Synthesis method of 6-hydroxy-6-methyl-1, 4-diazacycloheptane intermediate

Abstract

The invention provides a synthesis method of a 6-hydroxy-6-methyl-1, 4-diazacycloheptane intermediate, and belongs to the field of pharmacy. The brand-new synthesis method for preparing the 6-hydroxy-6-methyl-1, 4-diazacycloheptane intermediate is provided, raw materials and reagents are low in price and safe, compared with the prior art, the method is convenient to operate, the process efficiency is improved by 28.6%, the total yield is improved to 46.3%, the requirement for large-scale preparation in a laboratory can be met, and good application prospects are achieved.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmacy, and particularly relates to a synthesis method of 6-hydroxy-6-methyl-1,4-diazepane intermediate. BACKGROUND

[0002] 6-hydroxy-6-methyl-1,4-diazepane is a kind of valuable molecular building block and is widely used in the field of medicine. It has been reported that many drugs contain 6-hydroxy-6-methyl-1,4-diazepane fragments; for example, patent WO2022076625A1 reports a series of cystic fibrosis transmembrane conductance regulator (CFTR) modulators, compound A can be used for treating CFTR-mediated diseases such as cystic fibrosis; patent CN117659050A reports the following compound B, which can be used as a KRAS mutant small molecule inhibitor for treating various diseases caused by mutations, including cancer, such as pancreatic cancer, colorectal cancer and lung cancer.

[0003]

[0004] The synthesis method for preparing 6-hydroxy-6-methyl-1,4-diazepane molecular building block is only reported in the patent (WO2022076625A1), and the synthesis process is as follows:

[0005]

[0006] However, the synthesis route reported in the patent has long synthesis steps, complex operation and low total yield of only 5.3%. Moreover, the method reported in the patent is only at the milligram scale, and the problems existing in the scale-up synthesis process of 6-hydroxy-6-methyl-1,4-diazepane molecular building block have not been solved. Therefore, a new, safe and scalable synthesis scheme of 6-hydroxy-6-methyl-1,4-diazepane molecular building block is needed. SUMMARY

[0007] In view of the problems existing in the prior art, the purpose of the present application is to provide a synthesis method of 6-hydroxy-6-methyl-1,4-diazepane intermediate.

[0008] The present application provides a synthesis method of 6-hydroxy-6-methyl-1,4-diazepane intermediate, which comprises the following steps:

[0009]

[0010] (1) reacting compound II-1, BnX and a base to obtain compound III-1;

[0011] (2) reacting compound III-1, isopropyl chloroformate and a base to obtain compound IV-1;

[0012] (3) reacting compound IV-1 and a reducing agent to obtain compound V-1;

[0013] (4) reacting compound V-1 and a phosphine reagent to obtain compound VI-1;

[0014] (5) reacting compound VI-1, a catalyst and a reducing agent to obtain 6-hydroxy-6-methyl-1,4-diazepane intermediate;

[0015] wherein, R is an amino protecting group; X is halogen.

[0016] The "amino protecting group" refers to a chemical group added to an amino group in organic synthesis in order to protect the amino group from the reaction conditions. These protecting groups can be removed by appropriate conditions after the reaction is completed, thereby restoring the activity of the amino group. The introduction and removal of the amino protecting group can selectively protect the amino functional group while not affecting the reaction of other functional groups. For example, tert-butyloxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, trifluoroacetyl and the like.

[0017] The "halogen" represents fluorine, chlorine, bromine or iodine.

[0018] Further, in step (1), the molar ratio of compound II-1, BnX and base is 1:1-2:3; the base is an organic base; the solvent of the reaction is an organic solvent or a mixture of organic solvent and water; the temperature of the reaction is 10-40°C, and the time is 0.5-2 hours.

[0019] Further, in step (1), the molar ratio of compound II-1, BnX and base is 1:1.2:3; the BnX is BnBr; the base is selected from potassium carbonate, N,N-diisopropylethylamine, triethylamine or 4-dimethylaminopyridine, preferably potassium carbonate; the solvent of the reaction is selected from acetonitrile, tetrahydrofuran, dichloromethane, N,N-dimethylformamide, methyl tert-butyl ether or a mixture of tetrahydrofuran and water in a volume ratio of 1:1, preferably a mixture of tetrahydrofuran and water in a volume ratio of 1:1; the temperature of the reaction is 15-35°C, and the time is 1 hour.

[0020] Further, in step (2), the molar ratio of compound III-1, isopropyl chloroformate and base is 1:1-2:1-2; the base is an organic base; the solvent of the reaction is an organic solvent; the temperature of the reaction is -80-40°C, and the time is 1-3 hours.

[0021] Further, in step (2), the molar ratio of compound III-1, isopropyl chloroformate and base is 1:1.5:1.5; the base is selected from sodium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide or potassium bis(trimethylsilyl)amide, preferably sodium bis(trimethylsilyl)amide; the solvent of the reaction is tetrahydrofuran; and the reaction conditions are as follows: compound III-1 is mixed with the solvent, the base is added at -78℃, and then the reaction is carried out at -78~0℃ for 1 hour, and then isopropyl chloroformate is added at -78℃, and then the reaction is carried out at 15~35℃ for 1 hour.

[0022] Further, in step (3), the molar ratio of compound IV-1 and reducing agent is 1:1.5~3; the reducing agent is lithium aluminum hydride; the solvent of the reaction is an organic solvent; the reaction temperature is 10~40℃, and the reaction time is 10~30 hours.

[0023] Further, in step (3), the molar ratio of compound IV-1 and reducing agent is 1:2.5; the solvent of the reaction is tetrahydrofuran; the reaction temperature is 15~35℃, and the reaction time is 15~25 hours.

[0024] Further, after the reaction is completed, the following purification step is further included: after the reaction is completed, water and sodium hydroxide aqueous solution are added at 0℃ for quenching, and then stirring, filtration, collection of the filtrate, drying, concentration, addition of ether at 0℃ for beating, filtration to collect the filter cake, and drying are carried out, and then the compound VI-1 is obtained.

[0025] Further, in step (4), the molar ratio of compound V-1 and phosphine reagent is 1:1~2; the phosphine reagent is cyanomethylidene tri-n-butylphosphine; the solvent of the reaction is an organic solvent; the reaction temperature is 80~120℃, and the reaction time is 1~3 hours.

[0026] Further, in step (4), the molar ratio of compound V-1 and phosphine reagent is 1:1.5; the solvent of the reaction is toluene; the reaction temperature is 100℃, and the reaction time is 2 hours.

[0027] (5) compound VI-1, a catalyst and a reducing agent are reacted to obtain a 6-hydroxy-6-methyl-1,4-diazepane intermediate;

[0028] Further, in step (5), the mass ratio of compound VI-1 and catalyst is 30~35:2~4, preferably 32:3; the solvent of the reaction is an organic solvent, preferably methanol; the reaction temperature is 10~40℃, and the reaction time is 10~30 hours.

[0029] The present application has the following beneficial effects:

[0030] (1) Compared with the prior art (WO2022076625A1), the present application adopts a new route to synthesize 6-hydroxy-6-methyl-1,4-diazacycloheptane intermediate, which is convenient to operate, shortened from 7 steps to 5 steps, and the process efficiency is improved by 28.6%;

[0031] (2) Compared with the prior art (WO2022076625A1), the present application adopts a new route to synthesize 6-hydroxy-6-methyl-1,4-diazacycloheptane intermediate, and the total yield is improved from 5.3% to 46.3%, an increase of 9 times;

[0032] (3) Compared with the prior art (WO2022076625A1), the present application is synthesized on a scale of tens of grams, which meets the laboratory scale-up production requirements.

[0033] The present application provides a new synthesis method for preparing 6-hydroxy-6-methyl-1,4-diazacycloheptane intermediate, which only needs 5 steps of reaction, not only the raw materials and reagents are low in price and safe, but also the operation is simple and the yield is high, which can meet the laboratory scale-up production requirements.

[0034] Obviously, according to the above content of the present application, according to the ordinary technical knowledge and conventional means in the art, other various forms of modifications, substitutions or changes can be made without departing from the above basic technical idea of the present application.

[0035] The above content of the present application will be further described in detail through the specific embodiments below. However, it should not be understood that the scope of the above subject matter of the present application is limited to the following embodiments. Any technology realized based on the above content of the present application belongs to the scope of the present application. BRIEF DESCRIPTION OF DRAWINGS

[0036] Figure 1 H-NMR of compound III-1: (400M, DMSO-d6).

[0037] Figure 2 H-NMR of compound V-1: (400M, DMSO-d6).

[0038] Figure 3 H-NMR of compound VI-1: (400M, DMSO-d6).

[0039] Figure 4 H-NMR of compound I-1: (300M, CDCl3). DETAILED DESCRIPTION

[0040] The raw materials and equipment used in the present application are known products, which are obtained by purchasing commercially available products.

[0041] "room temperature" means 25±10°C, and "overnight" means 20±5 hours.

[0042] The route for preparing the 6-hydroxy-6-methyl-1,4-diazepane intermediate (Compound I-1) according to an embodiment of the present application is as follows:

[0043]

[0044] Preparation of Compound I-1 according to Example 1

[0045] Step 1, Preparation of Compound III-1:

[0046] Under nitrogen protection, a 2L three-necked flask was charged with Compound II-1 (57g, 1 eq.), THF (570 mL), H2O (570 mL), and cooled to 0°C, and K2CO3 (96.74g, 3 eq.) and BnBr (47.89g, 1.2 eq.) were slowly added while the temperature was controlled at about 0°C. After the addition was completed, the reaction was allowed to proceed at room temperature for 1 hour. After the completion of the reaction was monitored by spotting on a plate, the reaction solution was added to saturated brine (500 mL), and extracted with EA (3*500 mL). The organic phase was dried and concentrated, and purified by column chromatography (eluent: PE:EA=3:1, and the product was eluted with PE:EA=18%). The concentrated product was a colorless transparent oil, Compound III-1 (71.6g), with a yield of 91.7%. 1 H NMR (400 MHz, DMSO-d6) δ 7.37 - 7.20 (m, 5H), 3.92 - 3.74 (m, 2H), 3.71 - 3.60 (m, 5H), 3.36 - 3.32 (m, 2H), 2.98 - 2.91 (m, 2H), 2.32 (s, 1H), 1.37 (s, 9H) Figure 1 ).

[0047] Step 2, Preparation of Compound IV-1:

[0048] Under nitrogen protection, a 2L three-necked flask was charged with Compound III-1 (60.4g, 1 eq.) and THF (906 mL), and cooled to -78°C. NaHMDS (2.0M in THF) (135.5 mL, 1.5 eq.) was slowly added while the temperature was controlled at about -78°C. The reaction was allowed to proceed at a temperature between -78°C and 0°C for 1 hour. The temperature was then lowered to -78°C, and isopropyl chloroformate (33.2g, 1.5 eq.) was slowly added. The reaction was allowed to proceed at room temperature for about 1 hour. After the completion of the reaction was monitored by spotting on a plate, the reaction solution was poured into saturated aqueous ammonium chloride solution (500 mL) to quench, and extracted with EA (3*500 mL). The organic phase was dried and concentrated to give Compound IV-1 (crude, 84.5g) as a colorless transparent liquid.

[0049] Step 3, Preparation of compound V-1:

[0050] Under nitrogen protection, 2L three-necked flask was charged with LiAlH4(19.27g, 2.5eq.), THF (400mL), and cooled to 0°C. Compound IV-1 (85.4g, 1eq.) in THF (450mL) was added slowly, and the temperature was allowed to rise to room temperature overnight. After monitoring the reaction completion by TLC, the reaction was quenched by adding H2O (20mL), 15% NaOH aqueous solution (20mL), and H2O (60mL) successively at 0°C. After stirring at room temperature for 15 minutes, the mixture was filtered, and the filtrate was collected, dried, and concentrated. The crude product was slurried in ethyl ether (500mL) at 0°C for 30 minutes, filtered, and dried to obtain white solid compound V-1 (46.0g) in 67.3% yield for two steps. 1 H NMR (400 MHz, DMSO-d6) δ 7.41 - 7.10 (m, 5H), 4.43 (t, J = 5.0 Hz, 2H), 3.80 (s, 2H), 3.72 (dd, J = 11.0, 5.3 Hz, 2H), 3.50 (dd, J = 11.0, 4.8 Hz, 2H), 3.31 (s, 2H), 3.21 (t, J = 5.4 Hz, 2H), 2.48 - 2.39 (m, 2H), 1.39 (s, 9H) Figure 2 .

[0051] Step 4, Preparation of compound VI-1:

[0052] Under nitrogen protection, 1L three-necked flask was charged with compound V-1 (40.1g, 1eq.) and toluene (400mL), and cooled to 0°C. CMBP (43.15g, 1.5eq.) in toluene (400mL) was added slowly, and the temperature was allowed to rise to 100°C for 2h. After monitoring the reaction completion by TLC, the reaction was washed with saturated brine (2*200mL), and the organic phase was dried and concentrated. The product was purified by column chromatography (eluent: PE:EA = 3:1, product eluted at PE:EA = 25%), and concentrated to obtain yellow oil compound VI-1 (34.6g) in 91.2% yield. 1 H NMR (400 MHz, DMSO-d6) δ 7.35 - 7.21 (m, 5H), 3.77 - 3.60 (m, 2H), 3.57 - 3.21 (m, 4H), 2.76 - 2.51 (m, 6H), 1.40 (s, 9H) Figure 3 .

[0053] Step 5, Preparation of compound I-1:

[0054] Into a 500 mL hydrogenation flask was added compound VI-1 (32 g, 1 eq.), MeOH (320 mL), water Pd / C (3 g), and the reaction was hydrogenated at room temperature under 5 atm H2 overnight. After the reaction was monitored to be complete by TLC, the catalyst was removed by filtration, the filtrate was collected, concentrated, and purified by column (eluent: DCM:MeOH = 3:1, product eluted at DCM:MeOH = 3.8%) to give compound I-1 (19.1 g) as a light yellow oil, with a purity of 99.9% and a yield of 82.7%. 1 H NMR (300 MHz, Chloroform-d) δ 3.87-3.67 (m, 1H), 3.67-3.47 (m, 1H), 3.38-3.24 (m, 1H), 3.17-3.04 (m, 1H), 3.03-2.82 (m, 4H), 2.81-2.61 (m, 2H), 1.48 (s, 9H), 1.19 (s, 3H) Figure 4 ).

[0055] Preparation of compound I-1 in Examples 2-9

[0056] To optimize the preparation efficiency of the target product, Examples 2-9 explored the effects of different reaction conditions in Step 1 on the yield of the target product, and the reaction results are shown in Table 1. Except for the different reaction conditions of Step 1 shown in Table 1, the reaction conditions and operations of other synthesis steps in Examples 2-9 were consistent with those in Example 1.

[0057] Effects of different reaction conditions on Step 1

[0058]

[0059]

[0060] As can be seen from the experimental results in Table 1, under the condition of using equal amounts of BnBr, different bases (K2CO3, DIEA, TEA, DMAP) were compared, and K2CO3 had the best effect (Examples 1, 2, and 4-9); when K2CO3 was used as the base, different solvents had no obvious effect on the yield (Examples 4-6); further optimization of the equivalent amount of BnBr (Examples 1, 3, and 4) gave the optimal yield of 91.7% under the conditions of Example 1.

[0061] Preparation of compound I-1 in Examples 10-14

[0062] Meanwhile, the present application optimizes Step 4 and explores the effects of different reaction conditions on the yield of Step 4, and the optimization results are shown in Table 2. Except for the different reaction conditions of Step 4 shown in Table 2, the reaction conditions and operations of other synthesis steps in Examples 10-14 were consistent with those in Example 1.

[0063] Table 2 Effects of different reaction conditions on step 4

[0064] Example Example Solvent Temperature Time Yield 1 Example 1 Toluene 100℃ 2h 91.2％ 10 Example 9 THF Room temperature Overnight 60.0％ 11 Example 10 DCM Room temperature Overnight 63.0％ 12 Example 11 EA Room temperature Overnight 0％ 13 Example 12 THF 60℃ 2h 70.0％ 14 Example 13 THF 60℃ Overnight 80.0％

[0065] As can be seen from the experimental results in Table 2, the best reaction results were obtained by using toluene as the solvent and reacting under reflux conditions (100°C) for 2 hours (Examples 1 and Examples 10-14) in terms of the choice of reaction solvent, temperature and time.

[0066] The following section describes the preparation of comparative samples.

[0067] Comparative Example 1: Preparation of Compound IV-1

[0068]

[0069] Under nitrogen protection, compound III-1 (200 mg, 1 eq.) and THF (3.0 mL) were added to a 25 mL three-necked flask at room temperature. The temperature was lowered to -78 °C, and NaHMDS (2.0 M in THF) (0.793 mL, 1.5 eq.) was slowly added while maintaining the temperature at around -78 °C to 0 °C. The reaction was maintained between -78 °C and 0 °C for 1 h. The temperature was then lowered to -78 °C, and isopropyl chloroformate (97.15 mg, 1.5 eq.) was slowly added. The temperature was naturally raised to room temperature and the reaction was allowed to proceed overnight. The reaction was confirmed to be complete by LCMS. The reaction solution was quenched in a saturated ammonium chloride aqueous solution, extracted with EA, dried, concentrated, and column chromatography to obtain the product (developing solvent: PE:EA = 3:1, eluent: PE:EA = 10%): 182 mg.

[0070] Comparative Examples 2-4, Preparation of Compound IV-1

[0071] To optimize the preparation efficiency of the target product, Comparative Examples 2–4 investigated the effect of each reaction condition in step 2 on the yield of compound IV-1. The reaction results are shown in Table 3. Except for the different reaction conditions in step 2 shown in Table 3, the reaction conditions and operations of other synthesis steps in Comparative Examples 2–4 were the same as those in Comparative Example 1.

[0072] Table 3. Effects of different reaction conditions on step 2

[0073] Comparative Example Different base (equiv.) Reaction result 1 NaHMDS (1.5) Reaction complete 2 LiHMDS (1.5) Reaction complete 3 KHMDS (1.5) Reaction complete, system more complex 4 LDA (1.5) Not reacted completely, system more complex

[0074] As can be seen from the experimental results in Table 3, when using equivalent amounts of alkali, NaHMDS and LiHMDS both showed better performance compared to different alkali controls (NaHMDS, LiHMDS, KHMDS, LDA).

[0075] Comparative Example 5, Preparation of Compound V-1

[0076]

[0077] Into a 25 mL three-necked flask was placed LiAlH4(49.02 mg, 3.0 eq.), THF (1 mL) under nitrogen protection, and the mixture was cooled to 0 °C. A solution of compound IV-1 (200 mg, 1 eq.) in THF (1 mL) was slowly added, and the mixture was allowed to warm to room temperature and react for 1 h. LCMS detection showed that the reaction was complete to generate the de-Cbz product. The reaction system was cooled to 0 °C, and H2O (0.1 mL), 15% NaOH aqueous solution (0.1 mL), and H2O (0.3 mL) were slowly added in sequence. After being stirred at room temperature for 15 min, the mixture was filtered, and the filtrate was dried and concentrated to obtain a crude product.

[0078] Preparation of compounds V-1 in Comparative Examples 6-14

[0079] Meanwhile, the step 3 was also optimized, and the effects of different reaction conditions on the selectivity and yield of the product (compound V-1) of step 3 were explored. The optimization results are shown in Table 4. Except for the different reaction conditions of step 3 shown in Table 4, the reaction conditions and operations of other synthesis steps in Comparative Examples 6-14 were consistent with those in Comparative Example 5.

[0080] Effects of different reaction conditions on step 3

[0081]

[0082]

[0083] From the experimental results in Table 4, it can be seen that different amounts of LiAlH4all obtained the de-Cbz product (Comparative Examples 5-14). Using BH3 and NaBH4 as reducing agents, the expected product can be obtained, but the reaction yield is low.

[0084] Therefore, it is found by the present application that Example 1 is the best condition for preparing the 6-hydroxy-6-methyl-1,4-diazepane intermediate.

[0085] In summary, the present application provides a synthesis method of a 6-hydroxy-6-methyl-1,4-diazepane intermediate. The present application provides a novel synthesis method for preparing a 6-hydroxy-6-methyl-1,4-diazepane intermediate. The method is not only low in price and safe in raw materials and reagents, but also has the advantages of convenient operation, 28.6% improvement in process efficiency, and 46.3% improvement in total yield compared with the prior art. The method can meet the needs of laboratory scale-up preparation and has good application prospect.

Claims

1. A method for the synthesis of 6-hydroxy-6-methyl-l,4-diazepane intermediates, characterized in that, The method comprises the following steps: (1) reacting compound II-1, BnX and a base to obtain compound III-1; (2) reacting compound III-1, isopropyl chloroformate and a base to obtain compound IV-1; (3) reacting compound IV-1 and a reducing agent to obtain compound V-1; (4) reacting compound V-1 and a phosphine reagent to obtain compound VI-1; (5) reacting compound VI-1, a catalyst and a reducing agent to obtain 6-hydroxy-6-methyl-1,4-diazepane intermediate; wherein, R is an amino protecting group; X is halogen.

2. The method of synthesis of claim 1, wherein, In step (1), the molar ratio of compound II-1, BnX and the base is 1:1-2:3; the base is an organic base; the solvent of the reaction is an organic solvent or a mixture of an organic solvent and water; the temperature of the reaction is 10-40℃, and the time is 0.5-2 hours.

3. The method of synthesis of claim 2, wherein, In step (1), the molar ratio of compound II-1, BnX and the base is 1:1.2:3; the BnX is BnBr; the base is selected from potassium carbonate, N,N-diisopropyl ethylamine, triethylamine or 4-dimethylamino pyridine, preferably potassium carbonate; the solvent of the reaction is selected from acetonitrile, tetrahydrofuran, dichloromethane, N,N-dimethylformamide, methyl tert-butyl ether or a mixture of tetrahydrofuran and water in a volume ratio of 1:1, preferably a mixture of tetrahydrofuran and water in a volume ratio of 1:1; the temperature of the reaction is 15-35℃, and the time is 1 hour.

4. The method of synthesis of claim 1, wherein, In step (2), the molar ratio of compound III-1, isopropyl chloroformate and the base is 1:1-2:1-2; the base is an organic base; the solvent of the reaction is an organic solvent; the temperature of the reaction is -80-40℃, and the time is 1-3 hours.

5. The method of synthesis of claim 4, wherein, In step (2), the molar ratio of compound III-1, isopropyl chloroformate and the base is 1:1.5:1.5; the base is selected from sodium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide or potassium bis(trimethylsilyl)amide, preferably sodium bis(trimethylsilyl)amide; the solvent of the reaction is tetrahydrofuran; the reaction conditions are as follows: compound III-1 and the solvent are mixed, the base is added at -78℃, and then the reaction is carried out at -78-0℃ for 1 hour; isopropyl chloroformate is added at -78℃, and then the reaction is carried out at 15-35℃ for 1 hour.

6. The method of synthesis of claim 1, wherein, In step (3), the molar ratio of compound IV-1 and the reducing agent is 1:1.5-3; the reducing agent is lithium aluminum hydride; the solvent of the reaction is an organic solvent; the temperature of the reaction is 10-40℃, and the time is 10-30 hours.

7. The method of synthesis of claim 6, wherein, In step (3), the molar ratio of compound IV-1 and the reducing agent is 1:2.5; the solvent of the reaction is tetrahydrofuran; the temperature of the reaction is 15-35℃, and the time is 15-25 hours.

8. The method of synthesis of claim 1, wherein, In step (4), the molar ratio of compound V-1 and the phosphine reagent is 1:1-2; the phosphine reagent is cyanomethylidene tri-n-butyl phosphine; the solvent of the reaction is an organic solvent; the temperature of the reaction is 80-120℃, and the time is 1-3 hours.

9. The method of synthesis of claim 8, wherein, In step (4), the molar ratio of compound V-1 to phosphine reagent is 1:1.5; the solvent of the reaction is toluene; the temperature of the reaction is 100°C, and the time is 2 hours. (5) reacting compound VI-1, a catalyst and a reducing agent to obtain 6-hydroxy-6-methyl-1,4-diazepane intermediate; 10. The method of synthesis of claim 1, wherein, In step (5), the mass ratio of compound VI-1 to catalyst is 30-35:2-4, preferably 32:3; the solvent of the reaction is an organic solvent, preferably methanol; the temperature of the reaction is 10-40°C, and the time is 10-30 hours.

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