Method for synthesizing calononamine

Abstract

The invention discloses a method for synthesizing calononamine, which comprises the following steps: carrying out reduction reaction on 3, 3-dimethylcyclopropane-1, 2-dinitrile as shown in a formula I to carry out hydrogenation ring closing, and generating the calononamine as shown in a formula II in one step. According to the method, the target product can be prepared through one-step reaction, conditions are mild, side reactions are few, the product yield is high, and the industrial application prospect is wide. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis and relates to a novel method for synthesizing calonamine, namely 6,6-dimethyl-3-azabicyclo[3.1.0]hexane. Background Art

[0002] The chemical name of caronamide is 6,6-dimethyl-3-azabicyclo[3.1.0]hexane, which is an important drug intermediate. For example, it can be used to synthesize Nirmatrelvir (PF-07321332), the main antiviral ingredient of Paxlovid, a new oral antiviral drug for COVID-19. In November 2021, Pfizer announced the results of clinical trials of Paxlovid, an oral anti-COVID-19 therapy. In clinical trials of patients with a high risk of developing severe illness and those with a low risk of developing severe illness, Paxlovid was able to reduce the risk of hospitalization or death in patients. Paxlovid consists of Nirmatrelvir, an inhibitor of the COVID-19 3CL protease, and ritonavir, an antiviral therapy. Nirmatrelvir blocks the activity of the COVID-19 3CL protease, making the subsequent RNA replication process of the virus impossible. Ritonavir can help reduce the metabolism or degradation of Nirmatrelvir, allowing it to remain active in the body longer and help fight the virus. In addition, this intermediate is also widely used in other fields of organic synthesis. Their chemical formulas are as follows:

[0003]

[0004] The general synthetic route of Caronamine is as follows:

[0005]

[0006] The method starts from caron anhydride and takes two steps to obtain the target compound caronamine. However, caron anhydride has a relatively complex synthesis and a high cost. Summary of the invention

[0007] As we all know, in the industrial production of chemical products, each chemical reaction step needs to be operated independently, the reaction conditions are different, and each step needs to be extracted, purified and other post-processing operations after the reaction is completed before being used in the next reaction. Therefore, the more reaction steps there are, the longer the production cycle of the final product, which reduces the time-space yield, leads to high energy consumption, and thus increases production costs, and is not conducive to preventing and controlling environmental pollution.

[0008] Therefore, the most ideal chemical reaction concept is to start from commercially available chemical raw materials, produce the target product in one pot through a one-step reaction, and the reaction conditions are mild and easy to control. To achieve this goal, the inventors have designed a new synthesis route of calonamine in a unique way, using the commercially available chemical product 3,3-dimethylcyclopropane-1,2-dicarbonitrile as the raw material, and forming a bicyclic structure through a one-step reduction reaction. Specifically, the technical solution of the present invention is as follows.

[0009] A method for synthesizing calonamide comprises the following steps: subjecting 3,3-dimethylcyclopropane-1,2-dinitrile (Formula I) to a reduction reaction for hydrogenation ring closure (or cyano group reduction amination), thereby generating calonamide, i.e., 6,6-dimethyl-3-azabicyclo[3.1.0]hexane (Formula II) in one step:

[0010]

[0011] The reducing agent of the reduction reaction is hydrogen, and the catalyst is selected from Raney nickel, palladium carbon (Pd / C), Raney cobalt, Pt / C, Ru / C, Rh / C, or a mixture of two or more thereof, preferably Raney nickel.

[0012] When the catalyst is Raney nickel, the molar ratio of Raney nickel to 3,3-dimethylcyclopropane-1,2-dicarbonitrile is about 1:30-100, preferably 1:40-60, more preferably about 1:50.

[0013] Preferably, the reduction reaction is carried out under alkaline conditions, and the base used is selected from an organic base or an inorganic base. The organic base is selected from sodium / potassium methoxide, sodium / potassium ethoxide, sodium / potassium tert-butoxide, triethylamine, pyridine, ethanolamine, 2-hydroxyethylamine, isopropanolamine, morpholine, or a mixture of two or more thereof; the inorganic base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, ammonia water, or a mixture of two or more thereof. For example, the base can be sodium methoxide.

[0014] The above reduction reaction is preferably carried out in a solvent, and the solvent is selected from acetonitrile, propionitrile, methanol (MeOH), ethanol, isopropanol, sec-butanol, tert-butanol, 3-pentanol, 2-pentanol, tert-pentanol, 2-methylbutanol, 3-methyl-3-pentanol, ethylene glycol, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, glycerol, N,N-dimethylformamide (DMF), N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, ethyl formate, ethyl acetate (EA), isoamyl acetate, 1,2-dichloroethane, ethylenediamine, n-hexane, n-heptane, ether, petroleum ether, chloroform, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, benzene, toluene, xylene, mesitylene, chlorobenzene, dichlorobenzene, tert-butyl methyl ether, or a mixture of two or more thereof.

[0015] Preferably, the solvent is selected from dimethylformamide (DMF), ethyl acetate (EA), methanol (MeOH), liquid ammonia, 1,2-dichloroethane, ethylenediamine, or a mixture of two or more thereof.

[0016] The above reduction reaction is preferably carried out in the presence of ammonia (NH 3 ), ammonia can be present in the form of an alcoholic ammonia solution. The alcohol includes but is not limited to methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, tert-butanol. Since methanol and ethanol are relatively economical, ammonia is preferably present in the form of a methanolic ammonia solution or an ethanolic ammonia solution.

[0017] The molar ratio of ammonia to 3,3-dimethylcyclopropane-1,2-dicarbonitrile is about 20-50:1, preferably 25-40:1, more preferably 28-35:1, and more preferably about 30:1.

[0018] It should be understood that when expressing numerical characteristics in this document, the term "approximately" or "around" means that the represented number may have an error range or floating range of ±5%, ±4%, ±3%, ±2% or ±1%.

[0019] In the above reduction reaction, the hydrogen pressure is 10-50 bar, for example, 15-45 bar, 20-40 bar, 25-38° C., preferably 28-35 bar, more preferably 30-35 bar.

[0020] The reaction temperature of the reduction reaction is 20-100°C, for example, 25-90°C, 30-80°C, 40-70°C, preferably 45-70°C, more preferably 50-60°C.

[0021] The invention provides a new process route for synthesizing caronamine in one step. Compared with the prior art, the invention reduces the reaction steps, shortens the production cycle, increases the time-space yield, reduces energy consumption and thus reduces production costs, is beneficial to preventing and controlling environmental pollution, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 The H NMR spectrum of 3,3-dimethylcyclopropane-1,2-dicarbonitrile is shown.

[0023] Figure 2 The H NMR spectrum of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane is shown.

[0024] Figure 3 The mass spectrum of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane is shown. DETAILED DESCRIPTION

[0025] Based on the economic considerations of reducing the energy consumption per unit output of caronamine and preventing and controlling environmental pollution, the present invention provides a new route concept for a one-step synthesis method, in which 3,3-dimethylcyclopropane-1,2-dinitrile is reduced and aminated to form caronamine with a bicyclic structure, and its feasibility is verified by experiments, obtaining a high yield of not less than 80%.

[0026] Herein, for the convenience of description, the raw material 3,3-dimethylcyclopropane-1,2-dicarbonitrile is sometimes referred to as compound I or raw material I, and the product calonamine, i.e. 6,6-dimethyl-3-azabicyclo[3.1.0]hexane, is referred to as compound II or formula II.

[0027] The reduction reaction requires the use of a catalytic amount of a catalyst. When the catalyst is Raney nickel, the molar ratio of Raney nickel to raw material I is about 1:30-100, preferably 1:40-60. When the molar ratio of Raney nickel to raw material I is lower than 1:100, the reaction rate is slow and the side reaction tends to increase; when the molar ratio of Raney nickel to raw material I is higher than 1:30, the reaction rate is no longer significantly improved, and the balance between the improvement of reaction efficiency and the increase in the amount of catalyst cannot be achieved, resulting in an increase in production costs. The more preferred molar ratio is about 1:50.

[0028] The molar ratio of ammonia to raw material I is about 20-50:1, preferably 25-40: more preferably 28-35:1, for example about 30:1. When the molar ratio of ammonia to raw material I is lower than 1:50, the reaction rate is slow, which reduces the time-space yield; when the molar ratio of ammonia to raw material I is higher than 20:1, the reaction rate is no longer significantly improved, and the balance between the improvement of reaction efficiency and the increase of ammonia dosage cannot be achieved, resulting in an increase in production costs.

[0029] In the reduction reaction, the hydrogen pressure is 10-50 bar, for example, 15-45 bar, 20-40 bar, 25-38° C., preferably 28-35 bar, more preferably 30-35 bar. When the hydrogen pressure is lower than 10 bar, the reaction speed is slow, which reduces the time-space yield; when the hydrogen pressure is higher than 50 bar, the requirements for the reactor model are significantly increased, and the reactor price will also be significantly increased, resulting in an increase in production costs.

[0030] The reaction temperature is 20-100° C., for example, 25-90° C., 30-80° C., 40-70° C., preferably 45-70° C., more preferably 50-60° C. When the reaction temperature is lower than 20° C., the reaction rate is slow, which reduces the time-space yield; when the reaction temperature is higher than 100° C., the reaction rate is too fast, which easily leads to an increase in the content of by-products.

[0031] Those skilled in the art can explore the optimal combination of the types and dosage conditions of these reaction raw materials through specific experiments.

[0032] The present invention is further described below by way of examples. It should be understood that these examples are only for illustrative purposes and are not intended to limit the present invention.

[0033] Example

[0034] The examples involve the addition amounts, contents and concentrations of various substances, wherein the percentages described therein, unless otherwise specified, are all by mass percentages.

[0035] In the examples herein, if no specific description is given for the reaction temperature or the operating temperature, the temperature generally refers to room temperature (15-30° C.).

[0036] Reagents: The reactants used in the examples of the present invention are all chemically pure and can be used directly or after simple purification as needed; organic solvents are all analytically pure and used directly. Reagents were purchased from China Pharmaceutical (Group) Shanghai Chemical Reagent Company.

[0037] Testing instruments:

[0038] NMR instrument models: Bruker AV-500 and Bruker AV-600;

[0039] Mass spectrometer (liquid chromatography-mass spectrometry (LC / MS)), model: Agilent 6120B, detector: DAD;

[0040] Gas chromatograph (GC), model: Shimadzu 2030, detector: FID, gas chromatography column model: 30-mG0301-31.

[0041] Example 1: Synthesis of Caronamine

[0042] In an autoclave (ChemTron), 5g of compound I, 48mg of Raney nickel, 1g of sodium methoxide, and 30mL of 10% ammonia methanol solution were added respectively. The autoclave was then closed and filled with 30bar of hydrogen. The reaction was carried out at 50°C and 1200rpm for 12h. The heat was stopped, the temperature was lowered, and the gas in the autoclave was slowly released. After gas phase detection, 3.7g of the target product, caronamine (compound II), was obtained with a yield of 80%.

[0043] The NMR data of Caronamide are as follows: 1 H NMR (600 MHz, CDCl 3 )δ:2.89–2.87(m,2H),2.71–2.69(m,2H),1.94(br,1H),1.07–1.06(m,2H),2.71–2.69(m,2H),0.82(s,1H),0.80(s,1H).

[0044] The mass spectrum data are as follows: M / Z = 110

[0045] Example 2: Synthesis of Caronamine

[0046] In an autoclave (ChemTron), 5g of compound I, 40mg of Raney nickel, 1g of sodium methoxide, and 30mL of 10% ammonia methanol solution were added respectively. The autoclave was then closed and filled with 30bar of hydrogen. The reaction was carried out at 60°C and 1200rpm for 15h. The heat was stopped, the temperature was lowered, and the gas in the autoclave was slowly released. After gas phase detection, 3.9g of the target product, caronamine (compound II), was obtained with a yield of 84%.

[0047] Example 3: Synthesis of Caronamine

[0048] In an autoclave (ChemTron), 5g of compound I, 55mg of Raney nickel, 0.9g of sodium methoxide as an additive, and 30mL of 10% ammonia methanol solution were added respectively. The autoclave was then closed, and 30bar of hydrogen was introduced. The reaction was carried out at 55°C and 1000rpm under stirring conditions for 10h. The heat was stopped, the temperature was lowered, and the gas in the autoclave was slowly released. After gas phase detection, 3.8g of the target product, caronamine (compound II), was obtained with a yield of 82%.

[0049] Example 4: Synthesis of Caronamine

[0050] In an autoclave (ChemTron), 5 g of compound I, 10 mg of rhodium carbon, and 30 mL of methanol were added respectively. The autoclave was then closed and filled with 30 bar of hydrogen. The reaction was carried out at 80 ° C and 1200 rpm for 12 hours. The heat was stopped, the temperature was lowered, and the gas in the autoclave was slowly released. After gas phase detection, 3.3 g of the target product, caronamine, was obtained with a yield of 70%.

[0051] The above describes the specific embodiments of the present invention. It should be understood that the present invention is not limited to the above specific embodiments, and those skilled in the art can make various modifications or variations within the scope of the claims, which do not affect the essence of the present invention and should be included in the scope of the present invention.

Claims

1. A method for synthesizing caronamide, characterized in that: The following steps are involved: The 3,3-dimethylcyclopropane-1,2-dinitrile shown in formula I is subjected to a reduction reaction to generate calonamine shown in formula II, namely 6,6-dimethyl-3-azabicyclo[3.1.0]hexane:

2. The method according to claim 1, characterized in that In the reduction reaction, the reducing agent is hydrogen, and the catalyst is selected from Raney nickel, palladium carbon, Raney cobalt, Pt / C, Ru / C, Rh / C, or a mixture of two or more thereof.

3. The method according to claim 2, characterized in that When the catalyst is Raney nickel, the molar ratio of Raney nickel to 3,3-dimethylcyclopropane-1,2-dicarbonitrile is 1:30-100.

4. The method according to claim 1, characterized in that The reduction reaction is carried out under alkaline conditions, and the base used is selected from an organic base or an inorganic base.

5. The method according to claim 4, characterized in that The organic base is selected from sodium / potassium methoxide, sodium / potassium ethoxide, sodium / potassium tert-butoxide, triethylamine, pyridine, ethanolamine, 2-hydroxyethylamine, isopropanolamine, morpholine, or a mixture of two or more thereof; the inorganic base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, ammonia water, or a mixture of two or more thereof.

6. The method according to claim 1, characterized in that The reduction reaction is carried out in a solvent, and the solvent is selected from acetonitrile, propionitrile, methanol, ethanol, isopropanol, sec-butanol, tert-butanol, 3-pentanol, 2-pentanol, tert-pentanol, 2-methylbutanol, 3-methyl-3-pentanol, ethylene glycol, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, glycerol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, ethyl formate, ethyl acetate, isoamyl acetate, 1,2-dichloroethane, ethylenediamine, n-hexane, n-heptane, ether, petroleum ether, chloroform, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, benzene, toluene, xylene, mesitylene, chlorobenzene, dichlorobenzene, tert-butyl methyl ether, or a mixture of two or more thereof.

7. The method according to claim 1, characterized in that The reduction reaction is carried out in the presence of ammonia, which is in the form of an alcoholic ammonia solution.

8. The method according to claim 7, characterized in that The molar ratio of ammonia to 3,3-dimethylcyclopropane-1,2-dicarbonitrile is 20-50:

1.

9. The method according to claim 1, characterized in that The hydrogen pressure in the reduction reaction is 10-50 bar.

10. The method according to claim 1, characterized in that The reaction temperature is 20-100°C.

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