Aza-borane complex and its preparation method and use

Abstract

The application discloses aza-cycloborane complex and a preparation method and application thereof. The structure of the compound is shown in formula I.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of chemical synthesis, and particularly relates to a 6,6-dimethyl-3-azabicyclo[3.1.0]hexane borane complex and a preparation method and use thereof. BACKGROUND

[0002] 6,6-dimethyl-3-azabicyclo[3.1.0]hexane (CAS No: 943516-54-9 / compound of formula II) is a key intermediate of many drugs such as hepatitis C protease inhibitor Boceprevir and drug PF-07321332. The compound of formula II is usually obtained by reduction of a compound with CAS No: 194421-56-2 (compound of formula III), as described in WO2009073380, WO2014061034, etc. The 6,6-dimethyl-3-azabicyclo[3.1.0]hexane borane complex is generated in the reduction process using borane compounds (such as tetrahydrofuran borane complex, borane dimethyl sulfide, N,N-diethyl borane, borane pyridine, sodium borohydride plus Lewis acid). The borane complex reduction synthesis of formula II is the most economical method, however, after consulting a large amount of literature, no compound of formula I is described, and the physical property research of the compound of formula I is crucial for the synthesis of the compound of formula II.

[0003] Therefore, the present application focuses on the physical property research of the compound of formula I, including the preparation method, characterization and use of the compound. SUMMARY

[0004] The present application aims to provide a new compound and a preparation method and use thereof.

[0005] In a first aspect of the present application, a compound with a structure as shown in formula I is provided:

[0006]

[0007] In a second aspect of the present application, a preparation method of the compound with a structure as shown in formula I provided by the present application is provided, and the method comprises the step of: subjecting a compound with a structure as shown in formula II to a complexation reaction to obtain the compound with a structure as shown in formula I provided by the present application.

[0008]

[0009] In another embodiment, the complexation reaction is carried out in one or more than two solvents selected from the group consisting of tetrahydrofuran, tert-butyl methyl ether, ethylene glycol dimethyl ether.

[0010] In another embodiment, the complexation reaction temperature is -10-50℃.

[0011] In another embodiment, the complexation reaction time is 0.5-24 hours.

[0012] In another embodiment, the complexation reaction is carried out in the presence of a borane complex.

[0013] In another embodiment, the equivalent ratio of the compound having the structure as shown in Formula II to the borane complex used is 1:0.5-5.

[0014] In another embodiment, the borane complex is selected from one or more of the following: N,N-diethylanilinium borane complex, borane dimethyl sulfide, borane triethylamine, borane pyridine, borane tetrahydrofuran.

[0015] In a third aspect of the present application, there is provided another method for preparing the compound having the structure as shown in Formula I according to the present application, which comprises the step of: subjecting a compound having the structure as shown in Formula III to a reduction reaction to obtain the compound having the structure as shown in Formula I according to the present application.

[0016]

[0017] In another embodiment, the reducing agent for the reduction reaction comprises a borane complex and a boron reducing agent.

[0018] In another embodiment, the reducing agent is selected from one or more of the following: N,N-diethylanilinium borane complex, borane tetrahydrofuran, sodium borohydride, borane dimethyl sulfide, borane triethylamine, borane pyridine.

[0019] In another embodiment, the equivalent ratio of the compound having the structure as shown in Formula III to the reducing agent used is 1:1-5.

[0020] In a fourth aspect of the present application, there is provided the use of the compound having the structure as shown in Formula I according to the present application in the preparation of a compound having the structure as shown in Formula II.

[0021] In a fifth aspect of the present application, there is provided the use of the compound having the structure as shown in Formula I according to the present application as a reducing agent.

[0022] In a sixth aspect of the present application, there is provided a method for preparing a compound having the structure as shown in Formula II, which comprises the step of: subjecting a compound having the structure as shown in Formula I to a hydrolysis reaction to obtain the compound having the structure as shown in Formula II.

[0023] In another embodiment, the hydrolysis reaction reagent comprises an acidic aqueous solution.

[0024] In another embodiment, the acidic aqueous solution contains 5-50 wt% acid based on the total weight of the acidic aqueous solution.

[0025] In another embodiment, the temperature of the hydrolysis reaction is from room temperature to the reflux temperature of the reaction solvent.

[0026] Accordingly, the present application provides a compound of Formula I, as well as a method for preparing the compound, and its characterization and use. DETAILED DESCRIPTION

[0027] The inventors have unexpectedly obtained a compound having a structure as shown in Formula I, and have discovered that the compound is effective in producing 6,6-dimethyl-3-azabicyclo[3.1.0]hexane, and can also be used as a reducing agent in many reduction reactions. Based on this, the present application has been completed.

[0028] As used herein, "a compound having a structure as shown in Formula I" and "a compound of Formula I" are used interchangeably, and refer to 6,6-dimethyl-3-azabicyclo[3.1.0]hexane borane complex. Other compounds indicated by Roman numerals are used in the same way.

[0029] As used herein, "room temperature" refers to 15-35 °C, such as, but not limited to, 15-20 °C, 15-25 °C, 18-20 °C, 15-30 °C, 22-28 °C, 24-30 °C, 32-35 °C, etc.

[0030] As used herein, "borane" refers to a compound composed of boron and hydrogen (i.e., a borohydride), such as, but not limited to, BH3.

[0031] As used herein, "borane complex" refers to a complex formed by a trivalent nitrogen atom and a borane, such as, but not limited to, N,N-diethylaniline borane complex, borane tetrahydrofuran, borane dimethyl sulfide, borane triethylamine, borane pyridine, etc. The compound of Formula I provided in the present application is listed separately as a borane complex.

[0032] The compounds referred to herein are listed in Table 1:

[0033] Table 1

[0034]

[0035]

[0036] Compound

[0037] The present application provides a new compound having a structure as shown in Formula I, which can be referred to as 6,6-dimethyl-3-azabicyclo[3.1.0]hexane borane complex. The compound can be used as an intermediate for synthesizing a compound of Formula II; and the compound, as a stable borane complex, can also be widely used as a reducing agent in reduction reactions.

[0038] Preparation method

[0039] The compound of formula I can be prepared by the following steps:

[0040] In the first step, a solution containing the compound of formula II is combined with a borane complex to form a mixture 1.

[0041] In the second step, the mixture 1 is stirred to allow the complexation reaction to occur.

[0042] In the third step, the solvent is removed to form a solid.

[0043] In the fourth step, the solid is dissolved and the resulting solution is cooled, crystallized, and filtered to form the compound of formula I.

[0044] In the first step, the solution containing the compound of formula II is prepared by combining the compound of formula II with a solvent. In one embodiment, the solvent comprises tetrahydrofuran, t-butyl methyl ether, ethylene glycol dimethyl ether, or a mixture thereof, and preferably tetrahydrofuran.

[0045] In one embodiment, the mixture 1 is formed by adding the borane complex to the solution containing the compound of formula II. In one example, the borane complex and / or boron reducing agent is added dropwise to the solution containing the compound of formula II at about 0 °C, and the temperature is controlled to not exceed about 20 °C during the addition.

[0046] In one embodiment, the ratio of the equivalents of the compound of formula II to the equivalents of the borane complex used in the first step is 1 : 0.5-5, such as, but not limited to, 1 : 1.1-4.9, 1 : 1.5-3, 1 : 0.7-3.5, and the like. The number of equivalents of the borane complex used should be appropriate, as excess amounts can result in waste and can affect work-up, thereby reducing yield.

[0047] In one embodiment, the borane complex used in the first step can include, but is not limited to, N,N-diethylaniline borane complex, borane dimethyl sulfide, borane triethylamine, borane pyridine, borane tetrahydrofuran, or a mixture thereof.

[0048] In the second step, the stirring is typically performed at about -10 to -50 °C, such as, but not limited to, -5 to -37 °C, -5 to -42 °C, -10 to -47 °C, -12 to -28 °C, -15 to -32 °C, -2 to -22 °C, and the like. In one embodiment, the stirring is performed for about 0.5 to 24 hours, such as, but not limited to, 1.5 to 20 hours, 3 to 15 hours, 7 to 10 hours, and the like.

[0049] In the third step, the solvent used in the first step is removed, which can be performed by conventional methods, such as, but not limited to, rotary evaporation.

[0050] The solvent used to dissolve the solid in the fourth step above includes, but is not limited to, methyl tert-butyl ether, toluene, or a mixture thereof, as long as the solid can be completely dissolved. In some embodiments, the solid can be dissolved by increasing the temperature.

[0051] In one embodiment of the present application, the solution is cooled to room temperature before the fourth step above.

[0052] In one embodiment of the present application, the solution is cooled to about -20°C before the fourth step above, and the solid is allowed to precipitate by stirring the solution at this temperature for a period of time.

[0053] In one embodiment of the present application, the solution is filtered and dried to obtain the compound of formula I after the fourth step above. The filtering method that can be used includes, but is not limited to, suction filtration, centrifugation, etc. The drying method that can be used includes, but is not limited to, vacuum drying, etc.

[0054] The present application also provides a method for preparing the compound of formula I, which can be prepared by the following steps:

[0055] In the first step, a solution containing the compound of formula III is mixed with a reducing agent to obtain a mixture 2.

[0056] In the second step, the reaction is carried out at a temperature of about reflux temperature of the solvent to obtain the compound of formula I.

[0057] In the first step above, the solution containing the compound of formula III is obtained by mixing the compound of formula III with a solvent. In one embodiment of the present application, the solvent includes tetrahydrofuran, methyl tert-butyl ether, ethylene glycol dimethyl ether, or a mixture thereof, preferably tetrahydrofuran.

[0058] In one embodiment of the present application, the mixture 2 is obtained by dropping the reducing agent into the solution containing the compound of formula III in the first step above. In one example of the embodiment, the reducing agent is dropped into the solution containing the compound of formula III, and the temperature is controlled to be not more than about 40°C during the dropping process.

[0059] In one embodiment of the present application, the equivalent ratio of the compound of formula III to the reducing agent used in the first step above is 1:1-10, such as, but not limited to, 1:1.5-3, 1:2-7, 1:3.5-8, etc.

[0060] In one embodiment of the present application, the reducing agent that can be used in the first step above includes, but is not limited to, N,N-diethylaniline borane complex, borane dimethyl sulfide, borane triethylamine, borane pyridine, borane tetrahydrofuran, sodium borohydride, or a mixture thereof.

[0061] In one embodiment of the present application, the first step is adding sodium borohydride to a solution containing the compound of formula III, and adding concentrated sulfuric acid dropwise while stirring and raising the temperature to about 30°C, with the temperature controlled to not exceed about 40°C.

[0062] The second step is performed for about 20 to 60 hours.

[0063] Use

[0064] The present application uses a compound of formula I to synthesize a compound of formula II. The method includes the step of hydrolyzing the compound of formula I under acidic conditions to obtain the compound of formula II.

[0065] In one embodiment of the present application, the compound of formula I is hydrolyzed under acidic conditions and then basified to obtain the compound of formula II.

[0066] In one embodiment of the present application, a solution containing the compound of formula I is mixed with an aqueous acidic solution, and after the reaction, a base is added to adjust the pH to above about 9 to obtain the compound of formula II.

[0067] In one embodiment of the present application, the solution containing the compound of formula I is obtained by mixing the compound of formula I with an organic solvent, which includes tetrahydrofuran, ethylene glycol dimethyl ether, or a mixture thereof.

[0068] In one embodiment of the present application, the aqueous acidic solution is obtained by mixing an inorganic acid with water, which includes but is not limited to, hydrochloric acid, sulfuric acid, phosphoric acid; and the inorganic acid is contained in an amount of 5 to 50 wt% based on the total weight of the aqueous acidic solution, such as but not limited to, 10 to 30 wt%, 25 to 36 wt%, etc.

[0069] In one embodiment of the present application, the base added is an aqueous alkaline solution, which contains sodium hydroxide or potassium hydroxide in an amount of 10 to 50 wt% based on the total weight of the aqueous alkaline solution, such as but not limited to, 15 to 30 wt%, 25 to 35 wt%, etc.

[0070] In one embodiment of the present application, the solution containing the compound of formula I obtained by mixing the compound of formula I with tetrahydrofuran is mixed with an aqueous hydrochloric acid solution for 0.5 to 4 hours, and then an aqueous alkaline solution is used to adjust the pH to 11 to 12 to hydrolyze to obtain the compound of formula II.

[0071] In one embodiment of the present application, the reaction mixture after hydrolysis is allowed to separate into layers, the aqueous phase is extracted with an organic solvent, and then the organic phases are combined and the compound of formula II is refined; the refining includes but is not limited to, distillation.

[0072] The present application also uses the compound of formula I as a reducing agent. The reaction involved can include, for example but not limited to, carbonyl reduction, etc.

[0073] In one embodiment of the present application, the compound of formula I is used as a reducing agent in reactions such as reduction of amides to alkylamines, reduction of acids or esters to alcohols, and the like. These reactions can be carried out by, but not limited to, the following procedure: the starting material (amide, acid, or ester, etc.) is mixed with a solvent and the reducing agent (i.e., the compound of formula I) is added to the mixture to obtain the corresponding product. The solvent is selected from one or more of the following: toluene, benzene, ethylene glycol dimethyl ether, methyl tert-butyl ether, and the like. The reaction temperature, reaction time, and the like can vary greatly depending on the starting material, for example, it can range from about 50 °C to about 150 °C, and from about 18 hours to about 48 hours. The ratio of the equivalents of the starting material to the reducing agent can also range from about 1 :3.0 to 5.0.

[0074] The compound of formula II is a new borane complex and has its own advantages, for example, it is a solid compound and is more stable than other borane complexes and is easy to store and transport.

[0075] The features disclosed in the specification, or the features disclosed in the claims, can be combined in any combination. All features disclosed in the specification can be used in any combination with any other features disclosed in the specification. Each feature disclosed in the specification can be replaced by any alternative feature which provides the same, equivalent or similar functionality. Thus, unless expressly excluded, features disclosed in the specification and the claims are considered to be optional elements of the embodiments described in the specification.

[0076] Notwithstanding that the numerical ranges and parameters setting forth the broadest scope of the application are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. The numerical values should therefore be considered in the context of the test from which they are derived, and by virtue of the inherent inescapable errors in their respective testing, the numerical values should only be considered as approximations. Generally, "about" when used before a term or numeric value denotes that the term or numeric value can vary from the specified value by as much as 10%, 5%, 1%, or 0.5%. Alternatively, "about" means that the numeric value falls within an acceptable standard deviation from the mean, as would be appreciated by one of ordinary skill in the art. Except in the operating and comparative examples, or unless otherwise expressly indicated, all numerical ranges, numbers and percentages herein are approximations and are understood to be used in a generic sense, unless otherwise indicated. Thus, unless expressly stated otherwise, the numerical parameters in the specification and the claims include all values from the lower limit to the upper limit of the range, in increments of one unit used in the parameter. At the very least, each minimum numerical limitation should be construed in the context of the other claims attached to the same conceptual entity and of the prior art.

[0077] The main advantage of the present application is that a new compound of formula I is obtained using a simple method and the physical properties and uses of the new compound are investigated.

[0078] The application will be further described in conjunction with specific examples. It should be understood that these examples are intended to illustrate the application and are not intended to limit the scope of the application. The experimental procedures in the following examples, unless otherwise indicated, were carried out in accordance with conventional procedures or as recommended by the manufacturer. Unless otherwise indicated, all percentages, ratios, proportions, or parts are by weight. The units in the weight / volume percentages in the present application are well known to those skilled in the art, for example, refer to the weight (gram) of solute in 100 milliliters of solution. Unless otherwise defined, all other technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. In addition, any method and material similar or equivalent to those described herein can be used in the practice of the present application. The preferred methods and materials described herein are intended to be illustrative only and are not intended to be limiting.

[0079] The detection methods involved in the following examples are as follows:

[0080] NMR: Model: BRUKER 400

[0081] IR:

[0082] Model: BRUKER FT-IR ALPHA

[0083] Method: ATR, number of scans 32. Resolution: 2 cm -1

[0084] Software: OPUS 7.5

[0085] Example 1

[0086] Synthesis of compound of formula I by complexation reaction

[0087]

[0088] A 500 mL four-necked flask was equipped with a mechanical stirrer and a thermometer. After the flask was dried, 28 g of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane (formula II) (252.2 mmol, 1.0 eq) and 50 mL of anhydrous tetrahydrofuran were added under nitrogen protection, and the mixture was cooled to 0°C with an ice water bath. Then 252.2 mL of borane tetrahydrofuran solution (1M, 1.0 eq) was added dropwise, and the internal temperature was controlled to be no more than 20°C. The dropwise addition was completed in about 1 hour. After the dropwise addition was completed, the temperature was increased to 30-35°C, and the mixture was stirred at 30-35°C for 2 hours. The tetrahydrofuran was removed on a rotary evaporator to obtain a white solid. Then 60 mL of methyl tert-butyl ether was added, and the mixture was heated to 50°C and stirred until the solid was completely dissolved. After the mixture was naturally cooled to room temperature, it was cooled to -20°C and stirred at this temperature for 3 hours. The mixture was filtered and dried to obtain the final product (formula I), 30.7 g of white solid, with a yield of 95.5%, and a melting point of 87.2-90.2°C.

[0089] 1H-NMR (CDC13, ppm) δ 1.02-1.12 (m, 6H) 1.43-1.49 (m, 2H), 3.12-3.23 (m, 4H).

[0090] 13B-NMR (CDC13, ppm): δ -13.5.

[0091] IR: A strong B-H characteristic peak was found at 2306 cm -1

[0092] Example 2-5

[0093] Synthesis of compound of formula I by complexation reaction

[0094] The preparation method is basically the same as example 1, using different solvents: experiments show that using t-butyl methyl ether and ethylene glycol dimethyl ether as solvent, the yield is close to using tetrahydrofuran, using water as solvent can not get the product, using toluene as solvent has lower yield.

[0095] Example 2 Example 3 Example 4 Example 5 Compound of formula II 28.0g 28.0g 28.0g 28.0g Solvent used tert-butyl methyl ether ethylene glycol dimethyl ether water toluene temperature 30-35℃ 30-35℃ 30-35℃ 30-35℃ reaction time (hours) 2h 2h 2h 2h isolation yield of compound of formula I 92.4％ 92.8％ 0 45.9％

[0096] Example 6-9

[0097] Synthesis of compound of formula I by complexation reaction

[0098] The preparation method is basically the same as example 1, using different borane complexes: experiments show that different borane complexes can also obtain the product.

[0099]

[0100] Example 10-14

[0101] Synthesis of compound of formula I by complexation reaction

[0102] The preparation method is basically the same as example 1, the reaction time is different: experiments show that the reaction time can be between 24 hours, and has good reaction yield.

[0103]

[0104] Example 15-19

[0105] Synthesis of compound of formula I by complexation reaction

[0106] The preparation method is basically the same as example 1, the reaction temperature is different.

[0107]

[0108] Example 20-24

[0109] Synthesis of compound of formula I by complexation reaction​

[0110] The preparation method is substantially the same as that of Example 1, except that the number of equivalents of borane tetrahydrofuran is different.

[0111]

[0112] Example 25

[0113] Hydrolysis of the compound of Formula I to the compound of Formula II

[0114]

[0115] A 250 mL four-necked flask, mechanical stirring, thermometer. To the flask was added 15.0 g of the compound of Formula I, which was dissolved in 50 mL of tetrahydrofuran, followed by the addition of 30 mL of 6 N hydrochloric acid solution. After stirring at room temperature for 2 hours, the pH was adjusted to 11-12 with 40% sodium hydroxide solution. After separation of the layers, the aqueous phase was extracted with 150 mL of toluene, and the combined organic phase was distilled using a rectification column to obtain the compound of Formula II in a yield of 95.3% and a GC purity of 99.2%.

[0116] 1H-NMR (CDC13, ppm) δ 1.0 (m, 6H), 1.24-1.28 (m, 2H), 2.28-2.29 (m, 2H), 3.07-3.11 (m, 2H).

[0117] Examples 26-29

[0118] Hydrolysis or alcoholysis of the compound of Formula I to the compound of Formula II

[0119]

[0120] The results show that the hydrolysis or alcoholysis of the compound of Formula I to the compound of Formula II is difficult under neutral or basic conditions, and the alcoholysis or alcoholysis catalyzed by palladium on carbon is not complete.

[0121] Examples 30-35

[0122] Reduction reaction to synthesize the compound of Formula I

[0123]

[0124] Example 30

[0125] A 500 mL four-necked flask, mechanical stirring, thermometer and condenser and constant pressure funnel. Under nitrogen protection, the flask was charged with the starting material, compound of formula III (compound CAS No: 194421-56-2) (15.0 g, 107.5 mmol, 1.0 eq) and 150 mL of tetrahydrofuran, and sodium borohydride (17.08 g, 451.5 mmol, 4.2 eq) was added. The mixture was stirred and warmed to 30 °C, and stirred at 30 °C for 30 min. 22.5 g of 98% concentrated sulfuric acid was added dropwise (exothermic reaction, the internal temperature was controlled not to exceed 40 °C with an ice water bath). After the addition was completed, the temperature was raised to the reflux temperature of tetrahydrofuran, and refluxed for 48 h. GC monitoring showed that the starting material, compound of formula III, was about 5.0% remaining. After cooling to room temperature, the reaction was quenched with methanol, and then 100 mL of water and 100 mL of toluene were added to separate the layers. The aqueous phase was extracted with 150 mL of toluene, and the combined organic phases were dried over anhydrous sodium sulfate. The combined organic phases were rotary evaporated to give a white solid. 40 mL of methyl tert-butyl ether was added, and the mixture was heated to 50 °C and stirred until the solid was completely dissolved. The mixture was allowed to cool to room temperature, and then cooled to -20 °C and stirred at this temperature for 3 h. The mixture was filtered and dried to give the final product (formula I), 8.66 g of white solid, in 65.0% yield.

[0126] 1H-NMR (CDC13, ppm) δ 1.02-1.12 (m, 6H) 1.43-1.49 (m, 2H), 3.12-3.23 (m, 4H).

[0127] 13B-NMR (CDC13, ppm): δ -13.5.

[0128] Example 31

[0129] A 500 mL four-necked flask, mechanical stirring, thermometer, and condenser with a pressure-equalizing dropping funnel. The flask was charged with the starting material, compound of formula III (compound CAS No: 194421-56-2) (15.0 g, 107.5 mmol, 1.0 eq) and 150 mL of tetrahydrofuran, stirred and warmed to 30 °C, and borane tetrahydrofuran solution (1 M, 645 mL, 645 mmol, 6.0 eq) was added dropwise at 30 °C (vigorous heat, the internal temperature was controlled not to exceed 40 °C with an ice water bath). After the dropwise addition was completed, the temperature was raised to the reflux temperature of tetrahydrofuran, and reflux was maintained for 48 h. GC monitoring showed that about 6.3% of the starting material, compound of formula I, remained. After cooling to room temperature, the reaction was quenched with methanol, and then 100 mL of water and 100 mL of toluene were added to separate the layers. The aqueous phase was extracted with 150 mL of toluene, and the combined organic phases were dried over anhydrous sodium sulfate. The organic phase was concentrated to give a white solid, which was dissolved in 40 mL of methyl tert-butyl ether and heated to 50 °C. The solution was stirred until the solid was completely dissolved. The solution was then allowed to cool to room temperature, and then to -20 °C. The mixture was stirred at -20 °C for 3 h. The product was collected by filtration and dried to give the final product (compound of formula I), 8.32 g of a white solid, in 62.6% yield.

[0130] Examples 32-35

[0131] The preparation method was essentially the same as in Example 31, except that a different borane complex was used.

[0132]

[0133] Example 36

[0134] Reductive synthesis of nicotinic amide

[0135] A 250 mL four-necked flask, mechanical stirring, thermometer, and reflux condenser. After the flask was dried, 5.0 g of nicotinamide (40.9 mmol, 1.0 eq) and 50 mL of toluene were added under nitrogen. The temperature was raised to 50 °C, and 15.2 g of the reducing agent (compound of formula I) (122.7 mmol, 3.0 eq) was added in three portions. After the addition of the reducing agent was completed, the temperature was raised to the reflux temperature and reflux was maintained overnight (18 h). TLC monitoring showed that the reaction was complete. After the temperature was lowered to room temperature, 50 mL of 5 N hydrochloric acid was added, and the mixture was stirred for 2 h. The pH was then adjusted to 11-12 with a 40% sodium hydroxide solution. After the layers were separated, the organic phase was dried over anhydrous sodium sulfate. The final product, nicotinic amide, was obtained as a colorless liquid by distillation after filtration, in 87.5% yield.

[0136] 1H-NMR (CDC13, ppm) δ 1.61 (s, 2H), 3.80 (s, 2H), 7.15-7.58 (m, 2H), 8.39 (d, 1H), 8.48 (s, 1H).

[0137] Example 37

[0138] Reductive synthesis of benzylamine

[0139] 250 mL four necked flask, mechanical stirring, thermometer, reflux condenser. After drying the reaction flask, 5.0 g of benzamide (41.2 mmol, 1.0 eq) and 50 mL of ethylene glycol dimethyl ether were added under nitrogen atmosphere, the temperature was raised to 50 °C and 15.4 g of reducing agent (compound of formula I) (123.8 mmol, 3.0 eq) was added in three portions. After the addition of reducing agent was completed, the temperature was raised to reflux and maintained at reflux overnight (18 hours). The reaction was monitored by TLC. After cooling to room temperature, 50 mL of 5 N hydrochloric acid was added and stirred for 2 hours. The pH was adjusted to 11-12 using 40% sodium hydroxide solution. The organic layer was separated and dried over anhydrous sodium sulfate. The filtrate was distilled to obtain the final product, nicotine amine, as a colorless liquid 4.2 g in 95.1% yield.

[0140] 1H-NMR (CDC13, ppm) δ 1.59 (s, 2H), 3.88 (s, 2H), 7.24-7.42 (m, 5H).

[0141] Example 38

[0142] Reductive synthesis of 4-methoxybenzyl alcohol

[0143] 250 mL four necked flask, mechanical stirring, thermometer, reflux condenser. After drying the reaction flask, 5.0 g of benzamide (41.2 mmol, 1.0 eq) and 50 mL of ethylene glycol dimethyl ether were added under nitrogen atmosphere, the temperature was raised to 50 °C and 15.4 g of reducing agent (compound of formula I) (123.8 mmol, 3.0 eq) was added in three portions. After the addition of reducing agent was completed, the temperature was raised to reflux and maintained at reflux overnight (18 hours). The reaction was monitored by TLC. After cooling to room temperature, 50 mL of 5 N hydrochloric acid was added and stirred for 2 hours. The pH was adjusted to 11-12 using 40% sodium hydroxide solution. The organic layer was separated and dried over anhydrous sodium sulfate. The filtrate was distilled to obtain the final product, nicotine amine, as a colorless liquid 4.2 g in 95.1% yield.

[0144] 1H-NMR (CDC13, ppm) δ 1.59 (s, 2H), 3.88 (s, 2H), 7.24-7.42 (m, 5H).

[0145] Example 39

[0146] Reductive synthesis of 3-methyl-1-butanol

[0147] 250 mL four-necked flask, mechanical stirring, thermometer, reflux condenser. After the reaction flask was dried, 5.0 g of methyl isovalerate (43.0 mmol, 1.0 eq) and 50 mL of methyl tert-butyl ether were added under nitrogen protection, and the temperature was raised to 30°C. 15.0 g of the reducing agent (compound of formula I) (120.9 mmol, 3.0 eq) was added in three portions. After the reducing agent was added, the temperature was raised to reflux and maintained at reflux overnight (24 hours). TLC was used to monitor the completion of the reaction. After the temperature was lowered to room temperature, 50 mL of 5N hydrochloric acid was added, and stirred for 2 hours. Then 40% sodium hydroxide solution was added to adjust the pH to 11-12. After the layers were separated, the organic phase was dried over anhydrous sodium sulfate. After filtration, column chromatography was used to obtain the final product 3-methyl-1-butanol, colorless liquid, 3.8 g, yield 95.1%.

[0148] 1H-NMR (CDCI3, ppm) δ 0.86-0.90 (m, 6H), 1.42-1.47 (m, 2H), 1.64-1.72 (m, 1H), 2.04-2.06 (m, 1H, OH), 3.61-3.65 (m, 2H).

[0149] The above description is only the preferred embodiment of the present application, and is not intended to limit the scope of the technical content of the present application. The technical content of the present application is broadly defined in the scope of the claims, and any technical entity or method completed by others, if it is the same as or equivalent to the scope of the claims defined in the application, will be considered to be covered in the scope of the claims.

Claims

1. A compound with the structure shown in Formula I: 。 2. A method for preparing a compound with the structure shown in Formula I as described in claim 1, characterized in that, The method includes the step of: subjecting a compound with the structure shown in Formula II to a complexation reaction to obtain a compound with the structure shown in Formula I as described in claim 1; ； The method includes the following steps: The first step is to mix the solution containing compound II with the borane complex to obtain mixture 1; The second step is to stir mixture 1 to initiate a complexation reaction; The third step is to remove the solvent to obtain a solid. The fourth step involves dissolving the solid and cooling, crystallizing, and filtering the resulting solution to obtain compound I. The borane complex is selected from one or more of the following: N,N-diethylaniline borane complex, borane dimethyl sulfide, borane triethylamine, borane pyridine, and borane tetrahydrofuran.

3. The preparation method according to claim 2, characterized in that, The complexation reaction is carried out in one or more of the following solvents: tetrahydrofuran, tert-butyl methyl ether, and ethylene glycol dimethyl ether.

4. The preparation method according to claim 2, characterized in that, The complexation reaction temperature is -10 to -50°C.

5. The preparation method according to claim 2, characterized in that, The complexation reaction time is 0.5-24 hours.

6. The preparation method according to claim 2, characterized in that, The equivalent ratio of the compound with the structure shown in Formula II to the borane complex used is 1:0.5-5.

7. The preparation method according to claim 2, characterized in that, In the first step, the solution containing compound II is obtained by mixing compound II with a solvent.

8. The preparation method according to claim 2, characterized in that, In the first step, mixture 1 is obtained by adding a borane complex dropwise to a solution containing compound II.

9. The preparation method according to claim 2, characterized in that, In the first step, a borane complex is added dropwise to a solution containing compound II at 0°C, and the temperature is controlled not to exceed 20°C during the addition process.

10. The preparation method according to claim 2, characterized in that, In the fourth step, the solvent used to dissolve the solid includes methyl tert-butyl ether, toluene, or a mixture thereof.

11. The use of a compound of formula I as described in claim 1 as a reducing agent, wherein, Compounds of Formula I act as reducing agents in reactions that reduce amides to alkylamines and acids or esters to alcohols.

12. The application as described in claim 11, characterized in that, The reaction includes the steps of: mixing the raw material with a solvent and then adding a compound of formula I to react and obtain the corresponding product, wherein the raw material is selected from one or more of amides, acids and esters.

13. The application as described in claim 12, characterized in that, The solvent is selected from one or more of the following: toluene, benzene, ethylene glycol dimethyl ether, and methyl tert-butyl ether.

14. The application as described in claim 12, characterized in that, The reaction has one or more of the following characteristics: The reaction temperature is 50℃ to 150℃; The reaction time is 18 to 48 hours; The equivalent ratio of the raw material to the compound of formula I is 1:3.0-5.0.

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