A method for synthesizing 3-thiocyanatospiro cyclobutyloxy indole compounds

Abstract

The present application relates to the technical fields of medical and pharmaceutical chemical synthesis, and particularly relates to a synthesis method of 3-thiocyanatospiro cyclobutyl oxindole compounds, which comprises the following steps: in a reactor, compound 1, compound 2, a catalyst, an additive and a solvent are stirred for 30 minutes at room temperature, after the reaction is completed, the crude product is obtained by reduced pressure distillation, and the 3-thiocyanatospiro cyclobutyl oxindole compound is obtained by column chromatography and thin layer chromatography purification. N The present application takes phenyl bicyclo[1.1.0]butane-1-formamide compounds and thiocyanate as raw materials, and promotes the synthesis of 3-thiocyanatospiro cyclobutyl oxindole compounds by an oxidant. The present application has the advantages of simple synthesis steps, mild conditions, safe operation, good functional group compatibility, high reaction conversion, low cost and the like, and is conducive to industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical and chemical synthesis technology, specifically to a method for synthesizing 3-thiocyanospirocyclobutyloxyindole compounds. Background Technology

[0002] Spirocyclic compounds are common structural units in drug development and natural bioactive molecules, and are also indispensable molecular building blocks in organic synthesis reactions. Notably, bioactive molecules based on spirocyclobutylindole as their basic skeleton have attracted considerable attention, such as respiratory syncytial virus inhibitors, Wilwick indolone A isonitriles, phosphodiesterase 10A inhibitors, and bromine domain inhibitors. Given the wide range of applications of spirocyclobutylindole, developing novel and efficient synthetic methods for spirocyclobutylindole has always been a hot topic in organic synthesis.

[0003] The synthesis of cyclobutane spirocyclic structures is very challenging, mainly due to the following: 1. The high strain of the small ring leads to the instability of the compound; 2. The reaction selectivity is difficult to control; 3. The method of introducing heteroatoms onto the ring is plagued by functional group compatibility issues; 4. After scale-up synthesis, there are problems such as separation difficulties.

[0004] For example, Li Jinheng's research group recently... N Using phenylbicyclo[1.1.0]butane-1-carboxamide (BCB) and α-carbonylbromoalkane as raw materials, and employing an iridium complex as a photocatalyst, the reaction was carried out under light irradiation for nearly 2 days, thereby obtaining 3-substituted spirocyclic butylindole (P2O3). Org. Lett . 2024, 26, 2073). In the same year, Hari's team used BCB and sulfonyl compounds as substrates to obtain spirocyclobutylindole products by photo-induced iridium catalysis to construct C / C bonds / cyclization under strong base conditions. Org. Lett . 2024, 26, 6396). In addition to photoinduced reactions, Kündig and Gouverneur et al. developed a zero-valent palladium-catalyzed intramolecular C-C bond coupling cyclization reaction of bicyclic bromoamides, successfully constructing spirocyclobutylindole (…). Chem. Eur. J. 2013, 19 , 11916–11927; J. Am. Chem. Soc(2020, 142, 720). This synthetic strategy, besides using noble metals, suffers from cumbersome raw material preparation and substrate limitations. Recently, Maji's group reported an electrocatalytic method for constructing spirocyclobutylindole oxide. This method utilizes an equivalent amount of tetrabutylammonium bromide (nBu4NBr) as both a bromine source and electrolyte, achieving bromination and cyclization of BCB. Under mild conditions, the reaction yields high and exhibits good non-parametric selectivity, enabling gram-scale reactions. In this report, the authors pre-synthesized 3-bromospirocyclobutylindole and then reacted it with sodium thiocyanate via a nucleophilic substitution reaction to obtain 3-thiocyanospirocyclobutylindole oxide in moderate yields (ChemSusChem 2025, 18, e202401701). The above reactions can effectively yield furan compounds, but most have some shortcomings. For example, the use of precious metals is costly, has a long reaction time, is cumbersome to operate, and requires harsh reaction conditions. It may also result in low conversion rate and poor selectivity, making it difficult to serve industrial production.

[0005] Furthermore, the thiocyanate group is a very important functional group with wide applications in the biological and chemical fields. For example, the thiocyanate group has strong coordination ability, capable of coordinating with various metal ions, and can be used for rapid qualitative and quantitative detection of heavy metals through colorimetric reactions. Simultaneously, the thiocyanate group is a versatile reaction site for chemical transformations, readily undergoing addition, substitution, cyclization, hydrolysis, and other reactions, making it a powerful functional group in organic synthesis. In biology, compounds containing the thiocyanate group are common in drug molecules, exhibiting antibacterial, antiparasitic, and antitumor activities. For example, commercially available drugs such as erlotinib, propranolol, and erythromycin thiocyanate all contain the thiocyanate group. Against this backdrop, developing efficient methods to introduce the reactive thiocyanate group into the structure of spirocyclic indole would promote the synthesis of complex functional molecules. Summary of the Invention

[0006] The purpose of this invention is to address some shortcomings in the existing technology by proposing a new synthetic method for 3-thiocyanospirocyclobutyl oxyindole compounds. This method is safe and simple, operates under mild conditions, does not require strong bases, light, or complex devices such as electrodes, and has a high reaction conversion rate and low cost, which is beneficial for industrial production.

[0007] To achieve the above objectives, the technical solution adopted by the present invention is as follows: A method for synthesizing a 3-thiocyanospirocyclobutyl oxidized indole compound, comprising the following synthetic steps: In a reactor, compounds 1, 2, a catalyst, an additive, and a solvent were added and reacted at room temperature for 30 min. The solvent was then removed, and the product was purified by column chromatography or thin-layer chromatography to obtain 3-thiocyanospirocyclobutylindole oxide compounds. The reaction equation is as follows:

[0008] Compound 1 refers to a compound having the structure of formula (1): N -Phenylated bicyclo[1.1.0]butane-1-carboxamide; the compound 2 refers to a compound having the structure of formula (2): thiocyanate; wherein, R1 is a methyl, bromine or methoxy substituent; R2 is methyl or n-butyl. X is sodium, potassium, ammonium, zinc or copper; the value of n is 1 or 2.

[0009]

[0010] The compound 1 refers to N -methyl- N -Phenylbicyclo[1.1.0]butane-1-carboxamide, N -methyl- N -(2-methylphenyl)bicyclo[1.1.0]butane-1-carboxamide, N -methyl- N -(4-methoxyphenyl)bicyclo[1.1.0]butane-1-carboxamide, N -methyl- N Any one of (4-bromophenyl)bicyclo[1.1.0]butane-1-carboxamide.

[0011] Compound 2 refers to any one of sodium thiocyanate, potassium thiocyanate, ammonium thiocyanate, zinc thiocyanate, and copper thiocyanate.

[0012] Preferably, compound 2 is sodium thiocyanate.

[0013] Preferably, the molar ratio of compound 1 to compound 2 is 1:1-2. Here, the molar ratio is preferably 1:1.5.

[0014] Preferably, the solvent refers to acetonitrile, hexafluoroisopropanol, methanol, or ethanol. N , N -Dimethylformamide, N , N The solvent is any one of dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, and dioxane; the solvent-to-compound 1 ratio is 1-5 mL:0.1 mmol. Here, acetonitrile is preferred as the solvent; the solvent-to-compound 1 ratio is preferably 1 mL:0.1 mmol.

[0015] Preferably, the catalyst is any one of copper acetate, copper sulfate, and copper trifluoromethanesulfonate, and the molar ratio of the catalyst to compound 1 is 0.1-0.2:1. The catalyst is preferably copper trifluoromethanesulfonate; the molar ratio of copper trifluoromethanesulfonate to compound 1 is preferably 0.1:1.

[0016] Preferably, the additive is 2,2,6,6-tetramethylpiperidine nitrogen oxide (tempo), and the molar ratio of the oxidant to compound 1 is 0.1-0.2:1, preferably 0.1:1.

[0017] Preferably, the eluent used for column chromatography purification is any one or a mixture of two of petroleum ether, dichloromethane, ethyl acetate, and diethyl ether; here, the eluent is preferably a mixture of ethyl acetate and petroleum ether (volume ratio of 1:2-5).

[0018] Compared with the prior art, the present invention has the following beneficial effects: 1. This invention is based on N -methyl- N Using phenylbicyclo[1.1.0]butane-1-carboxamide compounds and thiocyanate as starting materials, a novel and efficient method for constructing multi-substituted spirocyclobutanes is achieved through a one-pot thiocyanation / cyclization process catalyzed by stable and inexpensive copper salts to synthesize 3-thiocyanospirocyclobutylindole compounds. Spirocyclobutylindole is a core skeleton of some important drug molecules, and the introduction of the thiocyanate group can promote rapid structural modification. It can be used for rapid qualitative and quantitative detection of heavy metals via colorimetric reactions and can also be applied to the synthesis of drug intermediates.

[0019] 2. This invention has the advantages of high flexibility, readily available raw materials, simple operation, mild conditions, and low cost, which is conducive to industrial production.

[0020] Of course, any product implementing this invention does not necessarily need to achieve all of the advantages described above at the same time. Attached Figure Description

[0021] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0022] Figure 1 The hydrogen spectrum of product 3a obtained in Example 1 of this invention; Figure 2 The carbon spectrum of product 3a obtained in Example 1 of this invention; Figure 3 The hydrogen spectrum of product 3b obtained in Example 2 of this invention; Figure 4 The carbon spectrum of product 3b obtained in Example 2 of this invention; Figure 5 The hydrogen spectrum of product 3c obtained in Example 3 of this invention; Figure 6The carbon spectrum of product 3c obtained in Example 3 of this invention; Figure 7 The hydrogen spectrum of the product obtained in Example 4 of this invention is shown in Figure 3. Figure 8 The carbon spectrum of the product obtained in Example 4 of this invention is shown in Figure 3. Figure 9 The hydrogen spectrum of the product obtained in Example 5 of this invention is shown in Figure 3. Figure 10 This is the carbon spectrum of the product obtained in Example 5 of the present invention, 3d. Detailed Implementation

[0023] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0024] Example 1 The reaction equation is shown below.

[0025] Add 1.0 millimole to the Schlenk tube N -methyl- N 1-Phenylbicyclo[1.1.0]butane-1-carboxamide, 1.5 mmol sodium thiocyanate, 0.1 mmol copper trifluoromethanesulfonate, 0.1 mmol 2,2,6,6-tetramethylpiperidine nitrogen oxide (tempo), 10 mL acetonitrile were added under air atmosphere and the mixture was reacted at room temperature for 30 minutes. After the reaction was completed, the crude product was obtained by vacuum distillation, which was purified by column chromatography and thin-layer chromatography to obtain product 3a. The column chromatography eluent was a mixed solvent of ethyl acetate / petroleum ether = 1 / 8 (v / v), with a yield of 86%.

[0026] The proton and carbon spectra of the obtained product 3a are as follows: Figure 1 and Figure 2 As shown, the structural characterization data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 7.2 Hz, 1H), 7.31 (t, J = 7.6Hz, 1H), 7.14 (t, J = 7.6 Hz, 2H), 6.81 (d, J = 8.0 Hz, 1H), 4.28 (p, J= 8.4Hz, 1H), 3.21 (s, 3H), 3.04-2.96 (m, 2H), 2.95-2.86 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 179.36, 142.99, 130.92, 128.79, 123.42,123.26, 110.70, 107.95, 44.86, 40.26, 34.82, 26.28. MS (EI, m / z): 244 [M] + . HRMS (ESI): Calculated for C 13 H 13 N2OS [M+H] + : 245.0743; found: 245.0740. Based on the above experimental results, the structure of product 3a is shown in the following formula: .

[0027] Example 2 The reaction equation is shown below.

[0028] Add 1.0 millimole to the Schlenk tube N -methyl- N -(2-methylphenyl)bicyclo[1.1.0]butane-1-carboxamide, 1.5 mmol sodium thiocyanate, 0.1 mmol copper trifluoromethanesulfonate, 0.1 mmol 2,2,6,6-tetramethylpiperidine nitrogen oxide, 10 mL acetonitrile were added under air atmosphere and the mixture was reacted at room temperature for 30 minutes. After the reaction was completed, the crude product was obtained by vacuum distillation, which was purified by column chromatography and thin-layer chromatography to obtain product 3b. The column chromatography eluent was a mixed solvent of ethyl acetate / petroleum ether = 1 / 8 (v / v), with a yield of 82%.

[0029] The proton and carbon spectra of the obtained product 3b are as follows: Figure 3 and Figure 4 As shown, the structural characterization data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.43 (t, J = 3.2 Hz, 1H), 7.08-6.97 (m, 2H), 4.27 (p, J= 8.4 Hz, 1H), 3.48 (s, 3H), 3.03-2.93 (m, 2H), 2.91-2.79 (m, 2H), 2.56 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 180.05, 140.71, 132.44, 131.61, 123.19,121.37, 119.64, 110.70, 44.45, 40.74, 34.84, 29.60, 18.79. MS (EI, m / z): 258 [M] + . HRMS (ESI): Calculated for C 14 H 15 N2OS [M+H] + : 259.0900; found: 259.0894. Based on the above experimental results, the structure of product 3b is shown in the following formula: .

[0030] Example 3 The reaction equation is shown below.

[0031] Add 1.0 millimole to the Schlenk tube N -methyl- N -(4-methoxyphenyl)bicyclo[1.1.0]butane-1-carboxamide, 1.5 mmol sodium thiocyanate, 0.1 mmol copper trifluoromethanesulfonate, 0.1 mmol 2,2,6,6-tetramethylpiperidine nitrogen oxide, 10 mL acetonitrile were added under air atmosphere and the mixture was reacted at room temperature for 30 minutes. After the reaction was completed, the crude product was obtained by vacuum distillation, and purified by column chromatography and thin-layer chromatography to obtain product 3c. The column chromatography eluent was a mixed solvent of ethyl acetate / petroleum ether = 1 / 8 (v / v), with a yield of 85%.

[0032] The proton and carbon spectra of the obtained product 3C are as follows: Figure 5 and Figure 6 As shown, the structural characterization data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.27 (d, J= 7.6 Hz, 1H), 6.96-6.67 (m, 2H), 4.42-4.20 (m, 1H), 3.82 (s, 3H), 3.18 (s, 3H), 3.16-2.80 (m, 4H). 13 C NMR (101 MHz, CDCl3) δ 179.01, 156.60, 136.36, 132.23, 113.50,110.74, 110.30, 108.40, 55.86, 45.16, 40.31, 34.78, 26.35. MS (EI, m / z): 274 [M] + . HRMS (ESI): Calculated for C 14 H 15 N₂O₂S [M+H] + : 275.0849; found: 275.0845. Based on the above experimental results, the structure of product 3c is shown in the following formula: .

[0033] Example 4 The reaction equation is shown below.

[0034] Add 1.0 millimole to the Schlenk tube N -methyl- N 1-(4-bromophenyl)bicyclo[1.1.0]butane-1-carboxamide, 1.5 mmol sodium thiocyanate, 0.1 mmol copper trifluoromethanesulfonate, 0.1 mmol 2,2,6,6-tetramethylpiperidine nitrogen oxide, and 10 mL acetonitrile were added under air atmosphere and reacted at room temperature for 30 minutes. After the reaction was completed, the crude product was obtained by vacuum distillation, and purified by column chromatography and thin-layer chromatography to obtain product 3d. The column chromatography eluent was a mixed solvent of ethyl acetate / petroleum ether = 1 / 6 (v / v), with a yield of 92%.

[0035] The 3d proton and carbon spectra of the obtained product are as follows: Figure 7 and Figure 8 As shown, the structural characterization data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.67 (s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 6.69(d,J = 8.4 Hz, 1H), 4.30 (p, J = 8.4 Hz, 1H), 3.19 (s, 3H), 3.06-2.94 (m, 2H), 2.93-2.79 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 178.71, 142.09, 132.69, 131.72, 126.65,115.79, 110.45, 109.44, 44.89, 40.19, 34.76, 26.39. MS (EI, m / z): 322 [M] + . HRMS (ESI): Calculated for C 13 H 12 BrN2OS [M+H] + : 322.9848; found: 322.9842. Based on the above experimental results, the 3D structure of the product is shown in the following formula: .

[0036] Example 5 The reaction equation is shown below.

[0037] Add 1.0 millimole to the Schlenk tube N -n-Butyl- N 1-Phenylbicyclo[1.1.0]butane-1-carboxamide, 1.5 mmol sodium thiocyanate, 0.1 mmol copper trifluoromethanesulfonate, 0.1 mmol 2,2,6,6-tetramethylpiperidine nitrogen oxide, and 10 mL acetonitrile were added under air atmosphere and reacted at room temperature for 30 minutes. After the reaction was completed, the crude product was obtained by vacuum distillation, and purified by column chromatography and thin-layer chromatography to obtain product 3d. The column chromatography eluent was a mixed solvent of ethyl acetate / petroleum ether = 1 / 8 (v / v), with a yield of 85%.

[0038] The proton and carbon spectra of the obtained product 3e are as follows: Figure 9 and Figure 10 As shown, the structural characterization data are as follows: 1H NMR (400 MHz, CDCl3) δ 7.67-7.52 (m, 1H), 7.49-7.31 (m, 1H), 7.16-7.05 (m, 1H), 6.90-6.72 (m, 1H), 4.38-4.12 (m, 1H), 3.67 (t, J = 8.0 Hz, 2H),3.04-2.79 (m, 4H), 1.71-1.56 (m, 2H), 1.41-1.28 (m, 2H), 0.94 (t, J = 8.0 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 179.28, 142.45, 131.09, 128.65, 123.51,122.97, 110.63, 108.22, 44.79, 40.37, 39.77, 34.83, 29.42, 20.07, 13.68. MS (EI, m / z): 286 [M] + . HRMS (ESI): Calculated for C 16 H 19 N2OS [M+H] + :287.1213; found: 287.1210. Based on the above experimental results, the structure of product 3e is shown in the following formula: .

[0039] The above description is merely an example and illustration of the concept of the present invention. Those skilled in the art can make various modifications or additions to the specific embodiments described or use similar methods to replace them, as long as they do not deviate from the concept of the invention or exceed the scope defined in the claims, they should all fall within the protection scope of the present invention.

Claims

1. A method for synthesizing 3-thiocyanospirocyclobutyl oxyindole compounds, characterized in that, The synthesis includes the following steps: In a reactor, compound 1 is added... N -Phenylbicyclo[1.1.0]butane-1-carboxamide, thiocyanate of compound 2, catalyst, additive and solvent were reacted at room temperature for 30 minutes. After the reaction was completed, the crude product was obtained by vacuum distillation, and purified by column chromatography to obtain thiocyano-substituted spirocyclic butylindole. The reaction equation is as follows: ； Wherein, R1 is a methyl, bromine, or methoxy substituent; R2 is methyl or n-butyl; X is sodium, potassium, ammonium, zinc, or copper; and n is 1 or 2.

2. The method for synthesizing a 3-thiocyanospirocyclobutyl oxyindole compound according to claim 1, characterized in that, Compound 1 is N -methyl- N -Phenylbicyclo[1.1.0]butane-1-carboxamide, N -methyl- N -(2-methylphenyl)bicyclo[1.1.0]butane-1-carboxamide, N -methyl- N -(4-methoxyphenyl)bicyclo[1.1.0]butane-1-carboxamide, N -methyl- N Any one of (4-bromophenyl)bicyclo[1.1.0]butane-1-carboxamide.

3. The method for synthesizing a 3-thiocyanospirocyclobutyl oxyindole compound according to claim 1, characterized in that, Compound 2 is any one of sodium thiocyanate, potassium thiocyanate, ammonium thiocyanate, iron thiocyanate, zinc thiocyanate, or copper thiocyanate.

4. The method for synthesizing a 3-thiocyanospirocyclobutyl oxyindole compound according to claim 1, characterized in that, The molar ratio of compound 1 to compound 2 is 1:1-2.

5. The method for synthesizing a 3-thiocyanospirocyclobutyl oxyindole compound according to claim 1, characterized in that, The solvent is acetonitrile, hexafluoroisopropanol, methanol, or ethanol. N , N -Dimethylformamide, N , N - Any one of dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, and dioxane; the solvent to compound 1 ratio is 1-5 mL: 0.1 mmol.

6. The method for synthesizing a 3-thiocyanospirocyclobutyl oxidized indole compound according to claim 1, characterized in that, The catalyst is any one of copper acetate, copper sulfate, and copper trifluoromethyl sulfonate, and the molar ratio of the catalyst to compound 1 is 0.1-0.2:

1.

7. The method for synthesizing a 3-thiocyanospirocyclobutyl oxyindole compound according to claim 1, characterized in that, The additive is 2,2,6,6-tetramethylpiperidine nitrogen oxide, and the molar ratio of the oxidant to compound 1 is 0.1-0.2:

1.

8. The method for synthesizing a 3-thiocyanospirocyclobutyl oxyindole compound according to claim 1, characterized in that, The eluent used for column chromatography purification is any one or a mixture of two of petroleum ether, dichloromethane, ethyl acetate, and diethyl ether.

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