A process for the preparation of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane

Abstract

The application discloses a preparation method of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane. The method comprises the following steps: subjecting a compound shown in formula I to a reduction reaction in the presence of a reducing agent to obtain a compound shown in formula II; and the reducing agent comprises N,N-diethyl aniline borane complex.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis, specifically relating to a method for preparing 6,6-dimethyl-3-azabicyclo[3.1.0]hexane. Background Technology

[0002] 6,6-Dimethyl-3-azabicyclo[3.1.0]hexane (CAS No: 943516-54-9 / Compound of Formula II) is a key intermediate for many drugs, such as the hepatitis C protease inhibitor Boceprevir and the COVID-19 drug PF-07321332. Current methods for reducing Formula I compounds to Formula II include reduction with lithium aluminum hydride, reduction with red aluminum, and reduction with sodium borohydride and Lewis acids (e.g., WO2009073380, WO2014061034, WO2007093364, WO2012049688, WO2021160602). Scale-up production with lithium aluminum hydride requires consideration of the large amount of aluminum salts involved, and the production process carries significant safety risks. Reduction with red aluminum also produces large amounts of aluminum salts and various impurities, resulting in low yields. The reduction method using sodium borohydride and Lewis acids has a long reaction time (24–48 hours) and incomplete reaction (typically yielding 70–75%).

[0003] Therefore, there is an urgent need in the art to provide a new method for obtaining 6,6-dimethyl-3-azabicyclo[3.1.0]hexane by reduction reaction. Summary of the Invention

[0004] The present invention aims to provide a novel method for preparing 6,6-dimethyl-3-azabicyclo[3.1.0]hexane.

[0005] This invention provides 1. a method for preparing a compound with the structure shown in Formula II, the method comprising the steps of: reducing a compound with the structure shown in Formula I in the presence of a reducing agent to obtain a compound with the structure shown in Formula II; wherein the reducing agent comprises an N,N-diethylaniline borane complex;

[0006]

[0007] In another embodiment, the reduction reaction is carried out in one or more of the following solvents: toluene, xylene, ethylene glycol dimethyl ether, and triethylene glycol dimethyl ether.

[0008] In another embodiment, the solvent is toluene and xylene in a volume ratio of 1:1-3.

[0009] In another embodiment, the reduction reaction temperature is 60-150°C.

[0010] In another embodiment, the reduction reaction temperature is 100-120°C.

[0011] In another embodiment, the reduction reaction temperature is the solvent reflux temperature.

[0012] In another embodiment, the reduction reaction time is 10-24 hours.

[0013] In another embodiment, the equivalent ratio of the compound with the structure shown in Formula I to the reducing agent is 1:1-10.

[0014] In another embodiment, the equivalent ratio of the compound with the structure shown in Formula I to the reducing agent is 1:1-8.

[0015] Accordingly, the present invention provides a novel method for obtaining 6,6-dimethyl-3-azabicyclo[3.1.0]hexane via a reduction reaction. Detailed Implementation

[0016] The inventors discovered a method for preparing 6,6-dimethyl-3-azabicyclo[3.1.0]hexane by using N,N-diethylanilineborane complex (CAS NO: 13289-97-9) as a reducing agent. Based on this, the present invention was completed.

[0017] As used in this invention, "compound with structure as shown in Formula I" and "compound of Formula I" are used interchangeably, both referring to the compound with CAS number 194421-56-2. Other compounds represented by Roman numerals follow the same principle.

[0018] The compounds discussed in this article are listed in Table 1:

[0019]

[0020] Specifically, the compound of formula II provided by the present invention can be prepared by the following steps:

[0021] The first step is to mix the compound of formula I with a solvent to obtain solution 1;

[0022] The second step involves mixing solution 1 with the N,N-diethylanilineborane complex to form a reaction system.

[0023] The third step is to complete the reaction to obtain compound II.

[0024] The solvent used in the first step above includes toluene, xylene, ethylene glycol dimethyl ether, triethylene glycol dimethyl ether, or a mixture thereof, with toluene being preferred.

[0025] In one embodiment of the present invention, the first step described above can be achieved by completely dissolving the compound of formula I in a solvent through means such as selecting a suitable temperature and stirring to obtain solution 1. The suitable temperature can be adjusted according to the solvent used.

[0026] In the second step described above, N,N-diethylaniline borane complex is added dropwise to solution 1. In one embodiment, the temperature is controlled during the dropwise addition process to keep it below 100°C.

[0027] In one embodiment of the present invention, the equivalent ratio of the compound of formula I used in the second step above to the equivalent ratio of the N,N-diethylaniline borane complex is 1:1-10, for example, but not limited to, 1:1.5-7, 1:3.5-9, 1:2-6, etc.

[0028] The reaction temperature in the third step is 60-150°C. In one embodiment, the reaction is carried out at the reflux temperature of the solvent used in the first step.

[0029] The reaction time for the third step mentioned above is approximately 10-24 hours, for example, but not limited to, 12-20 hours, 15-21 hours, etc.

[0030] In one embodiment of the present invention, the reaction is quenched after completion, and the pH is adjusted to separate the reaction products into layers. The aqueous phase is then extracted with an organic solvent, and the organic phases are combined to purify the compound of formula II. The purification includes, but is not limited to, distillation, purification by adjusting the pH value and then extracting, and purification by salt formation and then crystallization.

[0031] The features mentioned above in this invention, or the features mentioned in the embodiments, can be combined arbitrarily. All features disclosed in this specification can be used in any compositional form, and each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the disclosed features are merely general examples of equivalent or similar features.

[0032] While the numerical ranges and parameters used to define the broader scope of this invention are approximate, the relevant values ​​in the specific embodiments have been presented as precisely as possible. However, any numerical value inevitably contains standard deviations due to individual test methods. Here, "approximately" generally means that the actual value is within plus or minus 10%, 5%, 1%, or 0.5% of a particular value or range. Alternatively, the term "approximately" may mean that the actual value falls within the acceptable standard error of the average, as determined by those skilled in the art. Except for experimental examples, or unless explicitly stated otherwise, it is understood that all ranges, quantities, values, and percentages used herein (e.g., to describe material usage, duration, temperature, operating conditions, quantity ratios, and others similar) are modified with "approximately". Therefore, unless otherwise stated, the numerical parameters disclosed in this specification and the accompanying claims are approximate values ​​and are subject to change as needed. At a minimum, these numerical parameters should be understood as the indicated significant digits and values ​​obtained by applying general rounding.

[0033] The main advantages of this invention are: the preparation method provided significantly reduces the safety risks in the industrial production process, the reaction is complete and clean, easy to post-process, and has a high yield.

[0034] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, all percentages, ratios, proportions, or parts are by weight. The units of weight-volume percentages in this invention are well known to those skilled in the art, for example, referring to the weight (grams) of solute in 100 ml of solution. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0035] The GC detection method involved in the following embodiments:

[0036] The gas chromatography procedure was followed, using a capillary column (HP-5 30m 0.32mm 0.25um) with 5% phenylmethylsiloxane as the stationary phase.

[0037] Column temperature: 40℃; Carrier gas flow rate: 1 ml / min; Split ratio: 20:1

[0038] H2: 30ml / min Air: 300ml / min

[0039] Inlet temperature: 280℃; Detector temperature: 300℃; Injection volume: 1ul

[0040] Exhaust gas (N2): 25 ml / min

[0041] Record the chromatogram and calculate using the area normalization method.

[0042] Pretreatment of the reaction solution: dilute with methanol before injection.

[0043] 0 40 3 3 15 100 0 5.667 30 280 8 19.667

[0044] Compound of Formula I: 11.12 min

[0045] Compound of Formula II: 8.65 min

[0046] N,N-Diethylaniline: 10.78 min

[0047] Example 1

[0048] Synthesis of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane

[0049] A 500 mL four-necked flask was mechanically stirred and equipped with a thermometer, condenser, and constant-pressure funnel. Under nitrogen protection, the starting material (compound CAS No: 194421-56-2) (15.0 g, 107.5 mmol, 1.0 equivalent) and 150 mL of toluene were added to the reaction flask. The mixture was stirred and heated to 80 °C until the starting material was completely dissolved. N,N-diethylaniline borane complex (5.2 M, 322.5 mmol, 3.0 equivalent) was added dropwise, with exothermic addition, and the internal temperature was controlled below 100 °C. After the addition was complete, the temperature was raised to reflux with toluene and maintained under reflux for 18 hours. The reaction was monitored for completeness using GC. After quenching with 6N hydrochloric acid, the reaction solution was adjusted to pH 11–12. After separation, the aqueous phase was extracted with 150 mL of toluene. The combined organic phases were then distilled using a distillation column to obtain the target product with a yield of 85.0% and a GC purity of 98.4%.

[0050] 1H-NMR(CDCl3,ppm)δ1.0(m,6H),1.24~1.28(m,2H),2.28~2.29(m,2H),3.07~3.11(m,2H).

[0051] Examples 2-5

[0052] Synthesis of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane

[0053] The preparation method is basically the same as in Example 1, except that a different solvent is used:

[0054]

[0055] Examples 6-9

[0056] Synthesis of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane

[0057] Examples 6-9: The preparation method is basically the same as that in Example 1, except that the equivalence ratio of the compound of Formula I to the reducing agent is different. The results show that the reaction results are the best and the yield is the most ideal when the equivalence number is 3.0-3.3. More N,N-diethylaniline borane complex does not improve the reaction yield.

[0058]

[0059] Examples 10-12

[0060] Synthesis of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane

[0061] Examples 10-12: The preparation method was basically the same as in Example 1, but different borane complexes were used. The results showed that the yields of the other borane complexes under the same reaction conditions were much lower than those of the N,N-diethylaniline borane complex.

[0062] Compound of Formula I 15.0g 15.0g 15.0g Borane complexes Borane dimethyl sulfide Boranepyridine Borane triethylamine solvent Toluene Toluene Toluene temperature reflux reflux reflux Reaction time (hours) 18h 18h 18h Separation yield of compound of formula II 65.7％ 63.2％ 58.3％

[0063] Example 13

[0064] A 500 mL four-necked flask was mechanically stirred and equipped with a thermometer, condenser, and constant pressure funnel. Under nitrogen protection, starting material compound 1 (CAS No: 194421-56-2) (15.0 g, 107.5 mmol, 1.0 equivalent) and 150 mL of tetrahydrofuran were added to the reaction flask, followed by sodium borohydride (17.08 g, 451.5 mmol, 4.2 equivalent). The mixture was stirred and heated to 30 °C. Stirring was maintained at 30 °C for 30 minutes. Then, 22.5 g of 98% concentrated sulfuric acid was added dropwise (exothermic reaction; the internal temperature was controlled to not exceed 40 °C using an ice-water bath). After the addition was complete, the mixture was heated to reflux with tetrahydrofuran and maintained under reflux for 48 hours. GC monitoring showed that approximately 5.0% of starting material compound 1 remained. After quenching with 6N hydrochloric acid, the reaction solution was adjusted to pH 11-12. After separation, the aqueous phase was extracted with 150 mL of toluene, and the organic phases were combined. The combined organic phases were then distilled using a distillation column to obtain the target product with a yield of 65.0% and a GC purity of 98.5%.

[0065] 1H-NMR(CDCl3,ppm)δ1.0(m,6H),1.24~1.28(m,2H),2.28~2.29(m,2H),3.07~3.11(m,2H).

[0066] Example 14

[0067] A 500 mL four-necked flask was mechanically stirred and equipped with a thermometer, condenser, and constant-pressure funnel. Under nitrogen protection, 15.0 g (107.5 mmol, 1.0 equivalent) of starting compound 1 (CAS No: 194421-56-2) and 150 mL of tetrahydrofuran were added to the reaction flask. The mixture was stirred and heated to 30 °C. At 30 °C, a 1 M tetrahydrofuran solution (645 mL, 645 mmol, 6.0 equivalent) was added dropwise (exothermic reaction; the internal temperature was controlled to not exceed 40 °C using an ice-water bath). After the addition was complete, the mixture was heated to reflux with tetrahydrofuran and maintained under reflux for 48 hours. GC monitoring showed that approximately 6.3% of starting compound 1 remained. After quenching with 6N hydrochloric acid, the reaction solution was adjusted to pH 11-12. After separation, the aqueous phase was extracted with 150 mL of toluene, and the organic phases were combined. The combined organic phases were then distilled using a distillation column to obtain the target product with a yield of 67.3% and a GC purity of 98.9%.

[0068] 1H-NMR(CDCl3,ppm)δ1.0(m,6H),1.24~1.28(m,2H),2.28~2.29(m,2H),3.07~3.11(m,2H).

[0069] Examples 15-18

[0070] The preparation method is basically the same as in Example 14, except that different borane complexes are used.

[0071]

[0072] The above description is merely a preferred embodiment of the present invention and is not intended to limit the scope of the substantive technical content of the present invention. The substantive technical content of the present invention is broadly defined within the scope of the claims. Any technical entity or method completed by others that is completely identical to or an equivalent modification of the claims is considered to be covered within the scope of the claims.

Claims

1. A method for preparing a compound with the structure shown in Formula II, characterized in that, The method includes the step of: reducing a compound with the structure shown in Formula I in the presence of a reducing agent to obtain a compound with the structure shown in Formula II; wherein the reducing agent is an N,N-diethylanilineborane complex. The reduction reaction is carried out in one or more of the following solvents: toluene, xylene, ethylene glycol dimethyl ether, and triethylene glycol dimethyl ether.

2. The preparation method according to claim 1, characterized in that, The solvent is toluene and xylene in a volume ratio of 1:1-3.

3. The preparation method according to claim 1, characterized in that, The reduction reaction temperature is 60-150℃.

4. The preparation method according to claim 3, characterized in that, The reduction reaction temperature is 100-120℃.

5. The preparation method according to claim 3, characterized in that, The reduction reaction temperature is the solvent reflux temperature.

6. The preparation method according to claim 1, characterized in that, The reduction reaction takes 10-24 hours.

7. The preparation method according to claim 1, characterized in that, The equivalent ratio of the compound with the structure shown in Formula I to the reducing agent is 1:1-10.

8. The preparation method according to claim 7, characterized in that, The equivalent ratio of the compound with the structure shown in Formula I to the reducing agent is 1:1-8.

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