CN115572289A - Synthesis method of tesofensine - Google Patents
Synthesis method of tesofensine Download PDFInfo
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- CN115572289A CN115572289A CN202211304371.XA CN202211304371A CN115572289A CN 115572289 A CN115572289 A CN 115572289A CN 202211304371 A CN202211304371 A CN 202211304371A CN 115572289 A CN115572289 A CN 115572289A
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- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
Abstract
The invention discloses a synthetic method of tesofensine, which comprises the following steps: (5) Dissolving the intermediate 4 in a reaction solvent 5, adding alkali in batches under the protection of nitrogen, dropwise adding an ethyl reagent, dropwise adding a saturated ammonium chloride aqueous solution after the reaction is finished, carrying out extraction and quenching reaction, adding an organic solvent 3, layering, separating out an organic phase, extracting a water phase once with the corresponding organic solvent 3, combining the organic phases, washing once with saturated salt water, drying, filtering and spin-drying to obtain a crude product, pulping, purifying, filtering and drying the crude product to obtain a tesofensine white crystal; the method adopts 3, 4-dichlorobenzaldehyde and ethyl acetoacetate as raw materials, the raw materials are cheap and easy to obtain, no dangerous reaction, controllable reaction conditions, no harsh steps of extremely low temperature reaction conditions and yield in an acceptable range are used in the whole synthesis process, and in conclusion, the method for synthesizing tesofensine provided by the invention has the advantages of low cost, high efficiency and controllable reaction conditions, and is suitable for large-scale industrial production.
Description
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to a synthetic method of tesofensine.
Background
Tesofensine is a 5-hydroxytryptamine-norepinephrine-dopamine reuptake inhibitor, originally developed for the treatment of parkinson's disease and alzheimer's disease. The main current synthetic method of tesofensine is as follows: firstly, methyl esterification is carried out by tropinone, then reduction is carried out by a reducing agent to obtain an alcohol intermediate, then an alkene intermediate is obtained by a dehydrating agent, then alkene is subjected to Grignard reaction to obtain an intermediate ester compound, then ester is reduced by red aluminum to obtain an alcohol intermediate, finally, a final product crude product is obtained by ethanol etherification of the alcohol intermediate, and the obtained product is purified by column chromatography, wherein the synthetic method comprises the following steps:
the above route has long reaction steps, many high-risk reaction steps and harsh reaction conditions, wherein rare and noble reagents are also used, the overall yield is low, and the synthesis cost is quite high, so that the industrial production cannot be realized.
In view of the above drawbacks of the related art, it is necessary to develop a new synthetic route for tesofensine.
Disclosure of Invention
The invention provides a synthetic method of tesofensine.
The scheme of the invention is as follows:
a synthetic method of tesofensine comprises the following steps:
(1) Synthesizing an intermediate 1, dissolving 3, 4-dichlorobenzaldehyde in a reaction solvent 1, controlling the reaction temperature to be 15-30 ℃, adding ethyl acetoacetate, carrying out catalytic reaction under the catalysis of piperidine, wherein the catalytic reaction time is 1-4 hours, precipitating a solid after the reaction is finished, filtering the solid to obtain a crude product, and adding the crude product into the reaction solvent 1 to crystallize, filter and dry to obtain the intermediate 1;
(2) Synthesizing an intermediate 2, wherein in the step S1, 2, 5-dimethoxy tetrahydrofuran is dissolved in a reaction solvent 2, concentrated hydrochloric acid is added for catalysis, the reaction is carried out after the temperature is raised, and the temperature is lowered to 0 ℃ after the reaction is finished to obtain a solution for later use;
step S2, dissolving sodium acetate in water, cooling to 0 ℃, adding the intermediate 1 and methylamine hydrochloride, adding the solution obtained in the step S1, adjusting the pH to =8 by using 50% sodium hydroxide, controlling the temperature to be 0 ℃, completing the reaction after 2-4 hours, adding an organic solvent 1 for layering, extracting a water phase by using the organic solvent 1, combining organic phases, washing with saturated salt water once, drying, filtering and spin-drying to obtain an intermediate 2 crude product, and directly using the intermediate 2 crude product in the next reaction;
(3) Synthesizing an intermediate 3, dissolving the intermediate 2 in a reaction solvent 3, reacting at the temperature of 20-30 ℃ for 2-6 hours, adding an organic solvent 1 for layering after the reaction is finished, extracting a water phase with the organic solvent 1, combining organic phases, washing with saturated salt water for one time, drying, filtering and spin-drying to obtain a crude intermediate 3, and directly using the crude intermediate 3 in the next reaction;
(4) Synthesizing an intermediate 4, dissolving the intermediate 3 in a reaction solvent 4, controlling the temperature to be below 50 ℃, dropwise adding a reducing agent under the protection of nitrogen, carrying out heat preservation reaction at the temperature of 30-50 ℃ for 1-2 hours, naturally cooling after the reaction is finished, dropwise adding a sodium hydroxide solution, carrying out extraction and inactivation reaction, controlling the temperature to be below 30 ℃, layering, extracting a water phase once by using an organic solvent 2, combining organic phases, washing once by using saturated salt, drying, filtering and spin-drying to obtain an oily substance, adding methyl tert-butyl ether into the oily substance to separate out a solid, cooling to 0 ℃, leaching the filtered solid by using ice methyl tert-butyl ether, and drying to obtain the intermediate 4;
(5) Dissolving the intermediate 4 in a reaction solvent 5, adding alkali in batches under the protection of nitrogen, then adding an ethyl reagent dropwise, reacting at the temperature of 30-50 ℃ for 2-4 hours, adding a saturated ammonium chloride aqueous solution dropwise after the reaction is finished, carrying out extraction and quenching reaction, then adding an organic solvent 3 for layering, separating out an organic phase, extracting a water phase once with the corresponding organic solvent 3, then combining the organic phases, washing once with saturated salt, drying, filtering and spin-drying to obtain a crude product, pulping, purifying, filtering and drying the crude product to obtain a tesofensine white crystal.
As a preferable technical scheme, the reaction solvent 1 in the step (1) is one of 95% methanol or 95% ethanol, the reaction temperature is controlled to be 20 ℃, and the catalytic reaction time is 2-3 hours.
Preferably, the reaction solvent 2 in the step (2) is water, and the reaction is carried out for 1 hour after the temperature is raised to 60 to 70 ℃ in the step S1; the reaction temperature of the step S2 is 0 ℃, the reaction time is 2-3 hours, and the mode of controlling the temperature to be 0 ℃ is ice bath.
As a preferred technical scheme, the organic solution 1 is dichloromethane; the organic solution 2 is anhydrous toluene; the organic solution 3 is ethyl acetate.
Preferably, in the step (3), the reaction solvent 3 is one of a sodium hydrogen phosphate buffer solution and an ammonium hydrogen phosphate buffer solution, the reaction time is 25 ℃, and the reaction time is 4 hours.
As a preferable technical scheme, in the step (4), the reaction solvent 4 is one of tetrahydrofuran or toluene, the reducing agent is one of lithium aluminum hydride, borane or red aluminum, the reaction temperature is 50 ℃, and the reaction time is 1 hour.
As a preferable technical scheme, in the step (5), the reaction solvent 5 is one of tetrahydrofuran or 2-methyltetrahydrofuran; the alkali is sodium hydride, the ethyl reagent is one of ethyl iodide or diethyl sulfate, the reaction temperature is 50 ℃, and the reaction time is 2 hours.
As a preferable technical scheme, in the step (5), the crude product is pulped and purified into a crude product, and ethyl acetate is added for pulping.
Preferably, the drying in the step (2), the step (3), the step (4) and the step (5) is anhydrous sodium sulfate drying.
As a preferred technical scheme, the intermediate 1 is a white solid, the intermediate 2 is a light yellow liquid, the intermediate 3 is a light yellow liquid, and the intermediate 4 is a white crystal; the tesofensine is white crystals.
Specifically, the synthetic method comprises the following steps:
due to the adoption of the technical scheme, the synthesis method of the tesofensine comprises the following steps: (1) Synthesizing an intermediate 1, dissolving 3, 4-dichlorobenzaldehyde in a reaction solvent 1, controlling the reaction temperature to be 15-30 ℃, adding ethyl acetoacetate, carrying out catalytic reaction under the catalysis of piperidine, wherein the catalytic reaction time is 1-4 hours, precipitating a solid after the reaction is finished, filtering the solid to obtain a crude product, and adding the crude product into the reaction solvent 1 to crystallize, filter and dry to obtain the intermediate 1; (2) Synthesizing an intermediate 2, and step S1, dissolving 2, 5-dimethoxy tetrahydrofuran in a reaction solvent 2, adding concentrated hydrochloric acid for catalysis, heating and then reacting, and cooling to 0 ℃ after the reaction is finished to obtain a solution for later use; step S2, dissolving sodium acetate in water, cooling to 0 ℃, adding the intermediate 1 and methylamine hydrochloride, adding the solution obtained in the step S1, adjusting the pH to =8 by using 50% sodium hydroxide, controlling the temperature to be 0 ℃, completing the reaction after 2-4 hours, adding an organic solvent 1 for layering, extracting a water phase by using the organic solvent 1, combining organic phases, washing with saturated salt water once, drying, filtering and spin-drying to obtain an intermediate 2 crude product, and directly using the intermediate 2 crude product in the next reaction; (3) Synthesizing an intermediate 3, dissolving the intermediate 2 in a reaction solvent 3, reacting at the temperature of 20-30 ℃ for 2-6 hours, adding an organic solvent 1 for layering after the reaction is finished, extracting a water phase with the organic solvent 1, combining organic phases, washing with saturated salt water for one time, drying, filtering and spin-drying to obtain a crude intermediate 3, and directly using the crude intermediate 3 in the next reaction; (4) Synthesizing an intermediate 4, dissolving the intermediate 3 in a reaction solvent 4, controlling the temperature to be below 50 ℃, dropwise adding a reducing agent under the protection of nitrogen, carrying out heat preservation reaction at the temperature of 30-50 ℃ for 1-2 hours, naturally cooling after the reaction is finished, dropwise adding a sodium hydroxide solution, carrying out extraction and quenching reaction, controlling the temperature to be below 30 ℃, layering, extracting a water phase once by using an organic solvent 2, combining organic phases, washing once by using saturated salt water, drying, filtering and spin-drying to obtain an oily substance, adding methyl tert-butyl ether into the oily substance to separate out a solid, cooling to 0 ℃, leaching the filtered solid by using glacial methyl tert-butyl ether, and drying to obtain the intermediate 4; (5) Dissolving the intermediate 4 in a reaction solvent 5, adding alkali in batches under the protection of nitrogen, then adding an ethyl reagent dropwise, reacting at the temperature of 30-50 ℃ for 2-4 hours, adding a saturated ammonium chloride aqueous solution dropwise after the reaction is finished, carrying out extraction and quenching reaction, then adding an organic solvent 3 for layering, separating out an organic phase, extracting a water phase once with the corresponding organic solvent 3, then combining the organic phases, washing once with saturated salt, drying, filtering and spin-drying to obtain a crude product, pulping, purifying, filtering and drying the crude product to obtain a tesofensine white crystal.
The invention has the advantages that: the method adopts 3, 4-dichlorobenzaldehyde and ethyl acetoacetate as raw materials, the raw materials are easy to obtain and cheap, no dangerous reaction, controllable reaction conditions, no harsh steps of extremely low temperature reaction conditions and yield are in an acceptable range in the whole synthesis process, and in conclusion, the method for synthesizing tesofensine provided by the invention is low in cost, high in efficiency, controllable in reaction conditions and suitable for large-scale industrial production.
Drawings
FIG. 1 is the NMR chart of tesofensine synthesized in example 1 of the present invention.
Fig. 2 is a liquid chromatogram of tesofensine synthesized in example 1 of the present invention.
FIG. 3 is a mass spectrum of tesofensine synthesized in example 1 of the present invention.
Detailed Description
In order to make up for the above deficiency, the present invention provides a method for synthesizing tesofensine to solve the above problems in the background art.
A synthetic method of tesofensine comprises the following steps:
(1) Synthesizing an intermediate 1, dissolving 3, 4-dichlorobenzaldehyde in a reaction solvent 1, controlling the reaction temperature to be 15-30 ℃, adding ethyl acetoacetate, carrying out catalytic reaction under the catalysis of piperidine, wherein the catalytic reaction time is 1-4 hours, precipitating a solid after the reaction is finished, filtering the solid to obtain a crude product, and adding the crude product into the reaction solvent 1 to crystallize, filter and dry to obtain the intermediate 1;
(2) Synthesizing an intermediate 2, wherein in the step S1, 2, 5-dimethoxy tetrahydrofuran is dissolved in a reaction solvent 2, concentrated hydrochloric acid is added for catalysis, the reaction is carried out after the temperature is raised, and the temperature is lowered to 0 ℃ after the reaction is finished to obtain a solution for later use;
step S2, dissolving sodium acetate in water, cooling to 0 ℃, adding the intermediate 1 and methylamine hydrochloride, adding the solution obtained in the step S1, adjusting the pH to =8 by using 50% sodium hydroxide, controlling the temperature to be 0 ℃, completing the reaction after 2-4 hours, adding an organic solvent 1 for layering, extracting a water phase by using the organic solvent 1, combining organic phases, washing with saturated salt water once, drying, filtering and spin-drying to obtain an intermediate 2 crude product, and directly using the intermediate 2 crude product in the next reaction;
(3) Synthesizing an intermediate 3, dissolving the intermediate 2 in a reaction solvent 3, reacting at 20-30 ℃ for 2-6 hours, adding an organic solvent 1 for layering after the reaction is finished, extracting a water phase with the organic solvent 1, combining organic phases, washing with saturated salt water for one time, drying, filtering and spin-drying to obtain an intermediate 3 crude product, and directly using the intermediate 3 crude product in the next reaction;
(4) Synthesizing an intermediate 4, dissolving the intermediate 3 in a reaction solvent 4, controlling the temperature to be below 50 ℃, dropwise adding a reducing agent under the protection of nitrogen, carrying out heat preservation reaction at the temperature of 30-50 ℃ for 1-2 hours, naturally cooling after the reaction is finished, dropwise adding a sodium hydroxide solution, carrying out extraction and quenching reaction, controlling the temperature to be below 30 ℃, layering, extracting a water phase once by using an organic solvent 2, combining organic phases, washing once by using saturated salt water, drying, filtering and spin-drying to obtain an oily substance, adding methyl tert-butyl ether into the oily substance to separate out a solid, cooling to 0 ℃, leaching the filtered solid by using glacial methyl tert-butyl ether, and drying to obtain the intermediate 4;
(5) Dissolving the intermediate 4 in a reaction solvent 5, adding alkali in batches under the protection of nitrogen, then adding an ethyl reagent dropwise, reacting at the temperature of 30-50 ℃ for 2-4 hours, adding a saturated ammonium chloride aqueous solution dropwise after the reaction is finished, carrying out extraction and quenching reaction, then adding an organic solvent 3 for layering, separating out an organic phase, extracting a water phase once with the corresponding organic solvent 3, then combining the organic phases, washing once with saturated salt, drying, filtering and spin-drying to obtain a crude product, pulping, purifying, filtering and drying the crude product to obtain a tesofensine white crystal.
In the step (1), the reaction solvent 1 is one of 95% methanol or 95% ethanol, the reaction temperature is controlled to be 20 ℃, and the catalytic reaction time is 2-3 hours.
Preferably, in the step (2), the reaction solvent 2 is water, and the reaction is carried out for 1 hour after the temperature is raised to 60 to 70 ℃ in the step S1; the reaction temperature of the step S2 is 0 ℃, the reaction time is 2-3 hours, and the mode of controlling the temperature to be 0 ℃ is ice bath.
The organic solution 1 is dichloromethane; the organic solution 2 is anhydrous toluene; the organic solution 3 is ethyl acetate.
In the step (3), the reaction solvent 3 is one of sodium hydrogen phosphate buffer solution or ammonium hydrogen phosphate buffer solution, the reaction time is 25 ℃, and the reaction time is 4 hours.
In the step (4), the reaction solvent 4 is one of tetrahydrofuran or toluene, the reducing agent is one of lithium aluminum hydride, borane or red aluminum, the reaction temperature is 50 ℃, and the reaction time is 1 hour.
In the step (5), the reaction solvent 5 is one of tetrahydrofuran and 2-methyltetrahydrofuran; the alkali is sodium hydride, the ethyl reagent is one of ethyl iodide or diethyl sulfate, the reaction temperature is 50 ℃, and the reaction time is 2 hours.
And (5) pulping and purifying the crude product to obtain a crude product, and adding ethyl acetate for pulping.
The drying in the step (2), the step (3), the step (4) and the step (5) is anhydrous sodium sulfate drying.
The intermediate 1 is a white solid, the intermediate 2 is a light yellow liquid, the intermediate 3 is a light yellow liquid, and the intermediate 4 is a white crystal; the tesofensine is white crystals.
In order to make the technical means, the creation characteristics, the achievement purposes and the effects of the invention easy to understand, the invention is further described in the following combined with the specific embodiments.
Example 1
The embodiment provides a preferable synthesis method of tesofensine, which comprises the following steps:
step one, dissolving 3, 4-dichlorobenzaldehyde (35g, 0.2mol) in 95% ethanol (100 ml), cooling to 20 ℃, adding ethyl acetoacetate (52g, 0.4 mol), then adding piperidine (5 ml), preserving heat at 20 ℃, reacting for 2 hours, finishing the reaction, filtering, reacting to obtain a crude product, and crystallizing by using 2V95% ethanol to obtain a white solid intermediate 1 (66.7 g), wherein the yield is 80%.
In the second step, the first step is to perform the first step,
s1, dissolving 2, 5-dimethoxytetrahydrofuran (21.2g, 0.116mol) in water (100 ml), adding concentrated hydrochloric acid (8 ml), heating to 60 ℃, reacting for 1 hour, and cooling to 0 ℃ for later use.
S2, dissolving sodium acetate (39.4 g, 0.48mol) in water (150 ml), cooling to 0 ℃, adding the intermediate 1 (66.7 g, 0.16mol) and methylamine hydrochloride (10.8 g, 0.11ummol), simultaneously adding the solution obtained in the S1, after the addition is finished, adjusting the pH to be =8 by using 50% sodium hydroxide, controlling the temperature to be 0 ℃, keeping the temperature to be 0 ℃ for reaction for 2 hours, after the reaction is finished, adding dichloromethane (200 ml), layering, extracting the water phase once by using dichloromethane (150 ml), combining organic phases, washing the water phase by using saturated salt, drying the saturated salt by using anhydrous sodium sulfate, filtering and spin-drying to obtain a crude intermediate 2 (50 g), wherein the yield is 75%, and the intermediate 2 is a light yellow liquid and is directly used for the next reaction.
And step three, dissolving the intermediate 2 (50g, 0.12mol) in sodium hydrogen phosphate (250 ml), reacting for 2 hours at 25 ℃, adding dichloromethane (200 ml) after the reaction is finished, layering, extracting the water phase once with dichloromethane (150 ml), combining organic phases, washing with saturated salt water once, drying with anhydrous sodium sulfate, filtering, and spin-drying to obtain a crude intermediate 3 (28 g), wherein the yield is 68%, and the intermediate 3 is a light yellow liquid and is directly used for the next reaction.
Step four, under the protection of nitrogen, dissolving the intermediate 3 (28g, 0.08mol) in anhydrous toluene (250 ml), dropwise adding 50% (70g, 0.16mmol) of a toluene solution of red aluminum, controlling the temperature to be below 50 ℃, naturally cooling to 20 ℃ after dropwise adding, dropwise adding 20% sodium hydroxide (200 ml) for extraction and inactivation, controlling the temperature to be below 30 ℃, separating an organic phase after dropwise adding, extracting an aqueous phase once with toluene, combining the organic phases, washing with saturated salt water once, drying with anhydrous sodium sulfate, filtering, spin-drying to obtain an oily substance, adding methyl tert-butyl ether to separate out a solid, cooling to 0 ℃, filtering, leaching the solid with a small amount of ice methyl tert-butyl ether, and drying to obtain an intermediate 4 (12 g), wherein the yield is 49%, and the intermediate 4 is a white crystal.
Step five, dissolving the intermediate 4 (12g, 0.04mol) in anhydrous tetrahydrofuran, controlling the temperature below 50 ℃ under the protection of nitrogen, adding sodium hydride (2.4g, 0.06mol) in 5-6 batches, continuing to dropwise add ethyl iodide (6.9g, 0.044mol) after adding, after dropwise adding, naturally cooling for reaction for 1 hour, completing reaction, dropwise adding saturated ammonium chloride aqueous solution for quenching reaction, adding ethyl acetate (120 ml) for layering, separating out an organic phase, extracting the aqueous phase once with EA, combining the organic phases, washing with saturated salt water once, drying with anhydrous sodium sulfate, filtering, adding ethyl acetate (20 ml) into the rotary-dried solid for pulping, filtering, drying to obtain white crystals (10.3 g), wherein the yield is 78% of the white crystals, namely tesofensine.
LC-MS(ESI):(M+H + )＝328.2
1HNMR(400MHz,CDCl3)δ7.28(d,J＝8Hz,1H),7.22(d,J＝2Hz,1H),6.98(dd,J＝10Hz,1H),3.39-3.30(m,2H),3.25-3.16(m,3H),3.11-3.08(m,2H),2.49-2.32(m,2H),2.26-2.20(m,4H),2.11-2.03(m,1H),1.65-1.59(m,1H),1.53-1.40(m,2H),1.17-1.08(m,4H).
Example 2
The embodiment provides a preferable synthetic method of tesofensine, which comprises the following steps:
step one, dissolving 3, 4-dichlorobenzaldehyde (35g, 0.2 mol) in 95% methanol (100 ml), cooling to 20 ℃, adding acetyl ethyl ester (52g, 0.2 mol), then adding piperidine (5 ml), preserving the temperature at 30 ℃, reacting for 3 hours, finishing the reaction, filtering the reaction to obtain a crude product, and recrystallizing the crude product by using 2V95% methanol to obtain a white solid intermediate 1 (60 g) with the yield of 72%.
In the second step, the first step is that,
s1, dissolving 2, 5-dimethoxytetrahydrofuran (18.4 g, 0.14mol) in water (90 ml), adding concentrated hydrochloric acid (7 ml), heating to 60 ℃, reacting for 1 hour, and cooling to 0 ℃ for later use.
S2, dissolving sodium acetate (35.3 g, 0.43mol) in water (150 ml), cooling to 0 ℃, adding an intermediate (160g, 0.14mol) and methylamine hydrochloride (10.8g, 0.14mol), simultaneously adding the solution obtained in the S1, after the addition is finished, adjusting the pH =8 by using 50% sodium hydroxide, controlling the temperature to 0 ℃, keeping the temperature at 0 ℃ for reaction for 3 hours, after the reaction is finished, adding dichloromethane (200 ml), layering, extracting the water phase once by using dichloromethane (150 ml), combining organic phases, washing the water phase by using saturated common salt water, drying by using anhydrous sodium sulfate, filtering and spin-drying to obtain a crude product (34.7 g) of an intermediate 2, wherein the yield is 60%, and the intermediate 2 is a light yellow liquid and is directly used for the next reaction.
And step three, dissolving the intermediate 2 (34.7 g, 0.083mol) in ammonium hydrogen phosphate (200 ml), reacting for 1 hour at 30 ℃, adding dichloromethane (150 ml) after the reaction is finished, layering, extracting the water phase once with dichloromethane (100 ml), combining organic phases, washing with saturated salt water once, drying with anhydrous sodium sulfate, filtering, and spin-drying to obtain a crude intermediate 3 (18.5 g), wherein the yield is 65%, and the intermediate 3 is a light yellow liquid and is directly used for the next reaction.
Step four, under the protection of nitrogen, dissolving the intermediate 3 (18.5 g,0.054 mol) in anhydrous tetrahydrofuran (180 ml), dropwise adding borane tetrahydrofuran solution (11ml, 0.01mol), controlling the temperature to 50 ℃, keeping the temperature for reaction for 1 hour, naturally cooling to 20 ℃, dropwise adding 20% sodium hydroxide (100 ml), controlling the temperature to be below 30 ℃, separating an organic phase after dropwise adding, extracting an aqueous phase once with toluene, combining the organic phase, washing with saturated salt water once, drying with anhydrous sodium sulfate, filtering, spin-drying to obtain an oily substance, adding methyl tert-butyl ether to separate out a solid, cooling to 0 ℃, filtering, rinsing the solid with a small amount of ice methyl tert-butyl ether, and drying to obtain an intermediate 4 (6.3 g), wherein the yield is 40%, and the intermediate 4 is a white crystal.
Step five, dissolving the intermediate 4 (6.3 g, 0.02mol) in anhydrous tetrahydrofuran, controlling the temperature below 50 ℃ under the protection of nitrogen, slowly adding sodium hydride (1.2 g, 0.06mol) in batches, then dropwise adding diethyl sulfate (3.6 g, 0.022mol), naturally cooling to react for 2 hours after dropwise adding, dropwise adding saturated ammonium chloride aqueous solution to extract and kill the reaction, then adding ethyl acetate (80 ml) to stratify, separating out an organic phase, extracting the aqueous phase once with EA, combining the organic phases, washing with saturated salt water once, drying with anhydrous sodium sulfate, filtering, adding ethyl acetate (20 ml) to the rotary-dried solid for pulping, filtering, and drying to obtain white crystals (5.3 g), wherein the yield is 77%, and the white crystals are tesofensine.
LC-MS(ESI):(M+H + )＝328.2
1HNMR(400MHz,CDCl3)δ7.28(d,J＝8Hz,1H),7.22(d,J＝2Hz,1H),6.98(dd,J＝10Hz,1H),3.39-3.30(m,2H),3.25-3.16(m,3H),3.11-3.08(m,2H),2.49-2.32(m,2H),2.26-2.20(m,4H),2.11-2.03(m,1H),1.65-1.59(m,1H),1.53-1.40(m,2H),1.17-1.08(m,4H).
Example 3
The embodiment provides a preferable synthetic method of tesofensine, which comprises the following steps:
step one, dissolving 3, 4-dichlorobenzaldehyde (35g, 0.2mol) in 95% ethanol (100 ml), cooling to 20 ℃, adding ethyl acetoacetate (52g, 0.4 mol), then adding piperidine (5 ml), preserving the temperature at 20 ℃, reacting for 3 hours, finishing the reaction, filtering, reacting to obtain a crude product, and recrystallizing by using 2V95% ethanol to obtain a white solid intermediate 1 (65.8 g), wherein the yield is 79%.
In the second step, the first step is that,
s1, dissolving 2, 5-dimethoxytetrahydrofuran (20.8g, 0.158mol) in water (90 ml), adding concentrated hydrochloric acid (7 ml), heating to 60 ℃ for reaction for 1 hour, and then cooling to 0 ℃ for later use.
S2, dissolving sodium acetate (38.8g, 0.47mol) in water (180 ml), cooling to 0 ℃, adding the intermediate 1 (65.8g, 0.158mol) and methylamine hydrochloride (10.6, 0.158mol), simultaneously adding the solution obtained in S1, after the addition is finished, adjusting the pH =8 by using 50% sodium hydroxide, controlling the temperature to 0 ℃, keeping the temperature to 0 ℃ for reaction for 2 hours, after the reaction is finished, adding dichloromethane (200 ml), layering, extracting the aqueous phase once by using dichloromethane (150 ml), combining organic phases, washing the aqueous phase once by using saturated common salt, drying by using anhydrous sodium sulfate, filtering, and spin-drying to obtain an intermediate 2 crude product (37.8 g), wherein the yield is 60%, and the intermediate 2 is a light yellow liquid and is directly used for the next reaction.
Step three, dissolving the intermediate 2 (37.8g, 0.091mol) in sodium hydrogen phosphate buffer solution (230 ml), reacting for 1 hour at 20 ℃, adding dichloromethane (150 ml) after the reaction is finished, layering, extracting the water phase once with dichloromethane (100 ml), combining organic phases, washing with saturated salt water once, drying with anhydrous sodium sulfate, filtering, spinning to obtain a crude product (19.6 g) of the intermediate 3, wherein the yield is 63%, and the intermediate 3 is light yellow liquid and is directly used for the next reaction.
Step four, under the protection of nitrogen, dissolving the intermediate 3 (19.6 g, 0.057mol) in anhydrous 2-methyltetrahydrofuran (190 ml), dropwise adding a lithium aluminum hydride tetrahydrofuran solution (12ml, 0.12mol), controlling the temperature to 50 ℃, keeping the temperature for reaction for 1 hour, naturally cooling to 20 ℃, dropwise adding 20% sodium hydroxide (100 ml), controlling the temperature to be below 30 ℃, separating an organic phase after dropwise adding, extracting a water phase once with toluene, combining the organic phases, washing with saturated salt water once, drying with anhydrous sodium sulfate, filtering, spin-drying to obtain an oily substance, adding methyl tert-butyl ether to separate out a solid, cooling to 0 ℃, filtering, rinsing the solid with a small amount of ice methyl tert-butyl ether, and drying to obtain an intermediate 4 (6.6 g), wherein the yield is 39%, and the intermediate 4 is a white crystal.
Step five, dissolving the intermediate 4 (6.6 g, 0.022mol) in anhydrous 2-methyltetrahydrofuran, controlling the temperature below 50 ℃ under the protection of nitrogen, adding sodium hydride (1.3 g, 0.06mol) in 5-6 batches, after dropwise adding, then dropwise adding iodoethane (3.6 g, 0.022mol), after dropwise adding, naturally cooling and reacting for 3 hours, completing the reaction, dropwise adding saturated ammonium chloride aqueous solution to perform extraction and quenching reaction, then adding ethyl acetate (80 ml) to stratify, separating out an organic phase, extracting an aqueous phase once with EA, combining the organic phase, washing with saturated salt water once, drying with anhydrous sodium sulfate, filtering, adding ethyl acetate (12 ml) to a rotary-dried solid, pulping, filtering, drying to obtain white crystals (5.7 g), obtaining the yield of 80%, wherein the white crystals are tesofensine.
LC-MS(ESI):(M+H + )＝328.2
1HNMR(400MHz,CDCl3)δ7.28(d,J＝8Hz,1H),7.22(d,J＝2Hz,1H),6.98(dd,J＝10Hz,1H),3.39-3.30(m,2H),3.25-3.16(m,3H),3.11-3.08(m,2H),2.49-2.32(m,2H),2.26-2.20(m,4H),2.11-2.03(m,1H),1.65-1.59(m,1H),1.53-1.40(m,2H),1.17-1.08(m,4H).
The foregoing shows and describes the general principles, essential features, and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are given by way of illustration of the principles of the present invention, but that various changes and modifications may be made without departing from the spirit and scope of the invention, and such changes and modifications are within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (10)
1. A synthetic method of tesofensine is characterized by comprising the following steps:
(1) Synthesizing an intermediate 1, dissolving 3, 4-dichlorobenzaldehyde in a reaction solvent 1, controlling the reaction temperature to be 15-30 ℃, adding ethyl acetoacetate, carrying out catalytic reaction under the catalysis of piperidine, wherein the catalytic reaction time is 1-4 hours, precipitating a solid after the reaction is finished, filtering the solid to obtain a crude product, adding the crude product into the reaction solvent 1, crystallizing, filtering and drying to obtain the intermediate 1;
(2) Synthesizing an intermediate 2, and step S1, dissolving 2, 5-dimethoxy tetrahydrofuran in a reaction solvent 2, adding concentrated hydrochloric acid for catalysis, heating and then reacting, and cooling to 0 ℃ after the reaction is finished to obtain a solution for later use;
step S2, dissolving sodium acetate in water, cooling to 0 ℃, adding the intermediate 1 and methylamine hydrochloride, adding the solution obtained in the step S1, adjusting the pH to =8 by using 50% sodium hydroxide, controlling the temperature to be 0 ℃, completing the reaction after 2-4 hours, adding an organic solvent 1 for layering, extracting a water phase by using the organic solvent 1, combining organic phases, washing with saturated salt water once, drying, filtering and spin-drying to obtain an intermediate 2 crude product, and directly using the intermediate 2 crude product in the next reaction;
(3) Synthesizing an intermediate 3, dissolving the intermediate 2 in a reaction solvent 3, reacting at the temperature of 20-30 ℃ for 2-6 hours, adding an organic solvent 1 for layering after the reaction is finished, extracting a water phase with the organic solvent 1, combining organic phases, washing with saturated salt water for one time, drying, filtering and spin-drying to obtain a crude intermediate 3, and directly using the crude intermediate 3 in the next reaction;
(4) Synthesizing an intermediate 4, dissolving the intermediate 3 in a reaction solvent 4, controlling the temperature to be below 50 ℃, dropwise adding a reducing agent under the protection of nitrogen, carrying out heat preservation reaction at the temperature of 30-50 ℃ for 1-2 hours, naturally cooling after the reaction is finished, dropwise adding a sodium hydroxide solution, carrying out extraction and quenching reaction, controlling the temperature to be below 30 ℃, layering, extracting a water phase once by using an organic solvent 2, combining organic phases, washing once by using saturated salt water, drying, filtering and spin-drying to obtain an oily substance, adding methyl tert-butyl ether into the oily substance to separate out a solid, cooling to 0 ℃, leaching the filtered solid by using glacial methyl tert-butyl ether, and drying to obtain the intermediate 4;
(5) Dissolving the intermediate 4 in a reaction solvent 5, adding alkali in batches under the protection of nitrogen, then dropwise adding an ethyl reagent, reacting at the temperature of 30-50 ℃ for 2-4 hours, dropwise adding a saturated ammonium chloride aqueous solution after the reaction is finished, carrying out extraction and quenching reaction, then adding an organic solvent 3, layering, separating an organic phase, extracting a water phase once by using the corresponding organic solvent 3, then combining the organic phases, washing the organic phases once by using saturated salt, drying, filtering and spin-drying to obtain a crude product, pulping, purifying, filtering and drying the crude product to obtain a white crystal of the tesofensine.
2. A method of synthesizing tesofensine as claimed in claim 1, characterized in that: the reaction solvent 1 in the step (1) is one of 95% methanol or 95% ethanol, the reaction temperature is controlled to be 20 ℃, and the catalytic reaction time is 2-3 hours.
3. A method of synthesizing tesofensine as claimed in claim 1, characterized in that: the reaction solvent 2 in the step (2) is water, and the temperature is raised to 60-70 ℃ in the step S1, and then the reaction is carried out for 1 hour; the reaction temperature of the step S2 is 0 ℃, the reaction time is 2-3 hours, and the mode of controlling the temperature to be 0 ℃ is ice bath.
4. A method of synthesizing tesofensine as claimed in claim 1, characterized in that: the organic solution 1 is dichloromethane; the organic solution 2 is anhydrous toluene; the organic solution 3 is ethyl acetate.
5. A method of synthesizing tesofensine as claimed in claim 1, characterized in that: in the step (3), the reaction solvent 3 is one of sodium hydrogen phosphate buffer solution or ammonium hydrogen phosphate buffer solution, the reaction time is 25 ℃, and the reaction time is 4 hours.
6. A process for the synthesis of tesofensine according to claim 1, characterised in that: in the step (4), the reaction solvent 4 is one of tetrahydrofuran or toluene, the reducing agent is one of lithium aluminum hydride, borane or red aluminum, the reaction temperature is 50 ℃, and the reaction time is 1 hour.
7. A process for the synthesis of tesofensine according to claim 1, characterised in that: in the step (5), the reaction solvent 5 is one of tetrahydrofuran and 2-methyltetrahydrofuran; the alkali is sodium hydride, the ethyl reagent is one of ethyl iodide or diethyl sulfate, the reaction temperature is 50 ℃, and the reaction time is 2 hours.
8. A method of synthesizing tesofensine as claimed in claim 1, characterized in that: and (5) pulping and purifying the crude product to obtain a crude product, and adding ethyl acetate for pulping.
9. A method of synthesizing tesofensine as claimed in claim 1, characterized in that: and (3) drying in the step (2), the step (3), the step (4) and the step (5) by anhydrous sodium sulfate.
10. A process for the synthesis of tesofensine according to claim 1, characterised in that: the intermediate 1 is a white solid, the intermediate 2 is a light yellow liquid, the intermediate 3 is a light yellow liquid, and the intermediate 4 is a white crystal; the tesofensine is white crystals.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1211982A (en) * | 1996-02-22 | 1999-03-24 | 神经研究公司 | Tropane derivatives, their preparation and use |
| WO2002102801A1 (en) * | 2001-05-23 | 2002-12-27 | Neurosearch A/S | Tropane derivatives and their use as monoamine neurotransmitter re-uptake inhibitors |
| CN1910180A (en) * | 2004-01-31 | 2007-02-07 | 神经研究公司 | Process for the preparation of 2-(ethoxymethyl)-tropane derivatives |
| WO2017144978A1 (en) * | 2016-02-25 | 2017-08-31 | Замертон Холдинге Лимитед | Optically active acetylamino acid salts of (1r,2r,3s)-3-(3,4-dichlorophenyl)-2-(ethoxymethyl)-8-methyl-8-azabicyclo[3.2.1]octane and their use in the treatment of obesity |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1211982A (en) * | 1996-02-22 | 1999-03-24 | 神经研究公司 | Tropane derivatives, their preparation and use |
| WO2002102801A1 (en) * | 2001-05-23 | 2002-12-27 | Neurosearch A/S | Tropane derivatives and their use as monoamine neurotransmitter re-uptake inhibitors |
| CN1910180A (en) * | 2004-01-31 | 2007-02-07 | 神经研究公司 | Process for the preparation of 2-(ethoxymethyl)-tropane derivatives |
| WO2017144978A1 (en) * | 2016-02-25 | 2017-08-31 | Замертон Холдинге Лимитед | Optically active acetylamino acid salts of (1r,2r,3s)-3-(3,4-dichlorophenyl)-2-(ethoxymethyl)-8-methyl-8-azabicyclo[3.2.1]octane and their use in the treatment of obesity |
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