CN101747210A - Method for preparing alpha-(di-n-butylaminomethyl)-2,7-dichloro-4-fluorenemethanol and the hydrochloride thereof - Google Patents
Method for preparing alpha-(di-n-butylaminomethyl)-2,7-dichloro-4-fluorenemethanol and the hydrochloride thereof Download PDFInfo
- Publication number
- CN101747210A CN101747210A CN200810073965A CN200810073965A CN101747210A CN 101747210 A CN101747210 A CN 101747210A CN 200810073965 A CN200810073965 A CN 200810073965A CN 200810073965 A CN200810073965 A CN 200810073965A CN 101747210 A CN101747210 A CN 101747210A
- Authority
- CN
- China
- Prior art keywords
- chloro
- butyl amine
- ylmethyls
- reaction
- fluorenes
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for preparing benflumetol intermediate alpha-(di-n-butylaminomethyl)-2, 7- dichloro-4-fluorenemethanol and the hydrochloride thereof. The alpha-(di-n-butylaminomethyl)-2, 7- dichloro-4-fluorenemethanol is obtained by directly reacting 2, 7-Dichlorofluoren as raw material with the chloroacetyl chloride, then reducing the obtained mixture with potassium borohydride or sodium borohydride for 10 to 24 hours, washing the obtained solids with water, then adding the obtained solids into recycled ethanol mother solution concentrate, adding N-Dibutylamine into the mother solution concentrate and the target product is separated from the reaction mixture; the hydrochloride of the alpha-(di-n-butylaminomethyl)-2, 7- dichloro-4-fluorenemethanol is obtained by adding chlorhydric acid into the reaction mixture to salify the reaction mixture and then crystallizing the reaction mixture. The method has cheap raw materials, simple and convenient operations and high yield factor and in particular greatly reduces the production cost by reusing the ethanol mother solution.
Description
(1) technical field:
The present invention relates to prepare the method for benzfluorenol intermediate, be specially preparation α-(two n-butyl amine ylmethyls)-2, the method for 7-two chloro-4-Lumefantrines and hydrochloride thereof.
(2) background technology:
Benzfluorenol (I represents by formula) is new chemical structure medicine of Military Medical Science Institute's synthetic of BeiJing, China, chemistry (9Z)-2 by name, 7-two chloro-9-[(4-chloro-phenyl-s) methylene radical]-α-[(two n-butyl amine bases) methyl]-9H-fluorenes-4-methyl alcohol.
Benzfluorenol can be used for treating various malaria, is particularly useful for the treatment of the pernicious malaria due to the strain of anti-chloroquine worm.α-(two n-butyl amine ylmethyls)-2,7-two chloro-4-Lumefantrines and hydrochloride thereof are the intermediates of synthetic benzfluorenol, α-(two n-butyl amine ylmethyls)-2 of reporting in the Acta Pharmaceutica Sinica (920～924 pages) of the method for at present existing synthetic above-mentioned intermediate the 16th the 12nd phase of volume that to be people such as Deng Rongxian publish in December, 1981, the preparation method of 7-two chloro-4-Lumefantrines and hydrochloride thereof, this method is to be that raw material makes compound α-(two n-butyl amine ylmethyls)-2 with fluorenes-4-carboxylic acid, 7-two chloro-4-Lumefantrines, again with ether extraction, anhydrous magnesium sulfate drying, remove ether, again it is dissolved in the anhydrous diethyl ether, add the hydrogenchloride ether solution, the solid that collection is separated out, recrystallization make α-(two n-butyl amine ylmethyls)-2,7-two chloro-4-Lumefantrine hydrochlorides.In addition, also disclosed α-(two n-butyl amine ylmethyls)-2 in the synthetic method of disclosed benzfluorenol among Chinese invention patent CN1042535 (May 30 nineteen ninety is open), the patent of invention CN1865227 (on November 22nd, 2006 is open), the synthesis step of 7-two chloro-4-Lumefantrines is specially:
But directly by the synthetic α of method shown in above-mentioned-(two n-butyl amine ylmethyls)-2, during 7-two chloro-4-Lumefantrines, the cycle of preparation is long, and the raw material that expends is more, and cost is higher relatively; At preparation α-(two n-butyl amine ylmethyls)-2, during 7-two chloro-4-Lumefantrine hydrochlorides, the post-treating method of use is more loaded down with trivial details, is unfavorable for suitability for industrialized production.
(3) summary of the invention:
The technical problem to be solved in the present invention provides a kind of easy and simple to handle, preparation benzfluorenol intermediate α-(two n-butyl amine ylmethyls)-2 that production cost is low, be suitable for suitability for industrialized production, the method for 7-two chloro-4-Lumefantrines and hydrochloride thereof.
Preparation α of the present invention-(two n-butyl amine ylmethyls)-2, the method for 7-two chloro-4-Lumefantrines, its step is as follows:
1) with 2,7-dichloro fluorenes is a raw material, and aluminum trichloride (anhydrous) is a catalyzer, obtains 2,7-two chloro-4-chloracetyl fluorenes with the chloroacetyl chloride reaction in organic solvent;
Described organic solvent is a methylene dichloride, or trichloromethane, or 1, the 2-ethylene dichloride;
2) with the dehydrated alcohol be solvent, to 2,7-two chloro-4-chloracetyl fluorenes reduce with POTASSIUM BOROHYDRIDE or sodium borohydride, reaction 10～24h, and with gained reaction solution solid-liquid separation, the gained solid water is washed till neutral after drying, obtains 2,7-dichloro fluorenes-4-oxyethane; The mother liquid obtained ethanol that carries out reclaims, and obtains the mother liquor concentrated solution;
Compared with prior art, the method for the invention has prolonged the time of reduction reaction, and it is limited in 10～24 hours; Water is washed till neutrality with isolated solid in the reaction solution, can remove excessive POTASSIUM BOROHYDRIDE or sodium borohydride; Ethanol in mother liquid obtained reclaims behind the solid to isolating, and described ethanol reclaims the ethanol that just reclaims part in the mother liquor, specifically reclaims the alcoholic acid amount and be that dehydrated alcohol initially adds volume 50%～60%; This part ethanol that recovery obtains can be used for the reduction reaction step in the next batch production, and the solvent of mother liquor concentrated solution as subsequent handling used, and can make like this dehydrated alcohol recycling to greatly reduce production cost;
3) with step 2) obtain 2,7-dichloro fluorenes-4-oxyethane adds in the mother liquor concentrated solution, adds Di-n-Butyl Amine again and reacts, and separates obtaining α-(two n-butyl amine ylmethyls)-2,7-two chloro-4-Lumefantrines from reaction mixture.
In this step, with step 2) in the mother liquor concentrated solution that obtains use as solvent, after reaction was finished, the solid of separating out was collected in cooling, drying obtains α-(two n-butyl amine ylmethyls)-2,7-two chloro-4-Lumefantrines.
Above-mentioned α-(two n-butyl amine ylmethyls)-2, among the preparation method of 7-two chloro-4-Lumefantrines, the consumption proportion between used various raw materials, the catalyzer is same as the prior art.Prepare α-(two n-butyl amine ylmethyls)-2 by this method, 7-two chloro-4-Lumefantrines, yield can reach 51～60%.
The present invention also comprises α-(two n-butyl amine ylmethyls)-2, the preparation method of 7-two chloro-4-Lumefantrine hydrochlorides, and its step is as follows:
1) with 2,7-dichloro fluorenes is a raw material, and aluminum trichloride (anhydrous) is a catalyzer, obtains 2,7-two chloro-4-chloracetyl fluorenes with the chloroacetyl chloride reaction in organic solvent;
Described organic solvent is a methylene dichloride, or trichloromethane, or 1, the 2-ethylene dichloride;
2) with the dehydrated alcohol be solvent, to 2,7-two chloro-4-chloracetyl fluorenes reduce with POTASSIUM BOROHYDRIDE or sodium borohydride, reaction 10～24h, and with gained reaction solution solid-liquid separation, the gained solid water is washed till neutral after drying, obtains 2,7-dichloro fluorenes-4-oxyethane; Gained liquid carries out ethanol and reclaims, and obtains the mother liquor concentrated solution;
Compared with prior art, prolonged the time of reduction reaction, it has been limited in 10～24 hours; Water is washed till neutrality with isolated solid in the reaction solution, can remove excessive POTASSIUM BOROHYDRIDE or sodium borohydride; Ethanol in mother liquid obtained reclaims behind the solid to isolating, and described ethanol reclaims the ethanol that just reclaims part in the mother liquor, specifically reclaims the alcoholic acid amount and be that dehydrated alcohol initially adds volume 50%～60%; This part ethanol that recovery obtains can be used for the reduction reaction step in the next batch production, and the solvent of mother liquor concentrated solution as subsequent handling used, and can make like this dehydrated alcohol recycling to greatly reduce production cost;
3) with step 2) obtain 2,7-dichloro fluorenes-4-oxyethane adds in the mother liquor concentrated solution, adds Di-n-Butyl Amine again and reacts, and obtains containing α-(two n-butyl amine ylmethyls)-2, the reaction mixture of 7-two chloro-4-Lumefantrines;
4) to containing α-(two n-butyl amine ylmethyls)-2, add hydrochloric acid in the reaction mixture of 7-two chloro-4-Lumefantrines and be carried out to reactant salt, solvent evaporated after reaction is finished, residuum is with ethyl acetate or ether crystallization, obtain α-(two n-butyl amine ylmethyls)-2,7-two chloro-4-Lumefantrine hydrochlorides.
In order to guarantee α-(the two n-butyl amine ylmethyls)-2 in the reaction mixture, 7-two chloro-4-Lumefantrines can both salify, the add-on of described hydrochloric acid is: make and contain α-(two n-butyl amine ylmethyls)-2, pH value=1～6 of the reaction mixture of 7-two chloro-4-Lumefantrines, the pH value that preferably makes reaction mixture is 2～4; The consumption of described ethyl acetate or ether (volume) and 2, the ratio of the weight of 7-dichloro fluorenes is 2～10, is preferably 4～6.
Above-mentioned α-(two n-butyl amine ylmethyls)-2, among the preparation method of 7-two chloro-4-Lumefantrine hydrochlorides, consumption proportion between used various raw material, the catalyzer is same as the prior art, or obtains by the prior art conversion, as the consumption of ethyl acetate or ether.Prepare α-(two n-butyl amine ylmethyls)-2 by this method, 7-two chloro-4-Lumefantrine hydrochlorides, yield can reach 59～65%.
Compared with prior art, α provided by the invention-(two n-butyl amine ylmethyls)-2, the preparation method of 7-two chloro-4-Lumefantrines and α-(two n-butyl amine ylmethyls)-2, the preparation method of 7-two chloro-4-Lumefantrine hydrochlorides, the use raw material is cheap and easy to get, and the reaction conditions gentleness is easy and simple to handle, the yield height is fit to industrialized production; And the method for the invention makes production cost reduce greatly by the recycling to the ethanol mother liquor.
(4) embodiment:
The invention will be further described below in conjunction with embodiment, but they are not limitation of the invention.
Embodiment 1
Take by weighing aluminum trichloride (anhydrous) 20.2g (0.151mol), chloroacetyl chloride 12g (0.106mol) joins 300ml 1, in the 2-ethylene dichloride, reactant is cooled to 0～5 ℃, further reaction stirred 30 minutes under 0～5 ℃ of temperature, add 2,7-dichloro fluorenes 20g (0.085mol) 0～5 ℃ of following reaction stirred 2～3 hours, allows its natural temperature reaction 2～3 hours again; After reaction is finished, reactant is cooled to 0～5 ℃, in reactant, slowly adds the 400ml frozen water that contains the 120ml concentrated hydrochloric acid then, fully stirred 30 minutes, tell organic layer afterwards, with 1,2-ethylene dichloride 50ml aqueous layer extracted; Merge the organic layer that obtains, be washed with water to substantially apparent acidity, steaming desolventizes to doing then, and residuum is 2,7-two chloro-4-chloracetyl fluorenes.In residuum, add dehydrated alcohol 400ml, 40～45 ℃ of controlled temperature, add POTASSIUM BOROHYDRIDE 8g (0.148mol), 40～45 ℃ of reactions of holding temperature 24 hours are cooled to 0～5 ℃ with reaction solution after reaction is finished, and filter the solid of collecting wherein, be washed with water to filtrate and become neutral, dry below 60 ℃, obtain 2,7-dichloro fluorenes-4-oxyethane.From the ethanol mother liquor, reclaim ethanol 200～240ml, obtain the mother liquor concentrated solution; In the mother liquor concentrated solution, add exsiccant 2,7-dichloro fluorenes-4-oxyethane, add Di-n-Butyl Amine 16.4g (0.128mol) again, heating reflux reaction 14 hours is separated out solid after the cooling, filter collection solid, dry below 60 ℃, get α-(two n-butyl amine ylmethyls)-2,7-two chloro-4-Lumefantrine 17.7g, yield is 51.2%.
Embodiment 2
Take by weighing aluminum trichloride (anhydrous) 20.2g (0.151mol), chloroacetyl chloride 12g (0.106mol) joins in the 300ml methylene dichloride, reactant is cooled to 0～5 ℃, further reaction stirred 30 minutes under 0～5 ℃ of temperature, add 2,7-dichloro fluorenes 20g (0.085mol), 0～5 ℃ of following reaction stirred 2～3 hours, allow its natural temperature reaction 2～3 hours again; After reaction is finished, reactant is cooled to 0～5 ℃, in reactant, slowly adds the 400ml frozen water that contains the 120ml concentrated hydrochloric acid then, fully stirred 30 minutes, tell organic layer afterwards, with methylene dichloride 50ml aqueous layer extracted; Merge the organic layer that obtains, be washed with water to substantially apparent acidity, steaming desolventizes to doing then, and residuum is 2,7-two chloro-4-chloracetyl fluorenes.In residuum, add dehydrated alcohol 400ml, 40～45 ℃ of controlled temperature, add POTASSIUM BOROHYDRIDE 8g (0.148mol), 40～45 ℃ of reactions of holding temperature 24 hours are cooled to 0～5 ℃ with reaction solution after reaction is finished, and filter the solid of collecting wherein, be washed with water to filtrate and become neutral, dry below 60 ℃, obtain 2,7-dichloro fluorenes-4-oxyethane.From the ethanol mother liquor, reclaim ethanol 200～240ml, obtain the mother liquor concentrated solution; In the mother liquor concentrated solution, add exsiccant 2,7-dichloro fluorenes-4-oxyethane, add Di-n-Butyl Amine 16.4g (0.128mol) again, heating reflux reaction 14 hours is separated out solid after the cooling, filter collection solid, dry below 60 ℃, get α-(two n-butyl amine ylmethyls)-2,7-two chloro-4-Lumefantrine 21.8g, yield is 57.9%.
Embodiment 3
Aluminum trichloride (anhydrous) 50.5g (0.379mol), chloroacetyl chloride 30g (0.266mol) are joined in the 900ml methylene dichloride, reactant is cooled to 0～5 ℃, further reaction stirred 30 minutes under 0～5 ℃ of temperature, add 2,7-dichloro fluorenes 50g (0.213mol), 0～5 ℃ of following reaction stirred 2～3 hours, allow its natural temperature reaction 2～3 hours again; After reaction is finished, reactant is cooled to 0～5 ℃, in reactant, slowly adds the 1000ml frozen water that contains the 300ml concentrated hydrochloric acid then, fully stirred 30 minutes, tell organic layer afterwards, with methylene dichloride 100ml aqueous layer extracted; Merge the organic layer that obtains, be washed with water to apparent acidity, steaming desolventizes to doing then, and residuum is 2,7-two chloro-4-chloracetyl fluorenes.In residuum, add dehydrated alcohol 1000ml, 40～45 ℃ of controlled temperature, add POTASSIUM BOROHYDRIDE 20g (0.371mol), 40～45 ℃ of reactions of holding temperature 18 hours are cooled to 0～5 ℃ with reaction solution after reaction is finished, and filter the solid of collecting wherein, be washed with water to filtrate and become neutral, dry below 60 ℃, get 2,7-dichloro fluorenes-4-oxyethane.From the ethanol mother liquor, reclaim ethanol 550ml, obtain the mother liquor concentrated solution; Add exsiccant 2 in mother liquor concentrates, 7-dichloro fluorenes-4-oxyethane adds Di-n-Butyl Amine 41g (0.317mol) again, and heating reflux reaction 14 hours obtains containing α-(two n-butyl amine ylmethyls)-2, the reaction mixture of 7-two chloro-4-Lumefantrines.The hydrochloric acid soln of adding 30% makes its pH=3 in this reaction mixture, and reflux is steamed after 0.5 hour and desolventized to doing, and adds ethyl acetate 300ml in residuum, and reflux and stirred 30 minutes, the adding purified water, the washing ethyl acetate layer is to substantially showing acid; Tell organic layer, cooling and stirring is separated out solid, and filter collection solid is dry below 80 ℃, gets α-(two n-butyl amine ylmethyls)-2,7-two chloro-4-Lumefantrine hydrochloride 57g, and yield is 60.5%.
Embodiment 4
Aluminum trichloride (anhydrous) 50.5g (0.379mol), chloroacetyl chloride 30g (0.266mol) are joined 700ml 1, in the 2-ethylene dichloride, reactant is cooled to 0～5 ℃, further reaction stirred 30 minutes under 0～5 ℃ of temperature, add 2,7-dichloro fluorenes 50g (0.213mol) 0～5 ℃ of following reaction stirred 2～3 hours, allows its natural temperature reaction 2～3 hours again; After reaction is finished, reactant is cooled to 0～5 ℃, in reactant, slowly adds the 1000ml frozen water that contains the 300ml concentrated hydrochloric acid then, fully stirred 30 minutes, tell organic layer afterwards, with 1,2-ethylene dichloride 100ml aqueous layer extracted; Merge the organic layer that obtains, be washed with water to substantially apparent acidity, steaming desolventizes to doing then, and residuum is 2,7-two chloro-4-chloracetyl fluorenes.In residuum, add dehydrated alcohol 1000ml, 40～45 ℃ of controlled temperature, gradation adds sodium borohydride 13.5g (0.357mol), 40～45 ℃ of reactions of holding temperature 24 hours are cooled to 0～5 ℃ with reaction solution after reaction is finished, and filter the solid of collecting wherein, be washed with water to filtrate and become neutral, dry below 60 ℃, get 2,7-dichloro fluorenes-4-oxyethane.From the ethanol mother liquor, reclaim ethanol 600ml, obtain the mother liquor concentrated solution; In the mother liquor concentrated solution, add leach 2,7-dichloro fluorenes-4-oxyethane adds Di-n-Butyl Amine 41g (0.317mol) again, heating reflux reaction 14 hours obtains containing α-(two n-butyl amine ylmethyls)-2, the reaction mixture of 7-two chloro-4-Lumefantrines.Add concentrated hydrochloric acid and make its pH=1 in this reaction mixture, reflux is steamed after 1 hour and is desolventized to doing, and adds ethyl acetate 200ml in residuum, refluxes and stirs 1 hour, adds purified water, and the washing ethyl acetate layer is to not showing acid substantially; Tell organic layer, cooling and stirring is separated out solid, and filter collection solid is dry below 80 ℃, gets α-(two n-butyl amine ylmethyls)-2,7-two chloro-4-Lumefantrine hydrochloride 61g, and yield is 64.8%.
Embodiment 5
Aluminum trichloride (anhydrous) 56g (0.420mol), chloroacetyl chloride 34g (0.301mol) are joined in the 700ml trichloromethane, reactant is cooled to 0～5 ℃, further reaction stirred 30 minutes under 0～5 ℃ of temperature, add 2,7-dichloro fluorenes 50g (0.213mol), 0～5 ℃ of following reaction stirred 2～3 hours, allow its natural temperature reaction 2～3 hours again; After reaction is finished, reactant is cooled to 0～5 ℃, in reactant, slowly adds the 1000ml frozen water that contains the 300ml concentrated hydrochloric acid then, fully stirred 30 minutes, tell organic layer afterwards, with trichloromethane 100ml aqueous layer extracted; Merge the organic layer that obtains, be washed with water to substantially apparent acidity, steaming desolventizes to doing then, and residuum is 2,7-two chloro-4-chloracetyl fluorenes.In residuum, add dehydrated alcohol 1000ml, 40～45 ℃ of controlled temperature, add POTASSIUM BOROHYDRIDE 20g (0.371mol), 40～45 ℃ of reactions of holding temperature 18 hours are cooled to 0～5 ℃ with reaction solution after reaction is finished, and filter the solid of collecting wherein, be washed with water to filtrate and become neutral, dry below 60 ℃, get 2,7-dichloro fluorenes-4-oxyethane.From the ethanol mother liquor, reclaim ethanol 500ml, obtain the mother liquor concentrated solution; In the mother liquor concentrated solution, add leach 2,7-dichloro fluorenes-4-oxyethane adds Di-n-Butyl Amine 41g (0.317mol) again, heating reflux reaction 14 hours obtains containing α-(two n-butyl amine ylmethyls)-2, the reaction mixture of 7-two chloro-4-Lumefantrines.Add hydrochloric acid and make its pH=6 in this reaction mixture, reflux is steamed after 1 hour and is desolventized to doing, and adds ether 400ml in residuum, refluxes and stirs 1 hour, adds purified water, and the washing ether layer is to not showing acid; Tell organic layer, be cooled to 0～5 ℃ and stirred 2 hours, filter collection solid, dry below 80 ℃, get α-(two n-butyl amine ylmethyls)-2,7-two chloro-4-Lumefantrine hydrochloride 59g, yield is 62.6%.
Claims (8)
1. prepare α-(two n-butyl amine ylmethyls)-2, the method for 7-two chloro-4-Lumefantrines is characterized in that: may further comprise the steps:
1) with 2,7-dichloro fluorenes is a raw material, and aluminum trichloride (anhydrous) is a catalyzer, obtains 2,7-two chloro-4-chloracetyl fluorenes with the chloroacetyl chloride reaction in organic solvent;
2) with the dehydrated alcohol be solvent, to 2,7-two chloro-4-chloracetyl fluorenes reduce with POTASSIUM BOROHYDRIDE or sodium borohydride, reaction 10～24h, and with gained reaction solution solid-liquid separation, the gained solid water is washed till neutral after drying, obtains 2,7-dichloro fluorenes-4-oxyethane; The mother liquid obtained ethanol that carries out reclaims, and obtains the mother liquor concentrated solution;
3) with obtain in the above-mentioned steps 2,7-dichloro fluorenes-4-oxyethane adds in the mother liquor concentrated solution, adds Di-n-Butyl Amine again and reacts, and separates obtaining α-(two n-butyl amine ylmethyls)-2,7-two chloro-4-Lumefantrines from reaction mixture.
2. preparation α according to claim 1-(two n-butyl amine ylmethyls)-2, the method for 7-two chloro-4-Lumefantrines is characterized in that: step 2) in, the alcoholic acid amount from mother liquor, reclaimed and be that dehydrated alcohol initially adds volume 50%～60%.
3. the method for preparation α according to claim 1 and 2-(two n-butyl amine ylmethyls)-2,7 two chloro-4-Lumefantrines, it is characterized in that: the organic solvent in the step 1) is a methylene dichloride, or trichloromethane, or 1, the 2-ethylene dichloride.
4. prepare α-(two n-butyl amine ylmethyls)-2, the method for 7-two chloro-4-Lumefantrine hydrochlorides is characterized in that: may further comprise the steps:
1) with 2,7-dichloro fluorenes) be raw material, aluminum trichloride (anhydrous) is a catalyzer, obtains 2,7-two chloro-4-chloracetyl fluorenes with the chloroacetyl chloride reaction in organic solvent;
2) with the dehydrated alcohol be solvent, to 2,7-two chloro-4-chloracetyl fluorenes reduce with POTASSIUM BOROHYDRIDE or sodium borohydride, reaction 10～24h, and with gained reaction solution solid-liquid separation, the gained solid water is washed till neutral after drying, obtains 2,7-dichloro fluorenes-4-oxyethane; The mother liquid obtained ethanol that carries out reclaims, and obtains the mother liquor concentrated solution;
3) with step 2) obtain 2,7-dichloro fluorenes-4-oxyethane adds in the mother liquor concentrated solution, adds Di-n-Butyl Amine again and reacts, and obtains containing α-(two n-butyl amine ylmethyls)-2, the reaction mixture of 7-two chloro-4-Lumefantrines;
4) to containing α-(two n-butyl amine ylmethyls)-2, add hydrochloric acid in the reaction mixture of 7-two chloro-4-Lumefantrines and be carried out to reactant salt, solvent evaporated after reaction is finished, residuum is with ethyl acetate or ether crystallization, obtain α-(two n-butyl amine ylmethyls)-2,7-two chloro-4-Lumefantrine hydrochlorides.
5. preparation α according to claim 4-(two n-butyl amine ylmethyls)-2, the method for 7-two chloro-4-Lumefantrine hydrochlorides is characterized in that: step 2) in, the alcoholic acid amount from mother liquor, reclaimed and be that dehydrated alcohol initially adds volume 50%～60%.
6. preparation α according to claim 4-(two n-butyl amine ylmethyls)-2, the method for 7-two chloro-4-Lumefantrine hydrochlorides, it is characterized in that: the organic solvent in the step 1) is a methylene dichloride, or trichloromethane, or 1, the 2-ethylene dichloride.
7. preparation α according to claim 4-(two n-butyl amine ylmethyls)-2, the method of 7-two chloro-4-Lumefantrine hydrochlorides, it is characterized in that: in the step 4), the add-on of hydrochloric acid is: make and contain α-(two n-butyl amine ylmethyls)-2, pH value=1～6 of the reaction mixture of 7-two chloro-4-Lumefantrines.
8. preparation α according to claim 4-(two n-butyl amine ylmethyls)-2, the method of 7-two chloro-4-Lumefantrine hydrochlorides, it is characterized in that: the add-on of hydrochloric acid is: make and contain α-(two n-butyl amine ylmethyls)-2, pH value=2～4 of the reaction mixture of 7-two chloro-4-Lumefantrines.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810073965A CN101747210A (en) | 2008-12-06 | 2008-12-06 | Method for preparing alpha-(di-n-butylaminomethyl)-2,7-dichloro-4-fluorenemethanol and the hydrochloride thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810073965A CN101747210A (en) | 2008-12-06 | 2008-12-06 | Method for preparing alpha-(di-n-butylaminomethyl)-2,7-dichloro-4-fluorenemethanol and the hydrochloride thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101747210A true CN101747210A (en) | 2010-06-23 |
Family
ID=42474900
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200810073965A Pending CN101747210A (en) | 2008-12-06 | 2008-12-06 | Method for preparing alpha-(di-n-butylaminomethyl)-2,7-dichloro-4-fluorenemethanol and the hydrochloride thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101747210A (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102993029A (en) * | 2012-11-08 | 2013-03-27 | 浙江医药股份有限公司新昌制药厂 | Preparation method for 2-dibutylamido-1-1(2,7- dichloro-9H-fluorine-4base)-ethanol |
| WO2013114118A3 (en) * | 2012-01-31 | 2013-10-10 | Cambridge Display Technology Limited | Polymer |
| CN103408509A (en) * | 2013-07-17 | 2013-11-27 | 张家港威胜生物医药有限公司 | Anti-malaria medical raw material benflumetol intermediate 2,7-dichlorofluorene-4-ethylene oxide synthesis process |
| CN103412083A (en) * | 2013-07-17 | 2013-11-27 | 张家港威胜生物医药有限公司 | Reversed-phase high performance liquid chromatography method for determining benflumetol intermediate IV |
| CN106977410A (en) * | 2017-05-15 | 2017-07-25 | 张家港威胜生物医药有限公司 | One kind prepares lumefantrine intermediate α by fluorenes（Di-n-butylamine base）The preparation method of 2,7 dichloro-4,4 fluorenemethanols |
| CN114436866A (en) * | 2022-01-19 | 2022-05-06 | 舞阳威森生物医药有限公司 | Refining process of benflumetol crude product |
-
2008
- 2008-12-06 CN CN200810073965A patent/CN101747210A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013114118A3 (en) * | 2012-01-31 | 2013-10-10 | Cambridge Display Technology Limited | Polymer |
| GB2515909A (en) * | 2012-01-31 | 2015-01-07 | Cambridge Display Tech Ltd | Polymer |
| US9761820B2 (en) | 2012-01-31 | 2017-09-12 | Cambridge Display Technology Limited | Polymer |
| GB2515909B (en) * | 2012-01-31 | 2020-07-15 | Cambridge Display Tech Ltd | Composition comprising a fluorescent light-emitting material and triplet-accepting polymer and use thereof |
| CN102993029A (en) * | 2012-11-08 | 2013-03-27 | 浙江医药股份有限公司新昌制药厂 | Preparation method for 2-dibutylamido-1-1(2,7- dichloro-9H-fluorine-4base)-ethanol |
| CN103408509A (en) * | 2013-07-17 | 2013-11-27 | 张家港威胜生物医药有限公司 | Anti-malaria medical raw material benflumetol intermediate 2,7-dichlorofluorene-4-ethylene oxide synthesis process |
| CN103412083A (en) * | 2013-07-17 | 2013-11-27 | 张家港威胜生物医药有限公司 | Reversed-phase high performance liquid chromatography method for determining benflumetol intermediate IV |
| CN106977410A (en) * | 2017-05-15 | 2017-07-25 | 张家港威胜生物医药有限公司 | One kind prepares lumefantrine intermediate α by fluorenes（Di-n-butylamine base）The preparation method of 2,7 dichloro-4,4 fluorenemethanols |
| CN114436866A (en) * | 2022-01-19 | 2022-05-06 | 舞阳威森生物医药有限公司 | Refining process of benflumetol crude product |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101747210A (en) | Method for preparing alpha-(di-n-butylaminomethyl)-2,7-dichloro-4-fluorenemethanol and the hydrochloride thereof | |
| CN102617542B (en) | Method for preparing and purifying olmesartan intermediate | |
| CN110590587A (en) | Synthetic method of 3-chloro-L-alanine methyl ester hydrochloride | |
| CN104356111B (en) | A kind of method for preparing dabigatran etcxilate mesylate hydrolysis impurity | |
| CN112898299A (en) | Preparation method of palbociclib intermediate | |
| CN105330582A (en) | Preparation method for (R)-4-hydroxy-2-oxo-1-pyrrolidine acetamide | |
| CN102503829B (en) | Preparation methods for sitagliptin intermediates | |
| CN105130795A (en) | Preparation method for high-purity fenofibric acid crude drugs | |
| CN101323598B (en) | Preparation of 5,5-diethylmalonylurea | |
| CN107778233A (en) | A kind of preparation method of neuromuscular blocking agent intermediate | |
| CN106928149B (en) | Preparation method of olaparib | |
| CN111943937A (en) | Synthesis method of triphenyl candesartan | |
| US8058302B2 (en) | Process for preparing pure anastrozole | |
| CN102363599B (en) | A kind of sitagliptin intermediate chiral separation method | |
| CN102603595B (en) | Preparation method of (S)-oxiracetam | |
| CN111349075A (en) | Preparation method of trelagliptin succinate | |
| CN105294479B (en) | A kind of 3R amino replaces the preparation method of butanamide derivatives | |
| CN112341433A (en) | Preparation method of loratadine | |
| WO2021259051A1 (en) | Method for improving synthesis process of hypidone free base | |
| CN102584709B (en) | A kind of preparation technology of the Eprosartan intermediate aryl imidazole aldehyde of improvement | |
| CN102206185B (en) | Process for refining bendazac lysine and analogs thereof | |
| US20140371457A1 (en) | Process for production of quinuclidine compounds | |
| CN101585837B (en) | Method for separating matrine and oxymatrine from total matrines | |
| CN110498764B (en) | Synthesis method of doxylamine succinate | |
| CN107163032A (en) | A kind of piribedil preparation method in high yield |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20100623 |
|
| WD01 | Invention patent application deemed withdrawn after publication |