CN104327149B - Synthesis method of spironolactone intermediate testosterone lactone - Google Patents
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- CN104327149B CN104327149B CN201410458784.2A CN201410458784A CN104327149B CN 104327149 B CN104327149 B CN 104327149B CN 201410458784 A CN201410458784 A CN 201410458784A CN 104327149 B CN104327149 B CN 104327149B
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- C07—ORGANIC CHEMISTRY
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- C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
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Abstract
The invention relates to a synthesis method of a chemical medicine, and concretely relates to a synthesis method of a spironolactone intermediate testosterone lactone. The method is characterized in that a compound I 4-androstenedione (4AD) undergoes a two-step reaction of addition siloxane removal and oxidation cyclization to obtain the compound III testosterone lactone, and the reaction route is shown in the specification. Compared with traditional methods adopting a traditional raw material 16-dehydropregnenolone acetate with high price, the method provided by the invention adopting the cheap and easily available 4-androstenedione (4AD, I) as an initial raw material has extremely high production application and economic values under the affection of market supply and demand.
Description
Technical field
The present invention relates to the synthetic method of chemicals, the synthesis side of a kind of spironolactone intermediate Testosterone lactone
Method.
Background technology
Spironolactone (spironolactone) chemistry is entitled: (7 α, 17 α)-7-(acetyl group sulfydryl)-17-hydroxyl-3-oxo
Pregnant steroid-4-alkene-21-carboxylic acid-gamma lactone, is the aldosterone competitive inhibitor researched and developed by Pfizer Inc., multinational
Listing, clinical as diuretic, its chemical structural formula is as follows:
In the synthetic method of spironolactone, one of them key technique is structure 17,21-carboxylic lactone spirane structure.
At present according to the generation method of its volution the synthesis technique of spironolactone substantially can be divided into two classes: 1) with 4-AD
(4AD) it is raw material, utilizes Corey epoxidation reagent by the C17-ketone group epoxidation of cyclopentanoperhydro-phenanthrene, then react formation with malonate
Five yuan of volutions.
2) with dehydroepiandros-sterone and potassium acetylide react 17-acetenyl removes hydrogen meter hero alcohol, through grignard reaction, CO2Carboxylation, also
Former, lactonize etc. reacts and obtains five yuan of volutions.
The source of dehydroepiandros-sterone is all that diene alcohol ketone acetic ester completes through oximate, rearrangement reaction at present.Used is double
Alkene alcohol ketone acetic ester is with Dioscorea nipponica Mak. Ningpo Yam Rhizome, Dioscorea zingiberensis etc. as raw material, obtains diosgenin through extracting, and diosgenin is through several steps chemistry
It is synthesized into.Very fast due to Saponin (diene) rise in price at present, bring enormous pressure to the production of Related product, and along with micro-
The success of biodegradation synthesis 4-AD (4AD) so that the steroid drugs nowadays derived with 4AD for raw material and Related product
Great market competition advantage, prepares spironolactone with 4AD for raw material and certainly will have higher production application and economic worth.The opposing party
Face, traditional spironolactone synthesis technique, reactions steps is more, complex operation, and yield is relatively low, therefore, from raw material 4-AD
Set out, develop a more succinct structure 17, the new method of 21-carboxylic lactone spirane structure, will have particularly important economy
It is worth and practical value.
Summary of the invention
The technical issues that need to address of the present invention are the raw material 4-ADs (4AD, compound I) from more price advantage
Set out, it is provided that the synthetic method of the spironolactone intermediate Testosterone lactone that a kind of yield is higher.
The technical solution adopted for the present invention to solve the technical problems is:
The synthetic method of a kind of spironolactone intermediate Testosterone lactone, the method is with compound I 4-AD (4AD)
For raw material, through addition desiliconization ether and dioxide giving two-step reaction, obtaining compound III Testosterone lactone, reaction scheme is as follows:
4-AD (4AD, I) through the reaction of addition desiliconization ether, dioxide giving reaction, is prepared in spironolactone by the present invention
Mesosome Testosterone lactone (compound III).The method use the raw material 4-AD and more of more price advantage
Adding the 17 of simplicity, the construction method of 21-carboxylic lactone volution, whole piece route reaction condition is easily controllable, and post processing is simple, and yield is relatively
High.
As preferably, the method specifically includes following steps:
A, under inert gas shielding, by with silicon ether protection group halo propanol prepare generate organolithium reagent, with former
The C17 position carbonyl of material compound I 4-AD carries out additive reaction, removes subsequently under acid condition or fluorine reagent effect
Protection group, obtains compound II；
B, under oxidant, catalyst and phase transfer catalyst effect, the primary hydroxyl on compound II side chain aoxidizes
React, and cyclization of taking advantage of a situation forms required lactone spirane structure, obtains compound III.
The noble gas of the present invention is the gas not having an effect with reacting substance, such as nitrogen, helium, neon, argon, krypton
Gas, xenon or radon gas etc..Described acid condition is preferably hydrochloric acid, preferably 6N hydrochloric acid solution；Described fluorine reagent is preferably the tetrabutyl
Ammonium fluoride (TBAF).
In order to the preparation method of the organolithium reagent of Carbonyl addition to be in the present invention: by the halo with silicon ether protection group
Propanol mixes with organic solvent, adds highly basic and takes out halogen formation organolithium reagent.Organic solvent selected from oxolane, ether,
2-methyltetrahydrofuran or Isosorbide-5-Nitrae-dioxane, preferably oxolane；Described silicon ether protection group includes trimethyl silicane (TMS),
Triethyl group silicon (TES), tert-butyldimethyl silyl (TBS), triisopropylsilyl (TIPS) or tert-butyl diphenyl are silica-based
(TBDPS), preferred trimethyl silicane (TMS)；Described halo propanol includes that 3-bromo-1-propanol or trimethylene chlorohydrin, preferably 3-are bromo-
1-propanol；Described highly basic is n-BuLi (1.6M hexane solution), tert-butyl lithium (1.6M pentane solution) or s-butyl lithium
(1.3M cyclohexane solution), preferably n-BuLi (1.6M hexane solution).De-under acid condition or fluorine reagent effect subsequently
Going silicon ether protection group, described acid condition is hydrochloric acid, preferably 6N hydrochloric acid solution；Described fluorine reagent is tetrabutyl ammonium fluoride
(TBAF).It may further be preferable that the preparation method of described organolithium reagent is as follows: under inert gas shielding, the nothing being dried
Water oxolane and butyl lithium mix and blend are also cooled to-78～-60 DEG C, are then slowly added into (3-bromine propoxyl group) trimethyl silicane
Alkane, be maintained at-60～-40 DEG C stirring 30 minutes prepared organolithium reagents, standby.
In step a, before additive reaction, 4-AD is carried out organic base pretreatment, make 4-AD with enolate
Formal character ground protection 3-ketone-4-alkene structure, the most again with organolithium reagent generation additive reaction, so that it is guaranteed that to C17
Being smoothed out of position carbonyl addition, it is to avoid the generation of by-product.Organic base described in this step is preferably organolithium reagent,
Good for lithium diisopropylamine (LDA).The organic base preprocessing process of 4-AD particularly as follows: under inert gas shielding,
4-AD is dissolved in organic solvent, is cooled to-60～-40 DEG C, is subsequently adding lithium diisopropylamine (LDA), keep
Mixture B is obtained after stirring fully at a temperature of-60～-40 DEG C.
Concretely comprising the following steps of step a: the organolithium reagent of aforementioned fresh preparation is slowly added dropwise into mixture B, under room temperature
Reacting 1 hour, TLC display reaction terminates, and the cancellation that adds water is reacted；Whole reactant liquor is poured in saturated aqueous ammonium chloride,
Continuing stirring 15 minutes, layering under room temperature, water layer dichloromethane extracts repeatedly, merges organic layer, is dried and concentrates, obtains crude product,
Crude product is deprotection base under acid condition or fluorine reagent effect, extraction, is dried and concentrates, obtains compound II.
In the present invention, 4-AD and the weight ratio (W/W) with the halo propanol of silicon ether protection group are 1:4～1:5,
Preferably 1:4.2；In preprocessing process, the w/v (W/V) of 4-AD and organic base is 1:20～1:30, preferably
1W:20V.The weight ratio (W/W) of 4-AD and fluorine reagent is 1:3～1:4, preferably 1:3.15.
As preferably, in step b, described oxidant is stoichiometric hypochlorite, more preferably sodium hypochlorite,
Adding system during reaction in form of an aqueous solutions, described catalyst is by the TEMPO of catalytic amount
The alkali metal bromide composition of or derivatives thereof and catalytic amount, TEMPO or derivatives thereof is excellent
Elect 2 as, 2,6,6-tetramethyl piperidine-1-oxygen-derived free radicals (conventional be abbreviated as TEMPO), alkali metal bromide preferably be selected from sodium bromide or
Potassium bromide, further preferred potassium bromide；The required phase transfer catalyst of reaction is halogenated alkyl quaternary ammonium salt, preferably tetrabutyl chlorination
Ammonium.
Concretely comprising the following steps of step b: by alkali metal bromide and 2,2,6,6-tetramethyl piperidine-oxygen-derived free radicals or its derive
Thing, dichloromethane mix and blend, be subsequently added aqueous hypochlorite solution and phase transfer catalyst, and be cooled to less than 15 DEG C, control
Temperature processed insulation reaction in the range of 10～15 DEG C to reaction fully (about 6 hours), adds sodium sulfite and is neutralized to non-oxidative,
Compound III is obtained after product purification.Purge process is as follows: layering, and organic layer is washed 3 times, is evaporated to, without dichloromethane, add
Entering methanol and dilute hydrochloric acid solution, stir 0.5 hour, 0.5N sodium hydroxide solution is neutralized to neutrality, is evaporated to, without methanol, add
Water elutriation, filters, is dried to obtain compound III.
In the present invention, compound II is 1:0.5～1:1, preferably 1:0.7 with the weight ratio (W/W) of alkali metal bromide；Change
Compound II is 1:0.003～1:0.01 with the weight ratio (W/W) of TEMPO or derivatives thereof,
Preferably 1:0.005；Compound II is 1:0.04～1:0.1, preferably 1:0.05 with the weight ratio (W/W) of phase transfer catalyst；Change
Compound II is 1:3～1:5.5, preferably 1:4.0 with the w/v (W/V) of aqueous hypochlorite solution.
The invention has the beneficial effects as follows:
1. affected by relation between market supply and demand, with more cheap and easily-available 4-AD (4AD, I) for initiation material,
Under traditional raw material diene alcohol ketone acetic ester presents the situation of rapid rise of price at present, the success of this process route, will have pole
High production application and economic worth；
2. in the present invention, for important 17, the structure of 21-carboxylic lactone spirane structure, take different from former technique
Mode, develop more succinct quickly synthetic route, each step reaction independence is preferable, easy and simple to handle, is suitable for industrialization
Produce；
3. the present invention is on the premise of keeping high product purity (98.5%), and quality total recovery, up to 56.5%, is a kind of
The method efficiently quickly preparing spironolactone intermediate Testosterone lactone.
Detailed description of the invention
Below by specific embodiment, technical scheme is described in further detail.Should be appreciated that this
Bright enforcement is not limited to the following examples, and any pro forma accommodation and/or the change of being made the present invention all will fall
Enter scope.
In the present invention, if not refering in particular to, all of part, percentage ratio are unit of weight, the equipment used and raw material etc.
All it is commercially available or commonly used in the art.Method in following embodiment, if no special instructions, is the normal of this area
Rule method.W of the present invention represents that weight, V represent volume.When W unit is g, the unit of V is mL；When W unit is kg, V
Unit be L.
Aqueous sodium hypochlorite solution of the present invention is commercially available prod.
Embodiment 1: addition deprotection reaction
Reaction equation is as follows:
In reaction bulb A, under nitrogen protection, add 100mL dry tetrahydrofuran (through strict Non-aqueous processing KF <
0.05%), 60mL n-BuLi (hexane solution of 1.6M), it is cooled to-60 DEG C.It is slowly added to (3-bromine propoxyl group) trimethyl
Silane (12.6g), is maintained at-60 DEG C and stirs 30 minutes, standby.
In reaction bulb B, under nitrogen protection, dry compound I (3g) is dissolved in 30mL oxolane (through strict
Non-aqueous processing KF < 0.05%), be cooled to-40 DEG C.Previously prepared LDA (12mL, concentration is the tetrahydrofuran solution of 2M) delays
Slowly it is added dropwise to previous reaction system, is maintained at-40 DEG C and stirs 10 minutes, standby.
Solution system in reaction bulb A is slowly added dropwise the solution system into reaction bulb B, rises again to room temperature reaction 1 hour,
TLC display reaction terminates, and adds 80mL shrend and goes out reaction.Whole reactant liquor is poured in 100mL saturated aqueous ammonium chloride,
Continuing stirring 15 minutes, layering under room temperature, water layer dichloromethane extracts repeatedly, merges organic layer, is dried and concentrates, obtains crude product,
Deprotection reaction is may be directly applied to without processing.Crude product about 3.5g is dissolved in 100mL dry tetrahydrofuran, is dividedly in some parts
Tetrabutyl ammonium fluoride (9.45g), reacts 1.5 hours under room temperature, then adds 450mL, and water layer dichloromethane extracts repeatedly, closes
And organic layer, it is dried and concentrates, obtain compound II 1.95g, start to calculate mass yield from compound I: 65%.ESI MS:347
(M+1)。
Embodiment 2: addition deprotection reaction
In reaction bulb A, under nitrogen protection, add 100mL dry tetrahydrofuran (through strict Non-aqueous processing KF <
0.05%), 65mL s-butyl lithium (cyclohexane solution of 1.3M), it is cooled to-78 DEG C.It is slowly added to (3-bromine propoxyl group) triethyl group
Silane (13.2g), is maintained at-60 DEG C and stirs 30 minutes, standby.
In reaction bulb B, under nitrogen protection, dry compound I (3g) is dissolved in 30mL oxolane (through strict
Non-aqueous processing KF < 0.05%), be cooled to-40 DEG C.Previously prepared LDA (12mL, solubility is the tetrahydrofuran solution of 2M) delays
Slowly it is added dropwise to previous reaction system, is maintained at-40 DEG C and stirs 10 minutes, standby.
Solution system in reaction bulb A is slowly added dropwise the solution system into reaction bulb B, rises again to room temperature reaction 1 hour,
TLC display reaction terminates, and adds 80mL shrend and goes out reaction.Whole reactant liquor is poured in 100mL saturated aqueous ammonium chloride,
Continuing stirring 15 minutes, layering under room temperature, water layer dichloromethane extracts repeatedly, merges organic layer, is dried and concentrates, obtains crude product,
Deprotection reaction is may be directly applied to without processing.Crude product about 3.8g is dissolved in 100mL methanol makes it dissolve, and slowly drips 6N
Hydrochloric acid 2.5mL, after reacting 2 hours, is spin-dried for methanol under the conditions of 25 DEG C, adds saturated sodium bicarbonate solution and chloroform extraction, organic
Washing with saturated aqueous common salt, anhydrous sodium sulfate is dried, concentrating under reduced pressure, obtains compound II 1.74g, starts to calculate from compound I
Mass yield: 58%.ESI MS:347(M+1).
Embodiment 3: dioxide giving reacts
Reaction equation is as follows:
10g compound (II) is dissolved in 150mL dichloromethane, is sequentially added into 0.05g 2,2,6,6-tetramethyl piperazines
Pyridine-1-oxygen-derived free radicals (TEMPO) and 7g potassium bromide, add 40mL 10% aqueous sodium hypochlorite solution and 0.5g phase transfer catalyst
Tetrabutylammonium chloride, 10～15 DEG C of stirrings are reacted about 6 hours, react completely, add sodium sulfite solution (9g/9mL water) and neutralize
Oxidant, standing, branch vibration layer.It is concentrated into without dichloromethane, adds 30mL methanol and 10mL 10% dilute hydrochloric acid, 20～25 DEG C
Stir 0.5 hour, be neutralized to pH about 6.5 with 0.5N sodium hydroxide solution, be decompressed to, without methanol, add 100mL water, stir 0.5
Hour, filter, 60 DEG C be dried 24 hours 8.7g Testosterone lactone (III), mass yield about 87%, HPLC purity 98.5%.
Embodiment 4: dioxide giving reacts
10g compound (III) is dissolved in 150mL dichloromethane, is sequentially added into 0.1g 4-hydroxyl-2,2,6,6-tetra-
Methyl piperidine-1-oxygen-derived free radicals and 7g potassium bromide, add 40mL 14.5% aqueous sodium hypochlorite solution and 0.5g phase transfer catalysis
Agent tetrabutyl ammonium bromide, 10～15 DEG C of stirrings are reacted about 6 hours, react completely, add sodium sulfite solution (9g/9mL
Water) neutralize oxidant, standing, branch vibration layer.It is concentrated into without dichloromethane, adds 30mL methanol and 10mL 10% dilute hydrochloric acid, 20
～25 DEG C stirred 0.5 hour, it is neutralized to pH value about 6.5 with 0.5N sodium hydroxide solution, concentrating under reduced pressure, add 100mL water, stirring
0.5 hour, filtering, 60 DEG C are dried 24 hours to obtain 8.2g compound (IV), mass yield about 82%, HPLC purity 96.8%.
Although with reference to some specific embodiments, invention has been described and explanation, but this area knack people
Member should be appreciated that can carry out multiple amendment to described method and scheme, recombinate, change, modification, replace, delete or add,
This is without departing from the spirit and scope of the present invention.
Claims (1)
1. the synthetic method of a spironolactone intermediate Testosterone lactone, it is characterised in that: the method is with compound I 4-androstene
Diketone (4AD) is raw material, through addition desiliconization ether and dioxide giving two-step reaction, obtains compound III Testosterone lactone, reaction
Route is as follows:
The method specifically includes following steps:
A, in reaction bulb A, under nitrogen protection, add 100mL through the dry tetrahydrochysene furan of strict Non-aqueous processing KF < 0.05%
Mutter, the hexane solution of 60mL 1.6M n-BuLi, it is cooled to-60 DEG C, is slowly added to (3-bromine propoxyl group) trimethyl silane
12.6g, is maintained at-60 DEG C and stirs 30 minutes, standby；
In reaction bulb B, under nitrogen protection, dry compound I 3g is dissolved in 30mL through strict Non-aqueous processing KF <
The oxolane of 0.05%, is cooled to-40 DEG C, and the previously prepared LDA of 12mL is present in the tetrahydrofuran solution that concentration is 2M,
It is slowly added dropwise into previous reaction system, is maintained at-40 DEG C and stirs 10 minutes, standby；
Solution system in reaction bulb A is slowly added dropwise the solution system into reaction bulb B, rises again to room temperature reaction 1 hour, TLC
Display reaction terminates, and adds 80mL shrend and goes out reaction, is poured into by whole reactant liquor in 100mL saturated aqueous ammonium chloride, room
Temperature is lower continues stirring 15 minutes, layering, and water layer dichloromethane extracts repeatedly, merges organic layer, is dried and concentrates, obtains crude product, nothing
Need to process and directly apply to deprotection reaction；Crude product 3.5g is dissolved in 100mL dry tetrahydrofuran, is dividedly in some parts the tetrabutyl
Ammonium fluoride 9.45g, reacts 1.5 hours under room temperature, then adds 450mL, and water layer dichloromethane extracts repeatedly, merges organic
Layer, is dried and concentrates, obtain compound II；
B, 10g compound II is dissolved in 150mL dichloromethane, is sequentially added into 0.05g 2,2,6,6-tetramethyl piperidine-1-
Oxygen-derived free radicals and 7g potassium bromide, add 40mL 10% aqueous sodium hypochlorite solution and 0.5g phase transfer catalyst tetrabutylammonium chloride,
10～15 DEG C of stirrings are reacted 6 hours, and reaction completely, adds the aqueous solution of 9g/9mL sodium sulfite, neutralizes oxidant, stand, divide
Remove water layer；Being concentrated into without dichloromethane, add 30mL methanol and 10mL 10% dilute hydrochloric acid, 20～25 DEG C are stirred 0.5 hour, use
0.5N sodium hydroxide solution is neutralized to pH6.5, is decompressed to without methanol, adds 100mL water, stir 0.5 hour, filter, 60 DEG C dry
Within dry 24 hours, obtain 8.7g Testosterone lactone (III).
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3966714A (en) * | 1973-05-25 | 1976-06-29 | Schering Aktiengesellschaft | Process for the preparation of a Δ4 -3-keto steroid 17-propiolactone |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5855154B2 (en) * | 1975-10-01 | 1983-12-08 | 三菱化学株式会社 | 17 alpha-(3-hydroxypropyl)-17 beta-hydroxyandrost-4-ene-3-onoseizouhou |
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2014
- 2014-09-11 CN CN201410458784.2A patent/CN104327149B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3966714A (en) * | 1973-05-25 | 1976-06-29 | Schering Aktiengesellschaft | Process for the preparation of a Δ4 -3-keto steroid 17-propiolactone |
Non-Patent Citations (1)
| Title |
|---|
| From a Remarkable Manifestation of Polar Effects in a Radical Fragmentation to the Convergent Synthesis of Highly Functionalized Ketones;Laurent Debien, et al.;《J. Am. Chem. Soc.》;20130220;第135卷;3808-3811，S24 * |
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Denomination of invention: A synthetic method of spironolactone intermediate testosterone lactone Effective date of registration: 20210915 Granted publication date: 20170111 Pledgee: China Construction Bank Corporation Xianju sub branch Pledgor: ZHEJIANG SHENZHOU PHARMACEUTICAL Co.,Ltd. Registration number: Y2021330001637 |