A method for synthesizing chiral hydrogenated carbazole skeleton and ms-245 analogues

Abstract

This invention discloses a method for synthesizing a chiral hydrogenated carbazole skeleton and MS-245 analogs. Indole compound I, aldehyde compound II, and a catalyst are dissolved in a solvent and reacted at 20–75°C for 4–30 h to obtain compound III. This invention provides a synthetic method that does not use heavy metals, has a short synthetic route, mild reaction conditions, and is suitable for industrial production. It can also synthesize a large number of analogs with different substituents, promoting their medicinal chemistry research.

Description

Technical Field

[0001] This invention belongs to the field of compound synthesis technology, specifically relating to a method for synthesizing a chiral hydrogenated carbazole skeleton and MS-245 analogues. Background Technology

[0002] The statements herein provide only background information in relation to this invention and do not necessarily constitute prior art.

[0003] Carbazole is a common nitrogen-containing heterocyclic skeleton, and its structure is shown in Formula 1 below: .

[0004] Carbazole is widely found in nature, and modifications to its skeleton can yield compounds with various biological activities. Carbazole derivatives also exhibit many important materials-related properties. Therefore, the synthesis and study of carbazole compounds has long been an important topic in the fields of organic chemistry, medicinal chemistry, and materials chemistry.

[0005] MS-245 and its analogues are 5-HT6 inhibitors, with the structural formula shown below. By chemically modifying their structure, compounds with varying activities can be obtained; both their racemic and chiral forms exhibit excellent biological activity. MS-245's K... i = 2.3nM, K of Ms-245 analogues i = 2.0 nM, its R configuration as an IC50 inhibitor of 5-HT6 50 = 1.5nM.

[0006]

[0007] The following are some of the more typical methods reported in the literature for the synthesis of MS-245 analogues: Route 1:

[0008] In the synthetic method of Route 1 (Chem. Eur. J. 2012, 18, 13250 – 13254), the substrate 21 used in the above synthetic route requires multiple steps to prepare, and the synthesis of compound 22 requires 1.5 equivalents of the heavy metal reagent AgSbF6. Then, the nitro reduction of 22 requires 1.2 equivalents of metallic NiCl2.

[0009] In the synthetic route below (Angew. Chem. Int. Ed. 2015, 54, 14133 –14136), (-)-2PPTS is a chiral starting material that needs to be synthesized. The preparation of compound 24 requires high temperature (130°C) microwave conditions, which are very harsh and difficult to achieve industrial production.

[0010] Route 2:

[0011]

[0012] The synthetic method of route two (ACS Catal. 2017, 7, 4047) 4052) The starting material (R)-1c used is a chiral starting material that needs to be prepared, and it uses the precious metal [Rh(NBD)2]BF4. Another more important limitation is that this route does not include the preparation of the starting material, which requires six reaction steps, making the route too long.

[0013] In summary, the existing synthetic methods are lengthy, costly, and some require the use of large amounts of heavy metals, which can easily lead to metal residues. Summary of the Invention

[0014] Existing methods for synthesizing MS-245 analogs either involve the extensive use of heavy metals, demanding reaction conditions, or the use of precious metals and lengthy routes, making industrial-scale production difficult. To address these issues, this invention provides a synthetic method that does not use heavy metals, has a short synthetic route, mild reaction conditions, and is suitable for industrial production. It can also synthesize a large number of analogs with different substituents, thus promoting their medicinal chemistry research.

[0015] To achieve the above objectives, the present invention provides the following technical solution: In a first aspect, the present invention provides a method for synthesizing hydrogenated carbazole compounds, comprising the following steps: Compound III was prepared by dissolving indole compound I, aldehyde compound II, and a catalyst in a solvent and reacting at 20–75 °C for 4–30 h. The reaction equation for this synthetic method is as follows:

[0016] Wherein, R is hydrogen, C1-7 branched or branched alkyl, phenyl-substituted alkyl, phenyl or substituted phenyl; R' is an alkoxy, alkyl, or halogen, etc.; R'' is hydrogen or alkyl, and R'' may or may not be connected to R to form a ring; B1 is selected from p-toluenesulfonyl (Ts, chemical formula is p-CH3-C6H4-SO2-), methanesulfonyl (Ms), benzenesulfonyl (SO2Ph), CO2Me, Boc and CO2Bn; The catalyst was selected from Jørgensen-Hayashi catalysts. , (S)-2-(methoxydiphenylmethyl)pyrrolidine ,as well as At least one of them.

[0017] It also includes an acidic catalyst, which is selected from one or more of Tf2NH, TfOH, trifluoroacetic acid and boron trifluoride diethyl ether; The solvent is selected from one or more of dichloromethane (DCM), trifluoroethanol (TFE), chloroform, tetrahydrofuran, toluene, methyl tert-butyl ether, and ethyl tert-butyl ether.

[0018] Preferably, the molar ratio of the indole compound I, the aldehyde compound II, and the catalyst is 0.1:0.15~0.25:0.004~0.025.

[0019] Preferably, the amount of catalyst added is 25% equivalent to compound 1.

[0020] Preferably, the amount of acidic catalyst added is 5%-24% relative to compound I, more preferably 20%.

[0021] Preferably, the molar ratio of the catalyst to the acid catalyst is 1.05:1 to 10:1, more preferably 1.25:1.

[0022] Secondly, the present invention also provides a method for synthesizing Ms-245 analogues, comprising the following steps: Compound 5a reacts with dimethylamine in the presence of an acidic catalyst at a temperature of -40 to 0 °C. Then, sodium triacetylborohydride is added to the system to prepare hydrogenated carbazole compound 5c. The reaction equation is as follows: ; The acidic catalyst is selected from one or more of Tf2NH, TfOH, trifluoroacetic acid and boron trifluoride diethyl ether.

[0023] In some embodiments of the present invention, the method for synthesizing Ms-245 analogues includes the following steps: An acidic catalyst was added dropwise to a solution of compound 5c at a temperature of -40 to 0°C. After stirring, the reaction was quenched by adding an aqueous solution of sodium bicarbonate to obtain hydrogenated carbazole compound 5d. The reaction equation is as follows: ; The acidic catalyst is selected from one or more of Tf2NH, TfOH, trifluoroacetic acid and boron trifluoride diethyl ether.

[0024] In some embodiments of the present invention, the method for synthesizing Ms-245 analogues includes the following steps: Compound 4a / 4m reacts with dimethylamine in the presence of a catalyst at a temperature of -40 to 20°C. Then, sodium triacetylborohydride is added to the system to prepare 5e / 5f. The reaction equation is as follows: ; The catalyst is an acidic catalyst, which is selected from one or more of Tf2NH, TfOH, trifluoroacetic acid and boron trifluoride diethyl ether.

[0025] Thirdly, the present invention provides a hydrogenated carbazole intermediate having the structure shown in Formula IV: Formula IV; Wherein, R is hydrogen, C1-7 branched or branched alkyl, phenyl-substituted alkyl, phenyl or substituted phenyl; R' is an alkoxy, alkyl, or halogen; R'' is hydrogen or alkyl, and R'' may or may not be connected to R to form a ring; B1 is selected from p-toluenesulfonyl (Ts, chemical formula p-CH3-C6H4-SO2-), methanesulfonyl (Ms), benzenesulfonyl (SO2Ph), CO2Me, Boc, and CO2Bn.

[0026] Preferably, the hydrogenated carbazole intermediate is selected from any one of the following compounds: .

[0027] Preferably, the hydrogenated carbazole intermediate is selected from any one of the following compounds: .

[0028] Preferably, the hydrogenated carbazole intermediate is selected from any one of the following compounds: .

[0029] Fourthly, the present invention provides the use of the hydrogenated carbazole intermediate described in the third aspect in the preparation of Ms-245 analogs.

[0030] The beneficial effects achieved by one or more embodiments of the present invention described above are as follows: 1. This invention provides a method for synthesizing hydrogenated carbazole skeleton and Ms-245 analogs. The synthesis process does not use heavy metal reagents, but uses commercially available small molecule organic catalysts and conventional reagents. The reaction conditions are easy to operate, the steps are simple (3 steps), and a large number of analogs with different substituents can be synthesized, which has the potential for industrial production.

[0031] 2. This invention provides a hydrogenated carbazole intermediate, based on which diverse 4-aldehyde hydrogenated carbazole skeletons with different substituents can be constructed (more than 50 structurally similar compounds), thereby enabling more diversified MS-245 analogs. Attached Figure Description

[0032] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0033] Figure 1 This is the synthetic route diagram of compound 3b in Example 1.

[0034] Figure 2 This is the proton NMR spectrum of compound 3b from Example 1.

[0035] Figure 3 This is the carbon spectrum of compound 3b from Example 1.

[0036] Figure 4 This is the mass spectrum of compound 3b from Example 1.

[0037] Figure 5 This is the HPLC chromatogram of compound 3b from Example 1.

[0038] Figure 6 This is the SXRD pattern of compound 3k from Example 2.

[0039] Figure 7 This is the hydrogen spectrum of compound 5a from Example 3.

[0040] Figure 8 This is the carbon spectrum of compound 5a from Example 3.

[0041] Figure 9 This is the mass spectrum of compound 5a from Example 3.

[0042] Figure 10 This is the HPLC chromatogram of compound 5a from Example 3.

[0043] Figure 11 This is the hydrogen spectrum of compound 5c from Example 6.

[0044] Figure 12This is the carbon spectrum of compound 5c from Example 6.

[0045] Figure 13 This is the mass spectrum of compound 5c from Example 6.

[0046] Figure 14 This is the HPLC chromatogram of compound 5c from Example 6.

[0047] Figure 15 This is the proton NMR spectrum of compound 5d from Example 7.

[0048] Figure 16 This is the carbon spectrum of compound 5d from Example 7.

[0049] Figure 17 This is the mass spectrum of compound 5d from Example 7.

[0050] Figure 18 This is the HPLC chromatogram of compound 5d from Example 7. Detailed Implementation

[0051] It should be noted that the following detailed description is illustrative and intended to provide further explanation of the invention. Unless otherwise specified, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0052] The present invention will be further described below with reference to the embodiments.

[0053] The synthetic route provided by this invention is as follows:

[0054] In some embodiments of the present invention, the catalyst used includes Any one of them.

[0055] In some embodiments of the present invention, the following synthetic route is also provided: .

[0056] This invention can efficiently synthesize the racemic and asymmetric forms of 5a without using metal reagents, under mild conditions, and using inexpensive and readily available small organic molecule catalysts.

[0057] In some embodiments of the present invention, the following synthetic route is also provided:

[0058] After obtaining compound 5a, the synthesis of MS-245 analogs can be completed in just two steps, without the use of any metal reagents, making the operation convenient. Furthermore, by performing similar transformations on compounds 4a and 4m, analogs with alkyl and aryl substituents at the 3-position of MS-245 can be synthesized.

[0059] Example 1, Synthesis of compound 3b

[0060] Synthetic routes such as Figure 1 As shown in Figure a, p-methanesulfonyl-2-vinyl-1H-indole (0.1 mmol), crotonaldehyde (0.25 mmol), and catalyst E / Tf2NH (pre-prepared catalyst, catalyst E:Tf2NH = 0.025 mmol : 0.02 mmol) were added to 0.2 mL of trifluoroethanol and reacted at 45°C for 6.5 hours. After the solvent was evaporated, the remaining material was separated by column chromatography to obtain product 3b (70% yield, >20:1 dr, 99% ee).

[0061] 1 H NMR (600 MHz, CDCl3)δ 9.15 (s, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.53(d, J = 7.6 Hz, 2H), 7.32 – 7.25 (m, 1H), 7.15 (d, J = 7.7 Hz, 2H), 7.10 (t, J =7.4 Hz, 1H), 7.05 (d, J = 7.3 Hz, 1H), 6.11 (t, J = 3.4 Hz, 1H), 3.46 (s, 1H), 2.70 (dd, J = 5.6, 2.8 Hz, 1H), 2.50 – 2.37 (m, 2H), 2.35 (s, 3H), 1.94 (d, J =18.1 Hz, 1H), 1.00 (d, J = 7.0 Hz, 3H). 13C NMR(151 MHz, CDCl3)δ 202.09, 144.57, 142.65, 138.12, 134.82,130.90, 129.51, 128.51, 127.15, 125.45, 123.56, 117.66, 113.77, 51.99, 37.58,28.86, 27.37, 21.69, 20.64. HRMS (ESI)calcd for C 21 H 22 NO3S + ([M+H)) + ) 368.1315, found 368.1310. HPLC analysis: HPLC DAICEL Chiralpak ID, hexane:isopropanol = 94:6, 0.8 mL / min, 254 nm, t major = 44.752 min, t minor = 50.538 min. [α] 25 D = +103.2 ( c = 0.19, CHCl3) for a 99.5% ee sample.

[0062] The SXRD pattern of compound 3b is shown below. Figure 1 As shown in b, the proton, carbon, mass, and HPLC spectra are as follows: Figures 2-5 As shown.

[0063] Example 2, Synthesis of other similar compounds Examples 2-1 to 2-16 provide methods for synthesizing compounds that are structurally similar to compound 3b in Example 1. The synthesis methods are the same as those for compound 3b in Example 1. The conditions, product yields and optical purity are shown in Table 1.

[0064] Table 1 Synthesis conditions and results of compounds in Examples 2-1 to 2-16

[0065] Reaction conditions: 1a (0.10 mmol), 2a (0.15-0.25 mmol), and catalyst A-Tf₂NH₃ salt in a 1.25:1 ratio (20 mol%, based on acid equivalents, i.e., catalyst A is 0.025 mmol, acid is 0.02 mmol) were dissolved in 0.2 mL of trifluoroethanol, and the reaction was carried out in a sealed tube. Yield refers to the isolated yield; dr value is obtained by... 1 The ¹H NMR was used for determination, and the ee value was determined by chiral HPLC.

[0066] The SXRD analysis results of compound 3k are as follows: Figure 6 As shown.

[0067] Example 3, Synthesis of compound 5a The reaction route is as follows:

[0068] 0.1 mmol of 5-methoxy-1-(benzenesulfonyl)-2-vinyl-1H-indole, 0.15 mmol of acrolein, 0.025 mmol of catalyst E, and 0.020 mmol of boron trifluoride diethyl ether were reacted in 0.2 mL of dichloromethane for 19 hours. The product 5a was then separated by column chromatography (79% recovery yield, 32% separation yield, >20:1 dr, 98% ee). If the solvent was changed to trifluoroethanol, racemic 5a could be obtained by column chromatography at room temperature for 20 hours with a yield of 86%. Trifluoroethanol is a protic solvent, which easily causes racemization of the aldehyde group in the product, thus yielding a racemic product.

[0069] 1 H NMR (600 MHz, CDCl3)δ 9.28 (s, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.63(d, J = 7.8 Hz, 2H), 7.54 (t, J = 7.4 Hz, 1H), 7.37 (t, J = 7.5 Hz, 2H), 6.82 (d, J =8.8 Hz, 1H), 6.62 (s, 1H), 6.12 (s, 1H), 3.77 (s, 3H), 3.40 (s, 1H), 2.92 (s,1H), 2.28 (d, J = 11.9 Hz, 3H), 1.67 (ddq, J = 15.8, 11.3, 5.2 Hz, 1H). 13 C NMR(151 MHz, CDCl3)δ 201.86, 157.99, 139.16, 137.62, 135.66,133.44, 132.45, 128.90, 127.36, 118.79, 115.61, 113.41, 109.72, 55.77, 45.57,42.15, 22.88, 21.05. HRMS (ESI)calcd for C 20 H 20 NO4S + ([M+H)) + ) 370.1108, found 370.1117. HPLC analysis: HPLC DAICEL Chiralpak IE, hexane:isopropanol = 80:20, 0.8 mL / min, 254 nm, t major = 52.162 min, t minor = 30.690 min. [α] 25 D = -40.7 ( c = 0.086,CHCl3) for a 98%ee sample. The 1H N, 1C, mass, and HPLC spectra of 5a are as follows: Figures 7-10 As shown.

[0070] Example 4, Synthesis of compound 5b 0.1 mmol of 5a was dissolved in 1 mL of dichloromethane and cooled to -40 °C. 0.02 mmol of boron trifluoride was added dropwise to the system. After half an hour, the solution was quenched with sodium bicarbonate aqueous solution. The aqueous phase was extracted twice with dichloromethane (10 mL each time) after separation. The organic phases were combined and purified by column chromatography to obtain 5b (95% yield, 98% ee). The proton, carbon, and mass spectrometry data are shown below: 1 H NMR (600 MHz, CDCl3)δ 9.64 (d, J = 2.4 Hz, 1H), 8.08 (d, J = 9.1 Hz, 1H), 7.76 (d, J = 7.7 Hz, 2H), 7.54 (t, J = 7.3 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 6.91 (d, J= 9.0 Hz, 1H), 6.79 (s, 1H), 3.81 (s, 3H), 3.61 (s, 1H), 3.11 (d, J =17.8 Hz, 1H), 2.97 (dd, J = 16.4, 9.0 Hz, 1H), 2.18 (q, J = 9.1, 6.1 Hz, 1H),1.98 – 1.80 (m, 3H). 13 C NMR(151 MHz, CDCl3)δ 200.79, 156.86, 139.07, 138.39, 133.86,130.92, 130.28, 129.46, 126.44, 115.57, 113.42, 113.06, 101.43, 55.82, 45.97,24.51, 22.52, 20.67. HRMS (ESI)calcd for C 22 H 22 NO3 + ([M+H)) + ) 348.1594, found 348.1594. Example 5: Synthesis of compound 5a under other conditions Examples 5-1 to 5-6 provide a method for synthesizing compounds 5a and 5b, respectively. The method is the same as that in Example 3, except that the catalyst, solvent, and reaction conditions are replaced separately. The yield and optical purity of the products are shown in Table 2.

[0071] Table 2 Reaction conditions and results of Examples 5-1 to 5-6 entry catalyst acid solvent Conditions yield of 5a yield of 5b 5-1 b ]]> A Tf2NH DCM 55°C, 15 h <5% <10%, 57% ee 5-2 b ]] A Tf2NH TFE 55°C, 7 h <5% <10%, 10% ee 5-3 b,c ]] A BF3•Et2O CHCl3 rt,28 h 27%, 6:1 dr, 98%ee 9%, 85% ee 5-4 c ]] E BF3•Et2O CHCl3 rt,28 h 32%, 11:1 dr, 99%ee 7%, 67% ee 5-5 c ]]> E BF3•Et2O TFE rt,15 h 86%, >20:1 dr, 0%ee <5% 5-6 c ]] E BF3•Et2O DCM rt,19 h 32%, 79% (brsm) > 20:1 dr, 98% ee 7%, 98% ee Reaction conditions: 1a (0.10 mmol), 2a (0.12–0.25 mmol), and catalyst A-Tf₂NH salt in a 1.25:1 ratio (20 mol%, based on acid equivalents) were dissolved in 0.2 mL of solvent and reacted in a sealed tube. Yield refers to the separation yield; the ee value was determined by chiral HPLC.

[0072] b Conversely, stereoselectivity; c In-situ preparation of catalyst.

[0073] Example 6, Synthesis of compound 5c At -40°C, 0.16 mmol of boron trifluoride diethyl ether was added dropwise to a 0.2 mmol dimethylamine solution in dichloromethane (0.4 mL). After stirring for 20 minutes, 0.1 mmol of 5a was added to the system. The system was slowly restored to room temperature and then stirred for 2 hours. 0.3 mmol of sodium triacetate borohydride was then added to the system. After reacting at room temperature for 2 hours, column chromatography was used to separate 5c (69% yield, >20:1 dr, 98% ee).

[0074] 1 H NMR (600 MHz, CDCl3)δ 7.68 (d, J = 8.8 Hz, 1H), 7.61 (d, J = 7.7 Hz, 2H), 7.52 (t, J = 7.4 Hz, 1H), 7.35 (t, J = 7.4 Hz, 2H), 6.78 (d, J = 8.8 Hz, 1H), 6.58 (s, 1H), 6.04 (s, 1H), 3.79 (s, 3H), 3.29 (s, 1H), 2.46 (s, 1H), 2.35 –2.00 (m, 10H), 1.70 (d, J = 22.1 Hz, 1H), 1.58 – 1.45 (m, 1H). 13 C NMR(151 MHz, CDCl3)δ 157.68, 138.42, 137.64, 135.79, 133.27,128.77, 127.44, 118.52, 114.19, 112.74, 109.97, 55.79, 45.91, 44.66, 30.28,29.85, 23.56, 20.68. HRMS (ESI)calcd for C 22 H 27 N2O3S + ([M+H)) + ) 399.1737, found 399.1744. HPLC analysis: HPLC DAICEL Chiralpak ODH, hexane:isopropanol = 97:3, 0.8 mL / min, 254 nm, t major = 14.867 min, t minor= 18.047 min. The 1H, 1C, mass, and HPLC spectra of 5c are as follows: Figures 11-14 As shown.

[0075] Example 7, Synthesis of compound 5d At -40°C, boron trifluoride diethyl ether (0.12 mmol) was added dropwise to a 0.1 mmol solution of 5c in dichloromethane (0.5 mL). After stirring for 1 h, the reaction was quenched by adding sodium bicarbonate aqueous solution. The final product, MS-245 analog 5d ​​(91% yield, 98% ee), was obtained by column chromatography.

[0076] 1 H NMR (600 MHz, CDCl3)δ 8.06 (d, J = 9.0 Hz, 1H), 7.73 (d, J = 7.9 Hz, 2H), 7.51 (t, J = 7.5 Hz, 1H), 7.41 (t, J = 7.7 Hz, 2H), 6.94 (d, J = 2.1 Hz, 1H), 6.90 – 6.82 (m, 1H), 3.84 (d, J = 1.7 Hz, 3H), 3.10 (d, J = 17.6 Hz, 1H), 3.02(s, 1H), 2.86 – 2.74 (m, 1H), 2.38 (d, J = 54.5 Hz, 8H), 2.03 (d, J = 13.5 Hz,1H), 1.92 – 1.75 (m, 2H), 1.67 (s, 1H). 13 C NMR(151 MHz, CDCl3)δ 156.47, 139.20, 137.29, 133.58, 131.22,129.30, 126.42, 115.54, 111.65, 102.44, 62.64, 55.83, 46.06, 37.55, 25.01,24.94, 19.06. HRMS (ESI)calcd for C 22 H 27 N2O3S + ([M+H)) + ) 399.1737, found 399.1734. HPLC analysis: HPLC DAICEL Chiralpak ODH, hexane:isopropanol = 98:2, 0.8 mL / min, 254 nm, t major = 14.388 min, t minor = 15.477 min. The proton, carbon, mass, and HPLC spectra of compound 5d are shown below. Figures 15-18 As shown.

[0077] Example 8, Synthesis of 5g of compound Dissolve 0.1 mmol 5a in 1 mL of dichloromethane, cool to -40 °C, add 0.02 mmol boron trifluoride dropwise to the system, and after half an hour, add 0.025 mmol triethylamine to terminate the reaction. Warm up to 0 °C, add 0.2 mmol sodium borohydride, and after half an hour, add water to terminate the reaction. After separation, extract the aqueous phase with 10 mL*2 of dichloromethane, combine the organic phases, and purify by column chromatography to obtain 5 g (93% yield, 98% ee).

[0078] 1 H NMR (600 MHz, CDCl3)δ 8.06 (d, J = 9.0 Hz, 1H), 7.73 (d, J = 7.8 Hz, 2H), 7.52 (t, J = 7.4 Hz, 1H), 7.41 (t, J = 7.4 Hz, 2H), 6.94 (d, J = 2.6 Hz, 1H), 6.87 (d, J = 9.0 Hz, 1H), 3.88 (d, J = 9.8 Hz, 1H), 3.82 (s, 3H), 3.70 (t, J = 8.5Hz, 1H), 3.16 – 3.01 (m, 2H), 2.84 (dt, J = 17.1, 7.9 Hz, 1H), 1.99 (d, J = 13.9Hz, 1H), 1.87 (s, 2H), 1.77 – 1.67 (m, 1H), 1.42 (s, 1H). 13C NMR(151 MHz, CDCl3)δ 156.62, 139.02, 137.97, 133.66, 131.06,130.90, 129.32, 126.39, 118.44, 115.55, 112.31, 101.96, 64.98, 55.85, 35.00,24.88, 24.40, 19.45. HRMS (ESI)calcd for C 22 H 22 NO3 + ([M+H)) + ) 348.1594, found 348.1594.

[0079] Example 9, Synthesis of compound 5e Prepared from 4a, 0.1 mmol of compound 4a was reacted with dimethylamine in boron trifluoride diethyl ether (0.2 mmol: 0.16 mmol) at -20 to 0 °C. After 2 hours, 0.2 mmol of sodium triacetylborohydride was added to the system, and the product 5e was obtained by column chromatography (71% yield, 96% ee, >20:1 dr). 1 H NMR (600 MHz, CDCl3)δ 8.15 (d, J = 8.1 Hz, 1H), 7.63 (d, J = 7.7 Hz, 2H), 7.41 (d, J = 7.4 Hz, 1H), 7.24 (dd, J = 14.2, 7.8 Hz, 2H), 7.19 (d, J = 7.8Hz, 2H), 3.05 (d, J = 17.8 Hz, 1H), 2.90 – 2.75 (m, 2H), 2.47 (t, J = 11.4 Hz, 1H), 2.38 (d, J = 11.9 Hz, 1H), 2.33 (d, J = 8.0 Hz, 9H), 2.07 (d, J = 8.0 Hz, 1H),1.92 – 1.82 (m, 2H), 1.27 (dt, J = 14.5, 6.2 Hz, 2H), 0.98 – 0.90 (m, 3H). 13 C NMR(151 MHz, CDCl3)δ 144.62, 136.69, 136.35, 135.34, 130.31,129.90, 126.42, 123.92, 123.22, 118.35, 114.72, 63.32, 46.05, 35.37, 34.09,24.52, 21.78, 21.68, 20.62, 12.24. HRMS (ESI) calcd for C 22 H 22 NO3 + ([M+H)) + ) 348.1594, found 348.1594.

[0080] Example 10, Synthesis of compound 5f Compound 4m was prepared by reacting 0.1 mmol of compound 4m with dimethylamine in boron trifluoride diethyl ether (0.2 mmol: 0.16 mmol) at -20 to 0 °C. After 2 hours, 0.2 mmol of sodium triacetate borohydride was added to the system, and the product 5f was obtained by column chromatography (67% yield, 97% ee, >20:1 dr). 1 H NMR (600 MHz, CDCl3)δ 8.18 (d, J = 8.2 Hz, 1H), 7.67 (d, J = 7.5 Hz, 3H), 7.26 (ddt, J = 29.1, 20.6, 7.5 Hz, 9H), 3.34 (dd, J = 18.3, 5.7 Hz, 1H), 3.17 (d, J = 12.5 Hz, 2H), 3.02 (dt, J = 17.7, 8.4 Hz, 1H), 2.45 – 2.37 (m, 1H), 2.35 (s, 3H), 2.33 – 2.25 (m, 1H), 2.17 (d, J = 11.9 Hz, 2H), 1.84 (s, 6H). 13C NMR(151 MHz, CDCl3)δ 144.63, 143.86, 136.85, 136.48, 134.90,129.93, 129.53, 128.19, 127.17, 126.52, 126.28, 124.01, 123.30, 120.39,114.44, 60.77, 46.16, 43.26, 37.69, 25.10, 24.24, 21.71. HRMS (ESI)calcd for C 22 H 22 NO3 + ([M+H)) + ) 348.1594, found 348.1594.

[0081] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for synthesizing a hydrogenated carbazole compound, characterized in that, Includes the following steps: Compound III was prepared by dissolving indole compound I, aldehyde compound II, and a catalyst in a solvent and reacting at 20–75 °C for 4–30 h. The reaction equation for this synthetic method is as follows: Wherein, R is hydrogen, C1-7 branched or branched alkyl, phenyl-substituted alkyl, phenyl or substituted phenyl; R' is an alkoxy, alkyl, or halogen; R'' is hydrogen or alkyl, and R'' may or may not be connected to R to form a ring; B1 is selected from p-toluenesulfonyl, methanesulfonyl, benzenesulfonyl, CO2Me, Boc, and CO2Bn; The catalyst was selected from Jørgensen-Hayashi catalysts. , (S)-2-(methoxydiphenylmethyl)pyrrolidine ,as well as At least one of them.

2. The method for synthesizing hydrogenated carbazole compounds according to claim 1, characterized in that, It also includes an acidic catalyst, which is selected from one or more of Tf2NH, TfOH, CF3CO2H and boron trifluoride diethyl ether.

3. The method for synthesizing hydrogenated carbazole compounds according to claim 1, characterized in that, The molar ratio of the indole compound 1, the aldehyde compound 2, the catalyst, and the acid catalyst is 0.1:0.15~0.25:0.004~0.025:0.005~0.

024.

4. The method for synthesizing hydrogenated carbazole compounds according to claim 1, characterized in that, The molar ratio of the catalyst to the acid catalyst is 1.05:1 to 10:

1.

5. A method for synthesizing a Ms-245 analogue, characterized in that, Includes the following steps: Compound 5a reacts with dimethylamine in the presence of an acidic catalyst at a temperature of -40 to 0 °C. Then, sodium triacetylborohydride is added to the system to prepare hydrogenated carbazole compound 5c. The reaction equation is as follows: ； The acidic catalyst is selected from one or more of Tf2NH, TfOH, trifluoroacetic acid and boron trifluoride diethyl ether.

6. A method for synthesizing a Ms-245 analogue, characterized in that, Includes the following steps: At a temperature of -40 to 0°C, an octanoic acid catalyst was added dropwise to a solution of compound 5c. After stirring, the reaction was quenched by adding an aqueous solution of sodium bicarbonate to obtain hydrogenated carbazole compound 5d. The reaction equation is as follows: ； The acidic catalyst is selected from one or more of Tf2NH, TfOH, trifluoroacetic acid and boron trifluoride diethyl ether.

7. A method for synthesizing a Ms-245 analogue, characterized in that, Includes the following steps: Compound 4a / 4m was reacted with dimethylamine in the presence of a catalyst at a temperature of -40 to 20°C to prepare 5e / 5f. ； The catalyst is an acidic catalyst, which is selected from one or more of Tf2NH, TfOH, trifluoroacetic acid and boron trifluoride diethyl ether.

8. A hydrogenated carbazole intermediate, characterized in that, It has the structure shown in Equation IV: Formula IV; Wherein, R is hydrogen, C1-7 branched or branched alkyl, phenyl-substituted alkyl, phenyl or substituted phenyl; R' is an alkoxy, alkyl, or halogen; R'' is hydrogen or alkyl, and R'' may or may not be connected to R to form a ring; B1 is selected from p-toluenesulfonyl, methanesulfonyl, benzenesulfonyl, CO2Me, Boc, and CO2Bn.

9. The hydrogenated carbazole intermediate according to claim 8, characterized in that, The hydrogenated carbazole intermediate is selected from any one of the following compounds: 。 10. The use of the hydrogenated carbazole intermediate according to any one of claims 8 to 9 in the preparation of Ms-245 analogs.

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