A preparation method of 3-((1r,3r,5r,7r)-adamantan-2-yl)prop-2-yn-1-amine
Through the Favorsky reaction and desorption steps, 3-((1r,3r,5r,7r)-adamantane-2-yl)propan-2-ynyl-1-amine was successfully prepared, solving the problem of difficult obtaining this compound in the prior art, and achieving a high yield and high purity preparation effect.
Patent Information
- Application Number
- CN202411934319.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-26
- Publication Date
- 2025-04-04
AI Technical Summary
The lack of an effective preparation method for 3-((1r,3r,5r,7r)-adamantane-2-yl)propan-2-ynyl-1-amine in the prior art makes it difficult to obtain the compound.
The Favorsky reaction was used to react adamantane with N-(tert-butoxycarbonyl)propargylamine and organic base to produce compound 2, and then the hydroxyl and tert-butoxycarbonyl groups were removed through the action of boron trifluoride ether and triethylsilane to obtain the target product 3-((1r,3r,5r,7r)-adamantane-2-yl)propan-2-ynyl-1-amine.
The process of this method has short process routes, convenient operation, mild reaction conditions and easy to control, low cost, suitable for process amplification, easy to purify the product, high yield, high purity and good stability.
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Figure CN119751265A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of pharmaceutical intermediate synthesis, and in particular to a method for preparing 3-((1r, 3r, 5r, 7r)-adamantane-2-yl)prop-2-yn-1-amine. Background Art
[0002] Amantadine molecular building blocks are an important class of organic pharmaceutical intermediates. Due to their special cage-like spatial configuration, studies have found that many of these derivatives have good biological activity and are widely used in drugs for the treatment of tumors, Parkinson's disease, influenza and other diseases. Its derivatives can be used as heat-resistant agents, solvent-resistant agents, chemical stabilizers, synthetic lubricants, raw materials for photosensitive materials; epoxy resin curing agents; intermediates for cosmetics and surfactants, etc. They can also be used to manufacture special polymers, especially optical and photosensitive materials; they can also be used in gasoline production, catalysts, and lubricants. They can also be used as agricultural chemicals and daily chemicals, etc., and are a good new type of organic material. It is even more important to design and synthesize more novel molecular building blocks of this type, and then develop small molecule drugs with better activity.
[0003] 3-((1r,3r,5r,7r)-adamantan-2-yl)prop-2-yn-1-amine is a newly designed adamantane amine molecular building block, and its synthesis method has not been reported. Summary of the invention
[0004] In view of the deficiencies of the prior art, the present invention provides a method for preparing 3-((1r,3r,5r,7r)-adamantan-2-yl)prop-2-yn-1-amine. The preparation method of the present invention has a short process route, convenient operation, mild and easy-to-control reaction conditions, low cost, suitable for process amplification, easy purification of the product, and high yield.
[0005] The technical solution of the present invention is as follows:
[0006] A method for preparing 3-((1r,3r,5r,7r)-adamantan-2-yl)prop-2-yn-1-amine, wherein the preparation method is carried out according to the following process:
[0007]
[0008] The steps include:
[0009] (1) Compound 2 is prepared by using compound 1 as a starting material through Favorski reaction;
[0010] (2) Compound 2 is treated with boron trifluoride etherate and triethylsilane to remove the hydroxyl group and tert-butyloxycarbonyl group to obtain the target product, namely, the 3-((1r,3r,5r,7r)-adamantan-2-yl)prop-2-yn-1-amine.
[0011] Furthermore, in step (1), the specific process of the Favorsky reaction is:
[0012] Compound 1 was dissolved in solvent I, and N-(tert-butoxycarbonyl)propargylamine and an organic base were added, and the reaction was heated under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature and poured into water to quench. The crude product was then extracted and concentrated to obtain a crude product, which was then purified by silica gel column chromatography to obtain compound 2.
[0013] Furthermore, the solvent I is selected from at least one of tetrahydrofuran and dimethyl sulfoxide; the concentration of the compound 1 in the solvent I is 0.4-0.6 mol / L.
[0014] Furthermore, the organic base is potassium tert-butoxide; and the molar ratio of the compound 1 to the organic base is 1:1-2.
[0015] Furthermore, the molar ratio of the compound 1 to N-(tert-butoxycarbonyl)propargylamine is 1:1-2.
[0016] Furthermore, the reaction temperature is 40-80° C. and the reaction time is 2-16 hours.
[0017] Furthermore, in step (2), the specific process of removing the hydroxyl group and the tert-butyloxycarbonyl group is:
[0018] Compound 2 is dissolved in solvent II, and then boron trifluoride etherate and triethylsilane are added, and the reaction is heated under nitrogen protection. After the reaction is completed, it is cooled to room temperature and poured into water for quenching. Then, the crude product is obtained by extraction and concentration. The crude product is purified by silica gel column chromatography to obtain the 3-((1r,3r,5r,7r)-adamantan-2-yl)prop-2-yn-1-amine.
[0019] Furthermore, the solvent II is selected from at least one of dichloromethane, 1,2-dichloroethane, and chloroform; and the concentration of the compound 2 in the solvent II is 0.2 to 0.4 mol / L.
[0020] Furthermore, the molar ratio of the compound 2 to boron trifluoride ethyl ether is 1:2-4; the molar ratio of the compound 2 to triethylsilane is 1:5-7;
[0021] Furthermore, the reaction temperature is 30-50°C and the reaction time is 2-10 hours.
[0022] The beneficial technical effects of the present invention are:
[0023] The invention uses adamantanone as a reaction starting material, introduces alkynylamine by adopting the Favorski reaction, and then mildly removes the protective group by boron trifluoride etherate and triethylsilane to obtain a molecular building block containing adamantanamine. The synthesis method has a good yield.
[0024] The invention improves the yield of the target product by screening and optimizing the synthesis route and reaction conditions of 3-((1r,3r,5r,7r)-adamantan-2-yl)prop-2-yn-1-amine. The synthesis method of the invention is reported for the first time, and the raw materials are cheap and easy to obtain, the reaction selectivity is good, the by-products are small, the reaction conditions are mild and easy to operate, the cost is low, the obtained product has high purity and good stability, and is suitable for process scale-up. BRIEF DESCRIPTION OF THE DRAWINGS
[0025] Figure 1 It is a schematic diagram of the reaction flow of the present invention.
[0026] Figure 2 This is the H NMR spectrum of 3-((1r,3r,5r,7r)-adamantan-2-yl)prop-2-yn-1-amine prepared in Example 1 of the present invention. DETAILED DESCRIPTION
[0027] The present invention is described in detail below in conjunction with the accompanying drawings and embodiments.
[0028] Example 1
[0029] A method for preparing 3-((1r,3r,5r,7r)-adamantan-2-yl)prop-2-yn-1-amine comprises the following steps:
[0030] (1) Anhydrous tetrahydrofuran (100 mL, 1.23 mol) was added to a 500 mL single-necked flask, and compound 1 (adamantanone, 8.0 g, 0.05 mol, 1 eq) was added under stirring, and N-(tert-butyloxycarbonyl)propargylamine (9.0 g, 0.06 mol, 1.2 eq) and potassium tert-butoxide (9.0 g, 0.08 mol, 1.6 eq) were added successively, and the mixture was reacted at 60° C. for 5 h in a nitrogen atmosphere, and the reaction solution was cooled to room temperature and poured into a flask. The reaction mixture was added into water and extracted with ethyl acetate three times. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was then purified by silica gel column chromatography and eluted with petroleum ether:ethyl acetate = 8:1 (volume ratio) in an isocratic gradient to obtain the product eluate, which was concentrated to obtain 13.5 g of a light yellow solid, i.e., compound 2, (3-((1r,3r,5r,7r)-2-hydroxyadamantane-2-yl)prop-2-yn-1-yl)carbamic acid tert-butyl ester (yield 83%).
[0031] (2) Anhydrous dichloromethane (50 mL, 0.78 mmol) was added to a 250 mL three-necked flask, and boron trifluoride etherate (9.2 mL, 36 mmol, 3 eq) was added under stirring. Compound 2 (3.6 g, 12 mmol, 1 eq) and triethylsilane (11 mL, 72 mmol, 6 eq) were added thereto in sequence. The mixture was reacted at 40° C. for 4 h in a nitrogen atmosphere. The reaction solution was cooled to room temperature, poured into water, extracted with ethyl acetate three times, the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was then purified by silica gel column chromatography using a gradient elution of dichloromethane:methanol=50:1 (volume ratio) to obtain a product eluate. After concentration, 1.8 g of a light yellow solid was obtained, namely, the 3-((1r,3r,5r,7r)-adamantan-2-yl)prop-2-yn-1-amine (yield 81%).
[0032] The structural characterization data of the product of this example, 3-((1r,3r,5r,7r)-adamantan-2-yl)prop-2-yn-1-amine, are as follows: LCMS (ESI): m / z 190.10 [M+H] + .
[0033] 1 H NMR (400MHz, Methanol-d4) δ3.44(d,J=2.2Hz,2H),2.78–2.71(m,1H),2.29–2.20(m,2H),1.90–1.87(m,2H),1.85–1.72(m,8H),1.64–1.56(m,2H).
[0034] Example 2
[0035] A method for preparing 3-((1r,3r,5r,7r)-adamantan-2-yl)prop-2-yn-1-amine comprises the following steps:
[0036] (1) Anhydrous tetrahydrofuran (90 mL, 1.11 mol) was added to a 500 mL single-necked flask, and compound 1 (adamantanone, 8.0 g, 0.05 mol, 1 eq) was added under stirring, and N-(tert-butyloxycarbonyl)propargylamine (9.0 g, 0.06 mol, 1.2 eq) and potassium tert-butoxide (9.0 g, 0.08 mol, 1.6 eq) were added successively, and the mixture was reacted at 40° C. for 16 h in a nitrogen atmosphere, and the reaction solution was cooled to room temperature and poured into a flask. The reaction mixture was put into water and extracted with ethyl acetate three times. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was then purified by silica gel column chromatography and eluted with petroleum ether:ethyl acetate = 8:1 (volume ratio) in an isocratic gradient to obtain the product eluate, which was concentrated to obtain 12.0 g of a light yellow solid, i.e., compound 2, (3-((1r,3r,5r,7r)-2-hydroxyadamantane-2-yl)prop-2-yn-1-yl)carbamic acid tert-butyl ester (yield 74%).
[0037] (2) Anhydrous dichloromethane (40 mL, 0.62 mmol) was added to a 250 mL three-necked flask, and boron trifluoride etherate (9.2 mL, 36 mmol, 3 eq) was added under stirring. Compound 2 (3.6 g, 12 mmol, 1 eq) and triethylsilane (11 mL, 72 mmol, 6 eq) were added thereto in sequence. The mixture was reacted at 30° C. for 10 h in a nitrogen atmosphere. The reaction solution was cooled to room temperature, poured into water, extracted with ethyl acetate three times, the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was then purified by silica gel column chromatography using a gradient elution of dichloromethane:methanol=50:1 (volume ratio) to obtain a product eluate. After concentration, 1.7 g of a light yellow solid was obtained, namely, the 3-((1r,3r,5r,7r)-adamantan-2-yl)prop-2-yn-1-amine (yield 76%).
[0038] The structural characterization data of the product of this example, 3-((1r,3r,5r,7r)-adamantan-2-yl)prop-2-yn-1-amine, are as follows: LCMS (ESI): m / z 190.10 [M+H] + .
[0039] 1 H NMR (400MHz, Methanol-d4) δ3.44(d,J=2.2Hz,2H),2.78–2.71(m,1H),2.29–2.20(m,2H),1.90–1.87(m,2H),1.85–1.72(m,8H),1.64–1.56(m,2H).
[0040] Example 3
[0041] A method for preparing 3-((1r,3r,5r,7r)-adamantan-2-yl)prop-2-yn-1-amine comprises the following steps:
[0042] (1) Anhydrous dimethyl sulfoxide (100 mL, 1.4 mol) was added to a 500 mL single-necked flask, and compound 1 (adamantanone, 8.0 g, 0.05 mol, 1 eq) was added under stirring, and N-(tert-butyloxycarbonyl)propargylamine (9.0 g, 0.06 mol, 1.2 eq) and potassium tert-butoxide (9.0 g, 0.08 mol, 1.6 eq) were added successively, and the mixture was reacted at 80° C. for 2 h in a nitrogen atmosphere. The reaction solution was then cooled to room temperature and poured into a flask. The reaction mixture was put into water and extracted with ethyl acetate three times. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was then purified by silica gel column chromatography and eluted with petroleum ether:ethyl acetate = 8:1 (volume ratio) in an isocratic gradient to obtain the product eluate, which was concentrated to obtain 13.0 g of a light yellow solid, i.e., compound 2, (3-((1r,3r,5r,7r)-2-hydroxyadamantane-2-yl)prop-2-yn-1-yl)carbamic acid tert-butyl ester (yield 80%).
[0043] (2) Anhydrous chloroform (50 mL, 0.62 mmol) was added to a 250 mL three-necked flask, and boron trifluoride ether (9.2 mL, 36 mmol, 3 eq) was added under stirring. Compound 2 (3.6 g, 12 mmol, 1 eq) and triethylsilane (11 mL, 72 mmol, 6 eq) were added thereto in sequence. The mixture was reacted at 50° C. for 2 h in a nitrogen atmosphere. The reaction solution was cooled to room temperature, poured into water, extracted with ethyl acetate three times, the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was then purified by silica gel column chromatography using a gradient elution of dichloromethane:methanol=50:1 (volume ratio) to obtain a product eluate. After concentration, 1.7 g of a light yellow solid was obtained, namely, the 3-((1r,3r,5r,7r)-adamantan-2-yl)prop-2-yn-1-amine (yield 76%).
[0044] The structural characterization data of the product of this example, 3-((1r,3r,5r,7r)-adamantan-2-yl)prop-2-yn-1-amine, are as follows: LCMS (ESI): m / z 190.10 [M+H] + .
[0045] 1H NMR (400MHz, Methanol-d4) δ3.44(d,J=2.2Hz,2H),2.78–2.71(m,1H),2.29–2.20(m,2H),1.90–1.87(m,2H),1.85–1.72(m,8H),1.64–1.56(m,2H).
[0046] Comparative Example 1
[0047] A method for preparing 3-((1r,3r,5r,7r)-adamantan-2-yl)prop-2-yn-1-amine is carried out according to the following process:
[0048]
[0049] The specific steps are:
[0050] Anhydrous tetrahydrofuran (1 mL, 12 mmol) was added to a 500 mL single-necked flask, and compound 1 (adamantanone, 100 mg, 0.67 mmol, 1 eq) was added under stirring, and N-(tert-butyloxycarbonyl)propargylamine (124 mg, 0.80 mol, 1.2 eq) and potassium hydroxide (75 mg, 1.34 mol, 2 eq) were added successively, and the mixture was reacted at 60 ° C for 16 h in a nitrogen atmosphere, and then the reaction solution was cooled to room temperature and poured into The residue was added into water and extracted with ethyl acetate three times. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was then purified by silica gel column chromatography and eluted with petroleum ether:ethyl acetate = 8:1 (volume ratio) in an isocratic gradient to obtain the product eluate. After concentration, 25 mg of a light yellow solid was obtained, i.e., compound 2, (3-((1r,3r,5r,7r)-2-hydroxyadamantane-2-yl)prop-2-yn-1-yl)carbamic acid tert-butyl ester (yield 12%).
[0051] The yield of the intermediate product (tert-butyl 3-((1r,3r,5r,7r)-2-hydroxyadamantan-2-yl)prop-2-yn-1-yl)carbamate prepared by this method is low.
[0052] Comparative Example 2
[0053] A method for preparing 3-((1r,3r,5r,7r)-adamantan-2-yl)prop-2-yn-1-amine is carried out according to the following process:
[0054]
[0055] The specific steps are:
[0056] (1) The specific preparation method of step (1) of this comparative example is the same as step (1) of example 1.
[0057] (2) Anhydrous dichloromethane (1 mL, 0.016 mmol) was added to a 25 mL three-necked flask, and compound 2 (400 mg, 1.3 mmol, 1 eq) was added under stirring. Then, trifluoroacetic acid (0.3 mL, 3.9 mmol, 3 eq) and triethylsilane (0.6 mL, 3.9 mmol, 3 eq) were added successively, and the mixture was reacted at room temperature for 1 h under a nitrogen atmosphere. The reaction solution was poured into water, extracted three times with ethyl acetate, and the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was then purified by silica gel column chromatography, eluted with dichloromethane:methanol=50:1 (volume ratio) isocratic gradient to obtain the product eluate, which was concentrated to obtain 40 mg of a light yellow solid, i.e., the 3-((1r,3r,5r,7r)-adamantan-2-yl)prop-2-yn-1-amine (yield 16%).
[0058] The yield of the target compound 3-((1r,3r,5r,7r)-adamantan-2-yl)prop-2-yn-1-amine prepared by this method is low.
[0059] The above is only a preferred embodiment of the present invention, and the present invention is not limited to the above embodiments. It is understood that other improvements and changes directly derived or associated by those skilled in the art without departing from the spirit and concept of the present invention should be considered to be included in the protection scope of the present invention.
Claims
1. A method for preparing 3-((1r,3r,5r,7r)-adamantan-2-yl)prop-2-yn-1-amine, characterized in that: The preparation method is carried out according to the following process: The steps include: (1) Compound 2 is prepared by using compound 1 as a starting material through Favorski reaction; (2) Compound 2 is treated with boron trifluoride etherate and triethylsilane to remove the hydroxyl group and tert-butyloxycarbonyl group to obtain the target product, namely, the 3-((1r,3r,5r,7r)-adamantan-2-yl)prop-2-yn-1-amine.
2. The preparation method according to claim 1, characterized in that: In step (1), the specific process of the Favorsky reaction is: Compound 1 was dissolved in solvent I, and N-(tert-butoxycarbonyl)propargylamine and an organic base were added, and the reaction was heated under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature and poured into water to quench. The crude product was then extracted and concentrated to obtain a crude product, which was then purified by silica gel column chromatography to obtain compound 2.
3. The preparation method according to claim 2, characterized in that: The solvent I is selected from at least one of tetrahydrofuran and dimethyl sulfoxide; the concentration of the compound 1 in the solvent I is 0.4-0.6 mol / L.
4. The preparation method according to claim 2, characterized in that: The organic base is potassium tert-butoxide; the molar ratio of the compound 1 to the organic base is 1:1-2.
5. The preparation method according to claim 2, characterized in that: The molar ratio of the compound 1 to N-(tert-butyloxycarbonyl)propargylamine is 1:1-2.
6. The preparation method according to claim 2, characterized in that: The reaction temperature is 40-80° C. and the reaction time is 2-16 hours.
7. The preparation method according to claim 1, characterized in that: In step (2), the specific process of removing the hydroxyl group and the tert-butyloxycarbonyl group is: Compound 2 is dissolved in solvent II, and then boron trifluoride etherate and triethylsilane are added, and the reaction is heated under nitrogen protection. After the reaction is completed, it is cooled to room temperature and poured into water for quenching. Then, the crude product is obtained by extraction and concentration. The crude product is purified by silica gel column chromatography to obtain the 3-((1r,3r,5r,7r)-adamantan-2-yl)prop-2-yn-1-amine.
8. The preparation method according to claim 7, characterized in that: The solvent II is selected from at least one of dichloromethane, 1,2-dichloroethane and chloroform; the concentration of the compound 2 in the solvent II is 0.2-0.4 mol / L.
9. The preparation method according to claim 7, characterized in that: The molar ratio of the compound 2 to boron trifluoride ether is 1:2-4; the molar ratio of the compound 2 to triethylsilane is 1:5-7.
10. The preparation method according to claim 7, characterized in that: The reaction temperature is 30-50°C and the reaction time is 2-10 hours.