is methylene chloride, tetrahydrofuran, ethyl acetate, acetone, toluene, chloroform, methanol, ethyl alcohol, isopropanol, methyl tertiary butyl ether(MTBE).
Reaction temperature is 0 DEG C -70 DEG C.
6. the preparation method according to claim 4, it is characterised in that: by compound II to compound III reaction be 8,
9- epoxidation reactions, oxidant used are hydrogen peroxide, Peracetic acid, trifluoro peracetic acid, metachloroperbenzoic acid.
7. the preparation method according to claim 4, it is characterised in that: by compound III to compound IV reaction be water
Solution reaction.
8. the preparation method according to claim 4, it is characterised in that: by compound IV to compound V reaction be 9,11-
Position epoxidation reaction.
9. the preparation method according to claim 4, it is characterised in that: the reaction from V to VI is hydrolysis, acid used
Including sulfuric acid, perchloric acid, hydrochloric acid, phosphoric acid, nitric acid, acetic acid, alchlor, zinc chloride, lithium chloride, trifluoromethanesulfonic acid zinc, trifluoro
Copper methane sulfonate, the concentration of acid used are 1N-12N.
10. the preparation method according to claim 4, it is characterised in that: can directly prepare compound V by compound II.
11. application of the steroidal compounds VI according to claim 1 when preparing Desogestrel intermediate, it is characterised in that
Using compound VI as starting material, Desogestrel intermediate VI is generated by ketal, the reduction of lithium ammonia, hydrolysis, reaction route is as follows
It is shown:
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111848713A (en) * | 2020-06-26 | 2020-10-30 | 浙江神洲药业有限公司 | Preparation method of alkyl acid testosterone |
| CN111875655A (en) * | 2020-06-19 | 2020-11-03 | 浙江神洲药业有限公司 | Preparation method of testosterone propionate |
| CN112225771A (en) * | 2020-11-12 | 2021-01-15 | 湖南新合新生物医药有限公司 | Preparation method of desogestrel key intermediate and preparation method of desogestrel |
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| US3407217A (en) * | 1962-10-04 | 1968-10-22 | Smith | 8-iso-13-polycarbonalkyl gonanes |
| CN1865276A (en) * | 2005-05-20 | 2006-11-22 | 上海迪赛诺化学制药有限公司 | Method for synthesizing steroid progestogen |
| CN105541948A (en) * | 2015-12-25 | 2016-05-04 | 浙江仙琚制药股份有限公司 | Synthesis method of desogestrel drug intermediate |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3407217A (en) * | 1962-10-04 | 1968-10-22 | Smith | 8-iso-13-polycarbonalkyl gonanes |
| CN1865276A (en) * | 2005-05-20 | 2006-11-22 | 上海迪赛诺化学制药有限公司 | Method for synthesizing steroid progestogen |
| CN105541948A (en) * | 2015-12-25 | 2016-05-04 | 浙江仙琚制药股份有限公司 | Synthesis method of desogestrel drug intermediate |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111875655A (en) * | 2020-06-19 | 2020-11-03 | 浙江神洲药业有限公司 | Preparation method of testosterone propionate |
| CN111875655B (en) * | 2020-06-19 | 2021-12-21 | 浙江神洲药业有限公司 | Preparation method of testosterone propionate |
| CN111848713A (en) * | 2020-06-26 | 2020-10-30 | 浙江神洲药业有限公司 | Preparation method of alkyl acid testosterone |
| CN112225771A (en) * | 2020-11-12 | 2021-01-15 | 湖南新合新生物医药有限公司 | Preparation method of desogestrel key intermediate and preparation method of desogestrel |
| CN112225771B (en) * | 2020-11-12 | 2023-05-05 | 湖南新合新生物医药有限公司 | Preparation method of desogestrel key intermediate and preparation method of desogestrel |
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Application publication date: 20190226 |