A preparation method of tert-butyl (2-amino-1-cyanocyclopentyl)carbamate
Through a three-step reaction process, including addition reaction, acylation reaction and hydrogenation reduction reaction, the problem of synthesis of tert-butyl (2-amino-1-cyanocyclopentyl) carbamate in the prior art was successfully solved, and an efficient and simple synthesis method was achieved, ensuring the single configuration and stability of the product.
Patent Information
- Application Number
- CN202411964640.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-30
- Publication Date
- 2025-04-08
AI Technical Summary
The prior art lacks an efficient method for synthesizing tert-butyl (2-amino-1-cyanocyclopentyl)carbamate, and it is difficult to achieve a single configuration of the target compound.
A three-step reaction process is adopted: first introduce amino and cyano groups through addition reaction, then undergo acylation reaction, and finally undergo hydrogenation reduction reaction under hydrogenation conditions to prepare the target compound.
A synthesis method with high yield, simple operation and short process route is achieved, ensuring the single configuration and stability of the target compound.
Smart Images
Figure CN119775169A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of pharmaceutical intermediate synthesis, in particular to a method for preparing (2-amino-1-cyanocyclopentyl)carbamic acid tert-butyl ester. Background Art
[0002] In the pharmaceutical field, nitrogen-containing compounds are widely used, and many drugs are nitrogen-containing compounds, such as anesthetics, anticancer drugs, antidepressants, etc. For example, nitrogen-containing heterocyclic compounds are widely used in drugs, and many natural products and drug molecules belong to this type of compounds. The structural diversity and complexity of these compounds give them specific biological activities, and they can bind to target molecules in the body, thereby regulating physiological functions.
[0003] In addition, nitrogen-containing compounds are the basic skeletons of many natural compounds and synthetic drugs with important biological activities. According to the data of drugs approved by the US Food and Drug Administration, 60% of small molecule drugs contain nitrogen heterocyclic compounds.
[0004] Therefore, the biological activity of nitrogen-containing compounds is not only reflected in their basic biological functions, such as protein synthesis, signal transmission, etc., but also in the medical field, where they are used to treat various diseases. The development of efficient new synthetic methods for functionalized nitrogen-containing compounds has attracted much attention from chemists.
[0005] At present, there is no similar report on the preparation method of (2-amino-1-cyanocyclopentyl)carbamic acid tert-butyl ester. The development of a synthetic route with the advantages of short route, simple operation, single configuration, etc. is the main research direction of the current technicians. Summary of the invention
[0006] In view of the deficiencies of the prior art, the present invention provides a method for preparing tert-butyl (2-amino-1-cyanocyclopentyl)carbamate. The preparation method of the present invention has readily available raw materials, simple operation, high yield, and can obtain a single-configuration target compound.
[0007] The technical solution of the present invention is as follows:
[0008] A method for preparing tert-butyl (2-amino-1-cyanocyclopentyl)carbamate, wherein the preparation method is carried out according to the following process:
[0009]
[0010] The steps include:
[0011] (1) Compound 1 is used as a starting material, compound 1 is dissolved in solvent I, trimethylsilyl cyanide and ammonia methanol are added, and an addition reaction occurs under the action of catalyst I to obtain compound 2;
[0012] (2) Compound 2 is dissolved in solvent II, and di-tert-butyl dicarbonate is added to carry out an acylation reaction to obtain compound 3;
[0013] (3) Compound 3 is dissolved in solvent III, and catalyst II is added under the condition of introducing hydrogen to carry out hydrogenation reduction reaction to obtain the (2-amino-1-cyanocyclopentyl)carbamic acid tert-butyl ester.
[0014] Furthermore, in step (1), the solvent I is selected from any one of 1,2-dichloroethane, dichloromethane, and chloroform; and the concentration of the compound 1 in the solvent I is 0.05 to 0.2 g / mL.
[0015] Furthermore, in step (1), the molar ratio of compound 1 to trimethylsilyl cyanide is 1:1.1-2.0; the molar ratio of compound 1 to ammonia methanol is 1:1.61-16.15; the catalyst I is selected from any one of tetraisopropyl titanate, tetraethyl titanate, and tetrabutyl titanate; the molar ratio of compound 1 to catalyst I is 1:1.1-2.0.
[0016] Furthermore, in step (1), the temperature of the addition reaction is 25° C. and the time is 6 to 18 hours.
[0017] Furthermore, in step (2), the solvent II is selected from any one of 1,4-dioxane, 1,2-dichloroethane, and tetrahydrofuran; and the concentration of the compound 2 in the solvent II is 0.075 to 0.088 g / mL.
[0018] Furthermore, in step (2), the molar ratio of compound 2 to di-tert-butyl dicarbonate is 1:1.1-10.
[0019] Furthermore, in step (2), the temperature of the acylation reaction is 40° C. and the time is 12 to 48 hours.
[0020] Furthermore, in step (3), the solvent III is selected from any one of methanol, ethanol, and ethyl acetate; and the concentration of the compound 3 in the solvent III is 0.08 to 0.10 g / mL.
[0021] Furthermore, in step (3), the catalyst is selected from any one of palladium carbon and palladium hydroxide carbon; the mass fraction of palladium in the catalyst is 10%, and the mass ratio of the compound 3 to the catalyst is 1:0.05-0.2.
[0022] Furthermore, in step (3), the temperature of the hydrogenation reduction reaction is 25° C. and the time is 1 h.
[0023] The beneficial technical effects of the present invention are:
[0024] The present invention solves the disadvantage that small molecule compounds are difficult to synthesize by reasonably adopting macromolecular protecting groups, and utilizes CBz protection to make the three-step reaction in the present invention easy to monitor and have a high reaction yield. The present invention first utilizes a keto functional group to simultaneously introduce two groups, an amino group and a cyano group, and the position of introduction is fixed, and there is no problem of positioning selection. In view of the unstable characteristics of the product, the stability of the product is controlled by accurately controlling the reaction time. The preparation method of the present invention has a short process route, and the raw materials are easily available, and has the characteristics of short reaction steps, simple operation, etc. At the same time, by optimizing the reaction conditions, the problem of the stability of the target compound is solved. 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 tert-butyl (2-amino-1-cyanocyclopentyl)carbamate 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 tert-butyl (2-amino-1-cyanocyclopentyl)carbamate, the method comprising the following steps:
[0030] (1) Compound 1 (6.0 g, 0.026 mol) was dissolved in 1,2-dichloroethane (120 mL), tetraisopropyl titanate (8.2 g, 0.029 mol) and ammonia methanol (6 mL, 7 mol / L) were added, and the mixture was stirred at 25°C for 2 h. Trimethylsilyl cyanide (2.9 g, 0.029 mol) was added, and the mixture was stirred at 25°C for 6 h. After the reaction was completed, water was added to the reaction solution to quench the mixture, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. Petroleum ether / ethyl acetate (2 / 1, v / v) was used as the eluent, and the mixture was purified by column chromatography and concentrated by rotary evaporation to obtain 3.0 g of a yellow solid product, namely (2-amino-2-cyanocyclopentyl) benzyl carbamate, with a yield of 45% and a content of 95%.
[0031] (2) Compound 2 (3.0 g, 0.012 mol) was dissolved in 1,4-dioxane (40 mL), di-tert-butyl dicarbonate (2.9 g, 0.013 mol) was added, and the reaction solution was heated to 40°C and stirred for 12 h. After the reaction was complete, the reaction solution was directly dried to obtain a crude product. The crude product was purified by column chromatography using petroleum ether / ethyl acetate (10 / 1, v / v) as an eluent, and concentrated by rotary evaporation to obtain 4.0 g of a yellow solid product, namely benzyl tert-butyl (1-cyanocyclopentane-1,2-diyl) dicarbamate, with a yield of 96% and a content of 96%.
[0032] (3) Compound 3 (4.0 g, 0.013 mol) was dissolved in methanol (50 mL). Under nitrogen protection, catalyst palladium carbon (200 mg, 10 wt% Pd / C) was added to replace hydrogen, and the mixture was stirred at 25 °C for 1 h under a hydrogen atmosphere. After the reaction was complete, the reaction solution was directly filtered through diatomaceous earth, and the mother liquor was concentrated to obtain a crude product. The crude product was purified by column using dichloromethane / methanol (50 / 1, v / v) as an eluent, and concentrated by rotary evaporation to obtain 1.1 g of a yellow solid product, i.e., tert-butyl (2-amino-1-cyanocyclopentyl)carbamate, with a yield of 44% and a content of 96%.
[0033] The product H NMR spectrum is shown in Figure 2 As shown, 1 H NMR(400MHz,Chloroform-d)δ5.15(s,1H),3.34–3.19(m,1H),2.63(td,J=11.5,9.5,5.9Hz,1H),2.14(dddd,J=1 3.1,8.8,7.1,3.7Hz,1H),1.96–1.84(m,2H),1.75(dq,J=5.7,3.5,2.9Hz,2H),1.64–1.54(m,1H),1.49(s,10H).
[0034] Example 2
[0035] A method for preparing tert-butyl (2-amino-1-cyanocyclopentyl)carbamate, the method comprising the following steps:
[0036] (1) Compound 1 (6.0 g, 0.026 mol) was dissolved in dichloromethane (60 mL), tetraisopropyl titanate (11.1 g, 0.039 mol) and ammonia methanol (30 mL, 7 mol / L) were added, and the mixture was stirred at 25°C for 2 h. Trimethylsilyl cyanide (3.9 g, 0.039 mol) was added, and the mixture was stirred at 25°C for 12 h. After the reaction was completed, water was added to the reaction solution to quench the mixture, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. Petroleum ether / ethyl acetate (2 / 1, v / v) was used as the eluent, and the mixture was purified by column chromatography and concentrated by rotary evaporation to obtain 3.5 g of a yellow solid product, namely (2-amino-2-cyanocyclopentyl) benzyl carbamate, with a yield of 52% and a content of 97%.
[0037] (2) Compound 2 (3.5 g, 0.013 mol) was dissolved in 1,2-dichloroethane (40 mL), di-tert-butyl dicarbonate (14.2 g, 0.065 mol) was added, and the reaction solution was heated to 40°C and stirred for 24 h. After the reaction was complete, the reaction solution was directly dried to obtain a crude product. The crude product was purified by column chromatography using petroleum ether / ethyl acetate (10 / 1, v / v) as an eluent, and concentrated by rotary evaporation to obtain 4.8 g of a yellow solid product, namely benzyl tert-butyl (1-cyanocyclopentane-1,2-diyl) dicarbamate, with a yield of 99% and a content of 95%.
[0038] (3) Compound 3 (4.8 g, 0.013 mol) was dissolved in ethanol (50 mL). Under nitrogen protection, catalyst palladium carbon (480 mg, 10 wt% Pd / C) was added to replace hydrogen, and the mixture was stirred at 25 °C for 1 h under a hydrogen atmosphere. After the reaction was complete, the reaction solution was directly filtered through diatomaceous earth, and the mother liquor was concentrated to obtain a crude product. The crude product was purified by column using dichloromethane / methanol (50 / 1, v / v) as an eluent, and concentrated by rotary evaporation to obtain 1.6 g of a yellow solid product, i.e., tert-butyl (2-amino-1-cyanocyclopentyl)carbamate, with a yield of 53% and a content of 96%.
[0039] Example 3
[0040] A method for preparing tert-butyl (2-amino-1-cyanocyclopentyl)carbamate, the method comprising the following steps:
[0041] (1) Compound 1 (6.0 g, 0.026 mol) was dissolved in chloroform (30 mL), tetraisopropyl titanate (14.8 g, 0.052 mol) and ammonia methanol (60 mL, 7 mol / L) were added, and the mixture was stirred at 25°C for 2 h, and then trimethylsilyl cyanide (5.1 g, 0.052 mol) was added, and the mixture was stirred at 25°C for 18 h. After the reaction was completed, water was added to the reaction solution to quench the mixture, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. Petroleum ether / ethyl acetate (2 / 1, v / v) was used as the eluent, and the mixture was purified by column chromatography and concentrated by rotary evaporation to obtain 3.1 g of a yellow solid product, namely (2-amino-2-cyanocyclopentyl) benzyl carbamate, with a yield of 46% and a content of 97%.
[0042] (2) Compound 2 (3.1 g, 0.012 mol) was dissolved in tetrahydrofuran (40 mL), di-tert-butyl dicarbonate (26.2 g, 0.120 mol) was added, and the reaction solution was heated to 40°C and stirred for 48 h. After the reaction was complete, the reaction solution was directly dried to obtain a crude product. The crude product was purified by column with petroleum ether / ethyl acetate (10 / 1, v / v) as eluent, and concentrated by rotary evaporation to obtain 4.1 g of a yellow solid product, namely benzyl tert-butyl (1-cyanocyclopentane-1,2-diyl) dicarbamate, with a yield of 98% and a content of 95%.
[0043] (3) Compound 3 (4.1 g, 0.011 mol) was dissolved in ethyl acetate (50 mL). Under nitrogen protection, a catalyst of palladium hydroxide on carbon (820 mg, mass percentage of Pd was 10 wt%) was added to replace the hydrogen, and the mixture was stirred at 25 °C for 1 h under a hydrogen atmosphere. After the reaction was complete, the reaction solution was directly filtered through diatomaceous earth, and the mother liquor was concentrated to obtain a crude product. The crude product was purified by column using dichloromethane / methanol (50 / 1, v / v) as an eluent, and concentrated by rotary evaporation to obtain 1.2 g of a yellow solid product, i.e., tert-butyl (2-amino-1-cyanocyclopentyl)carbamate, with a yield of 47% and a content of 96%.
[0044] Comparative Example 1
[0045] The preparation method of Comparative Example 1 is basically the same as that of Example 1, except that the reaction time in step (3) of this comparative example is 6 h, and the rest remains unchanged.
[0046] Results: The step (3) of this comparative example was concentrated by rotary evaporation to obtain 0.5 g of a yellow solid product, namely (2-amino-1-cyanocyclopentyl)carbamic acid tert-butyl ester, with a yield of 20% and a content of 96%.
[0047] Comparative Example 2
[0048] The preparation method of Comparative Example 2 is basically the same as that of Example 1, except that the reaction time in step (3) of this comparative example is 18 h, and the rest remains unchanged.
[0049] Results: The step (3) of this comparative example was concentrated by rotary evaporation to obtain 0 g of a yellow solid product, namely, tert-butyl (2-amino-1-cyanocyclopentyl)carbamate, with a yield of 0%.
[0050] 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 tert-butyl (2-amino-1-cyanocyclopentyl)carbamate, characterized in that: The preparation method is carried out according to the following process: The steps include: (1) Compound 1 is used as a starting material, compound 1 is dissolved in solvent I, trimethylsilyl cyanide and ammonia methanol are added, and an addition reaction occurs under the action of catalyst I to obtain compound 2; (2) Compound 2 is dissolved in solvent II, and di-tert-butyl dicarbonate is added to carry out an acylation reaction to obtain compound 3; (3) Compound 3 is dissolved in solvent III, and catalyst II is added under the condition of introducing hydrogen to carry out hydrogenation reduction reaction to obtain the (2-amino-1-cyanocyclopentyl)carbamic acid tert-butyl ester.
2. The preparation method according to claim 1, characterized in that: In step (1), the solvent I is selected from any one of 1,2-dichloroethane, dichloromethane, and chloroform; and the concentration of the compound 1 in the solvent I is 0.05 to 0.2 g / mL.
3. The preparation method according to claim 1, characterized in that: In step (1), the molar ratio of compound 1 to trimethylsilyl cyanide is 1:1.1-2.0; the molar ratio of compound 1 to ammonia methanol is 1:1.61-16.15; the catalyst I is selected from any one of tetraisopropyl titanate, tetraethyl titanate, and tetrabutyl titanate; the molar ratio of compound 1 to catalyst I is 1:1.1-2.
0.
4. The preparation method according to claim 1, characterized in that: In step (1), the temperature of the addition reaction is 25° C. and the time is 6 to 18 hours.
5. The preparation method according to claim 1, characterized in that: In step (2), the solvent II is selected from any one of 1,4-dioxane, 1,2-dichloroethane, and tetrahydrofuran; and the concentration of the compound 2 in the solvent II is 0.075 to 0.088 g / mL.
6. The preparation method according to claim 1, characterized in that: In step (2), the molar ratio of compound 2 to di-tert-butyl dicarbonate is 1:1.1-10.
7. The preparation method according to claim 1, characterized in that: In step (2), the temperature of the acylation reaction is 40° C. and the time is 12 to 48 hours.
8. The preparation method according to claim 1, characterized in that: In step (3), the solvent III is selected from any one of methanol, ethanol, and ethyl acetate; and the concentration of the compound 3 in the solvent III is 0.08 to 0.10 g / mL.
9. The preparation method according to claim 1, characterized in that: In step (3), the catalyst is selected from any one of palladium carbon and palladium hydroxide carbon; the mass fraction of palladium in the catalyst is 10%, and the mass ratio of the compound 3 to the catalyst is 1:0.05-0.
2.
10. The preparation method according to claim 1, characterized in that: In step (3), the temperature of the hydrogenation reduction reaction is 25° C. and the time is 1 h.