CN110776429A - Improved preparation method of rasagiline racemic intermediate - Google Patents
Improved preparation method of rasagiline racemic intermediate Download PDFInfo
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- C07C209/24—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds
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Abstract
The invention discloses an improved preparation method of a rasagiline racemic intermediate, belongs to the technical field of medicinal chemistry, and particularly relates to an improved method for preparing an N- (2-propargyl) -2, 3-dihydro-1H-indene-1-amine racemate. The method takes 1-indanone and propargylamine as raw materials, and adopts a one-pot method to prepare the N- (2-propargyl) -2, 3-dihydro-1H-indene-1-amine racemate in the presence of a dehydrating agent. The method is simple to operate, high in yield and good in purity, and lays a good foundation for the subsequent preparation of rasagiline mesylate.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to an improved method for preparing an N- (2-propargyl) -2, 3-dihydro-1H-indene-1-amine racemate. The method takes 1-indanone and propargylamine as raw materials, adopts a one-pot method to prepare the N- (2-propargyl) -2, 3-dihydro-1H-indene-1-amine racemate, and has the advantages of simple operation, high yield and good product purity.
Background
Rasagiline Mesylate (Rasagiline Mesylate), chemical name (R) -N- (2-propargyl) -2, 3-dihydro-1H-inden-1-amine Mesylate. Rasagiline mesylate is a selective monoamine oxidase B (MAO-B) inhibitor developed by Teva company and Lundbeck company, can efficiently, selectively and irreversibly inhibit MAO-B, and has the advantages of good chemical stability, convenient use, less side effect, stronger effect and higher safety. The drug was first marketed in israel for 3 months in 2005 and has been marketed in the uk, irish and china under the name Azilect, mainly for the treatment of symptoms and signs of primary parkinson's disease, as well as for initial monotherapy and adjuvant therapy of levodopa.
There are many methods for preparing N- (2-propargyl) -2, 3-dihydro-1H-inden-1-amine racemate, and there are two methods for preparing N- (2-propargyl) -2, 3-dihydro-1H-inden-1-amine racemate by reductive amination. One is a method of firstly generating N- (2, 3-dihydro-1H-indene-subunit) -2-propargyl-1-amine (formula III) from 1-indanone and propargylamine, and then reducing the N- (2-propargyl) -2, 3-dihydro-1H-indene-1-amine to generate N- (2-propargyl) -2, 3-dihydro-1H-indene-1-amine racemate by a reducing agent, which is called as a two-step method, and for example, Chinese patents CN1990455B, CN102476998A and WO2011048612A3 have different reports. The process is due to imidization of the formula III
The method has unstable chemical properties, is easy to hydrolyze into 1-indanone and propargylamine, has low yield, still has low yield in the imine reduction process, has more byproducts, and is not suitable for large-scale production.
The other method is a one-pot method of amination reduction, which adopts a preparation method that 1-indanone is taken as a raw material to react with propargylamine in acetic acid and sodium borohydride to directly generate racemate rasagiline. This process is reported in US2010029987a 1. The method is to reduce the generated imine (formula III) intermediate without separation to generate N- (2-propargyl) -2, 3-dihydro-1H-indene-1-amine racemate, but the preparation method reported in the literature has the defects of difficult generation of the formula III intermediate, low yield, more byproducts, dark color of the obtained product, difficult decoloration and unsuitability for large-scale production.
The rasagiline racemate (formula V) obtained by the two methods can be separated from L- (+) -tartaric acid to form salt, and R- (+) -N- (2-propargyl) -2, 3-dihydro-1H-indene-1-amine-L- (+) -tartrate (formula VI) can be obtained, and then the salt is alkalized and salified with methanesulfonic acid to obtain rasagiline mesylate (formula IV).
Based on the above-mentioned disadvantages of the prior art and the practical need for alternative and improved methods for the preparation of rasagiline racemate (formula V) and rasagiline mesylate (formula iv), there is still a need for the skilled person to develop a process for the preparation of compound V which is simple to operate, has a high yield and purity of the product and has a good color profile.
Disclosure of Invention
Aiming at the defects of low yield, more byproducts, heavy reaction color and the like in the existing synthetic method for preparing rasagiline by a reductive amination method, the invention provides a preparation method of rasagiline and an intermediate thereof, which is simple and convenient to operate, environment-friendly, excellent in product color state and suitable for industrial production, and particularly fully embodies the cost and the yield.
In a first aspect, the present invention provides a process for producing an N- (2-propargyl) -2, 3-dihydro-1H-inden-1-amine racemate (compound V), which comprises: in the presence of a dehydrating agent, 1-indanone and propargylamine react in a reaction solvent under the action of a reducing agent to prepare a compound V.
Wherein the dehydrating agent is selected from one or more of tetraisopropyl titanate, tetraethyl titanate and tetrabutyl titanate, and tetraisopropyl titanate is preferred.
Wherein the reducing agent is selected from one or more of sodium borohydride, potassium borohydride and sodium triacetoxyborohydride; the reaction solvent is selected from one or more of methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile and acetic acid, and preferably one or more of tetrahydrofuran, ethanol and acetic acid.
Preferably, the reaction temperature is-10 to 60 ℃, preferably 0 to 50 ℃, and more preferably 0 to 30 ℃.
Preferably, the molar ratio of reducing agent to 1-indanone is 1: 1-5, preferably 1; 2 to 4, more preferably 1: 3.
preferably, the molar ratio of dehydrating agent to 1-indanone is 1: 0.5 to 1, preferably 1: 0.6 to 0.8, more preferably 1: 0.83.
preferably, the molar ratio of propargylamine to 1-indanone is 1: 0.4 to 1, preferably 1: 0.5-0.8 or 1: 0.6 to 0.8.
Preferably, the reaction time is 6-10 h.
In one embodiment of the present invention, the above-mentioned method for preparing N- (2-propargyl) -2, 3-dihydro-1H-inden-1-amine racemate (compound V) comprises the steps of:
(1) adding a reducing agent and glacial acetic acid into a reaction solvent, and stirring for reaction for 0.5-2 h;
(2) sequentially adding 1-indanone, propargylamine and a dehydrating agent into the reaction solution obtained in the step (1), and stirring for reaction for 6-10 h;
(3) stopping the reaction, adding a potassium carbonate solution for quenching, separating out an organic phase, washing, drying, and distilling the solvent under reduced pressure to obtain a compound V;
wherein the reducing agent is selected from one or more of sodium borohydride, potassium borohydride and sodium triacetoxyborohydride; the reaction solvent is selected from one or more of methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile and acetic acid, and preferably one or more of tetrahydrofuran, ethanol and acetic acid; the dehydrating agent is selected from one or more of tetraisopropyl titanate, tetraethyl titanate and tetrabutyl titanate, and tetraisopropyl titanate is preferred.
Preferably, the reaction temperature in the step (1) is preferably 0 to 30 ℃, more preferably 0 to 20 ℃ or 0 to 10 ℃.
Preferably, the stirring reaction temperature in the step (2) is-10 to 60 ℃, preferably 0 to 50 ℃, and more preferably 0 to 30 ℃.
Preferably, the molar charge ratio of the reducing agent to the glacial acetic acid in the step (1) is 1: 1-5, preferably 1: 2 to 4, more preferably 1: 3.
preferably, the volume mass ratio of the reaction solvent to the glacial acetic acid is 1-10: 1, preferably 2 to 8: 1, more preferably 6: 1, unit ml/g.
Preferably, the molar charge ratio of the dehydrating agent to the 1-indanone in the step (2) is 1: 0.5 to 1, preferably 1: 0.6-0.8, more preferably 1: 0.83;
preferably, the molar charge ratio of propargylamine to 1-indanone in step (2) is 1: 0.4 to 1, preferably 1: 0.5 to 0.8, more preferably 1: 0.6 to 0.8.
Preferably, the mass fraction of the potassium carbonate solution in the step (3) is 20%.
Preferably, step (3) is specifically operated as follows: adding 20% potassium carbonate solution for quenching, extracting twice with ethyl acetate, extracting twice with dilute hydrochloric acid for the organic phase, adjusting the pH value to 11 with 20% sodium hydroxide, extracting twice with ethyl acetate, combining the organic phases, washing once with water, washing once with saturated saline solution, drying with anhydrous sodium sulfate, performing suction filtration, and distilling off the solvent under reduced pressure to obtain a reddish brown liquid, namely the compound V.
Preferably, the product obtained in step (1) can be directly replaced by a tetrahydrofuran solution of sodium triacetoxyborohydride; wherein the amount of the sodium triacetoxyborohydride can be equimolar according to the amount of the sodium borohydride in the step (1), and the amount of the tetrahydrofuran is the same as the amount of the reaction solvent in the step (1).
In another embodiment of the present invention, the process for preparing the N- (2-propargyl) -2, 3-dihydro-1H-inden-1-amine racemate (compound V) comprises the following steps:
adding sodium borohydride into tetrahydrofuran, stirring, adding glacial acetic acid, stirring for reaction for 0.5-2 h, adding 1-indanone and propargylamine, adding tetraisopropyl titanate, controlling the reaction temperature to be 0-30 ℃, stirring for reaction for about 6-8 h, and stopping reaction. Adding 20% by mass of potassium carbonate aqueous solution for quenching, extracting twice with ethyl acetate, extracting twice with dilute hydrochloric acid for an organic phase, adjusting the pH value to 10-11 with 20% by mass of sodium hydroxide aqueous solution, extracting twice with ethyl acetate, combining the organic phases, washing once with water and saturated saline solution respectively, drying with anhydrous sodium sulfate, carrying out suction filtration, and evaporating the solvent to obtain a compound V.
In a second aspect, the present invention provides a process for the preparation of R- (+) -N- (2-propargyl) -2, 3-dihydro-1H-inden-1-amine-L- (+) -tartrate, the process comprising the steps of:
dissolving N- (2-propargyl) -2, 3-dihydro-1H-indene-1-amine racemate (compound V) in isopropanol; then, an isopropanol solution of L- (+) -tartaric acid was added dropwise. And refluxing for 1.5 hours after the dropwise addition is finished, cooling to room temperature, performing suction filtration, and performing vacuum drying to obtain a white-like solid, namely the target compound.
In a third aspect, the present invention provides a process for preparing rasagiline mesylate, comprising the steps of:
adding R- (+) -N- (2-propargyl) -2, 3-dihydro-1H-indene-1-amine-L- (+) -tartrate into purified water for dissolving; adjusting the pH value to about 9-10 by using a 20% potassium carbonate solution, extracting by using ethyl acetate, combining organic phases, washing by using water, washing by using saturated salt solution, drying by using anhydrous sodium sulfate, performing suction filtration, and reducing and steaming to dryness; adding isopropanol to dissolve, dripping methanesulfonic acid, stirring to precipitate a product in a salifying mode, performing suction filtration and drying to obtain a white-like solid, namely the target compound.
It should be noted that, in the present invention, unless otherwise specified, the amounts of the reaction solvent and the related reagents are the conventional amounts for the reaction, and can be determined by those skilled in the art according to the prior art; the reagents used in the present invention are conventional reagents and commercially available, and the starting materials and reactants used can be prepared by the prior art or the published literature. Although the present invention is limited to the ratio of the reactants and the amount of the reaction solvent, the amount of the reaction solvent is not limited to the range outside the specification, and the inventors have found that the amount of the reaction solvent is more suitable for the present invention or the reaction, because the reaction conditions, the post-treatment operation, the reaction cost, and the like are integrated. The skilled person can still determine the amount of the reactants and solvents in the range outside the range of the amounts recited in the present invention based on the common general knowledge of the basic chemistry principle. In the present invention, unless a solvent is specifically mentioned, the solution generally refers to an aqueous solution; if the expression method of the concentration is not explained, the concentration of the solution is mass fraction or mass percentage concentration.
The invention has the beneficial effects that: the invention overcomes the defects of lower yield, more byproducts, heavy reaction color and the like in the prior art, has the advantages of simple and convenient operation, environmental protection, excellent product color state and low cost, is suitable for industrial production, and has the advantages that the HPLC purity of the prepared N- (2-propargyl) -2, 3-dihydro-1H-indene-1-amine racemate (compound V) reaches 97 percent, the yield reaches 92 percent and good industrial prospect is realized.
Detailed Description
The foregoing and other aspects of the present invention are achieved by the following detailed description, which should not be construed to limit the claimed subject matter in any way. All technical solutions realized based on the above contents of the present invention belong to the scope of the present invention. The present invention has been described generally and/or specifically with respect to materials used in testing and testing methods. It is clear to those skilled in the art that, unless otherwise specified, the operation of the present invention is carried out under the ambient temperature conditions conventional in the art, and the ambient temperature has the technical meaning well known in the art, and generally means 10 to 30 ℃, preferably 15 to 25 ℃, and more preferably 20 to 25 ℃.
Example 1 preparation of N- (2-propargyl) -2, 3-dihydro-1H-inden-1-amine racemate:
in a 3000ml three-necked flask, 43.1g (1.139mol) of sodium borohydride and 560ml of tetrahydrofuran were added, and the mixture was stirred in suspension. 209.9g (3.495mol) of glacial acetic acid is added, stirring and reaction are carried out for 0.5-2 h, 70.0g (0.530mol) of 1-indanone is added after the reaction is finished, and stirring and reaction are continued. 46.7g (0.848mol) of propargylamine and then 180.6g (0.635mol) of tetraisopropyl titanate were added, the reaction temperature was controlled not to exceed 50 ℃ and the reaction was stirred for about 8 hours to stop the reaction. 1400ml of 20% potassium carbonate solution is added for quenching, extraction is carried out twice with ethyl acetate, the organic phase is extracted twice with dilute hydrochloric acid, the pH value is adjusted to 11 with 20% sodium hydroxide, extraction is carried out twice with ethyl acetate, the organic phases are combined, washed once with water, washed once with saturated saline, dried with anhydrous sodium sulfate, filtered, reduced to dryness, and 84.9g of reddish brown liquid is obtained, the yield is 93.6%, and the HPLC purity is 95.67%.
EXAMPLE 2 preparation of R- (+) -N- (2-propargyl) -2, 3-dihydro-1H-inden-1-amine-L- (+) -tartrate
In a 3000ml three-necked flask, 83.9g (0.490mol) of N- (2-propargyl) -2, 3-dihydro-1H-inden-1-amine racemate prepared by the method of example 1 was added, and 1259ml of isopropanol was added to dissolve the racemate. 21.0g (0.140mol) of L- (+) -tartaric acid was added to a 1000ml single-necked flask, 839ml of isopropanol was added to dissolve the mixture, and after both reaction flasks were dissolved, the isopropanol solution of L- (+) -tartaric acid was added dropwise to the isopropanol solution of N- (2-propargyl) -2, 3-dihydro-1H-inden-1-amine racemate. After the dropwise addition, the mixture was heated and refluxed for 1.5 hours, cooled to room temperature, filtered, and vacuum-dried to obtain 47.0g of off-white solid with a yield of 39.0%. HPLC purity 99.46%, optical purity 95.54%.
Example 3 preparation of rasagiline mesylate:
in a 2000ml three-necked flask, 46.0g (0.187mol) of R- (+) -N- (2-propargyl) -2, 3-dihydro-1H-inden-1-amine-L- (+) -tartrate prepared by the method of example 2 was added, and 500ml of purified water was added for dissolution. Adjusting pH to about 10 with 20% potassium carbonate solution, extracting with ethyl acetate twice, mixing organic phases, washing with water once, washing with saturated saline solution once, drying with anhydrous sodium sulfate, filtering, and steaming to dryness. The mixture was transferred into a 1000ml three-necked flask, dissolved in 230ml of isopropyl alcohol, and 23.3g (0.242mol) of methanesulfonic acid was added dropwise. After the dropwise addition, the mixture was stirred at room temperature for 1.5 hours, filtered by suction and dried in vacuum to obtain an off-white solid (43.8 g) with a yield of 87.6%. HPLC purity 99.80%, max mono-heterozygote 0.06%; the optical purity was 99.80%.
Example 4 preparation of N- (2-propargyl) -2, 3-dihydro-1H-inden-1-amine racemate:
in a 50L glass reactor, 0.59kg (15.60mol) of sodium borohydride and 7.6L of tetrahydrofuran were added, and the mixture was suspended and stirred. Adding 2.85kg (47.46mol) of glacial acetic acid, stirring for reaction, adding 0.95kg (7.19mol) of 1-indanone after the reaction is finished, and continuing stirring for reaction. 0.63kg (11.44mol) of propargylamine and then 2.45kg (8.62mol) of tetraisopropyl titanate were added, the reaction temperature was controlled not to exceed 50 ℃ and the reaction was stirred for about 8 hours to stop the reaction. Adding 20L of 20% potassium carbonate solution for quenching, extracting twice with ethyl acetate, extracting the organic phase twice with dilute hydrochloric acid, adjusting the pH value to about 11 with 20% sodium hydroxide, extracting twice with ethyl acetate, combining the organic phases, washing once with water, washing once with saturated saline, drying with 0.80kg of anhydrous sodium sulfate, filtering, and evaporating to dryness to obtain 1.40kg of reddish brown liquid, the yield is 92.6%, and the HPLC purity is 97.44%.
EXAMPLE 5 preparation of R- (+) -N- (2-propargyl) -2, 3-dihydro-1H-inden-1-amine-L- (+) -tartrate salt (formula VI)
0.28kg (1.865mol) of L- (+) -tartaric acid is added into a 50L glass reaction kettle, 11.4L of isopropanol is added for dissolution, and the mixture is placed into a special plastic bucket for temporary storage after dissolution. To a 50L glass reactor, 17L of isopropanol was added, and 1.136kg (6.63mol) of the N- (2-propargyl) -2, 3-dihydro-1H-inden-1-amine racemate prepared in example 4 was added and dissolved with stirring. After the two solutions are clear, the isopropanol solution of the L- (+) -tartaric acid is dripped into the isopropanol solution of the N- (2-propargyl) -2, 3-dihydro-1H-indene-1-amine racemate. After the dropwise addition, the temperature was raised and the reflux was carried out for 1.5 hours, the temperature was lowered to room temperature, and the white solid was obtained in an amount of 0.664kg with a yield of 37.5% by suction filtration and vacuum drying. HPLC purity 99.71%, optical purity 97.26%.
Example 6 preparation of rasagiline mesylate:
0.662kg (2.69mol) of R- (+) -N- (2-propargyl) -2, 3-dihydro-1H-inden-1-amine-L- (+) -tartrate prepared by the method of example 5 was added to a 50L glass reaction vessel, and dissolved in 10L of purified water. Adjusting pH to about 10 with 20% potassium carbonate solution, extracting with ethyl acetate twice, mixing organic phases, washing with water once, washing with saturated saline solution once, drying with anhydrous sodium sulfate, filtering, and steaming to dryness. The mixture was transferred to a 50L glass reactor, dissolved in 3.3L of isopropanol, and a solution of 0.34kg (3.54mol) of methanesulfonic acid and 0.7L of isopropanol was added dropwise. After the dropwise addition, the mixture was stirred at room temperature for 1.5 hours, filtered by suction, and dried in vacuum to obtain 0.666kg of a white solid with a yield of 92.6%. HPLC purity 99.92%, max mono-hetero 0.04%; the optical purity was 99.77%.
Comparative test reference patent US20100029987A1 example 1 repeat the test and the decolorization treatment
Adding 2.3g of sodium borohydride and 32ml of tetrahydrofuran into a 250ml three-necked flask, stirring and cooling to 0-5 ℃, and dropwise adding 11.7g of glacial acetic acid, wherein the dropwise adding temperature is controlled not to exceed 15 ℃. After the dropwise addition, the temperature is raised to 20-25 ℃ and the reaction is stirred for 20 minutes. The temperature is increased to 30 to 35 ℃, 4.0g of 1-indanone is added, and the mixture is stirred for 5 minutes. 4.3g propargylamine were added dropwise over 2.5 hours. After the dropwise addition, the reaction is carried out for a short time under heat preservation. Adding 30ml of water, adjusting the pH value to 10 with 30% sodium hydroxide solution, extracting 2 times with 50ml of ethyl acetate each time, combining the organic phases, extracting 2 times with 50ml of 2N diluted hydrochloric acid each time, retaining the hydrochloric acid phase, adjusting the pH value to 10 with 30% sodium hydroxide solution, extracting 2 times with 50ml of ethyl acetate each time, combining the organic phases, washing with 50ml of saturated saline solution, and drying with anhydrous sodium sulfate. Filtering, washing and evaporating to obtain brown-black oily matter. Adding 100ml of isopropanol, stirring for dissolving, adding 1.3g L- (+) -tartaric acid, heating for refluxing for 1 hour, cooling to 20-25 ℃, stirring for crystallizing for 2 hours, filtering, washing and drying to obtain brown solid. Adding 40ml of absolute methanol, heating, refluxing and dissolving, adding 40ml of isopropanol, cooling to 20-25 ℃, stirring, crystallizing for 5 hours, performing suction filtration, washing with isopropanol, and drying to obtain 1.8g of brown solid, wherein the total yield is 24.3%, the chemical purity is 99.40%, and the optical purity is 99.47%.
Adding the obtained R- (+) -N- (2-propargyl) -2, 3-dihydro-1H-indene-1-amine-L- (+) -tartaric acid into 30ml of anhydrous methanol, heating to 60 ℃, stirring for dissolving, adding a proper amount of 0.09g of activated carbon, refluxing and stirring for 30min, cooling to 55-60 ℃, filtering while hot, adding 25ml of isopropanol into the filtrate, cooling for crystallization, filtering, washing and drying to obtain 1.6g of brown solid, wherein the yield is 88.8%. Has no obvious difference with the color before refining.
Claims (8)
1. A preparation method of N- (2-propargyl) -2, 3-dihydro-1H-indene-1-amine racemate shown as a formula V comprises the following steps: in the presence of a dehydrating agent, reacting 1-indanone and propargylamine in a reaction solvent under the action of a reducing agent to obtain a compound V;
wherein the dehydrating agent is selected from one or more of tetraisopropyl titanate, tetraethyl titanate and tetrabutyl titanate, and tetraisopropyl titanate is preferred.
2. The preparation method according to claim 1, wherein the reducing agent is selected from one or more of sodium borohydride, potassium borohydride and sodium triacetoxyborohydride; the reaction solvent is selected from one or more of methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile and acetic acid, and preferably one or more of tetrahydrofuran, ethanol and acetic acid.
3. The method according to claim 1, wherein the reaction temperature is-10 to 60 ℃, preferably 0 to 50 ℃, and more preferably 0 to 30 ℃; the reaction time is 6-10 h; the molar ratio of the reducing agent to the 1-indanone is 1: 1-5, preferably 1; 2 to 4, more preferably 1: 3; the molar ratio of the dehydrating agent to the 1-indanone is 1: 0.5 to 1, preferably 1: 0.6 to 0.8, more preferably 1: 0.83; the molar ratio of propargylamine to 1-indanone is 1: 0.4 to 1, preferably 1: 0.5-0.8 or 1: 0.6 to 0.8.
4. The method of claim 1 or 2, comprising the steps of:
(1) adding a reducing agent and glacial acetic acid into a reaction solvent, and stirring for reaction for 0.5-2 h;
(2) sequentially adding 1-indanone, propargylamine and a dehydrating agent into the reaction solution obtained in the step (1), and stirring for reaction for 6-10 h;
(3) stopping the reaction, adding potassium carbonate solution for quenching, separating out an organic phase, washing, drying, and distilling the solvent under reduced pressure to obtain the compound V.
5. The method according to claim 4, wherein the reaction temperature in step (1) is preferably 0 to 30 ℃, more preferably 0 to 20 ℃ or 0 to 10 ℃; in the step (2), the stirring reaction temperature is-10-60 ℃, preferably 0-50 ℃, and more preferably 0-30 ℃.
6. The preparation method according to claim 4, wherein the molar ratio of the reducing agent to the glacial acetic acid in the step (1) is 1: 1-5, preferably 1: 2 to 4, more preferably 1: 3; the volume mass ratio of the reaction solvent to the glacial acetic acid is 1-10: 1, preferably 2 to 8: 1, more preferably 6: 1, unit ml/g; in the step (2), the molar charge ratio of the dehydrating agent to the 1-indanone is 1: 0.5 to 1, preferably 1: 0.6-0.8, more preferably 1: 0.83; in the step (2), the molar charge ratio of propargylamine to 1-indanone is 1: 0.4 to 1, preferably 1: 0.5 to 0.8, more preferably 1: 0.6 to 0.8.
7. The process according to claim 4, wherein the product obtained in step (1) is directly replaced by a solution of sodium triacetoxyborohydride in tetrahydrofuran; wherein the amount of the sodium triacetoxyborohydride can be equimolar according to the amount of the sodium borohydride in the step (1), and the amount of the tetrahydrofuran is the same as the amount of the reaction solvent in the step (1).
8. The method of claim 4, comprising the steps of:
adding sodium borohydride into tetrahydrofuran, stirring, adding glacial acetic acid, stirring for reaction for 0.5-2 h, adding 1-indanone and propargylamine, adding tetraisopropyl titanate, controlling the reaction temperature to be 0-30 ℃, stirring for reaction for about 6-8 h, and stopping reaction. Adding 20% by mass of potassium carbonate aqueous solution for quenching, extracting twice with ethyl acetate, extracting twice with dilute hydrochloric acid for an organic phase, adjusting the pH value to 10-11 with 20% by mass of sodium hydroxide aqueous solution, extracting twice with ethyl acetate, combining the organic phases, washing once with water and saturated saline solution respectively, drying with anhydrous sodium sulfate, carrying out suction filtration, and evaporating the solvent to obtain the target compound.
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| CN110776429B (en) | 2022-12-02 |
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