A method for preparing a chiral intermediate of a drug for treating ocular hypertension

Abstract

The invention discloses a preparation method of a chiral intermediate (S)-3-methyl-1-tert-butoxycarbonyl-1,4-diazepane for treating ocular hypertension, relating to the technical field of pharmaceutical chemicals. The invention comprises the following steps: using 1-benzyl-3-methylpiperidin-4-one as a starting raw material, performing chiral resolution to obtain an intermediate 1, performing an addition-elimination reaction on the intermediate 1 and hydroxylamine hydrochloride to obtain an intermediate 2, performing a Beckmann rearrangement reaction on the intermediate 2 to obtain an intermediate 3, performing an amino deprotection reaction on the intermediate 3 to obtain an intermediate 4, performing an amino protection reaction on the intermediate 4 and di-tert-butyl dicarbonate to obtain an intermediate 5, and performing a decarbonylation reaction on the intermediate 5 to obtain the (S)-3-methyl-1-tert-butoxycarbonyl-1,4-diazepane. The preparation method has the characteristics of readily available raw materials, a simple process and a high product yield, and is suitable for the industrial production of the (S)-3-methyl-1-tert-butoxycarbonyl-1,4-diazepane.

Description

Technical field:

[0001] The present invention relates to the technical field of pharmaceutical organic synthesis, and in particular to a method for preparing a chiral intermediate (S)-3-methyl-1-tert-butoxycarbonyl-1,4-diazepane, a drug for treating ocular hypertension. Background technology:

[0002] Glaucoma is a group of diseases characterized by optic disc atrophy and depression, visual field loss, and decreased vision. Pathologically elevated intraocular pressure and insufficient blood supply to the optic nerve are primary risk factors for its development. The optic nerve's tolerance to pressure damage is also associated with the development and progression of glaucoma. Any obstruction in the aqueous humor circulation pathway can lead to elevated intraocular pressure and pathological changes, but some patients also experience normal-tension glaucoma. Glaucoma is one of the three major causes of blindness in humans, with an incidence of 1% in the general population and 2% after the age of 45. Clinically, glaucoma is classified into primary, secondary, and congenital categories based on etiology, anterior chamber angle, and intraocular pressure measurements.

[0003] Secondary glaucoma is caused by certain eye or systemic diseases that interfere with normal aqueous humor circulation. Examples include glaucoma caused by ocular trauma, neovascular glaucoma, iridocyclitis-induced glaucoma, and glucocorticoid-induced glaucoma. The causes of these conditions are relatively clear. Congenital glaucoma is caused by abnormal embryonic development and congenital variations in the anterior chamber angle structure.

[0004] Ripasudil (K-115, ripasudil hydrochloride dihydrate) is a ROCK-specific inhibitor that can inhibit the activity of ROCK1 and ROCK2. Its IC 50 The values ​​are 51nM and 19nM, respectively. Ripasudil is a Rho kinase inhibitor with a potent intraocular pressure-lowering effect and can be used to treat glaucoma and intraocular hypertension. The structural formula of Ripasudil is as follows:

[0005]

[0006] Ripasudil is composed of a quinoline ring and a chiral homopiperazine ring (S)-3-methyl-1-tert-butoxycarbonyl-1,4-diazepane connected by a sulfonamide bond. Currently, the commonly used synthesis methods of Ripasudil include the convergence method and the step-by-step cascade method. Among them, the convergence method is to first synthesize (S)-3-methyl-1-tert-butoxycarbonyl-1,4-diazepane, and then condense it with 4-fluoroisoquinoline-5-sulfonyl chloride to obtain it. This method has a short route, high chiral purity, does not require chiral separation and step-by-step chromatography, and is easy to industrialize.

[0007] There are two main methods reported in the literature for synthesizing (S)-3-methyl-1-tert-butoxycarbonyl-1,4-diazepane. One uses N-tert-butoxycarbonylethylenediamine as the starting material, undergoes a multi-step cyclization reaction, and then undergoes chiral resolution. However, this method suffers from low yields and low chiral purity, making it unsuitable for industrial production. The other method uses chiral sources such as (3R)-3-{[(1R)-1-phenylethyl]benzylamino}butyric acid methyl ester, (R)-3-aminobutyric acid, and L-2-aminopropanol as starting materials, extends the carbon chain through ester amidation, and finally cyclizes to obtain the product. Although L-2-aminopropanol is inexpensive and readily available, it requires two protection steps in the reaction route, resulting in a low overall yield of the target product. Summary of the invention:

[0008] The technical problem to be solved by the present invention is to provide a preparation method for (S)-3-methyl-1-tert-butoxycarbonyl-1,4-diazepane, a chiral intermediate of a drug for treating ocular hypertension. 1-benzyl-3-methylpiperidin-4-one is used as a starting material to synthesize (S)-3-methyl-1-tert-butoxycarbonyl-1,4-diazepane through a six-step reaction. The preparation method has the characteristics of readily available raw materials, simple process, and high product yield. The method is suitable for the industrial production of (S)-3-methyl-1-tert-butoxycarbonyl-1,4-diazepane, and can be used as a raw material in the synthesis of Ripasudil, a drug for treating ocular hypertension.

[0009] The technical problem to be solved by the present invention is achieved by adopting the following technical solutions:

[0010] A method for preparing (S)-3-methyl-1-tert-butoxycarbonyl-1,4-diazepane comprises the following steps: using 1-benzyl-3-methylpiperidin-4-one as a starting material, performing chiral resolution to obtain an intermediate 1, performing an addition-elimination reaction on the intermediate 1 and hydroxylamine hydrochloride to obtain an intermediate 2, performing a Beckmann rearrangement reaction on the intermediate 2 to obtain an intermediate 3, performing an amino deprotection reaction on the intermediate 3 to obtain an intermediate 4, performing an amino protection reaction on the intermediate 4 and di-tert-butyl dicarbonate to obtain an intermediate 5, and performing a decarbonylation reaction on the intermediate 5 to obtain (S)-3-methyl-1-tert-butoxycarbonyl-1,4-diazepane.

[0011] The synthetic route is as follows:

[0012]

[0013] The beneficial effects of the present invention are as follows: the present invention provides a method for preparing a key chiral intermediate of rosudil, which uses inexpensive starting materials and obtains the target product through chiral resolution, addition-elimination reaction, Beckmann rearrangement reaction, amino deprotection reaction, amino protection reaction, and decarbonylation reaction. The method has the advantages of low cost, short route, good process operability, etc., and can be further applied to industrial production. Description of the drawings:

[0014] Figure 1 This is the H NMR spectrum of (S)-3-methyl-1-tert-butoxycarbonyl-1,4-diazepane. Specific implementation method:

[0015] In order to make the technical means, creative features, objectives and effects achieved by the present invention easier to understand, the present invention is further described below with reference to specific embodiments and illustrations.

[0016] The invention provides a preparation method of (S)-3-methyl-1-tert-butoxycarbonyl-1,4-diazepane. The method comprises the following steps: using 1-benzyl-3-methylpiperidin-4-one as a starting material, performing chiral resolution to obtain an intermediate 1, performing an addition-elimination reaction on the intermediate 1 and hydroxylamine hydrochloride to obtain an intermediate 2, performing a Beckmann rearrangement reaction on the intermediate 2 to obtain an intermediate 3, performing an amino deprotection reaction on the intermediate 3 to obtain an intermediate 4, performing an amino protection reaction on the intermediate 4 and di-tert-butyl dicarbonate to obtain an intermediate 5, and performing a decarbonylation reaction on the intermediate 5 to obtain (S)-3-methyl-1-tert-butoxycarbonyl-1,4-diazepane.

[0017] The synthetic route is as follows:

[0018]

[0019] In a further technical solution, the chiral resolution is performed using at least one of (2S,3S)-2,3-bis((4-methylbenzoyl)oxy)succinic acid hydrate and L-tartaric acid as a catalyst, with the molar ratio of catalyst to 1-benzyl-3-methylpiperidin-4-one being (0.1-4):1. The presence of the catalyst improves the efficiency of the chiral resolution and the yield of intermediate 1.

[0020] In a further technical solution, the addition-elimination reaction is carried out in the presence of an acid binding agent, and the molar feed ratio of the acid binding agent to hydroxylamine hydrochloride is (1-2): 1. Under the action of the acid binding agent, the reaction rate is accelerated and the yield of intermediate 2 is increased.

[0021] In a further technical solution, the molar feed ratio of the intermediate 1 to hydroxylamine hydrochloride is 1:(1.2-3). The excess hydroxylamine hydrochloride allows the intermediate 1 to react completely, thereby increasing the conversion rate of the intermediate 1 and the yield of the intermediate 2.

[0022] In a further technical solution, the Beckmann rearrangement reaction uses p-toluenesulfonyl chloride as a catalyst, and the molar feed ratio of the catalyst to the intermediate 2 is (0.1-1.5): 1. Under the action of the catalyst and the acid binding agent, the reaction rate is accelerated and the yield of the intermediate 3 is improved.

[0023] In a further technical solution, the Beckmann rearrangement reaction is carried out in the presence of an acid binding agent, and the molar feed ratio of the acid binding agent to the intermediate 2 is (1-2): 1. Excessive acid binding agent allows the intermediate 2 to react completely, thereby increasing the conversion rate of the intermediate 2 and the yield of the intermediate 3.

[0024] In a further technical solution, the amino deprotection reaction is carried out under a hydrogen atmosphere at a hydrogen pressure of 1-2 MPa, using at least one of palladium hydroxide, palladium-carbon, and rhodium-carbon as a catalyst, with the catalyst amount being 5-10% of the mass of intermediate 3. The catalyst accelerates the reaction rate and improves the yield of intermediate 4.

[0025] In a further technical solution, the amino protection reaction is carried out in the presence of an acid binding agent, and the molar feed ratio of the acid binding agent to the intermediate 4 is (1-3): 1. Under the action of the acid binding agent, the reaction rate is accelerated and the yield of the intermediate 5 is improved.

[0026] In a further technical solution, the molar feed ratio of the intermediate 4 to di-tert-butyl dicarbonate is 1:(0.5-2).

[0027] In a further technical solution, the acid-binding agent for the addition-elimination reaction, Beckmann rearrangement reaction and amino protection reaction is at least one of sodium carbonate, potassium carbonate, sodium hydroxide and triethylamine.

[0028] In a further technical solution, the decarbonylation reaction uses lithium aluminum hydride as a catalyst, and the mass feed ratio of the catalyst to the intermediate 5 is (1-3):1. Under the action of the catalyst, the decarbonylation reaction is promoted, the conversion rate of the intermediate 5 and the yield of the target product (S)-3-methyl-1-tert-butoxycarbonyl-1,4-diazepane are increased.

[0029] Example 1

[0030] Synthesis of Intermediate 1: 1-Benzyl-3-methylpiperidin-4-one (0.05 mol, 10 g) was added to 100 mL of acetonitrile and heated to 40°C. (2S,3S)-2,3-bis((4-methylbenzoyl)oxy)succinic acid hydrate (0.05 mol, 20.6 g) was then added and reacted at 40°C for 24 hours. After completion of the reaction, the mixture was filtered, and the residue was washed with acetonitrile and dried at 40°C to obtain Intermediate 1. The yield was 95% and the purity was 98%.

[0031] Synthesis of Intermediate 2: Intermediate 1 (0.015 mol, 3.05 g) was added to 50 mL of dichloromethane and freed with sodium hydroxide (0.018 mol, 0.72 g). The organic layer was concentrated and dissolved in ethanol and water. Hydroxylamine hydrochloride (0.018 mol, 1.25 g) and sodium carbonate (0.018 mol, 1.91 g) were then added and allowed to react at room temperature for 12 hours. After completion of the reaction, ethanol was recovered by distillation under reduced pressure, and the product was extracted with water and dichloromethane. The organic layer was concentrated to obtain Intermediate 2. The yield was 97% and the purity was 95%.

[0032] Synthesis of Intermediate 3: Intermediate 2 (0.02 mol, 4.36 g) was dissolved in 30 mL of acetone (acetone and water, 1:1 volume ratio). Sodium carbonate (0.04 mol, 4.24 g) was added, followed by the slow addition of p-toluenesulfonyl chloride (0.03 mol, 5.72 g). The mixture was allowed to react at room temperature for 24 hours. After completion of the reaction, the acetone was recovered by distillation under reduced pressure, and the product was extracted with water and dichloromethane. The organic layer was concentrated to obtain Intermediate 3. The yield was 90% and the purity was 96%.

[0033] Synthesis of Intermediate 4: Intermediate 3 (0.09 mol, 20 g) was added to a hydrogenation reactor. The nitrogen atmosphere was replaced three times, and 100 mL of methanol and 2 g of 20% palladium hydroxide were added. Hydrogen was introduced to a pressure of 1 MPa. The reaction was carried out at 30°C for 12 h. After the reaction, the methanol was recovered by distillation under reduced pressure to obtain Intermediate 4. The yield was 95% and the purity was 98%.

[0034] Synthesis of Intermediate 5: To 150 mL of acetonitrile were added Intermediate 4 (0.12 mol, 15 g) and triethylamine (0.2 mol, 20 g). Di-tert-butyl dicarbonate (0.09 mol, 20 g) was then slowly added dropwise with stirring at 0°C. The reaction was allowed to proceed at room temperature for 12 hours. After completion of the reaction, the acetonitrile was recovered by distillation under reduced pressure, and the residue was dissolved in 200 mL of dichloromethane and washed three times with 200 mL of saturated sodium chloride solution. The dichloromethane was then recovered by distillation under reduced pressure to yield Intermediate 5. The yield was 65% and the purity was 96%.

[0035] Synthesis of (S)-3-methyl-1-tert-butoxycarbonyl-1,4-diazepane: To 100 mL of tetrahydrofuran was added 10 g of intermediate 5. 12 g of lithium aluminum hydride was added portionwise with stirring at -30°C. The mixture was allowed to react at room temperature for 12 hours. After completion of the reaction, the tetrahydrofuran was recovered by distillation under reduced pressure. The residue was dissolved in 100 mL of ethyl acetate and washed three times with saturated brine. When the volume was concentrated to 1 / 2, n-heptane was added. The mixture was stirred at low temperature overnight. A white solid precipitated and was filtered to obtain the desired product. The yield was 78% and the purity was 98%.

[0036] Example 2

[0037] Synthesis of Intermediate 1: 1-Benzyl-3-methylpiperidin-4-one (0.05 mol, 10 g) was added to 100 mL of acetonitrile and heated to 40°C. (2S,3S)-2,3-bis((4-methylbenzoyl)oxy)succinic acid hydrate (0.05 mol, 20.6 g) was then added and reacted at 40°C for 24 hours. After completion of the reaction, the mixture was filtered, and the residue was washed with acetonitrile and dried at 40°C to obtain Intermediate 1. The yield was 96% and the purity was 98%.

[0038] Synthesis of Intermediate 2: Intermediate 1 (0.015 mol, 3.05 g) was added to 50 mL of dichloromethane and freed with sodium hydroxide (0.018 mol, 0.72 g). The organic layer was concentrated and dissolved in ethanol and water. Hydroxylamine hydrochloride (0.018 mol, 1.25 g) and sodium carbonate (0.018 mol, 1.91 g) were then added. The reaction was allowed to proceed at 40°C for 12 h. After completion of the reaction, ethanol was recovered by distillation under reduced pressure, and the product was extracted with water and dichloromethane. The organic layer was concentrated to obtain Intermediate 2. The yield was 97% and the purity was 96%.

[0039] Synthesis of Intermediate 3: Intermediate 2 (0.02 mol, 4.36 g) was dissolved in 30 mL of acetone (acetone and water, 1:1 volume ratio). Sodium carbonate (0.03 mol, 3.18 g) was added, followed by the slow addition of p-toluenesulfonyl chloride (0.03 mol, 5.72 g). The mixture was allowed to react at room temperature for 24 hours. After completion of the reaction, the acetone was recovered by distillation under reduced pressure, and the product was extracted with water and dichloromethane. The organic layer was concentrated to obtain Intermediate 3. The yield was 89% and the purity was 96%.

[0040] Synthesis of Intermediate 4: Intermediate 3 (0.09 mol, 20 g) was added to a hydrogenation reactor. The nitrogen atmosphere was replaced three times, and 100 mL of methanol and 2 g of 20% palladium hydroxide were added. Hydrogen was introduced to a pressure of 1.5 MPa. The reaction was carried out at 30°C for 12 h. After the reaction, the methanol was recovered by distillation under reduced pressure to obtain Intermediate 4. The yield was 96% and the purity was 98%.

[0041] Synthesis of Intermediate 5: To 150 mL of acetonitrile were added Intermediate 4 (0.12 mol, 15 g) and triethylamine (0.2 mol, 20 g). Di-tert-butyl dicarbonate (0.12 mol, 26 g) was then slowly added dropwise with stirring at 0°C. The reaction was allowed to proceed for 12 hours at room temperature. After completion of the reaction, the acetonitrile was recovered by distillation under reduced pressure. The residue was dissolved in 200 mL of dichloromethane and washed three times with 200 mL of saturated sodium chloride solution. The dichloromethane was then recovered by distillation under reduced pressure to yield Intermediate 5. The yield was 70% and the purity was 97%.

[0042] Synthesis of (S)-3-methyl-1-tert-butoxycarbonyl-1,4-diazepane: To 100 mL of tetrahydrofuran was added 10 g of intermediate 5. 20 g of lithium aluminum hydride was added portionwise with stirring at -30°C. The mixture was allowed to react at room temperature for 24 hours. After completion of the reaction, the tetrahydrofuran was recovered by distillation under reduced pressure. The residue was dissolved in 100 mL of ethyl acetate and washed three times with saturated brine. When the volume was concentrated to 1 / 2, n-heptane was added. The mixture was stirred at low temperature overnight. A white solid precipitated and was filtered to obtain the desired product. The yield was 82% and the purity was 98%.

[0043] Example 3

[0044] Synthesis of Intermediate 1: 1-Benzyl-3-methylpiperidin-4-one (0.05 mol, 10 g) was added to 100 mL of acetonitrile and heated to 40°C. (2S,3S)-2,3-bis((4-methylbenzoyl)oxy)succinic acid hydrate (0.05 mol, 20.6 g) was then added and reacted at 40°C for 28 hours. After completion of the reaction, the mixture was filtered, and the residue was washed with acetonitrile and dried at 40°C to obtain Intermediate 1. The yield was 95% and the purity was 98%.

[0045] Synthesis of Intermediate 2: Intermediate 1 (0.015 mol, 3.05 g) was added to 50 mL of dichloromethane and freed with sodium hydroxide (0.018 mol, 0.72 g). The organic layer was concentrated and dissolved in ethanol and water. Hydroxylamine hydrochloride (0.03 mol, 2.08 g) and sodium carbonate (0.018 mol, 1.91 g) were then added and allowed to react at room temperature for 12 hours. After completion of the reaction, ethanol was recovered by distillation under reduced pressure, and the product was extracted with water and dichloromethane. The organic layer was concentrated to obtain Intermediate 2. The yield was 98% and the purity was 96%.

[0046] Synthesis of Intermediate 3: Intermediate 2 (0.02 mol, 4.36 g) was dissolved in 30 mL of acetone (acetone and water, 1:1 volume ratio). Sodium carbonate (0.04 mol, 4.24 g) was added, followed by the slow addition of p-toluenesulfonyl chloride (0.02 mol, 3.81 g). The mixture was allowed to react at room temperature for 24 hours. After completion of the reaction, the acetone was recovered by distillation under reduced pressure, and the product was extracted with water and dichloromethane. The organic layer was concentrated to obtain Intermediate 3. The yield was 88% and the purity was 95%.

[0047] Synthesis of Intermediate 4: Intermediate 3 (0.09 mol, 20 g) was added to a hydrogenation reactor. The nitrogen atmosphere was replaced three times, and 100 mL of methanol and 1 g of 20% palladium hydroxide were added. Hydrogen was introduced to a pressure of 1 MPa. The reaction was carried out at 30°C for 12 h. After the reaction, the methanol was recovered by distillation under reduced pressure to obtain Intermediate 4. The yield was 92% and the purity was 97%.

[0048] Synthesis of Intermediate 5: To 150 mL of acetonitrile were added Intermediate 4 (0.12 mol, 15 g) and triethylamine (0.2 mol, 20 g). Di-tert-butyl dicarbonate (0.18 mol, 39 g) was then slowly added dropwise with stirring at 0°C. The reaction was allowed to proceed at room temperature for 12 hours. After completion of the reaction, the acetonitrile was recovered by distillation under reduced pressure. The residue was dissolved in 200 mL of dichloromethane and washed three times with 200 mL of saturated sodium chloride solution. The dichloromethane was then recovered by distillation under reduced pressure to yield Intermediate 5. The yield was 72% and the purity was 97%.

[0049] Synthesis of (S)-3-methyl-1-tert-butoxycarbonyl-1,4-diazepane: To 100 mL of tetrahydrofuran was added 10 g of intermediate 5. 10 g of lithium aluminum hydride was added portionwise with stirring at -30°C. The mixture was allowed to react at room temperature for 12 hours. After completion of the reaction, the tetrahydrofuran was recovered by distillation under reduced pressure. The residue was dissolved in 100 mL of ethyl acetate and washed three times with saturated brine. When the volume was concentrated to 1 / 2, n-heptane was added. The mixture was stirred at low temperature overnight. A white solid precipitated and was filtered to obtain the desired product. The yield was 78% and the purity was 97%.

[0050] As can be seen from the above-described examples 1-3, in the last step decarbonylation reaction of synthesizing target product (S) -3- methyl -1- tert-butyloxy formyl -1,4- diazepane, the consumption of catalyst lithium aluminum hydride is very large, causes the cost of catalyst to increase, but product yield is not high. In order to improve product yield while reducing catalyst dosage, the inventor attempts to add a promotor to improve reaction activity, through the screening of dozens of promotor catalysts, finally using copper lysine as promotor, and it is necessary to control the consumption of promotor within a certain range. The decarbonylation reaction uses lithium aluminum hydride as catalyst, and copper lysine is as promotor, and the quality feed ratio of catalyst, promotor and intermediate 5 is (0.5-1): (0.25-0.5): 1.

[0051] Example 4

[0052] Synthesis of intermediate 1-5: same as in Example 1.

[0053] Synthesis of (S)-3-methyl-1-tert-butoxycarbonyl-1,4-diazepane: To 100 mL of tetrahydrofuran was added 10 g of intermediate 5. 8 g of lithium aluminum hydride and 5 g of copper lysinate were added portionwise with stirring at -30°C. The mixture was allowed to react at room temperature for 12 hours. After completion of the reaction, the tetrahydrofuran was recovered by distillation under reduced pressure. The residue was dissolved in 100 mL of ethyl acetate and washed three times with saturated brine. When the volume was concentrated to 1 / 2, n-heptane was added. The mixture was stirred at low temperature overnight. A white solid precipitated and was filtered to obtain the desired product. The yield was 89% and the purity was 98%.

[0054] Example 5

[0055] Synthesis of intermediate 1-5: same as in Example 1.

[0056] Synthesis of (S)-3-methyl-1-tert-butoxycarbonyl-1,4-diazepane: To 100 mL of tetrahydrofuran was added 10 g of intermediate 5. With stirring at -30°C, 10 g of lithium aluminum hydride and 2.5 g of copper lysinate were added portionwise. The mixture was allowed to react at room temperature for 12 hours. After completion of the reaction, the tetrahydrofuran was recovered by distillation under reduced pressure. The residue was dissolved in 100 mL of ethyl acetate and washed three times with saturated brine. When the volume was concentrated to 1 / 2, n-heptane was added. The mixture was stirred at low temperature overnight. A white solid precipitated and was filtered to obtain the desired product. The yield was 84% ​​and the purity was 98%.

[0057] Example 6

[0058] Synthesis of intermediate 1-5: same as in Example 1.

[0059] Synthesis of (S)-3-methyl-1-tert-butoxycarbonyl-1,4-diazepane: To 100 mL of tetrahydrofuran was added 10 g of intermediate 5. With stirring at -30°C, 10 g of lithium aluminum hydride and 5 g of copper lysinate were added portionwise. The mixture was allowed to react at room temperature for 12 hours. After completion of the reaction, the tetrahydrofuran was recovered by distillation under reduced pressure. The residue was dissolved in 100 mL of ethyl acetate and washed three times with saturated brine. When the volume was concentrated to 1 / 2, n-heptane was added. The mixture was stirred at low temperature overnight. A white solid precipitated and was filtered to obtain the desired product. The yield was 92% and the purity was 99%.

[0060] The basic principles, main features, and advantages of the present invention are shown and described above. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The above embodiments and descriptions are merely illustrative of the principles of the present invention. Various changes and modifications may be made to the present invention without departing from the spirit and scope of the present invention. Such changes and modifications are intended to fall within the scope of the present invention. The scope of protection claimed in the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing (S)-3-methyl-1-tert-butoxycarbonyl-1,4-diazepane, characterized in that: Starting from 1-benzyl-3-methylpiperidin-4-one, intermediate 1 is obtained through chiral resolution, intermediate 1 is reacted with hydroxylamine hydrochloride through addition-elimination reaction to obtain intermediate 2, intermediate 2 is subjected to Beckmann rearrangement reaction to obtain intermediate 3, intermediate 3 is subjected to amino deprotection reaction to obtain intermediate 4, intermediate 4 is subjected to amino protection reaction with di-tert-butyl dicarbonate to obtain intermediate 5, and intermediate 5 is subjected to decarbonylation reaction to obtain (S)-3-methyl-1-tert-butoxycarbonyl-1,4-diazepane; The synthetic route is as follows: ； The chiral resolution uses at least one of (2S,3S)-2,3-bis((4-methylbenzoyl)oxy)succinic acid hydrate and L-tartaric acid as a catalyst; The addition-elimination reaction is carried out in the presence of an acid binding agent; The Beckmann rearrangement reaction uses p-toluenesulfonyl chloride as a catalyst; The Beckmann rearrangement reaction is carried out in the presence of an acid binding agent; The amino deprotection reaction is carried out under a hydrogen atmosphere with a hydrogen pressure of 1-2 MPa, using at least one of palladium hydroxide, palladium carbon, and rhodium carbon as a catalyst; The amino protection reaction is carried out in the presence of an acid binding agent; The acid-binding agent for the addition-elimination reaction, Beckmann rearrangement reaction and amino protection reaction is at least one of sodium carbonate, potassium carbonate, sodium hydroxide and triethylamine; The decarbonylation reaction uses lithium aluminum hydride as a catalyst.

2. The method for preparing (S)-3-methyl-1-tert-butoxycarbonyl-1,4-diazepane according to claim 1, wherein: The molar feed ratio of the chiral resolution catalyst to 1-benzyl-3-methylpiperidin-4-one is (0.1-4):

1.

3. The method for preparing (S)-3-methyl-1-tert-butoxycarbonyl-1,4-diazepane according to claim 1, wherein: The molar feed ratio of the acid-binding agent to hydroxylamine hydrochloride in the addition-elimination reaction is (1-2):1; the molar feed ratio of the intermediate 1 to hydroxylamine hydrochloride is 1:(1.2-3).

4. The method for preparing (S)-3-methyl-1-tert-butoxycarbonyl-1,4-diazepane according to claim 1, wherein: The molar feed ratio of the catalyst to the intermediate 2 in the Beckmann rearrangement reaction is (0.1-1.5):

1.

5. The method for preparing (S)-3-methyl-1-tert-butoxycarbonyl-1,4-diazepane according to claim 1, characterized in that: The molar feed ratio of the acid-binding agent to the intermediate 2 in the Beckmann rearrangement reaction is (1-2):

1.

6. The method for preparing (S)-3-methyl-1-tert-butoxycarbonyl-1,4-diazepane according to claim 1, characterized in that: The amount of catalyst used in the amino deprotection reaction is 5-10% of the mass of the intermediate 3.

7. The method for preparing (S)-3-methyl-1-tert-butoxycarbonyl-1,4-diazepane according to claim 1, characterized in that: The molar feed ratio of the acid binding agent to the intermediate 4 in the amino protection reaction is (1-3):

1.

8. The method for preparing (S)-3-methyl-1-tert-butoxycarbonyl-1,4-diazepane according to claim 1, wherein: The molar feed ratio of the intermediate 4 to di-tert-butyl dicarbonate is 1:(0.5-2).

9. The method for preparing (S)-3-methyl-1-tert-butoxycarbonyl-1,4-diazepane according to claim 1, characterized in that: The mass feed ratio of the catalyst for the decarbonylation reaction to the intermediate 5 is (1-3):1.

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