A process for the synthesis of a 6-hydroxy-6-methyl-1,4-diazepane intermediate

Abstract

The application provides a synthesis method of 6-hydroxy-6-methyl-1,4-diazapentane intermediate, and belongs to the field of pharmacy. The application provides a novel synthesis method for preparing 6-hydroxy-6-methyl-1,4-diazapentane intermediate. The method has the advantages of low price and safety of raw materials and reagents, convenient operation, 28.6% improvement in process efficiency, and 46.3% improvement in total yield compared with prior art, and can meet the needs of laboratory scale-up preparation, and has good application prospect.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field, specifically relating to a method for synthesizing a 6-hydroxy-6-methyl-1,4-diazacycloheptane intermediate. Background Technology

[0002] 6-Hydroxy-6-methyl-1,4-diazacycloheptane is a valuable class of molecular building blocks with wide applications in the pharmaceutical field. Many drugs have been reported to contain fragments of 6-hydroxy-6-methyl-1,4-diazacycloheptane; for example, patent WO2022076625A1 reports a series of cystic fibrosis transmembrane conduction regulator (CFTR) modulators, with compound A potentially used to treat CFTR-mediated diseases such as cystic fibrosis; patent CN117659050A reports compound B as a small molecule inhibitor of KRAS mutations for the treatment of various diseases caused by mutations, including cancers such as pancreatic cancer, colorectal cancer, and lung cancer.

[0003]

[0004] The only reported method for preparing molecular building blocks containing 6-hydroxy-6-methyl-1,4-diazacycloheptane is patent (WO2022076625A1), and its synthesis process is as follows:

[0005]

[0006] However, the reported synthetic route in this patent is lengthy, complex, and has a low overall yield of only 5.3%. Furthermore, the method described in this patent is only at the milligram scale and has not yet solved the problems associated with the scale-up synthesis of 6-hydroxy-6-methyl-1,4-diazacycloheptane building blocks. Therefore, a new, safe, and scalable synthetic scheme for 6-hydroxy-6-methyl-1,4-diazacycloheptane building blocks is needed. Summary of the Invention

[0007] To address the problems existing in the prior art, the present invention aims to provide a method for synthesizing a 6-hydroxy-6-methyl-1,4-diazacycloheptane intermediate.

[0008] This invention provides a method for synthesizing a 6-hydroxy-6-methyl-1,4-diazacycloheptane intermediate, the method comprising the following steps:

[0009]

[0010] (1) Compound II-1, BnX and base react to give compound III-1;

[0011] (2) Compound III-1, isopropyl chloroformate and base react to give compound IV-1;

[0012] (3) Compound IV-1 reacts with a reducing agent to give compound V-1;

[0013] (4) Compound V-1 reacts with a phosphine reagent to give compound VI-1;

[0014] (5) The reaction of compound VI-1, catalyst and reducing agent yields 6-hydroxy-6-methyl-1,4-diazacycloheptane intermediate;

[0015] Where R is an amino protecting group and X is a halogen.

[0016] An "amino protecting group" refers to a chemical group added to an amino group in organic synthesis to protect it from the effects of reaction conditions. These protecting groups can be removed after the reaction is complete, restoring the amino group's reactivity. The introduction and removal of amino protecting groups selectively protect the amino functional group without affecting the reaction of other functional groups. Examples of protecting groups include tert-butyloxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0017] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

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

[0019] Further, in step (1), the molar ratio of compound II-1, BnX, and the base is 1:1.2:3; BnX is BnBr; the base is selected from potassium carbonate, N,N-diisopropylethylamine, triethylamine, or 4-dimethylaminopyridine, preferably potassium carbonate; the solvent for 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 reaction temperature is 15–35°C, and the reaction time is 1 hour.

[0020] Further, in step (2), the molar ratio of compound III-1, isopropyl chloroformate and base is 1:1 to 2:1 to 2; the base is an organic base; the solvent for the reaction is an organic solvent; the reaction temperature is -80 to 40°C, and the time is 1 to 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)amino, lithium bis(trimethylsilyl)amino, or potassium bis(trimethylsilyl)amino, preferably sodium bis(trimethylsilyl)amino; the solvent for the reaction is tetrahydrofuran; the reaction conditions are: compound III-1 and solvent are mixed, and after adding base at -78°C, the reaction is carried out at -78 to 0°C for 1 hour, and after adding isopropyl chloroformate at -78°C, the reaction is carried out at 15 to 35°C for 1 hour.

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

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

[0024] Furthermore, after the reaction is complete, the following purification steps are included: after the reaction is complete, water and sodium hydroxide aqueous solution are added at 0°C to quench the reaction, the mixture is stirred and filtered, the filtrate is collected, dried, concentrated, ether is added at 0°C to slurry, the filter cake is collected by filtration and dried to obtain the final product.

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

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

[0027] (5) The reaction of compound VI-1, catalyst and reducing agent yields 6-hydroxy-6-methyl-1,4-diazacycloheptane intermediate;

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

[0029] The present invention has achieved the following beneficial effects:

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

[0031] (2) Compared with the prior art (WO2022076625A1), the present invention uses a novel route to synthesize 6-hydroxy-6-methyl-1,4-diazacycloheptane intermediate, increasing the total yield from 5.3% to 46.3%, an increase of 9 times;

[0032] (3) Compared with the prior art (WO2022076625A1), the synthesis scale of the present invention is greatly increased from the milligram level reported in the literature to the tens of grams level, which meets the requirements of laboratory scale-up preparation.

[0033] This invention provides a novel synthetic method for preparing the intermediate 6-hydroxy-6-methyl-1,4-diazacycloheptane. This method requires only 5 reaction steps, and not only are the raw materials and reagents inexpensive and safe, but it is also simple to operate and has a high yield, which can meet the needs of laboratory scale-up preparation.

[0034] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0035] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following embodiments. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Attached Figure Description

[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 Implementation

[0040] The raw materials and equipment used in this invention are all known products, obtained by purchasing commercially available products.

[0041] In this invention, "room temperature" means 25±10℃, and "overnight" means 20±5 hours.

[0042] The route for preparing the 6-hydroxy-6-methyl-1,4-diazacycloheptane intermediate (compound I-1) according to embodiments of the present invention is as follows:

[0043]

[0044] Example 1: Preparation of Compound I-1

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

[0046] Under nitrogen protection, compound II-1 (57 g, 1 eq.), THF (570 mL), and H2O (570 mL) were added to a 2 L three-necked flask. The temperature was lowered to 0 °C, and K2CO3 (96.74 g, 3 eq.) and BnBr (47.89 g, 1.2 eq.) were slowly added while maintaining the temperature at around 0 °C. After the addition was complete, the reaction was allowed to proceed at room temperature for 1 hour. After the reaction was monitored by TLC to ensure it was complete, saturated saline solution (500 mL) was added to the reaction solution, and the mixture was extracted with EA (3 x 500 mL). The organic phase was dried and concentrated, and purified by column chromatography (the developing solvent was PE:EA = 3:1, and the eluent was PE:EA = 18%). The product was obtained by concentration and yield of colorless, transparent, oily compound III-1 (71.6 g), with a yield of 91.7%. 1 H NMR (400MHz, DMSO-d6) δ7.37–7.20(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, compound III-1 (60.4 g, 1 eq.) and THF (906 mL) were added to a 2 L three-necked flask. The temperature was lowered to -78 °C, and NaHMDS (2.0 M in THF) (135.5 mL, 1.5 eq.) was slowly added while maintaining the temperature at around -78 °C to 0 °C for 1 h. The temperature was then lowered to -78 °C, and isopropyl chloroformate (33.2 g, 1.5 eq.) was slowly added. The temperature was then naturally raised to room temperature for about 1 h. After the reaction was monitored by TLC to ensure it was complete, the reaction solution was quenched in a saturated ammonium chloride aqueous solution (500 mL), and then extracted with EA (3 x 500 mL). The solution was dried and concentrated to obtain a colorless and transparent liquid compound IV-1 (crude product, 84.5 g).

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

[0050] Under nitrogen protection, LiAlH4 (19.27 g, 2.5 eq.) and THF (400 mL) were added to a 2 L three-necked flask. The temperature was lowered to 0 °C, and a THF solution (450 mL) of compound IV-1 (85.4 g, 1 eq.) was slowly added. The mixture was allowed to warm to room temperature and reacted overnight. After the reaction was monitored by TLC to ensure it was complete, the temperature was lowered to 0 °C, and H2O (20 mL), 15% sodium hydroxide aqueous solution (20 mL), and H2O (60 mL) were slowly added sequentially to quench the reaction. The mixture was then heated to room temperature and stirred for 15 minutes before filtration. The filtrate was collected, dried, and concentrated. The crude product was slurried with ice-cold ether (500 mL) at 0 °C for 30 minutes, then filtered. The filter cake was collected, dried, and a white solid compound V-1 (46.0 g) was obtained. The yield of the two-step reaction was 67.3%. 1 H NMR (400MHz, DMSO-d6) δ7.41–7.10(m,5H),4.43(t,J=5.0Hz,2H),3.80(s,2H),3.72(dd,J=11.0,5.3Hz ,2H),3.50(dd,J=11.0,4.8Hz,2H),3.31(s,2H),3.21(t,J=5.4Hz,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, compound V-1 (40.1 g, 1 eq.) and toluene (400 mL) were added to a 1 L three-necked flask. The mixture was cooled to 0 °C, and a toluene solution of CMBP (43.15 g, 1.5 eq.) (400 mL) was slowly added. The mixture was heated to 100 °C and stirred for 2 h. After the reaction was monitored by TLC to ensure complete reaction, the reaction solution was backwashed with saturated saline (2 x 200 mL). The organic phase was dried and concentrated, and purified by column chromatography (the product was obtained when the developing solvent was PE:EA = 3:1 and the eluent was PE:EA = 25%). The product was concentrated to obtain a pale yellow oily compound VI-1 (34.6 g), with a yield of 91.2%. 1 H NMR (400MHz, DMSO-d6) δ7.35–7.21(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] Compound VI-1 (32 g, 1 eq.), MeOH (320 mL), and aqueous Pd / C (3 g) were added to a 500 mL hydrogenation reactor and hydrogenated overnight at 5 atm H2. After the reaction was monitored by TLC to ensure complete reaction, the catalyst was removed by filtration, the filtrate was collected, concentrated, and subjected to column chromatography (the product was obtained when the developing solvent was DCM:MeOH = 3:1 and the eluent was DCM:MeOH = 3.8%) to obtain a pale yellow oily compound I-1 (19.1 g), with a purity of 99.9% and a yield of 82.7%. 1 H NMR(300MHz,Chloroform-d)δ3.87–3.67(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] Examples 2-9: Preparation of Compound I-1

[0056] To optimize the preparation efficiency of the target product, Examples 2-9 investigated the effect of different reaction conditions in step 1 on the yield of the target product. The reaction results are shown in Table 1. Except for the different reaction conditions in step 1 shown in Table 1, the reaction conditions and operations of other synthesis steps in Examples 2-9 are the same as in Example 1.

[0057] Table 1. Effects of different reaction conditions on step 1

[0058]

[0059]

[0060] As can be seen from the experimental results in Table 1, when using the same amount of BnBr, K2CO3 showed the best effect among different base controls (K2CO3, DIEA, TEA, DMAP) (Examples 1 and 2, Examples 4-9); when using K2CO3 as the base, different solvent controls had no significant effect on the yield (Examples 4-6); further optimization of the equivalent amount of BnBr (Examples 1, 3, and 4) yielded the optimal yield of 91.7% under the conditions of Example 1.

[0061] Examples 10-14: Preparation of Compound I-1

[0062] Meanwhile, this invention optimized step 4 and explored the effect of different reaction conditions on the yield of step 4. 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 to 14 are the same as 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 Experimental Example 9 THF room temperature overnight 60.0％ 11 Experimental Example 10 DCM room temperature overnight 63.0％ 12 Experimental Example 11 EA room temperature overnight 0％ 13 Experimental Example 12 THF 60℃ 2h 70.0％ 14 Experimental 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 bases (equivalents) reaction results 1 NaHMDS(1.5) Complete reaction 2 LiHMDS(1.5) Complete reaction 3 KHMDS(1.5) The reaction was complete, but the system was relatively complex. 4 LDA(1.5) The reaction was incomplete, and the system was quite 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] Under nitrogen protection, LiAlH4 (49.02 mg, 3.0 eq.) and THF (1 mL) were added to a 25 mL three-necked flask. The mixture was cooled to 0 °C, and a THF solution (1 mL) of compound IV-1 (200 mg, 1 eq.) was slowly added. The mixture was then allowed to warm naturally to room temperature for 1 h. LCMS analysis showed that the reaction was complete, producing a product de-Cbzed. The reaction system was cooled to 0 °C, and H2O (0.1 mL), 15% sodium hydroxide aqueous solution (0.1 mL), and H2O (0.3 mL) were slowly added sequentially to quench the reaction. The mixture was then heated to room temperature and stirred for 15 minutes before filtration. The filtrate was collected, dried, and concentrated to obtain the crude product.

[0078] Comparative Examples 6–14, Preparation of Compound V-1

[0079] Meanwhile, this invention also optimized step 3 and explored the effects of different reaction conditions on the selectivity and yield of the product (compound V-1) in step 3. 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 to 14 are the same as those in Comparative Example 5.

[0080] Table 4. Effects of different reaction conditions on step 3

[0081]

[0082]

[0083] As shown in Table 4, different equivalents of LiAlH4 all yielded products after Cbz removal (Comparative Examples 5–14). Using BH3 and NaBH4 as reducing agents, the expected products could be obtained, but the reaction yields were low.

[0084] Therefore, the present invention found that Example 1 was the optimal condition for preparing the 6-hydroxy-6-methyl-1,4-diazacycloheptane intermediate.

[0085] In summary, this invention provides a synthetic method for the intermediate 6-hydroxy-6-methyl-1,4-diazacycloheptane. This novel synthetic method for preparing the intermediate 6-hydroxy-6-methyl-1,4-diazacycloheptane not only uses inexpensive and safe raw materials and reagents, but also, compared with existing technologies, is convenient to operate, improves process efficiency by 28.6%, and increases the overall yield to 46.3%, meeting the needs of laboratory-scale preparation and showing good application prospects.

Claims

1. A method for synthesizing a 6-hydroxy-6-methyl-1,4-diazacycloheptane intermediate, characterized in that, The method includes the following steps: (1) Compound II-1, BnX and base react to give compound III-1; the base is selected from potassium carbonate, N,N-diisopropylethylamine, triethylamine or 4-dimethylaminopyridine; (2) Compound III-1, isopropyl chloroformate and base react to give compound IV-1; the base is selected from sodium bis(trimethylsilyl)amino, lithium bis(trimethylsilyl)amino or potassium bis(trimethylsilyl)amino. (3) Compound IV-1 reacts with a reducing agent to obtain compound V-1; the reducing agent is lithium aluminum hydride; (4) Compound V-1 reacts with a phosphine reagent to give compound VI-1; the phosphine reagent is cyanomethylenetri-n-butylphosphine; (5) The reaction of compound VI-1, catalyst and reducing agent yields 6-hydroxy-6-methyl-1,4-diazacycloheptane intermediate; the catalyst is Pd / C; the reducing agent is hydrogen. Where R is an amino protecting group and X is a halogen.

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

3. The synthesis method according to claim 2, characterized in that, In step (1), the molar ratio of compound II-1, BnX and base is 1:1.2:3; BnX is BnBr; the base is potassium carbonate; the solvent for 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; the reaction temperature is 15~35℃ and the reaction time is 1 hour.

4. The synthesis method according to claim 3, characterized in that, The solvent for the reaction is a mixture of tetrahydrofuran and water in a volume ratio of 1:

1.

5. The synthesis method according to claim 1, characterized in that, In step (2), the molar ratio of compound III-1, isopropyl chloroformate and base is 1:1~2:1~2; the solvent for the reaction is an organic solvent; the reaction temperature is -80~40℃ and the time is 1~3 hours.

6. The synthesis method according to claim 5, characterized in that, In step (2), the molar ratio of compound III-1, isopropyl chloroformate, and base is 1:1.5:1.5; the base is sodium bis(trimethylsilyl)amino; the solvent for the reaction is tetrahydrofuran; the reaction conditions are: compound III-1 and solvent are mixed, base is added at -78°C, and the reaction is carried out at -78~0°C for 1 hour; isopropyl chloroformate is added at -78°C, and the reaction is carried out at 15~35°C for 1 hour.

7. The synthesis method according to claim 1, characterized in that, In step (3), the molar ratio of compound IV-1 to reducing agent is 1:1.5~3; the solvent for the reaction is an organic solvent; the reaction temperature is 10~40℃ and the time is 10~30 hours.

8. The synthesis method according to claim 7, characterized in that, In step (3), the molar ratio of compound IV-1 to reducing agent is 1:2.5; the solvent for the reaction is tetrahydrofuran; the reaction temperature is 15~35℃ and the reaction time is 15~25 hours.

9. The synthesis method according to claim 1, characterized in that, In step (4), the molar ratio of compound V-1 to phosphine reagent is 1:1~2; the solvent for the reaction is an organic solvent; the reaction temperature is 80~120℃ and the time is 1~3 hours.

10. The synthesis method according to claim 9, characterized in that, In step (4), the molar ratio of compound V-1 to phosphine reagent is 1:1.5; the solvent for the reaction is toluene; the reaction temperature is 100°C and the reaction time is 2 hours.

11. The synthesis method according to claim 1, characterized in that, In step (5), the mass ratio of compound VI-1 to catalyst is 30~35:2~4; the solvent for the reaction is an organic solvent; the reaction temperature is 10~40℃ and the time is 10~30 hours.

12. The synthesis method according to claim 11, characterized in that, The mass ratio of compound VI-1 to the catalyst is 32:3; the solvent for the reaction is methanol.

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