CN108047116A - The preparation method of R-5- (2- aminopropyls) -1- (3- hydroxypropyls) -7- itrile group indolines - Google Patents
The preparation method of R-5- (2- aminopropyls) -1- (3- hydroxypropyls) -7- itrile group indolines Download PDFInfo
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- CN108047116A CN108047116A CN201711453155.0A CN201711453155A CN108047116A CN 108047116 A CN108047116 A CN 108047116A CN 201711453155 A CN201711453155 A CN 201711453155A CN 108047116 A CN108047116 A CN 108047116A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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Abstract
The present invention relates to the preparation method of 7 itrile group indolines of R 5 (2 aminopropyl) 1 (3 hydroxypropyl), its preparation method is：
Description
Technical field
The present invention relates to medicinal chemistry art, more particularly, to R-5- (2- aminopropyls) -1- (3- hydroxypropyls) -7- nitriles
The preparation method of base indoline.
Background technology
Silodosin (Silodosin), entitled 2,3- dihydros -1- (3- the hydroxypropyls) -5- of chemistry [(2R) -2- [2- [2- (2,
2,2- trifluoro ethoxies) phenoxy group] ethylamino-] propyl] -1H- indoles -7- formamides are researched and developed by Japanese Kissei companies
Adrenoceptor antagonists are clinically used for treatment benign prostatic hyperplasis.This product is in 2 months 2006 for the first time in Japan's approval
City, U.S. FDA had received New Drug Application in 2 months 2008.
According to the literature, Silodosin intermediate R-5- (2- aminopropyls) -1- (3- hydroxypropyls) -7- itrile group indoles
The preparation process of quinoline has following 2 kinds.
The first is the method disclosed in WO2012131710,
The method reaction step is more, and wherein two-step reaction uses Vilsmeier process for hydroformylation, and environment influences greatly, to give up
There are many water.The buying of reagent nitroethane is difficult, and toxicity is larger, and long-time heating has the danger of explosion.
It is for second the method disclosed in CN104744336,
The method reaction scheme is long, and design is not quite reasonable, and total recovery is low.
In conclusion existing synthesis technology step is tediously long, total recovery is relatively low, and the toxicity such as reagent nitroethane are larger, and
There is the hazardous reaction that long-time heating can explode, it is therefore necessary to improve Silodosin intermediate R-5- (2- aminopropans
Base) -1- (3- hydroxypropyls) -7- itrile group indolines synthesis technology, improve yield, reduce production cost and security risk.
The content of the invention
The purpose of the present invention is overcoming defect existing in the prior art, provide a kind of high income, reaction step be few, operation into
The preparation method of this cheap R-5- (2- aminopropyls) -1- (3- hydroxypropyls) -7- itrile group indoline.
The technical solution adopted by the present invention to solve the technical problems is：
The preparation method of R-5- (2- aminopropyls) -1- (3- hydroxypropyls) -7- itrile group indolines：
It concretely comprises the following steps：
Step 1, using indoline as raw material, alkali obtains compound 2 as acid binding agent through acetic acid anhydride acylation；
Step 2, compound 3 is obtained by the reaction with 2- chlorpromazine chlorides with Louis's acid as catalyst in compound 2；
Step 3, compound 3 adds in hydrochloric acid removing acetyl group, obtains compound 4 in ethanol solution；
Step 4, compound 4 is reacted with 3- bromopropyl alcohols, and acid binding agent is organic or inorganic alkali, and compound 5 is obtained by the reaction；
Step 5, compound 5 is reacted with a-R- (+) phenyl ethylamine, and acid binding agent is organic or inorganic alkali, and reaction completes laggard one
Step splits isomers and obtains compound 6 using lower alcohol as solvent；
Step 6, for compound 6 using Pd/C as catalyst, hydrogenation obtains compound 7；
Step 7, compound 7 obtains compound 8 with bromine generation bromination reaction；
Step 8, compound 8 is reacted with cuprous cyanide, obtains target compound 1.
Preferably, in step 1, catalyst is sodium hydroxide；Reaction temperature is 10-30 DEG C；Reaction time is 10-15h.
Preferably, in step 2, catalyst is aluminum trichloride (anhydrous)；Reaction temperature is 8-12 DEG C；Reaction dissolvent is selected from dichloro
Ethane, dichloromethane, nitrobenzene or o-dichlorohenzene.
Preferably, in step 3, the reflux temperature of reaction is 70-80 DEG C.
Preferably, in step 4, acid binding agent is potassium carbonate；Reaction time is 15-20h；Reaction dissolvent be selected from acetonitrile, THF,
DMF, toluene or absolute ethyl alcohol.
Preferably, in step 5, acid binding agent is triethylamine；Reaction dissolvent is selected from methanol, absolute ethyl alcohol or isopropanol.
Preferably, in step 6, Hydrogen Vapor Pressure 2-4MPa；Hydrogenation temperature is 50-55 DEG C.
Preferably, in step 7, reaction system is bromine/methanol；Reaction temperature is -5-0 DEG C；Reaction time is 1-1.2h.
Preferably, in step 8, the molar ratio of compound 8 and CuCN is 1:2；Reaction temperature is 55-65 DEG C；Reaction time
For 10-16h.
Advantageous effect of the present invention is：
(1) raw material used in is commercially available product, cheap, at low cost.
(2) present invention simplifies synthesis step, and synthetic route is shorter, and each reaction yield that walks is higher, overall yield
Height reduces industrial cost.
(3) reagent used in is not poisoned or danger, and each step operation is simple, convenient for industrialization.
Specific embodiment
Presently preferred embodiments of the present invention is described in detail below, so that advantages and features of the invention can be more easy to by this
Field personnel understanding, so as to make a clearer definition of the protection scope of the present invention.
The embodiment of the present invention includes：
Embodiment 1：Step 1：The preparation of compound 2
At room temperature, 200ml dichloroethanes and 200ml sodium hydrate aqueous solutions are added in into reaction vessel, adds indoles
Quinoline 50g, is cooled to 0 DEG C, is added dropwise acetic anhydride 45g, when reaction 12 is small under the conditions of 20 DEG C after be layered, organic layer washing is collected organic
Layer, dry, filtrate decompression is concentrated to dryness to obtain gray solid compound 2.
Embodiment 2：Step 2：The preparation of compound 3
102.9g aluminum trichloride (anhydrous)s are added in reaction vessel, are cooled to 0 DEG C, 2- chlorpromazine chlorides are added dropwise, control temperature is not
More than 10 DEG C；The compound 2 that step 1 obtains is dissolved in 300ml dichloromethane, is added portionwise, 6h is reacted at room temperature after adding.It will
It has reacted and has poured into trash ice, stirring and dissolving, layering.Organic layer is by washing, saturated sodium bicarbonate washing, saturated common salt washing
It washs.Collected organic layer, dry, filtrate decompression is concentrated to dryness to obtain solid, with re crystallization from toluene, obtains off-white powder compound 3.Step
Rapid 1 adds the total recovery 72.9% of step 2.
Embodiment 3：Step 3：The preparation of compound 4
20.0g compounds 3 are added in reaction vessel, 220ml absolute ethyl alcohols add 30ml hydrochloric acid.It is warming up to 76 DEG C
Back flow reaction 7h, cooling, decompression evaporate solvent.500ml water dissolutions are added in, solution of potassium carbonate are slowly added into, until pH about 11 or so.
1h is stirred, is filtered, washing.Obtain gray solid compound 4, yield 85.2%.
Embodiment 4：Step 4：The preparation of compound 5
15.0g compounds 4 are taken, 50ml DMF and 19.6g 3- bromopropyl alcohols is added in, adds 35.1g potassium carbonate.It is warming up to
Reflux keeps the temperature 16h.Filtering, filtrate pour into 300ml water and stir 2h.It filters, washing obtains faint yellow solid, crude product is with acetic acid second
Ester is recrystallized to give compound 5, yield 79.6%.
Embodiment 5：Step 5：The preparation of compound 6
73.6g compounds 5 are taken, 300ml absolute ethyl alcohols and 115g triethylamines is added in, adds 41.0g a-R- (+) benzene second
Amine is warming up to back flow reaction 5h, is cooled to room temperature, removed under reduced pressure solvent, and gains add in 500ml water stirring 1h, filtering, filter cake
With ethyl acetate：N-hexane=1:1 stirring, obtains compound 6, yield 92.5%.
Embodiment 6：Step 6：The preparation of compound 7
19.0g compounds 6 are taken, add in 300ml methanol and 1.0g Pd/C (10%).In Hydrogen Vapor Pressure 2.5MPa, temperature
Under conditions of 50-55 DEG C, hydrogenation time 16h.Room temperature is cooled to, filters out catalyst, mother liquor decompression steams methanol.Gains add
Enter re-crystallizing in ethyl acetate, obtain Light brown solid compound 7, yield 92.5%.
Embodiment 7：Step 7：The preparation of compound 8
27.3g compounds 7 are taken, the dissolving of 150ml methanol is added in, is cooled to -5~0 DEG C, 26.5g bromines are slowly added dropwise, heat preservation is anti-
1h is answered, is filtered, filter cake is added in 300ml water and stirred, and is slowly added into solution of potassium carbonate, until pH is about 10, is stirred for 1h.It filters,
Washing.Obtain brown solid compound 8, yield 76.3%.
Embodiment 8：Step 8：The preparation of compound 1
24.9g compounds 8 are taken, add in 50ml DMF and CuCN, the molar ratio of compound 8 and CuCN is 1:2, it is warming up to 60
DEG C heat preservation 14h.Room temperature is cooled to, is filtered.Filtrate is poured into 400ml water and is stirred overnight, and filters, washing.Gains are with acetic acid second
Ester recrystallizes twice, obtains compound as white solid 1, yield 69.7%.
It should be appreciated that specific embodiment described above is only used for explaining the present invention, it is not intended to limit the present invention.By
The obvious changes or variations that the spirit of the present invention is extended out is still in the protection scope of this invention.
Claims (9)
- The preparation method of 1.R-5- (2- aminopropyls) -1- (3- hydroxypropyls) -7- itrile group indolines, it is characterised in that：It is made Preparation Method is：It concretely comprises the following steps：Step 1, using indoline as raw material, alkali obtains compound 2 as acid binding agent through acetic acid anhydride acylation；Step 2, compound 3 is obtained by the reaction with 2- chlorpromazine chlorides with Louis's acid as catalyst in compound 2；Step 3, compound 3 adds in hydrochloric acid removing acetyl group, obtains compound 4 in ethanol solution；Step 4, compound 4 is reacted with 3- bromopropyl alcohols, and acid binding agent is organic or inorganic alkali, and compound 5 is obtained by the reaction；Step 5, compound 5 and a-R- (+) phenyl ethylamine react, and acid binding agent is organic or inorganic alkali, after the completion of reaction further with Lower alcohol is solvent, splits isomers and obtains compound 6；Step 6, for compound 6 using Pd/C as catalyst, hydrogenation obtains compound 7；Step 7, compound 7 obtains compound 8 with bromine generation bromination reaction；Step 8, compound 8 is reacted with cuprous cyanide, obtains target compound 1.
- 2. the preparation side of R-5- (2- aminopropyls) -1- (3- hydroxypropyls) -7- itrile group indolines according to claim 1 Method, it is characterised in that：In step 1, catalyst is sodium hydroxide；Reaction temperature is 10-30 DEG C；Reaction time is 10-15h.
- 3. the preparation side of R-5- (2- aminopropyls) -1- (3- hydroxypropyls) -7- itrile group indolines according to claim 1 Method, it is characterised in that：In step 2, catalyst is aluminum trichloride (anhydrous)；Reaction temperature is 8-12 DEG C；Reaction dissolvent is selected from dichloro Ethane, dichloromethane, nitrobenzene or o-dichlorohenzene.
- 4. the preparation side of R-5- (2- aminopropyls) -1- (3- hydroxypropyls) -7- itrile group indolines according to claim 1 Method, it is characterised in that：In step 3, the reflux temperature of reaction is 70-80 DEG C.
- 5. the preparation side of R-5- (2- aminopropyls) -1- (3- hydroxypropyls) -7- itrile group indolines according to claim 1 Method, it is characterised in that：In step 4, acid binding agent is potassium carbonate；Reaction time is 15-20h；Reaction dissolvent be selected from acetonitrile, THF, DMF, toluene or absolute ethyl alcohol.
- 6. the preparation side of R-5- (2- aminopropyls) -1- (3- hydroxypropyls) -7- itrile group indolines according to claim 1 Method, it is characterised in that：In step 5, acid binding agent is triethylamine；Reaction dissolvent is selected from methanol, absolute ethyl alcohol or isopropanol.
- 7. the preparation side of R-5- (2- aminopropyls) -1- (3- hydroxypropyls) -7- itrile group indolines according to claim 1 Method, it is characterised in that：In step 6, Hydrogen Vapor Pressure 2-4MPa；Hydrogenation temperature is 50-55 DEG C.
- 8. the preparation side of R-5- (2- aminopropyls) -1- (3- hydroxypropyls) -7- itrile group indolines according to claim 1 Method, it is characterised in that：In step 7, reaction system is bromine/methanol；Reaction temperature is -5-0 DEG C；Reaction time is 1-1.2h.
- 9. the preparation side of R-5- (2- aminopropyls) -1- (3- hydroxypropyls) -7- itrile group indolines according to claim 1 Method, it is characterised in that：In step 8, the molar ratio of compound 8 and CuCN is 1:2；Reaction temperature is 55-65 DEG C；Reaction time is 10-16h。
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| CN201711453155.0A CN108047116B (en) | 2017-12-28 | 2017-12-28 | Preparation method of R-5- (2-aminopropyl) -1- (3-hydroxypropyl) -7-nitrilindoline |
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| CN201711453155.0A CN108047116B (en) | 2017-12-28 | 2017-12-28 | Preparation method of R-5- (2-aminopropyl) -1- (3-hydroxypropyl) -7-nitrilindoline |
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Citations (7)
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|---|---|---|---|---|
| CN102690223A (en) * | 2012-05-24 | 2012-09-26 | 临海天宇药业有限公司 | Preparation method for 1-acetyl-7-cyanopyridine-5-(2-amino propyl) indoline |
| WO2012131710A2 (en) * | 2011-03-30 | 2012-10-04 | Panacea Biotec Ltd | Novel process for the synthesis of indoline derivatives |
| CN103848772A (en) * | 2012-11-30 | 2014-06-11 | 苏州四同医药科技有限公司 | Preparation method of important intermediate of Silodosin |
| KR20150066782A (en) * | 2013-12-09 | 2015-06-17 | 동우신테크 주식회사 | Method of preparing 1-(indolin-5-yl)propan-2-ol derivatives |
| CN104744336A (en) * | 2013-12-26 | 2015-07-01 | 安徽省庆云医药化工有限公司 | Silodosin intermediate, preparation method of silodosin intermediate and method for preparing silodosin from silodosin intermediate |
| CN104974072A (en) * | 2014-04-10 | 2015-10-14 | 江苏和成新材料有限公司 | Preparation method of silodosin intermediate |
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|---|---|---|---|---|
| WO2012131710A2 (en) * | 2011-03-30 | 2012-10-04 | Panacea Biotec Ltd | Novel process for the synthesis of indoline derivatives |
| CN102690223A (en) * | 2012-05-24 | 2012-09-26 | 临海天宇药业有限公司 | Preparation method for 1-acetyl-7-cyanopyridine-5-(2-amino propyl) indoline |
| CN103848772A (en) * | 2012-11-30 | 2014-06-11 | 苏州四同医药科技有限公司 | Preparation method of important intermediate of Silodosin |
| KR20150066782A (en) * | 2013-12-09 | 2015-06-17 | 동우신테크 주식회사 | Method of preparing 1-(indolin-5-yl)propan-2-ol derivatives |
| CN104744336A (en) * | 2013-12-26 | 2015-07-01 | 安徽省庆云医药化工有限公司 | Silodosin intermediate, preparation method of silodosin intermediate and method for preparing silodosin from silodosin intermediate |
| CN104974072A (en) * | 2014-04-10 | 2015-10-14 | 江苏和成新材料有限公司 | Preparation method of silodosin intermediate |
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Non-Patent Citations (1)
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| 吴建才，等: "西洛多辛合成路线图解", 《中国医药工业杂志》 * |
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