CN112341406B - Synthesis method of trans-4- [4- (3-methoxy-4-nitrophenyl) -1-piperazinyl ] adamantane-1-ol - Google Patents
Synthesis method of trans-4- [4- (3-methoxy-4-nitrophenyl) -1-piperazinyl ] adamantane-1-ol Download PDFInfo
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
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- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
- C07D295/033—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to carbocyclic rings
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Abstract
The invention relates to the technical field of organic synthesis, and provides a method for synthesizing trans-4- [4- (3-methoxy-4-nitrophenyl) -1-piperazinyl ] adamantane-1-ol. The invention takes 2-nitro-5-fluoroanisole as an initial raw material, and prepares trans-4- [4- (3-methoxy-4-nitrophenyl) -1-piperazinyl ] adamantane-1-ol through three steps of nucleophilic substitution reaction. The synthesis method provided by the invention has the advantages of simple steps, easy operation, difficult generation of cis-isomer, high product yield, high purity and easy amplification production.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing trans-4- [4- (3-methoxy-4-nitrophenyl) -1-piperazinyl ] adamantane-1-ol.
Background
Trans-4- [4- (3-methoxy-4-nitrophenyl) -1-piperazinyl ] adamantan-1-ol is an important pharmaceutical intermediate, often used in the development of drugs for the treatment of cancer.
Currently, the common synthetic scheme for trans-4- [4- (3-methoxy-4-nitrophenyl) -1-piperazinyl ] adamantan-1-ol is: firstly, 2-methoxy-4- (piperazine-1-yl) nitrobenzene is synthesized, and then 5-hydroxyadamantane-2-ketone is used for reductive amination reaction. However, the cis-trans isomer exists in the product prepared by the method, the cis-form product is difficult to remove in subsequent purification, the purity of the obtained product is low (only about 95 percent), and the yield of the trans-4- [4- (3-methoxy-4-nitrophenyl) -1-piperazinyl ] adamantan-1-ol is low (only about 10 percent), so that the method is not favorable for industrial scale-up production.
Disclosure of Invention
In view of the above, the present invention aims to provide a method for synthesizing trans-4- [4- (3-methoxy-4-nitrophenyl) -1-piperazinyl ] adamantan-1-ol. The synthesis method provided by the invention has the advantages of simple steps, difficult occurrence of cis-isomer, high product yield, high purity and easy amplification production.
In order to achieve the above object, the present invention provides the following technical solutions:
the synthesis method of trans-4- [4- (3-methoxy-4-nitrophenyl) -1-piperazinyl ] adamantan-1-ol comprises the following steps:
(1) Under the action of an alkaline compound, carrying out a first nucleophilic substitution reaction on 2-nitro-5-fluoroanisole and diethanolamine to obtain 2- [ N- (2-hydroxyethyl) -3-methoxy-4-nitroaniline ] ethanol;
(2) Under the action of an alkaline compound, carrying out a second nucleophilic substitution reaction on the 2- [ N- (2-hydroxyethyl) -3-methoxy-4-nitroaniline ] ethanol and thionyl chloride to obtain bis- (2-chloroethyl) - (3-methoxy-4-nitrophenyl) -amine;
(3) And (2) carrying out a third nucleophilic substitution reaction on the bis- (2-chloroethyl) - (3-methoxy-4-nitrophenyl) -amine and trans-4-aminoadamantan-1-ol under the action of a basic compound and potassium iodide to obtain trans-4- [4- (3-methoxy-4-nitrophenyl) -1-piperazinyl ] adamantan-1-ol.
Preferably, the basic compound in the steps (1) to (3) independently comprises one or more of sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, triethylamine and diisopropylethylamine.
Preferably, the molar ratio of the 2-nitro-5-fluoroanisole, the diethanolamine and the alkaline compound in the step (1) is 1 (3-3.5) to 1-1.2;
the first nucleophilic substitution reaction solvent comprises one or more of dimethyl sulfoxide, acetonitrile, N-dimethylformamide, methanol, ethanol and isopropanol;
the temperature of the first nucleophilic substitution reaction is 55-65 ℃, and the time is 40-48 h.
Preferably, after the first nucleophilic substitution reaction is completed, the method further comprises post-treating the obtained product liquid, wherein the post-treating comprises the following steps:
mixing the first nucleophilic substitution reaction product feed liquid and a neutral saline solution, and then sequentially stirring and centrifuging to obtain a crude product;
and mixing the crude product with water, pulping and centrifuging in sequence, and drying the obtained solid product to obtain the 2- [ N- (2-hydroxyethyl) -3-methoxy-4-nitroaniline ] ethanol.
Preferably, the molar ratio of the 2- [ N- (2-hydroxyethyl) -3-methoxy-4-nitroaniline ] ethanol, the thionyl chloride and the alkaline compound in the step (2) is 1 (3-3.5) to 1 (1-1.5);
the second nucleophilic substitution solvent comprises one or more of dichloromethane, chloroform, toluene, acetonitrile and methyl tert-butyl ether;
the temperature of the second nucleophilic substitution reaction is 35-45 ℃ and the time is 15-35 h.
Preferably, after the second nucleophilic substitution reaction is completed, the method further comprises post-treating the obtained product solution, wherein the post-treatment comprises the following steps:
mixing the second nucleophilic substitution reaction product feed liquid and a sodium bicarbonate aqueous solution, and then standing and separating the mixture to obtain an organic phase;
and (3) decoloring and dehydrating the organic phase, sequentially filtering and concentrating, mixing the obtained concentrate with methyl tert-butyl ether, and sequentially pulping, filtering and drying to obtain the bis- (2-chloroethyl) - (3-methoxy-4-nitrophenyl) -amine.
Preferably, the molar ratio of the bis- (2-chloroethyl) - (3-methoxy-4-nitrophenyl) -amine, the trans-4-aminoadamantan-1-ol, the basic compound and the potassium iodide in the step (3) is 1 (1-1.02) to (2-7) to (0.05-0.2);
the solvent for the third nucleophilic substitution reaction is an alcohol solvent;
the third nucleophilic substitution reaction is carried out under the reflux condition, and the reaction time is 40-50 h.
Preferably, after the third nucleophilic substitution reaction is completed, the method further comprises post-treating the obtained product liquid, wherein the post-treating comprises the following steps:
filtering the third nucleophilic substitution reaction product liquid to obtain a crude product;
mixing the crude product and methyl tert-butyl ether, and then sequentially pulping and filtering to obtain a solid product;
mixing the solid product with a sodium hydroxide aqueous solution and dichloromethane, stirring and filtering in sequence, and standing and separating the obtained liquid phase to obtain an organic phase;
and (3) removing water from the organic phase, sequentially filtering and concentrating, mixing the obtained concentrate with isopropyl ether, sequentially pulping, filtering and drying to obtain the trans-4- [4- (3-methoxy-4-nitrophenyl) -1-piperazinyl ] adamantane-1-ol.
The invention provides a method for synthesizing trans-4- [4- (3-methoxy-4-nitrophenyl) -1-piperazinyl ] adamantane-1-ol, which comprises the steps of taking 2-nitro-5-fluoroanisole as an initial raw material, firstly carrying out a first nucleophilic substitution reaction on the 2-nitro-5-fluoroanisole and diethanolamine to obtain 2- [ N- (2-hydroxyethyl) -3-methoxy-4-nitroaniline ] ethanol, then carrying out a second nucleophilic substitution reaction on the 2- [ N- (2-hydroxyethyl) -3-methoxy-4-nitroaniline ] ethanol and thionyl chloride to obtain bis- (2-chloroethyl) - (3-methoxy-4-nitrophenyl) -amine, and then carrying out a third nucleophilic substitution reaction on the bis- (2-chloroethyl) - (3-methoxy-4-nitrophenyl) -amine and the trans-4-aminoadamantane-1-ol to obtain the trans-4- [4- (3-methoxy-4-nitrophenyl) -1-piperazinyl ] adamantane-1-ol. The synthesis method provided by the invention comprises three steps of nucleophilic substitution reaction, and has the advantages of simple steps, easy operation, difficult generation of cis-isomer, high product yield and easy amplification production.
Detailed Description
The invention provides a method for synthesizing trans-4- [4- (3-methoxy-4-nitrophenyl) -1-piperazinyl ] adamantane-1-ol, which comprises the following steps:
(1) Under the action of an alkaline compound, carrying out a first nucleophilic substitution reaction on 2-nitro-5-fluoroanisole and diethanolamine to obtain 2- [ N- (2-hydroxyethyl) -3-methoxy-4-nitroaniline ] ethanol;
(2) Under the action of an alkaline compound, carrying out a second nucleophilic substitution reaction on the 2- [ N- (2-hydroxyethyl) -3-methoxy-4-nitroaniline ] ethanol and thionyl chloride to obtain bis- (2-chloroethyl) - (3-methoxy-4-nitrophenyl) -amine;
(3) And (2) carrying out a third nucleophilic substitution reaction on the bis- (2-chloroethyl) - (3-methoxy-4-nitrophenyl) -amine and trans-4-aminoadamantan-1-ol under the action of a basic compound and potassium iodide to obtain trans-4- [4- (3-methoxy-4-nitrophenyl) -1-piperazinyl ] adamantan-1-ol.
The route for synthesizing trans-4- [4- (3-methoxy-4-nitrophenyl) -1-piperazinyl ] adamantane-1-ol is shown as formula I:
the synthesis method of the present invention is described in detail below with reference to formula I.
Under the action of an alkaline compound, 2-nitro-5-fluoroanisole (the structural formula is shown as A in the formula I) and diethanol amine are subjected to a first nucleophilic substitution reaction to obtain 2- [ N- (2-hydroxyethyl) -3-methoxy-4-nitroaniline ] ethanol (the structural formula is shown as B in the formula I). In the present invention, the basic compound preferably includes one or more of sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, triethylamine and diisopropylethylamine, and more preferably sodium bicarbonate; the basic compound provides a basic environment for the first nucleophilic substitution reaction and neutralizes the hydrogen fluoride produced.
In the present invention, the first nucleophilic substitution reaction solvent includes one or more of dimethyl sulfoxide, acetonitrile, N-dimethylformamide, methanol, ethanol, and isopropanol, and more preferably dimethyl sulfoxide; the volume of the solvent is preferably 2 to 5 times that of 2-nitro-5-fluoroanisole.
In the invention, the molar ratio of the 2-nitro-5-fluoroanisole, the diethanolamine and the alkaline compound is preferably 1 (3-3.5) to 1-1.2, more preferably 1 (3.2-3.4) to 1.05-1.1; the temperature of the first nucleophilic substitution reaction is preferably 55 to 65 ℃, more preferably 58 to 62 ℃, and the time of the first nucleophilic substitution reaction is preferably 40 to 48 hours, more preferably 42 to 45 hours.
In the embodiment of the present invention, it is preferable that the solvent, 2-nitro-5-fluoroanisole and diethanolamine are stirred and mixed for 15min, then the alkaline compound is added, and then the temperature is raised to the first nucleophilic substitution reaction temperature for reaction.
After the first nucleophilic substitution reaction is completed, the present invention preferably performs a post-treatment on the obtained product liquid, and the post-treatment preferably comprises the following steps:
mixing the first nucleophilic substitution reaction product feed liquid and a neutral saline solution, and then sequentially stirring and centrifuging to obtain a crude product;
and mixing the crude product with water, pulping and centrifuging in sequence, and drying the obtained solid product to obtain the 2- [ N- (2-hydroxyethyl) -3-methoxy-4-nitroaniline ] ethanol.
In the present invention, the neutral brine solution is preferably an aqueous sodium chloride solution or an aqueous sodium sulfate solution, more preferably an aqueous sodium chloride solution; the volume of the neutral salt water solution is preferably 15-20 times of that of the 2-nitro-5-fluoroanisole; the mass fraction of the central brine solution is preferably 15%; the method preferably comprises the steps of cooling the first nucleophilic substitution reaction product feed liquid to room temperature, and then mixing the first nucleophilic substitution reaction product feed liquid with a sodium chloride aqueous solution; the stirring time is preferably 2-4 h; the dosage ratio of the crude product to the water is preferably 3 times; the beating time is preferably 2-4 h. The present invention does not require special conditions for the centrifugation and drying, and conditions well known to those skilled in the art may be used. The method utilizes the neutral saline solution to remove unreacted raw materials in the feed liquid of the first nucleophilic substitution reaction product, and can play a role in salting out and reduce the loss of the product; the invention removes residual neutral salt by pulping.
After the 2- [ N- (2-hydroxyethyl) -3-methoxy-4-nitroaniline ] ethanol is obtained, under the action of an alkaline compound, the 2- [ N- (2-hydroxyethyl) -3-methoxy-4-nitroaniline ] ethanol and thionyl chloride are subjected to a second nucleophilic substitution reaction to obtain bis- (2-chloroethyl) - (3-methoxy-4-nitrophenyl) -amine (the structural formula is shown as C in the formula I). In the present invention, the basic compound preferably includes one or more of sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, triethylamine and diisopropylethylamine, and more preferably triethylamine; the solvent for the second nucleophilic substitution reaction preferably comprises one or more of dichloromethane, chloroform, toluene, acetonitrile and methyl tert-butyl ether, more preferably dichloromethane, and the volume of the solvent is preferably 15-25 times of that of 2- [ N- (2-hydroxyethyl) -3-methoxy-4-nitroaniline ] ethanol.
In the invention, the molar ratio of the 2- [ N- (2-hydroxyethyl) -3-methoxy-4-nitroaniline ] ethanol to the thionyl chloride to the alkaline compound is preferably 1 (3-3.5) to 1-1.5, more preferably 1 (3.2-3.3) to 1.2-1.4; the temperature of the second nucleophilic substitution reaction is preferably 35 to 45 ℃, more preferably 38 to 42 ℃, and the time of the second nucleophilic substitution reaction is preferably 15 to 35 hours, more preferably 20 to 30 hours.
In the specific embodiment of the invention, preferably, 2- [ N- (2-hydroxyethyl) -3-methoxy-4-nitroaniline ] ethanol, the alkaline compound and the solvent are mixed, then the temperature is reduced to 10-20 ℃, the thionyl chloride solution (the solvent used for preparing the thionyl chloride solution is consistent with the solvent for the second nucleophilic substitution reaction) is dripped at the temperature of 10-20 ℃, and the temperature is raised to the temperature of the second nucleophilic substitution reaction for reaction after the dripping is finished.
After the second nucleophilic substitution reaction is completed, the present invention preferably performs a post-treatment on the obtained product liquid, wherein the post-treatment comprises the following steps:
mixing the second nucleophilic substitution reaction product feed liquid and a sodium bicarbonate aqueous solution, and then standing and separating the mixture to obtain an organic phase;
and (3) decoloring and dehydrating the organic phase, sequentially filtering and concentrating, mixing the obtained concentrate with methyl tert-butyl ether, and sequentially pulping, filtering and drying to obtain the bis- (2-chloroethyl) - (3-methoxy-4-nitrophenyl) -amine.
In the present invention, the aqueous sodium bicarbonate solution is preferably a saturated solution; the dosage ratio of the sodium bicarbonate water solution to the 2- [ N- (2-hydroxyethyl) -3-methoxy-4-nitroaniline ] ethanol is preferably 10mL:1g of the total weight of the composition. Preferably, the second nucleophilic substitution reaction product feed liquid is cooled to room temperature and then is mixed with a sodium bicarbonate water solution; the invention has no special requirements on the specific operation method of standing and liquid separation, and the operation method well known by the technical personnel in the field can be adopted. The invention utilizes sodium bicarbonate aqueous solution to quench reaction, and leads impurities to enter into a water phase through standing and liquid separation, and a target product enters into an organic phase, thereby realizing impurity removal.
In the invention, the decoloring and dewatering specifically comprises the steps of mixing the organic phase, anhydrous sodium sulfate and activated carbon, and then decoloring and dewatering, wherein the addition amount of the anhydrous sodium sulfate is preferably 50% of the weight of 2- [ N- (2-hydroxyethyl) -3-methoxy-4-nitroaniline ] ethanol, the addition amount of the activated carbon is preferably 30% of the weight of 2- [ N- (2-hydroxyethyl) -3-methoxy-4-nitroaniline ] ethanol, and the time for decoloring and dewatering is preferably 2-4 h; the filtration is preferably carried out by using diatomite, and the concentration is preferably concentrated to 1/2-1/3 of the original volume; the volume ratio of the obtained concentrate to the methyl tert-butyl ether is preferably 3 times, and the pulping time is preferably 2-4 h; the invention further carries out decoloration and impurity removal by pulping.
After the bis- (2-chloroethyl) - (3-methoxy-4-nitrophenyl) -amine is obtained, under the action of an alkaline compound and potassium iodide, the bis- (2-chloroethyl) - (3-methoxy-4-nitrophenyl) -amine and trans-4-aminoadamantan-1-ol (the structural formula is shown as D in the formula I) are subjected to a third nucleophilic substitution reaction to obtain trans-4- [4- (3-methoxy-4-nitrophenyl) -1-piperazinyl ] adamantan-1-ol (the structural formula is shown as E in the formula I). In the present invention, the basic compound preferably includes one or more of sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, triethylamine and diisopropylethylamine, and more preferably sodium bicarbonate; the solvent for the third nucleophilic substitution reaction is preferably an alcohol solvent, and the alcohol solvent is preferably n-butanol; the volume of the solvent is preferably 2 to 10 times that of bis- (2-chloroethyl) - (3-methoxy-4-nitrophenyl) -amine.
In the present invention, the molar ratio of bis- (2-chloroethyl) - (3-methoxy-4-nitrophenyl) -amine, trans-4-aminoadamantan-1-ol, the basic compound and potassium iodide is preferably 1 (1-1.02): 2-7): 0.05-0.2, more preferably 1 (1-1.02): 3-5): 0.1-0.15. In the present invention, the action of potassium iodide increases the activity of nucleophilic substitution reaction.
In the present invention, the third nucleophilic substitution reaction is preferably performed under reflux conditions, and the time for the third nucleophilic substitution reaction is preferably 40 to 50 hours, and more preferably 43 to 45 hours.
After the third nucleophilic substitution reaction is completed, the method further comprises the step of carrying out post-treatment on the obtained product liquid, wherein the post-treatment preferably comprises the following steps:
filtering the third nucleophilic substitution reaction product liquid to obtain a crude product;
mixing the crude product and methyl tert-butyl ether, and then sequentially pulping and filtering to obtain a solid product;
mixing the solid product with a sodium hydroxide aqueous solution and dichloromethane, stirring and filtering in sequence, and standing and separating the obtained liquid phase to obtain an organic phase;
and (2) dewatering the organic phase, sequentially filtering and concentrating, mixing the obtained concentrate with isopropyl ether, sequentially pulping, filtering and drying to obtain the trans-4- [4- (3-methoxy-4-nitrophenyl) -1-piperazinyl ] adamantane-1-ol.
In the invention, the temperature of the third nucleophilic substitution reaction product feed liquid is preferably reduced to room temperature and then filtered. In the present invention, the amount ratio of the crude product to the methyl t-butyl ether is preferably 5 times; the pulping temperature is preferably 50 ℃, and the time is preferably 5-8 hours; the concentration of the sodium hydroxide aqueous solution is preferably 1mol/L, and the using ratio of the solid product to the sodium hydroxide aqueous solution and dichloromethane is preferably 5 times and 10 times; the stirring time is preferably 1 to 2 hours. In the third nucleophilic substitution reaction process, part of the product can form hydrochloride, and the invention can free hydrochloric acid in hydrochloride by adding sodium hydroxide and dichloromethane, thereby improving the product yield.
In the invention, the organic phase water removal is specifically to mix the organic phase and anhydrous sodium sulfate for water removal, and then remove the anhydrous sodium sulfate through filtration; the concentration is preferably to dry or 1/2 to 1/3 of the original volume; the volume ratio of the concentrate to the isopropyl ether is preferably 2 to 3 times; the preferable time of beating is 3-5 hours; the invention further removes impurities by adding isopropyl ether for pulping, thereby improving the purity of the product. The invention has no special requirements on the specific operating conditions of the filtration, standing, liquid separation and drying, and can be operated by adopting a method well known by the technical personnel in the field.
The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention.
Example 1 laboratory preparation
(1) Adding 300mL of dimethyl sulfoxide, 100.0g (0.58mol, 1.00equ.) of 2-nitro-5-fluoroanisole and 184.0g (1.75mol, 3.00equ.) of diethanolamine into a reaction bottle, stirring for 15min, adding 48.7g (0.58mol, 1.00equ.) of sodium bicarbonate, raising the temperature to 55-65 ℃, reacting for 48h, completely reacting the raw materials, cooling to room temperature, dropwise adding 1500mL of 15wt% sodium chloride solution, stirring for 2h, and centrifuging to obtain a crude product. Adding 300mL of water into the crude product, pulping for 2h, centrifuging and drying to obtain 120.0g of 2- [ N- (2-hydroxyethyl) -3-methoxy-4-nitroaniline ] ethanol, wherein the yield is as follows: 80.7 percent.
1 H NMR(300MHz,CDCl 3 ):δ7.96(1H,d,J＝9.3Hz),δ6.27(1H,dd,J＝9.3Hz，2.4Hz),δ6.22(1H,S),δ3.97(4H,t,J＝4.8Hz),δ3.94(3H,S),δ3.71(4H,t,J＝4.8Hz),δ3.12(2H,brs)。
(2) Adding 100.0g (0.39mol, 1.00equ.) of 2- [ N- (2-hydroxyethyl) -3-methoxy-4-nitroaniline ] ethanol, 1000mL (dichloromethane), 39.5g (0.39mol, 1.00equ.) into a reaction bottle, cooling to 10-20 ℃, dropwise adding 1000mL (1.17mol, 3.00equ.) of dichloromethane solution containing 139.4g (1.17mol, 3.00equ.) of thionyl chloride, raising the temperature to 35-45 ℃ after dropwise adding, reacting for 30 hours, completely reacting the raw materials, and cooling to room temperature. 1000mL of a saturated aqueous sodium bicarbonate solution was added dropwise thereto, and the mixture was allowed to stand for liquid separation. 50.0g of anhydrous sodium sulfate (50% of 2- [ N- (2-hydroxyethyl) -3-methoxy-4-nitroaniline ] ethanol) and 30g of activated carbon (30% of 2- [ N- (2-hydroxyethyl) -3-methoxy-4-nitroaniline ] ethanol) were added to the organic phase, and the mixture was decolorized and dried for 2 hours, filtered through celite, concentrated to 1/2 of the original volume, then 300.0mL of methyl t-butyl ether was added to the concentrate, slurried for 2 hours, and filtered. Drying the wet product to obtain 100.0g of bis- (2-chloroethyl) - (3-methoxy-4-nitrophenyl) -amine, wherein the yield is as follows: 87 percent.
1 H NMR(300MHz,CDCl 3 ):δ8.05(1H,d,J＝9.3Hz),δ6.28(1H,dd,J＝9.3Hz,2.4Hz),δ6.21(1H,S),δ3.98(3H,S),δ3.86(4H,t,J＝6.9Hz),δ3.71(4H,t,J＝6.9Hz)。
(3) 500mL of n-butanol and 52.0g (0.31mol, 1.00equ.) of trans-4-aminoadamantan-1-ol, 100.0g (0.34mol, 1.10 equ.) of bis- (2-chloroethyl) - (3-methoxy-4-nitrophenyl) -amine are added into a reaction kettle, after stirring for 30 minutes, 183.0g (2.2 mol, 7.00equ.) of sodium bicarbonate and 10.0g (0.06mol, 0.20 equ.) of potassium iodide are added, the temperature is raised to reflux for 40 hours, the raw materials are completely reacted, the temperature is reduced to room temperature, a crude product is obtained by filtration, 1500.0mL of methyl tert-butyl ether is added into the crude product, the mixture is pulped at 50 ℃ and is filtered overnight. Adding 1500.0mL of 1mol/L aqueous solution of sodium hydroxide and 3000mL of dichloromethane into the filter cake, stirring for 1 hour, filtering to remove insoluble substances, standing the filtrate for liquid separation, adding anhydrous sodium sulfate into the organic phase, drying overnight, filtering, concentrating the filtrate to 1/2 of the original volume, adding 300mL of isopropyl ether, pulping overnight, filtering, and drying to obtain 55g of trans-4- [4- (3-methoxy-4-nitrophenyl) -1-piperazinyl ] adamantan-1-ol, wherein the yield is as follows: 45.8 percent and the purity is more than 99 percent.
1 H NMR(300MHz,CDCl 3 ):δ8.03(1H,d,J＝9.6Hz),δ6.44(1H,d,J＝9.6Hz),δ6.34(1H,S),δ3.97(3H,S)，δ3.42(4H,t,J＝4.8Hz),δ2.62(4H,t,J＝4.8Hz)，δ2.30(2H,S),δ2.12(2H,S),δ2.04(2H,m)，δ1.76(6H,m)，δ1.30(3H,m)。
MS(ESI + , m/z)＝388.2。
The trans product and the cis product have different chemical shifts and coupling constants in the high-field region of the hydrogen spectrum, for example, the trans product is delta 2.12 (2H, S), while the cis product has multiple peaks at the same position. As can be seen from the hydrogen spectrum data of the product, trans-4- [4- (3-methoxy-4-nitrophenyl) -1-piperazinyl ] adamantan-1-ol prepared in this example does not contain the cis-isomer.
Example 2 kilogram-scale laboratory production
(1) Adding 15.0L of dimethyl sulfoxide, 5.0kg of 2-nitro-5-fluoroanisole (29.2mol, 1.0eq.), 9.2kg of diethanolamine (87.5mol, 3.0eq.), 2.4kg of sodium bicarbonate (29.2mol, 1.0eq.) into a 100-liter jacketed reaction kettle, raising the temperature to 55-65 ℃ after the addition, reacting for 40 hours, completely reacting the raw materials, cooling to room temperature, dropwise adding 75.0L of 15.0wt% sodium chloride aqueous solution, stirring for 2 hours at room temperature after the dropwise addition, filtering, adding a filter cake into the reaction kettle, adding 9.0L of water into the reaction kettle, pulping for 2 hours at the room temperature, filtering, and drying the material for 20 hours at the temperature of 50 ℃ to obtain 6.2kg of 2- [ N- (2-hydroxyethyl) -3-methoxy-4-nitroaniline ] ethanol, wherein the yield is as follows: 83.0 percent.
1 H NMR(300MHz,CDCl 3 ):δ7.96(1H,d,J＝9.3Hz),δ6.27(1H,dd,J＝9.3Hz，2.4Hz),δ6.22(1H,S),δ3.97(4H,t,J＝4.8Hz),δ3.94(3H,S),δ3.71(4H,t,J＝4.8Hz),δ3.12(2H,brs)。
(2) Adding 3.0kg (11.72mol, 1.00equ.), 30.0L dichloromethane and 1.2kg triethylamine (11.72mol, 1.00equ.), cooling to 10 ℃, dropwise adding 30.0L thionyl chloride solution (35.116mol, 3.00equ.), heating to 35-45 ℃ after dropwise adding, refluxing for 15 hours until the temperature is completely raised, the raw materials are completely reacted, cooling to room temperature, slowly dropwise adding 30.0L saturated sodium bicarbonate water solution into the product feed liquid, separating, adding 1.5kg anhydrous sodium sulfate (accounting for 50% of the weight of 2- [ N- (2-hydroxyethyl) -3-methoxy-4-nitroaniline ] ethanol) and 0.9kg active carbon (accounting for 30% of the weight of 2- [ N- (2-hydroxyethyl) -3-methoxy-4-nitroaniline ] ethanol) into the organic phase, drying for 2 hours, filtering, concentrating the filtrate to 1.9 h, adding methyl tert-butyl ether, and filtering to decolor the volume of the filtrate, and filtering to obtain the filtrate. Drying the wet product to obtain 2.8kg of bis- (2-chloroethyl) - (3-methoxy-4-nitrophenyl) -amine, yield: 81.5 percent.
1 H NMR(300MHz,CDCl 3 ):δ8.05(1H,d,J＝9.3Hz),δ6.28(1H,dd,J＝9.3Hz,2.4Hz),δ6.21(1H,S),δ3.98(3H,S),δ3.86(4H,t,J＝6.9Hz),δ3.71(4H,t,J＝6.9Hz)。
(3) 28.0L of n-butanol, 2.9kg (17.30mol, 1.00equ.) of trans-4-aminoadamantan-1-ol, 5.6kg (19.10 mol,1.10 equ.) of bis- (2-chloroethyl) - (3-methoxy-4-nitrophenyl) -amine, 1.0kg (121.4mol, 7.00equ.) of sodium bicarbonate, 0.6kg (3.50mol, 0.20equ.) of potassium iodide were added to a 100L jacketed reaction vessel, stirred for 30 minutes, and then refluxed at elevated temperature for 40 hours, the reaction of the raw materials was completed, and cooled to room temperature. Centrifuging to obtain crude product, adding 70.0L methyl tert-butyl ether, pulping at 50 deg.C overnight, and filtering. The filter cake was stirred for 1 hour with 70.0L of a 10 mol/L aqueous solution of sodium hydroxide and 140.0L of methylene chloride. Insoluble matter was removed by filtration, the filtrate was allowed to stand for liquid separation, and the organic phase was dried overnight with 4.0kg of anhydrous sodium sulfate and filtered. Concentrating the filtrate to dryness, adding 15L of isopropyl ether into the obtained solid, pulping overnight, filtering a small amount of isopropyl ether, leaching, and drying to obtain 3.4kg of trans-4- [4- (3-methoxy-4-nitrophenyl) -1-piperazinyl ] adamantan-1-ol, wherein the yield is as follows: 50.7 percent and the purity is more than 99 percent.
1 H NMR(300MHz,CDCl 3 ):δ8.03(1H,d,J＝9.6Hz),δ6.44(1H,d,J＝9.6Hz),δ6.34(1H,S),δ3.97(3H,S)，δ3.42(4H,t,J＝4.8Hz),δ2.62(4H,t,J＝4.8Hz)，δ2.30(2H,S),δ2.12(2H,S),δ2.04(2H,m)，δ1.76(6H,m)，δ1.30(3H,m)。
MS(ESI + ,m/z)＝388.2。
As can be seen from the hydrogen spectrum data of the product, trans-4- [4- (3-methoxy-4-nitrophenyl) -1-piperazinyl ] adamantan-1-ol prepared in this example does not contain the cis-isomer.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (7)
1. The synthesis method of trans-4- [4- (3-methoxy-4-nitrophenyl) -1-piperazinyl ] adamantan-1-ol is characterized by comprising the following steps of:
(1) Under the action of an alkaline compound, carrying out a first nucleophilic substitution reaction on 2-nitro-5-fluoroanisole and diethanolamine to obtain 2- [ N- (2-hydroxyethyl) -3-methoxy-4-nitroaniline ] ethanol; the first nucleophilic substitution reaction solvent is one or more of dimethyl sulfoxide, acetonitrile, N-dimethylformamide, methanol, ethanol and isopropanol;
(2) Under the action of an alkaline compound, carrying out a second nucleophilic substitution reaction on the 2- [ N- (2-hydroxyethyl) -3-methoxy-4-nitroaniline ] ethanol and thionyl chloride to obtain bis- (2-chloroethyl) - (3-methoxy-4-nitrophenyl) -amine; the solvent for the second nucleophilic substitution reaction is one or more of dichloromethane, chloroform, toluene, acetonitrile and methyl tert-butyl ether;
(3) Carrying out a third nucleophilic substitution reaction on the bis- (2-chloroethyl) - (3-methoxy-4-nitrophenyl) -amine and trans-4-aminoadamantan-1-ol under the action of an alkaline compound and potassium iodide to obtain trans-4- [4- (3-methoxy-4-nitrophenyl) -1-piperazinyl ] adamantan-1-ol; the solvent for the third nucleophilic substitution reaction is an alcohol solvent;
the alkaline compound in the steps (1) - (3) is one or more of sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, triethylamine and diisopropylethylamine.
2. The synthesis method of claim 1, wherein the molar ratio of the 2-nitro-5-fluoroanisole, the diethanolamine and the alkaline compound in the step (1) is 1 (3-3.5) to (1-1.2);
the temperature of the first nucleophilic substitution reaction is 55-65 ℃, and the time is 40-48 h.
3. The synthesis method according to any one of claims 1 to 2, further comprising, after the first nucleophilic substitution reaction is completed, post-treating the resultant product liquor, wherein the post-treating comprises the steps of:
mixing the first nucleophilic substitution reaction product feed liquid and a neutral saline solution, and then sequentially stirring and centrifuging to obtain a crude product;
and mixing the crude product with water, pulping and centrifuging in sequence, and drying the obtained solid product to obtain the 2- [ N- (2-hydroxyethyl) -3-methoxy-4-nitroaniline ] ethanol.
4. The synthesis method of claim 1, wherein the molar ratio of the 2- [ N- (2-hydroxyethyl) -3-methoxy-4-nitroaniline ] ethanol, the thionyl chloride and the basic compound in the step (2) is 1 (3-3.5) to (1-1.5);
the temperature of the second nucleophilic substitution reaction is 35-45 ℃ and the time is 15-35 h.
5. The synthesis method according to claim 1 or 4, wherein after the second nucleophilic substitution reaction is completed, the method further comprises post-treating the obtained product liquor, wherein the post-treatment comprises the following steps:
mixing the second nucleophilic substitution reaction product feed liquid and a sodium bicarbonate aqueous solution, and then standing and separating the mixture to obtain an organic phase;
and (3) decoloring and dehydrating the organic phase, sequentially filtering and concentrating, mixing the obtained concentrate with methyl tert-butyl ether, and sequentially pulping, filtering and drying to obtain the bis- (2-chloroethyl) - (3-methoxy-4-nitrophenyl) -amine.
6. The synthesis method according to claim 1, wherein the molar ratio of bis- (2-chloroethyl) - (3-methoxy-4-nitrophenyl) -amine, trans-4-aminoadamantan-1-ol, basic compound and potassium iodide in step (3) is 1 (1-1.02): 2-7: 0.05-0.2;
the third nucleophilic substitution reaction is carried out under the reflux condition, and the reaction time is 40-50 h.
7. The synthesis method according to claim 1 or 6, further comprising, after the third nucleophilic substitution reaction is completed, post-treating the resultant product liquor, wherein the post-treating comprises the steps of:
filtering the third nucleophilic substitution reaction product liquid to obtain a crude product;
mixing the crude product and methyl tert-butyl ether, and then sequentially pulping and filtering to obtain a solid product;
mixing the solid product with a sodium hydroxide aqueous solution and dichloromethane, stirring and filtering in sequence, and standing and separating the obtained liquid phase to obtain an organic phase;
and (2) dewatering the organic phase, sequentially filtering and concentrating, mixing the obtained concentrate with isopropyl ether, sequentially pulping, filtering and drying to obtain the trans-4- [4- (3-methoxy-4-nitrophenyl) -1-piperazinyl ] adamantane-1-ol.
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| CN101622252A (en) * | 2006-12-29 | 2010-01-06 | 里格尔制药公司 | Substituted triazoles useful as AXL inhibitors |
| JP2015206919A (en) * | 2014-04-21 | 2015-11-19 | Jsr株式会社 | Manufacturing method of liquid crystal display element, liquid crystal alignment agent, and liquid crystal alignment film |
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| CN101622252A (en) * | 2006-12-29 | 2010-01-06 | 里格尔制药公司 | Substituted triazoles useful as AXL inhibitors |
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