CN106349327A - Preparation method of dutasteride - Google Patents
Preparation method of dutasteride Download PDFInfo
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- CN106349327A CN106349327A CN201510411617.7A CN201510411617A CN106349327A CN 106349327 A CN106349327 A CN 106349327A CN 201510411617 A CN201510411617 A CN 201510411617A CN 106349327 A CN106349327 A CN 106349327A
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Abstract
The invention relates to a preparation method of dutasteride. The preparation method comprises the following steps: dissolving 3-keto-4-aza-5-alpha-androst-1-ene-17beta carboxylic acid into an organic solvent, adding dichlorosulfane, performing a reaction on the 3-keto-4-aza-5alpha-androst-1-ene-17beta carboxylic acid and the dichlorosulfane, adding 2, 5-bis (trifluoromethyl) aniline and piperidine after basical completion of the reaction to obtain the ditamine after the completion of the reaction. Compared with the prior art, the preparation method has the advantages as follows: by preparation method, the yield of the dutasteride is greatly increased and the preparation cost is reduced; the preparation method is easy and convenient to operate and is more suitable for industrial production.
Description
Technical field
The invention belongs to drug world, be related to a kind of preparation method of compound and in particular to a kind of degree he
The preparation method of male amine.
Background technology
Dutasteride (dutasteride), chemical entitled (5 α, 17 β)-n- [2,5- double (trifluoromethyl) phenyl] -3- ketone
- 4- aza-5 alpha-androstane -1- alkene -17 β-carboxylic acid amides (formula i)
Dutasteride is the dual 5α-reductase inhibitor that GlaxoSmithKline PLC (gsk) company develops.2002
Year, November dutasteride listed in US and European, trade name avodart (suitable urine is logical).2011
In on April 11, in, Chinese food Drug Administration approval Dutasteride Soft Capsules are sold in Discussion on Chinese Listed,
Trade name Avodart.This medicine is used clinically for the treatment of Benign Prostatic Hypertrophy, can change for a long time
Kind prostatic hyperplasia symptom, reduces the sickness rate of carcinoma of prostate.
3- ketone -4- aza-5 alpha-androstane -1- alkene -17 β-carboxylic acid (referred to as m4) is the key of synthesis dutasteride
Intermediate, its synthesis technique is perfect in China, and the yield of its synthesis, quality are all at the forefront in the world,
Cheap and easy to get.At present, by 3- ketone -4- aza-5 alpha-androstane -1- alkene -17 β-carboxylic acid intermediate synthesis dutasteride
Method mainly have following several:
1. chloride method:
Chinese patent cn1473165a discloses 3- ketone -4- aza-5 alpha-androstane -1- alkene -17 β-carboxylic acid, first
The mixture of benzene, pyridine and catalyst dimethylformamide stirs and is cooled to less than -5 DEG C, adds dichloro
Sulfoxide, after keeping 2-3 hour at 15-25 DEG C, adds 2,5- (trifluoromethyl) aniline and catalyst diformazan
Base aminopyridine, the method that heating 18-24 hour prepares dutasteride at 95-105 DEG C, but according to
This operation and order preparation dutasteride, impurity is many, and yield is only 30% about so that industrialized production
High cost.
2. mixed anhydride method
Document wo2009/083258a2, public in wo2011/004242a2, us2009/0203724a2
Opened with acetonitrile as solvent, by 3- ketone -4- aza-5 alpha-androstane -1- alkene -17 β-carboxylic acid dbu catalysis under with
Pivaloyl chloride or mesyl chloride make mixed acid anhydride, then with 2,5- double (trifluoromethyl) aniline reaction degree of preparation he
The method of male amine, its yield about 70%, need low temperature (- 30 DEG C) and strong lewis acid bf3- ether is molten
Agent catalytic reaction.High energy consumption, commercial production is dangerous big, and purifying products are more difficult, is unfavorable for extensive
Produce.
3. new intermediate method
Disclose 3- ketone -4- aza-5 alpha-androstane -1- alkene -17 β-carboxylic in document us2005/0059692a1
Acid, toluene, pyridine, thionyl chloride mixture at 25-35 DEG C stirring reaction 2-3 hour, reacted
It is passed through ammonia reaction after one-tenth, make 3- ketone -4- aza-5 alpha-androstane -1- alkene -17 β-Methanamide (ii), by 2,5-
Double (trifluoromethyl) aniline diazotising is replaced into 2,5- bis trifluoromethyl iodobenzene (vi), the two with potassium carbonate with
Copper powder is catalyzed, the method that back flow reaction 50-60 hour prepares dutasteride, yield about 60%.The method
Response time is long, high energy consumption, and post processing is complicated, is unfavorable for large-scale production.
The method synthesizing dutasteride in prior art is mainly with 3- ketone -4- aza-5 alpha-androstane -1- alkene
- 17 β-carboxylic acid is raw material, with toluene as solvent, after pyridine is for reacting with thionyl chloride under conditions of alkali, then
Prepare dutasteride with corresponding aniline reaction, but the method yield is relatively low, by-product is many, leads to work
Industry high cost, is not suitable for the large-scale industrial production of dutasteride.
Content of the invention
The present invention be in view of the above-mentioned problems in the prior art and make, it is an object of the invention to
A kind of high yield is provided, low cost, and process is simple, suitable industrialized production with 3- ketone -4- azepine -5 α -
The method that androstane -1- alkene -17 β-carboxylic acid prepares dutasteride for raw material.
Present inventor has invented feasible process by lot of experiments, cost is reasonable, it is high-quality to obtain
The synthetic route of volume production product.This synthetic route is with 3- ketone -4- aza-5 alpha-androstane -1- alkene -17 β-carboxylic acid (m4)
For raw material, obtain target compound through two steps, charging sequence in the course of reaction of preparation dutasteride
And the use of catalyst serves unexpected effect to the raising of yield.3- ketone -4- azepine -5 α -
Without piperidines when androstane -1- alkene -17 β-carboxylic acid is reacted with thionyl chloride, but with 2,5- bis- (fluoroform
Base) add piperidines after aniline reaction, the yield of dutasteride's crude product significantly improves, up to 80%-90%.
Simultaneously in the reaction of this step, add the receipts that catalyst (as lithium bromide) can significantly improve dutasteride's crude product
Rate.
The synthetic route of the present invention has also carried out that 50g/ criticizes, 100g/ criticizes and 350g/ criticizes three batches of scale experiments
Room pilot scale research, and three batches of scale about factory's pilot scale checkings of 350g, its proof all can ensure technique bar
Part is gentle, stable, quality controllable, safety and environmental protection.
Especially, the concrete technical scheme of the present invention is as follows:
For the condensation reaction of 3- ketone -4- aza-5 alpha-androstane -1- alkene -17 β-carboxylic acid and thionyl chloride, inventor
The catalyst of this reaction is studied.It was found that using tea, dbu, phosphorus oxychloride, chlorine
Change lithium or be not added with catalyst and all can not obtain target product, and use boron trifluoride diethyl etherate (50%) and bromination
Lithium, as catalyst, can obtain target product dutasteride's crude product of high yield, and during using lithium bromide
Yield more slightly higher than using yield during boron trifluoride diethyl etherate, therefore applicant selects bromine in this reaction scheme
Change lithium as the catalyst of condensation reaction.
According to one embodiment of the invention, the invention provides a kind of side preparing dutasteride
Method, specifically, 3- ketone -4- aza-5 alpha-androstane -1- alkene -17 β-carboxylic acid (referred to as m4) is dissolved in organic molten
In agent, add thionyl chloride reaction, be subsequently added lithium bromide, 2,5- bis- (trifluoromethyl) aniline and piperidines,
Dutasteride is obtained after the completion of reaction, yield about 80%, purity about 99%.Then use 95% second further
Alcohol and water carries out purification to product, and purity reaches 99.8%.
Wherein, above-mentioned organic solvent be selected from dichloromethane, toluene, dimethylbenzene, chloroform, acetonitrile, acetone,
Ethyl ketone, oxolane, ether, normal hexane, 1,4- dioxane, ethyl acetate, Ethyl formate；
More preferably dichloromethane.Described organic solvent and the ratio of 3- ketone -4- aza-5 alpha-androstane -1- alkene -17 β-carboxylic acid
Example is the volume of solvent: the quality of 3- ketone -4- aza-5 alpha-androstane -1- alkene -17 β-carboxylic acid
=100:1～5:1 (ml:g), preferably 30:1～10:1 (ml:g).
Described 3- ketone -4- aza-5 alpha-androstane -1- alkene -17 β-carboxylic acid (m4) is dissolved in after organic solvent, by temperature
Control at -20 DEG C～40 DEG C, preferably 0 DEG C～10 DEG C, in reaction system, be slowly added into thionyl chloride, with
Add the n of catalytic amount, n- dimethylformamide afterwards.Reacting by heating to 10 DEG C～40 DEG C of interior temperature, preferably
35-40 DEG C, it is incubated 1～5 hour, preferably 1～2 hour, is then cooled to less than 30 DEG C, is dividedly in some parts
Lithium bromide and 2,5- bis- (trifluoromethyl) aniline, are basically completed through hplc or tlc detection reaction.It is down to
After room temperature, it is dividedly in some parts piperidines, flow back after completion of dropping about 1-8 hour altogether, preferably 6 hours,
Complete through hplc or tlc detection reaction.
Further, described thionyl chloride and 3- ketone -4- aza-5 alpha-androstane -1- alkene -17 β-carboxylic acid (m4) is anti-
Ying Zhong, the mol ratio of thionyl chloride and 3- ketone -4- aza-5 alpha-androstane -1- alkene -17 β-carboxylic acid (m4) is
1:1～5:1, preferably 1.5:1～2:1, more preferably 1.5:1.
Inventor is studied for the consumption of lithium bromide, and result shows if lithium bromide is with respect to 3- ketone
More than 1eq, then the bromo impurity producing contains the mol ratio of -4- aza-5 alpha-androstane -1- alkene -17 β-carboxylic acid (m4)
Amount is higher, and this impurity, once generating, is difficult to be removed by refined, can lead to end product quality not
Qualified, the consumption of therefore lithium bromide should be less than 1 equivalent.Thus, described lithium bromide and 3- ketone -4- azepine
- 5 α-androstane -1- alkene -17 β-carboxylic acid (m4) mol ratio can be 1:1～1:5, preferably 1:2, more preferably 0.9:1.
Further, described 2,5- bis- (trifluoromethyl) aniline and 3- ketone -4- aza-5 alpha-androstane -1- alkene -17 β -
Carboxylic acid (m4) mol ratio is 1:1～5:1, preferably 1:1～2:1, more preferably 1.3:1.
Further, inventor is studied for the consumption of agent such as piperidines, and result shows to add
After agent piperidines, chloro impurity in crude product can be converted into dutasteride, and piperidines consumption with respect to
3- ketone -4- aza-5 alpha-androstane -1- alkene -17 β-carboxylic acid (m4) needs more than 1.5eq, but the amount of piperidines is not yet
Can be significantly excessive, another kind of impurity (i.e. m4 acid and piperidines condensation) can be generated, this impurity can be by tying again
Brilliant removing.Therefore, applicant has done substantial amounts of test, determine agent piperidines and 3- ketone -4- azepine -5 α -
The mol ratio of androstane -1- alkene -17 β-carboxylic acid (m4) is 1.5:1～5:1, preferably 1.5:1～2.5:1.By this
The purity of the dutasteride of bright method preparation can reach more than 99.8%, and yield can reach more than 65%.With
Prior art is compared, and drastically increases the yield of dutasteride, reduces preparation cost, and operates letter
Just, it is more suitable for industrialized production.
Specific embodiment
For making the object, technical solutions and advantages of the present invention clearer, below, by the tool to the present invention
Body embodiment is described in detail.Obviously, described embodiment is only that a present invention part is implemented
Example, rather than whole embodiments.Based on the embodiment in the present invention, those of ordinary skill in the art exist
The every other embodiment being obtained on the premise of not making creative work, broadly falls into present invention protection
Scope.
It should be noted that herein, term " inclusion ", "comprising" or its any other change
Body is intended to comprising of nonexcludability, so that including a series of process of key elements, method, article
Or equipment not only includes those key elements, but also includes other key elements being not expressly set out, or
Also include for this process, method, article or the intrinsic key element of equipment.
Embodiment 1: the synthesis of dutasteride
In 10l there-necked flask, 450g 3- ketone -4- aza-5 alpha-androstane -1- alkene -17 β-carboxylic acid (m4) is dissolved in
8800ml dcm, is cooled to 0～10 DEG C.It is slowly added dropwise 253.35g socl in this reaction system2, then
Add 9ml dmf, temperature control is less than 30 degrees Celsius.It is heated to interior temperature 18-25 DEG C, be incubated 1～2 hour.
Sampling carries out tlc (methanol-ethyl acetate is developing solvent) analysis.Reaction adds 61.65g bromination completely afterwards
Lithium, instills 357.75g 2,5- bis- (trifluoromethyl) aniline, is heated to reflux, and sampling carries out tlc (methanol-second
Acetoacetic ester is developing solvent) analysis.Add 30.9g lithium bromide, Deca 32.5g 2,5- bis- (trifluoromethyl) aniline.
Continue to flow back, sampling carries out tlc (methanol-ethyl acetate is developing solvent) analysis until reacting substantially completely.
It is down to room temperature, adds 181.26g piperidines, completion of dropping flows back 2 hours.Sampling carry out tlc (methanol-
Ethyl acetate is developing solvent) analysis, add 23g piperidines, completion of dropping return stirring 2 hours is to having reacted
Entirely.
Reaction system is cooled to room temperature, adds 4.5l saturated ammonium chloride solution that reaction is quenched, stir 15
Minute.Standing 15 minutes, point liquid, add 2.25l dcm in water layer, stir 15 minutes.Standing
15 minutes, point liquid.Merge organic faciess, add 3.6l 2% sodium hydroxide solution, stir 15 minutes.Quiet
Put 15 minutes, point liquid.Add 3.6l 2% sodium hydroxide solution in organic faciess, stir 15 minutes.
Standing 15 minutes, point liquid.Merge the sodium hydrate aqueous solution washing twice, add 670ml dcm,
Stirring 15 minutes.Standing 15 minutes, point liquid.Sodium hydrate aqueous solution adds 670ml dcm, stirs
Mix 15 minutes.Standing 15 minutes, point liquid.Merge all of organic faciess, add 3.6l 1mol/l dilute
Hydrochloric acid, stirs 15 minutes.Standing 15 minutes, point liquid.3.6l 1mol/l is added dilute in organic faciess
Hydrochloric acid, stirs 15 minutes.Standing 15 minutes, point liquid.Merge the dilute hydrochloric acid solution washing twice, plus
Enter 670ml dcm, stir 15 minutes.Standing 15 minutes, point liquid.Merge all of organic faciess, plus
Enter 2.2l saturated aqueous common salt, stir 15 minutes.Standing 15 minutes, point liquid.1000g is added in organic faciess
Anhydrous sodium sulfate, stir 15 minutes.Filter, concentrate the filtrate to dry obtain 850g crude product (purity:
90.8%, yield: 95%).
Embodiment 2: dutasteride's is refined
Add 850g crude product obtained above in the there-necked flask of 10l, add the 95% of 4740ml
Ethanol, is heated to 70～80 DEG C.After being stirred to dissolving, continue backflow 30min.It is slowly added dropwise 2010ml water,
Maintain the temperature at 70～80 DEG C.Solid is had to separate out during Deca.Finish, Temperature fall is taken the photograph to 20-25
Family name's degree, and in 20-25 degree Celsius of insulated and stirred 24h.Solid filters, and (water temperature 45 is Celsius in vacuum for filter cake
Degree, 20～30mmhg) under be dried 4～5 hours.Obtain 625g product.The there-necked flask of 10l adds
Enter 625g product obtained above, add 95% ethanol of 4500ml, be heated to 70～80 DEG C.Stirring
To after dissolving, continue backflow 30min.Temperature fall to 20-25 degree Celsius, and protect at 20-25 degree Celsius
Temperature stirring 24h.Solid filters, and filter cake is dried 4～5 under vacuum (45 degrees Celsius of water temperature, 20～30mmhg)
Hour.Obtain 493g product.493g product obtained above is added in the there-necked flask of 10l, plus
Enter 95% ethanol of 4100ml, be heated to 70～80 DEG C.After being stirred to dissolving, continue backflow 30min.
Add 50g activated carbon, heated and stirred 30min.Filtered while hot.Filtrate is reheated to 70～80 DEG C.
After being stirred to dissolving, continue backflow 30min.Temperature fall to 20-25 degree Celsius, and take the photograph in 20-25
Family name's degree insulated and stirred 24h.Solid filters, and filter cake is at vacuum (45 degrees Celsius of water temperature, 20～30mmhg)
Lower drying 4～5 hours.Obtain 384g product.By 384g product in vacuum drying oven, 100 degrees Celsius,
2～3mmhg baking material 24h, obtains 380g solid (wherein moisture is less than 1%).
According to above-mentioned similar reaction method, by the amount of feed change, high yield and purity are obtained
Dutasteride.
The synthesis of table 1 dutasteride's crude product is got the raw materials ready
Above-described specific embodiment is only used for illustrating the spirit of the present invention, the protection of the present invention
Scope is not limited thereto, to those of ordinary skill in the art, certainly can be according to this specification
Disclosed in technology contents, by change, displacement or modification by way of make other embodiment party easily
Formula, these other embodiments all should be included within the scope of the present invention.
Claims (9)
1. a kind of preparation method of dutasteride, methods described includes: by 3- ketone -4- aza-5 alpha-androstane -1-
Alkene -17 β-carboxylic acid is dissolved in organic solvent, adds thionyl chloride, makes 3- ketone -4- aza-5 alpha-androstane -1- alkene
- 17 β-carboxylic acid and thionyl chloride react, and after the completion of reaction is basic, add lithium bromide, 2,5- bis- (fluoroform
Base) aniline and piperidines, obtain dutasteride after the completion of reaction.
2. the preparation method of dutasteride according to claim 1, wherein said organic solvent is selected from:
Dichloromethane, toluene, dimethylbenzene, chloroform, acetonitrile, acetone, ethyl ketone, oxolane, ether,
Normal hexane, 1,4- dioxane, ethyl acetate, Ethyl formate；More preferably dichloromethane.
3. the preparation method of dutasteride according to claim 1 and 2, wherein said organic solvent
Ratio with 3- ketone -4- aza-5 alpha-androstane -1- alkene -17 β-carboxylic acid is the volume of solvent: 3- ketone -4- azepine -5 α -
Quality=100:1～the 5:1 (ml:g) of androstane -1- alkene -17 β-carboxylic acid, preferably 30:1～10:1 (ml:g).
4. the preparation method of the dutasteride according to any one of claim 1-3, wherein said 3-
Ketone -4- aza-5 alpha-androstane -1- alkene -17 β-carboxylic acid is -20 DEG C～40 DEG C with the reaction temperature of thionyl chloride, preferably
18 DEG C～25 DEG C, more preferably 35 DEG C -40 DEG C.
5. the preparation method of the dutasteride according to any one of claim 1-4, wherein said 3-
After ketone -4- aza-5 alpha-androstane -1- alkene -17 β-carboxylic acid is reacted with thionyl chloride, add lithium bromide and 2,5- bis- (three
Methyl fluoride) aniline, then it is down to room temperature and adds piperidines, flow back about 1-8 hour, preferably 6 hours.
6. the preparation method of the dutasteride according to any one of claim 1-5, wherein described
In the reaction of thionyl chloride and 3- ketone -4- aza-5 alpha-androstane -1- alkene -17 β-carboxylic acid, thionyl chloride and 3- ketone -4-
The mol ratio of aza-5 alpha-androstane -1- alkene -17 β-carboxylic acid (m4) is 1:1～5:1, preferably 1.5:1～2:1, more
It is preferably 1.5:1.
7. the preparation method of dutasteride according to claim 5, wherein said lithium bromide and 3-
Ketone -4- aza-5 alpha-androstane -1- alkene -17 β-carboxylic acid (m4) mol ratio is 1:1～1:5, preferably 1:2, more preferably
For 0.9:1.
8. the preparation method of the dutasteride according to any one of claim 1-7, wherein said
2,5- bis- (trifluoromethyl) aniline with 3- ketone -4- aza-5 alpha-androstane -1- alkene -17 β-carboxylic acid (m4) mol ratio is
1:1～5:1, preferably 1:1～2:1, more preferably 1.3:1.
9. the preparation method of the dutasteride according to any one of claim 1-8, wherein said piperazine
Pyridine and 3- ketone -4- aza-5 alpha-androstane -1- alkene -17 β-carboxylic acid (m4) mol ratio are 1.5:1～5:1, preferably
1.5:1～2.5:1.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050059692A1 (en) * | 2003-09-09 | 2005-03-17 | Dr. Reddy's Laboratories Limited | Process for the preparation of 17beta-N-[2,5-bis(trifluoromethyl)phenyl] carbamoyl-4-aza-5-alpha-androst-1-en-3-one |
| WO2012035553A1 (en) * | 2010-09-15 | 2012-03-22 | Ind-Swift Laboratories Limited | Process for preparing androstenone derivatives |
| CN103059098A (en) * | 2011-10-24 | 2013-04-24 | 成都国为医药科技有限公司 | Preparation method of dutasteride |
| CN104231033A (en) * | 2014-09-17 | 2014-12-24 | 广东众生药业股份有限公司 | Preparation method of dutasteride |
| CN104292293A (en) * | 2014-09-17 | 2015-01-21 | 广东众生药业股份有限公司 | Preparation method of dutasteride impurity I |
-
2015
- 2015-07-14 CN CN201510411617.7A patent/CN106349327B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050059692A1 (en) * | 2003-09-09 | 2005-03-17 | Dr. Reddy's Laboratories Limited | Process for the preparation of 17beta-N-[2,5-bis(trifluoromethyl)phenyl] carbamoyl-4-aza-5-alpha-androst-1-en-3-one |
| WO2012035553A1 (en) * | 2010-09-15 | 2012-03-22 | Ind-Swift Laboratories Limited | Process for preparing androstenone derivatives |
| CN103059098A (en) * | 2011-10-24 | 2013-04-24 | 成都国为医药科技有限公司 | Preparation method of dutasteride |
| CN104231033A (en) * | 2014-09-17 | 2014-12-24 | 广东众生药业股份有限公司 | Preparation method of dutasteride |
| CN104292293A (en) * | 2014-09-17 | 2015-01-21 | 广东众生药业股份有限公司 | Preparation method of dutasteride impurity I |
Non-Patent Citations (1)
| Title |
|---|
| 陈国广 等: ""度他雄胺的合成工艺研究"", 《中国新药杂志》 * |
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