Thiazolamine compound containing large-steric-hindrance alkynyl substituted quaternary carbon center and asymmetric coupling synthesis method thereof

Abstract

The invention relates to the technical field of organic chemical synthesis, and discloses a thiazolamine compound containing a large-steric-hindrance alkynyl substituted quaternary carbon center and an asymmetric coupling synthesis method thereof. The invention aims to solve the problem of direct construction of large steric hindrance alkynyl substituted quaternary carbon center so as to realize efficient synthesis of chiral thiazolamine compounds, the molecular structure is a key structure of an alpha protein kinase 1 inhibitor, and the inhibitor is used for treating kidney diseases and kidney related diseases. According to the method provided by the invention, the chiral thiazolamine compound can be obtained at the average conversion yield of 80% in each step, and the synthesis yield gt can be obtained; gt is controlled by chirality; 80% ee of alkynyl substituted chiral compound. The new synthesis route not only greatly reduces large and tedious steps of post-treatment, but also reduces the cost and improves the efficiency.

Description

Technical Field

[0001] The present invention relates to the technical field of organic chemical synthesis, and particularly relates to a thiazolamine compound containing a quaternary carbon center substituted with a bulky alkynyl group and an asymmetric coupling synthesis method thereof. Background Art

[0002] The application of alkynyl groups in medicinal chemistry can be traced back to 1959. Whether in improving the activity of compounds or drug-like properties, alkynyl groups have a very wide range of applications in the design and optimization of drug molecules. At the same time, chiral structures widely exist in many approved drug molecules. And it is worth noting that among the top 200 small molecule drugs in terms of sales in 2022, approximately 10% of the molecules contain quaternary carbon chiral centers.

[0003] CN110627610A discloses a method for catalytic asymmetric cross-coupling synthesis of alkynyl-substituted tertiary carbon center compounds by using cuprous salts and related ligands as catalysts. CN114702445A realizes the construction of chiral tertiary carbon centers of some compounds through tridentate nitrogen ligands.

[0004] If a compound substituted with an alkynyl group is designed to be obtained through functional group transformation, highly active, highly toxic, and high-energy reagents are required in multiple steps, which poses great risks in the experimental and production processes. Moreover, in the direct functional group transformation route, it is very difficult to control the target configuration, resulting in a great waste of materials.

[0005] Therefore, through research and development and reaction condition optimization, a synthetic route containing a new type of catalytic system is designed to achieve the enantioselective asymmetric C(sp 3 )-C(sp) type of Sonogashira cross-coupling reaction, with the aim of reducing the preparation cost of compounds and lowering the production risk, which is an urgent problem to be solved at present.

[0006] The present invention aims to solve the direct construction of a quaternary carbon center substituted with a bulky alkynyl group to achieve the efficient synthesis of chiral thiazolamine compounds. This molecular structure is a key structure of an alpha protein kinase 1 inhibitor, and this inhibitor is used to treat kidney diseases and kidney-related diseases. Therefore, exploring a green and efficient synthetic route is very valuable. Through this method, a chiral compound substituted with an alkynyl group is obtained with a synthesis yield of >80% and chiral control of >80% ee. Then, a series of functional group transformations are carried out to obtain the final chiral thiazolamine compounds, with a conversion yield of >80% in each step, and the enantioselectivity of the final product is not affected. The new synthetic route not only greatly reduces the cumbersome post-treatment steps but also reduces costs and increases efficiency. Summary of the Invention

[0007] Objective of the present invention: Based on the above technical problems, a thiazolamine compound containing a quaternary carbon center substituted with a bulky alkynyl group and an asymmetric coupling synthesis method thereof are provided.

[0008] To achieve the above objective, a first aspect of the present invention provides a method for preparing a thiazolamine compound containing a quaternary carbon center substituted with a bulky alkynyl group, and the method includes the following steps:

[0009] (1) In a round-bottom flask equipped with a magnetic stirrer, methyl 3-methylphenylacetate is added, and under a nitrogen atmosphere, tetrahydrofuran is added to fully dissolve the solid. Then, at -25°C, lithium bis(trimethylsilyl)amide is added dropwise, and the mixture is stirred at -25°C for 1 h. Then, methyl iodide is added dropwise, and the mixture is stirred at -25°C for 1 h. Then, the temperature is slowly raised to 10°C, and the mixture is continuously stirred at 10°C for 5 h. After the reaction is complete, the reaction is quenched with saturated ammonium chloride, extracted with ethyl acetate, the organic phase is taken, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain S1;

[0010] (2) In a round-bottom flask equipped with a magnetic stirrer, S1 and aniline are added, and under a nitrogen atmosphere, toluene is added to fully dissolve the solid. Then, at 10°C, lithium bis(trimethylsilyl)amide is added dropwise, and the mixture is stirred at room temperature for 15 h. After the reaction is complete, the reaction is quenched with saturated ammonium chloride, extracted with ethyl acetate, the organic phase is taken, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized to obtain S2;

[0011] (3) In a round-bottom flask equipped with a magnetic stirrer, S2 is added, and under a nitrogen atmosphere, tetrahydrofuran is added to fully dissolve the solid. Then, at -78°C, lithium diisopropylamide is added dropwise, and the mixture is stirred at -78°C for 1 h. Then, at -78°C, carbon tetrachloride is added dropwise to the reaction solution, and the mixture is stirred at -50°C for 7 h. After the reaction is complete, the reaction is quenched with saturated ammonium chloride, extracted with ethyl acetate, the organic phase is taken, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain S3;

[0012] (4) In a round-bottom flask equipped with a magnetic stirrer, S3, copper(II) trifluoromethanesulfonate, Ligand-DF1, and cesium carbonate are added, and under a nitrogen atmosphere, an organic solvent is added to fully dissolve the solid. Trimethylsilylacetylene is added, and the mixture is stirred at 10°C for 36 - 48 h. After the reaction is complete, the mixture is filtered through diatomaceous earth, washed with CH2Cl2, the organic phase is taken, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain S4;

[0013] (5) In a round-bottom flask equipped with a magnetic stir bar, add S4. Under a nitrogen atmosphere, add tetrahydrofuran to fully dissolve the solid. Then, at 0 °C, add tetrabutylammonium fluoride and glacial acetic acid, and stir for 1 h at 0 °C. After the reaction is complete, quench the reaction with a small amount of water, extract with ethyl acetate, take the organic phase, dry it with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a yellow oily liquid, which is directly used in the next step. Add 4-dimethylaminopyridine to the reaction flask. Under a nitrogen atmosphere, add tetrahydrofuran to fully dissolve the solid, then add di-tert-butyl dicarbonate, and stir overnight at room temperature. After the reaction is complete, quench the reaction with a small amount of water, extract with ethyl acetate, take the organic phase, dry it with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain S5;

[0014] (6) In a round-bottom flask equipped with a magnetic stir bar, add S5 and cesium fluoride. Under a nitrogen atmosphere, add acetonitrile to fully dissolve the solid. Then, add methanol and stir for 15 h at 80 °C. After the reaction is complete, concentrate under reduced pressure and purify by silica gel column chromatography to obtain S6;

[0015] (7) In a round-bottom flask equipped with a magnetic stir bar, add S6 and N,O-dimethylhydroxylamine hydrochloride. Under a nitrogen atmosphere, add tetrahydrofuran to fully dissolve the solid. Then, at -20 °C, dropwise add the first batch of methylmagnesium chloride within 1 h, gradually warm up to -10 °C, and react for 30 min. Then, dropwise add the second batch of methylmagnesium chloride within 1 h and stir at -10 °C for 30 min. After the reaction is complete, quench the reaction with saturated ammonium chloride, extract with ethyl acetate, take the organic phase, dry it with anhydrous sodium sulfate, and concentrate under reduced pressure and purify by silica gel column chromatography to obtain S7;

[0016] (8) In a round-bottom flask equipped with a magnetic stir bar, add S7 and ketone bromide. Under a nitrogen atmosphere, add an equal volume of chloroform and ethyl acetate to fully dissolve the solid. Then, stir overnight at 80 °C. After the reaction is complete, quench the reaction with a small amount of water, extract with ethyl acetate, take the organic phase, wash it with saturated sodium chloride, and dry it with anhydrous sodium sulfate, and concentrate under reduced pressure and purify by silica gel column chromatography to obtain S8;

[0017] (9) In a round-bottom flask equipped with a magnetic stir bar, add S8, thiourea (28 mmol, 1.4 equiv), and sodium bicarbonate. Under a nitrogen atmosphere, add methanol to fully dissolve the solid. Then, stir overnight at 50 °C. After the reaction is complete, quench the reaction with a small amount of water, extract with ethyl acetate, take the organic phase, wash it with saturated sodium chloride, and dry it with anhydrous sodium sulfate, and concentrate under reduced pressure and purify by silica gel column chromatography to obtain the product, denoted as S9.

[0018] Preferably, in step (1), S1 has the following structural formula:

[0019]

[0020] Further preferably, in step (1), the dosage of methyl 3-methylphenylacetate is 100 mmol.

[0021] Preferably, in step (1), corresponding to 100 mmol of methyl 3-methylphenylacetate, the dosage of lithium bis(trimethylsilyl)amide is 110 mmol.

[0022] Preferably, in step (1), corresponding to 100 mmol of methyl 3-methylphenylacetate, the dosage of methyl iodide is 110 mmol.

[0023] Further preferably, in step (2), S2 has the structural formula as shown below:

[0024]

[0025] Preferably, in step (3), the dosage of S1 is 100 mmol.

[0026] Preferably, in step (2), corresponding to 100 mmol of S1, the dosage of aniline is 120 mmol.

[0027] Preferably, in step (2), corresponding to 100 mmol of S1, the dosage of lithium bis(trimethylsilyl)amide is 200 mmol.

[0028] More preferably, in step (3), S3 has the structural formula as shown below:

[0029]

[0030] Preferably, in step (3), the dosage of S2 is 83 mmol.

[0031] Preferably, in step (3), corresponding to 83 mmol of S2, the dosage of lithium diisopropylamide is 207 mmol.

[0032] Further preferably, in step (3), corresponding to 83 mmol of S2, the dosage of carbon tetrachloride is 166 mmol.

[0033] Preferably, in step (4), S4 has the structural formula as shown below:

[0034]

[0035] Preferably, in step (4), the dosage of S3 is 45.6 mmol.

[0036] Further preferably, in step (4), corresponding to 45.6 mmol of S3, the amount of copper(II) trifluoromethanesulfonate used is 4.6 mmol.

[0037] Preferably, in step (4), corresponding to 45.6 mmol of S3, the amount of Ligand-DF1 used is 6.8 mmol.

[0038] Preferably, in step (4), the Ligand-DF1 has the structural formula shown below:

[0039]

[0040] Further preferably, in step (4), corresponding to 45.6 mmol of S3, the amount of cesium carbonate used is 137 mmol.

[0041] More preferably, in step (4), corresponding to 45.6 mmol of S3, the amount of trimethylsilylacetylene used is 456 mmol.

[0042] Preferably, in step (4), the organic solvent is trifluorotoluene or chlorobenzene.

[0043] Preferably, in step (5), the S5 has the structural formula shown below:

[0044]

[0045] Further preferably, in step (5), the amount of S4 used is 40 mmol.

[0046] Preferably, in step (5), corresponding to 40 mmol of S4, the amount of tetrabutylammonium fluoride used is 48 mmol.

[0047] More preferably, in step (5), corresponding to 40 mmol of S4, the amount of glacial acetic acid used is 40 mmol.

[0048] Preferably, in step (5), corresponding to 40 mmol of S4, the amount of 4-dimethylaminopyridine used is 80 mmol.

[0049] Preferably, in step (5), corresponding to 40 mmol of S4, the amount of di-tert-butyl dicarbonate used is 200 mmol.

[0050] Preferably, in step (6), the S6 has the structural formula shown below:

[0051]

[0052] More preferably, in step (6), the amount of S5 used is 33 mmol.

[0053] Further preferably, in step (6), corresponding to 33 mmol of S5, the amount of cesium fluoride used is 6.6 mmol.

[0054] Preferably, in step (6), corresponding to 33 mmol of S5, the amount of methanol used is 40 mmol.

[0055] Preferably, in step (7), S7 has the structural formula shown below:

[0056]

[0057] Preferably, in step (7), the amount of S6 used is 28 mmol.

[0058] Further preferably, in step (7), corresponding to 28 mmol of S6, the amount of N,O-dimethylhydroxylamine hydrochloride used is 34 mmol.

[0059] Preferably, in step (7), corresponding to 28 mmol of S6, the amount of the first batch of methylmagnesium chloride used is 70 mmol.

[0060] Preferably, in step (7), corresponding to 28 mmol of S6, the amount of the second batch of methylmagnesium chloride used is 78 mmol.

[0061] Preferably, in step (8), S8 has the structural formula shown below:

[0062]

[0063] Preferably, in step (8), the amount of S7 used is 23 mmol.

[0064] More preferably, in step (8), corresponding to 23 mmol of S7, the amount of bromoketone used is 35 mmol.

[0065] Further preferably, in step (9), S9 has the structural formula shown below:

[0066]

[0067] Preferably, in step (9), the amount of S8 used is 20 mmol.

[0068] Further preferably, in step (9), corresponding to 20 mmol of S8, the amount of thiourea used is 28 mmol.

[0069] Preferably, in step (9), corresponding to 20 mmol of S8, the amount of sodium bicarbonate used is 20 mmol.

[0070] The method provided by the present invention has at least the following beneficial effects:

[0071] (1) The method provided by the present invention can obtain alkynyl-substituted chiral compounds with a synthesis yield > 80% and a chiral control > 80% ee.

[0072] (2) The method provided by the present invention can obtain chiral thiazolamine compounds with an average conversion yield of 80% per step. Description of the Drawings Figure 1 It is a flow chart of the preparation method of the thiazolamine compound containing a bulky alkynyl-substituted quaternary carbon center of the present invention. Detailed Embodiments

[0073] In the ranges disclosed herein, the endpoints and any values are not limited to the exact ranges or values, and these ranges or values should be understood to include values close to these ranges or values. For numerical ranges, between the endpoint values of each range, between the endpoint values of each range and individual point values, and between individual point values, they can be combined with each other to obtain one or more new numerical ranges, and these numerical ranges should be regarded as specifically disclosed herein.

[0074] The present invention will be described in detail below through examples. In the following examples, unless otherwise specified, the raw materials are commercially available products.

[0075] In the following examples, unless otherwise specified, the yield of the obtained product is obtained from the results of a nuclear magnetic resonance spectrometer, and the model of the nuclear magnetic resonance spectrometer is Bruker 400 MHz and Brucker 600 MHz nuclear magnetic resonance spectrometers.

[0076] Example 1

[0077] This example is used to combine Figure 1 To provide a method for preparing a thiazolamine compound containing a bulky alkynyl-substituted quaternary carbon center, the method includes: (1)

[0079]

[0080] In a round-bottom flask equipped with a magnetic stir bar, methyl 3-methylphenylacetate (100 mmol, 1.0 equiv) was added. Under a nitrogen atmosphere, 120 mL of tetrahydrofuran was added to completely dissolve the solid. Then, at -25 °C, lithium bis(trimethylsilyl)amide (110 mmol, 1.1 equiv) was added dropwise, and the mixture was stirred at -25 °C for 1 h. Next, methyl iodide (110 mmol, 1.1 equiv) was added dropwise, and the mixture was stirred at -25 °C for 1 h. Subsequently, the temperature was slowly raised to 10 °C, and the mixture was stirred at 10 °C for 5 h. After the reaction was complete, 50 mL of saturated ammonium chloride was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain S1 as a yellow oily liquid. (2)

[0082]

[0083] In a round-bottom flask equipped with a magnetic stir bar, S1 (100 mmol, 1.0 equiv) and aniline (120 mmol, 1.2 equiv) were added. Under a nitrogen atmosphere, 120 mL of toluene was added to completely dissolve the solid. Then, at 10 °C, lithium bis(trimethylsilyl)amide (200 mmol, 2.0 equiv) was added dropwise, and the mixture was stirred at room temperature for 15 h. After the reaction was complete, 50 mL of saturated ammonium chloride was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Recrystallization (PE:EA) was performed to obtain S2.

[0084] S2, with a yield of 83%, 1 H NMR (600 MHz, Chloroform-d) δ 9.97 (s, 1H), 8.42 (s, 1H), 8.02 (d, J = 7.5 Hz, 1H), 7.95–7.50 (m, 4H), 7.54 (d, J = 7.5, 1H), 7.48 (t, J = 7.4 Hz, 1H), 7.35 (s, 1H), 7.25–7.08 (d, J = 8.0 Hz 2H), 3.68 (q, J = 7.1 Hz, 1H), 2.31 (s, 3H), 1.31 (dd, J = 7.0, 1.8 Hz, 3H).

[0085] HRMS (ESI-MS) m / z [M+H] + calcd for C 20 H 20 NO: 290.1467, found: 290.1568. (3)

[0087]

[0088] In a round-bottom flask equipped with a magnetic stir bar, S2 (83 mmol, 1.0 equiv) was added. Under a nitrogen atmosphere, 120 mL of tetrahydrofuran was added to dissolve the solid completely. Then, at -78 °C, lithium diisopropylamide (207 mmol, 2.5 equiv) was added dropwise and stirred for 1 h at -78 °C. Subsequently, at -78 °C, carbon tetrachloride (166 mmol, 2.0 equiv) was added dropwise to the reaction mixture and stirred for 7 h at -50 °C. After the reaction was complete, 50 mL of saturated ammonium chloride was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain S3.

[0089] S3, a yellow solid, with a yield of 55%. 1 H NMR (400 MHz, Chloroform-d) δ 9.97 (s, 1H), 8.42 (s, 1H), 8.02 (d, J = 7.5 Hz, 1H), 7.91–7.80 (m, 4H), 7.54 (d, J = 7.5, 1H), 7.51 (t, J = 7.4 Hz, 1H), 7.48–7.05 (d, J = 8.0 Hz, 2H), 7.19 (s, 1H), 2.31 (s, 3H), 2.18 (s, 3H).

[0090] HRMS (ESI-MS) m / z [M+H] + calcd for C 20 H 19 ClNO: 324.1077, found: 324.2013. (4)

[0092]

[0093] In a round-bottom flask equipped with a magnetic stir bar, S3 (45.6 mmol, 1.0 equiv), copper(II) trifluoromethanesulfonate (4.6 mmol, 0.1 equiv), Ligand-DF1 (68 mmol, 1.5 eq), and cesium carbonate (137 mmol, 3.0 eq) were added. Under a nitrogen atmosphere, 120 mL of trifluorotoluene was added to dissolve the solid completely. Trimethylsilylacetylene (456 mmol, 10.0 equiv) was added, and the mixture was stirred at 10 °C for 48 h. After the reaction was complete, the mixture was filtered through diatomaceous earth, washed with CH2Cl2, and the organic phase was concentrated under reduced pressure and purified by silica gel column chromatography to obtain S4.

[0094] S4, a yellow oily liquid. 11H NMR (400 MHz, Chloroform-d) δ 9.97 (s, 1H), 8.42 (s, 1H), 8.02 (d, J = 7.5 Hz, 1H), 7.91–7.80 (m, 4H), 7.54 (d, J = 7.5, 1H), 7.48 (t, J = 7.4 Hz, 1H), 7.35 (s, 1H), 7.34–7.08 (d, J = 8.0 Hz, 2H), 2.31 (s, 3H), 1.87 (s, 3H), 0.98 (s, 9H), 0.08 (s, 6H).

[0095] HRMS (ESI-MS) m / z [M+H] + calcd for C 28 H 34 NOSi: 428.2341, found: 428.2350. (5)

[0097]

[0098] In a round-bottom flask equipped with a magnetic stir bar, S4 (40 mmol, 1.0 equiv) was added. Under a nitrogen atmosphere, 120 mL of tetrahydrofuran was added to dissolve the solid completely. Then, at 0 °C, tetrabutylammonium fluoride (48 mmol, 1.2 equiv) and glacial acetic acid (40 mmol, 1.0 equiv) were added, and the mixture was stirred at 0 °C for 1 h. After the reaction was complete, the reaction was quenched with a small amount of water, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a yellow oily liquid, which was directly used in the next step. 4-Dimethylaminopyridine (80 mmol, 2.0 equiv) was added to the reaction flask. Under a nitrogen atmosphere, 120 mL of tetrahydrofuran was added to dissolve the solid completely. Then, di-tert-butyl dicarbonate (200 mmol, 5.0 equiv) was added, and the mixture was stirred overnight at room temperature. After the reaction was complete, the reaction was quenched with a small amount of water, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain S5.

[0099] S5, white solid. 1 1H NMR (600 MHz, Chloroform-d) δ 8.38 (s, 1H), 8.02 (d, J = 7.5 Hz, 1H), 7.91–7.80 (m, 4H), 7.54 (d, J = 7.5, 1H), 7.48 (t, J = 7.4 Hz, 1H), 7.35 (s, 1H), 7.34–7.09 (d, J = 8.0 Hz, 2H), 3.05 (s, 1H), 2.31 (s, 3H), 1.84 (s, 3H), 1.42 (s, 9H).

[0100] HRMS(ESI-MS) m / z [M+H] + calcd for C 27 H 28 NO3: 414.2270, found: 414.2237. (6)

[0102]

[0103] In a round-bottom flask equipped with a magnetic stir bar, S5 (33 mmol, 1.0 equiv), cesium fluoride (5.6 mmol, 0.2 equiv) were added. Under a nitrogen atmosphere, 120 mL of acetonitrile was added to dissolve the solids completely. Then, methanol (40 mmol, 1.2 equiv) was added, and the mixture was stirred at 80 °C for 15 h. After the reaction was complete, it was concentrated under reduced pressure and purified by silica gel column chromatography to obtain S6.

[0104] S6, a transparent oily liquid. 1 H NMR (600 MHz, Chloroform-d) δ 7.53 (t, J = 7.3 Hz, 1H), 7.36 (s, 1H), 7.34–7.08 (m, 2H), 3.05 (s, 1H), 3.69 (s, 3H), 2.31 (s, 3H), 1.82 (s, 3H).

[0105] HRMS(ESI-MS) m / z [M+H] + calcd for C 13 H 15 O2: 203.1004, found: 203.1267. (7)

[0107]

[0108] In a round-bottom flask equipped with a magnetic stir bar, S6 (28 mmol, 1.0 equiv), N,O-dimethylhydroxylamine hydrochloride (34 mmol, 1.2 equiv) were added. Under a nitrogen atmosphere, 120 mL of tetrahydrofuran was added to dissolve the solids completely. Then, the first batch of methylmagnesium chloride (70 mmol, 2.5 equiv) was added dropwise at -20 °C within 1 h, and the temperature was gradually raised to -10 °C and reacted for 30 min. Then, the second batch of methylmagnesium chloride (78 mmol, 2.8 equiv) was added dropwise within 1 h, and stirred at -10 °C for 30 min. After the reaction was complete, the reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate, the organic phase was taken, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain S7.

[0109] S7, a yellow oily liquid. 1¹H NMR (600 MHz, Chloroform-d) δ 7.53 (t, J = 7.3 Hz, 1H), 7.36 (s, 1H), 7.34–7.08 (m, 2H), 3.05 (s, 1H), 2.46 (s, 3H), 2.31 (s, 3H), 1.78 (s, 3H).

[0110] HRMS (ESI-MS) m / z [M+H] + calcd for C 13 H 15 O: 187.1045, found: 187.1146. (8)

[0112]

[0113] In a round-bottom flask equipped with a magnetic stir bar, S7 (23 mmol, 1.0 equiv) and ketone bromide (35 mmol, 1.5 equiv) were added. Under a nitrogen atmosphere, chloroform and ethyl acetate with a volume ratio of 1:1 (where the volume of chloroform used was 50 mL) were added to completely dissolve the solids. Then, the mixture was stirred overnight at 80 °C. After the reaction was complete, a small amount of water was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain S8.

[0114] S8, a yellow oily liquid. 1 ¹H NMR (600 MHz, Chloroform-d) δ 7.49 (t, J = 7.3 Hz, 1H), 7.36 (s, 1H), 7.34–7.08 (m, 2H), 4.49 (d, J = 14.9 Hz, 1H), 4.02 (d, J = 14.9 Hz, 1H), 3.05 (s, 1H), 2.31 (s, 3H), 1.78 (s, 3H).

[0115] HRMS (ESI-MS) m / z [M+H] + calcd for C 13 H 14 BrO: 265.0150, found: 265.1754. (9)

[0117]

[0118] In a round-bottom flask equipped with a magnetic stir bar, add S8 (20 mmol, 1.0 equiv), thiourea (28 mmol, 1.4 equiv), sodium bicarbonate (20 mmol, 1.0 equiv), and under a nitrogen atmosphere, add methanol to fully dissolve the solids. Then stir overnight at 50 °C. After the reaction is complete, quench the reaction with a small amount of water, extract with ethyl acetate, take the organic phase, wash with 50 mL of saturated sodium chloride, and dry over anhydrous sodium sulfate. Concentrate under reduced pressure and purify by silica gel column chromatography to obtain the product, denoted as S9.

[0119] S9, a pale yellow solid. 1 H NMR (400 MHz, Chloroform-d) δ 7.49 (t, J = 7.3 Hz, 1H), 7.15 (s, 1H), 7.10–6.98 (m, 2H), 6.23 (s, 1H), 5.51 (s, 2H), 3.05 (s, 1H), 2.31 (s, 3H), 1.91 (s, 3H).

[0120] HRMS (ESI-MS) m / z [M+H] + calcd for C 14 H 15 N2S: 243.1878, found: 243.2041.

[0121] Example 2

[0122]

[0123] Carry out according to the method of Example 1, except that in step (4), in a round-bottom flask equipped with a magnetic stir bar, add S3 (45.6 mmol, 1.0 equiv), copper(II) trifluoromethanesulfonate (4.6 mmol, 0.1 equiv), Ligand-DF1 (68 mmol, 1.5 equiv), cesium carbonate (137 mmol, 3.0 equiv), and under a nitrogen atmosphere, add 120 mL of chlorobenzene to fully dissolve the solids. Add trimethylsilylacetylene (456 mmol, 10.0 equiv) and stir at 10 °C for 48 h. After the reaction is complete, filter through diatomaceous earth, wash with CH2Cl2, take the organic phase, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain S4. The remaining steps and parameters are the same as in Example 1.

[0124] Example 3

[0125]

[0126] The procedure was carried out according to the method of Example 1, except that in step (4), in a round-bottomed flask equipped with a magnetic stirrer, S3 (45.6 mmol, 1.0 equiv), copper(II) trifluoromethanesulfonate (4.6 mmol, 0.1 equiv), Ligand-DF1 (68 mmol, 1.5 equiv), cesium carbonate (137 mmol, 3.0 equiv) were added, and under a nitrogen atmosphere, 120 mL of trifluorotoluene was added to fully dissolve the solids. Trimethylsilylacetylene (456 mmol, 10.0 equiv) was added, and the mixture was stirred at 10 °C for 36 h. After the reaction was complete, it was filtered through diatomaceous earth, washed with CH2Cl2, the organic phase was taken, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain S4. The remaining steps and parameters were the same as those in Example 1.

[0127] Comparative Example 1

[0128]

[0129] The procedure was carried out according to the method of Example 1, except that in step (4), in a round-bottomed flask equipped with a magnetic stirrer, S3 (45.6 mmol, 1.0 equiv), copper(II) trifluoromethanesulfonate (4.6 mmol, 0.1 equiv), Ligand-DF1 (68 mmol, 1.5 equiv), cesium carbonate (137 mmol, 3.0 equiv) were added, and under a nitrogen atmosphere, a mixed solution of methyl tert-butyl ether and cyclohexane with a volume ratio of 2:3 (where the amount of methyl tert-butyl ether used was 120 mL) was added to fully dissolve the solids. Trimethylsilylacetylene (456 mmol, 10.0 equiv) was added, and the mixture was stirred at 10 °C for 36 h. After the reaction was complete, it was filtered through diatomaceous earth, washed with CH2Cl2, the organic phase was taken, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain S4. The remaining steps and parameters were the same as those in Example 1.

[0130] Comparative Example 2

[0131]

[0132] It was carried out according to the method of Example 1, except that in step (4), in a round-bottomed flask equipped with a magnetic stirrer, S3 (45.6 mmol, 1.0 equiv), copper(II) trifluoromethanesulfonate (4.6 mmol, 0.1 equiv), Ligand-DF1 (68 mmol, 1.5 equiv), cesium carbonate (137 mmol, 3.0 equiv) were added, and 120 mL of trifluorotoluene was added under a nitrogen atmosphere to fully dissolve the solids. Trimethylsilylacetylene (456 mmol, 10.0 equiv) was added and stirred at 25 °C for 36 h. After the reaction was complete, it was filtered through diatomaceous earth, washed with CH2Cl2, the organic phase was taken, concentrated under reduced pressure, and purified by silica gel column to obtain S4. The remaining steps and parameters were the same as those in Example 1.

[0133] The yields and ee values of the products prepared in the above examples and comparative examples were calculated, and the results are shown in Tables 1 and 2.

[0134] Table 1

[0135]

[0136] Table 2

[0137]

[0138] It can be seen from the results in Tables 1 and 2 that the yields and enantioselectivities of the thiazolamine compounds containing bulky alkynyl-substituted quaternary carbon centers prepared by the method of the examples of the present invention are higher.

[0139] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited thereto. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solutions of the present invention, including any other suitable combination of each technical feature. These simple modifications and combinations should also be regarded as the content disclosed by the present invention and fall within the protection scope of the present invention.

Claims

1. A method for preparing thiazolamine compounds containing a quaternary carbon center substituted with a sterically hindered alkynyl group, characterized in that, The method comprises the following steps: (1) Add methyl 3-methylphenylacetate into a round-bottomed flask equipped with a magnetic stirrer. Under a nitrogen atmosphere, add tetrahydrofuran to fully dissolve the solid. Then, dropwise add lithium bis(trimethylsilyl)amide at -25°C and stir for 1 h at -25°C. Next, dropwise add methyl iodide and stir for 1 h at -25°C. Then, slowly warm up to 10°C and continue stirring for 5 h at 10°C. After the reaction is complete, quench the reaction with saturated ammonium chloride, extract with ethyl acetate, take the organic phase, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain S1; (2) Add S1 and aniline into a round-bottomed flask equipped with a magnetic stirrer. Under a nitrogen atmosphere, add toluene to fully dissolve the solid. Then, dropwise add lithium bis(trimethylsilyl)amide at 10°C and stir for 15 h at room temperature. After the reaction is complete, quench the reaction with saturated ammonium chloride, extract with ethyl acetate, take the organic phase, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and recrystallize to obtain S2; (3) Add S2 into a round-bottomed flask equipped with a magnetic stirrer. Under a nitrogen atmosphere, add tetrahydrofuran to fully dissolve the solid. Then, dropwise add lithium diisopropylamide at -78°C and stir for 1 h at -78°C. Next, at -78°C, dropwise add carbon tetrachloride to the reaction solution and stir for 7 h at -50°C. After the reaction is complete, quench the reaction with saturated ammonium chloride, extract with ethyl acetate, take the organic phase, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain S3; (4) Add S3, copper(II) trifluoromethanesulfonate, Ligand-DF1, and cesium carbonate into a round-bottomed flask equipped with a magnetic stirrer. Under a nitrogen atmosphere, add an organic solvent to fully dissolve the solid. Then, add trimethylsilylacetylene and stir for 36 - 48 h at 10°C. After the reaction is complete, filter through diatomaceous earth, wash with CH2Cl2, take the organic phase, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain S4; (5) Add S4 into a round-bottomed flask equipped with a magnetic stirrer. Under a nitrogen atmosphere, add tetrahydrofuran to fully dissolve the solid. Then, add tetrabutylammonium fluoride and glacial acetic acid at 0°C and stir for 1 h at 0°C. After the reaction is complete, quench the reaction with a small amount of water, extract with ethyl acetate, take the organic phase, dry with anhydrous sodium sulfate, concentrate under reduced pressure to obtain a yellow oily liquid, which is directly used in the next step. Add 4-dimethylaminopyridine to the reaction flask. Under a nitrogen atmosphere, add tetrahydrofuran to fully dissolve the solid. Then, add di-tert-butyl dicarbonate and stir overnight at room temperature. After the reaction is complete, quench the reaction with a small amount of water, extract with ethyl acetate, take the organic phase, dry with anhydrous sodium sulfate, concentrate under reduced pressure to obtain S5; (6) Add S5 and cesium fluoride into a round-bottomed flask equipped with a magnetic stirrer. Under a nitrogen atmosphere, add acetonitrile to fully dissolve the solid. Then, add methanol and stir for 15 h at 80°C. After the reaction is complete, concentrate under reduced pressure and purify by silica gel column chromatography to obtain S6; (7) In a round-bottom flask equipped with a magnetic stir bar, add S6 and N,O-dimethylhydroxylamine hydrochloride. Under a nitrogen atmosphere, add tetrahydrofuran to dissolve the solids completely. Then, within 1 h at -20 °C, add the first batch of methylmagnesium chloride dropwise, gradually warm up to -10 °C, and react for 30 min. Then, within 1 h, add the second batch of methylmagnesium chloride dropwise and stir at -10 °C for 30 min. After the reaction is complete, quench the reaction with saturated ammonium chloride, extract with ethyl acetate, take the organic phase, dry it with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain S7; (8) In a round-bottom flask equipped with a magnetic stir bar, add S7 and ketone bromide. Under a nitrogen atmosphere, add an equal volume of chloroform and ethyl acetate to dissolve the solids completely. Then, stir overnight at 80 °C. After the reaction is complete, quench the reaction with a small amount of water, extract with ethyl acetate, take the organic phase, wash it with saturated sodium chloride, dry it with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain S8; (9) In a round-bottom flask equipped with a magnetic stir bar, add S8, thiourea (28 mmol, 1.4 equiv), and sodium bicarbonate. Under a nitrogen atmosphere, add methanol to dissolve the solids completely. Then, stir overnight at 50 °C. After the reaction is complete, quench the reaction with a small amount of water, extract with ethyl acetate, take the organic phase, wash it with saturated sodium chloride, dry it with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain the product, denoted as S9.

2. The method according to claim 1, wherein In step (1), S1 has the structural formula shown below: And / or, in step (1), the amount of methyl 3-methylphenylacetate used is 100 mmol; And / or, in step (1), corresponding to 100 mmol of methyl 3-methylphenylacetate, the amount of lithium bis(trimethylsilyl)amide used is 110 mmol; And / or, in step (1), corresponding to 100 mmol of methyl 3-methylphenylacetate, the amount of methyl iodide used is 110 mmol.

3. The method according to claim 1, wherein In step (2), S2 has the structural formula shown below: And / or, in step (2), the amount of S1 used is 100 mmol; And / or, in step (2), corresponding to 100 mmol of S1, the amount of aniline used is 120 mmol; And / or, in step (2), corresponding to 100 mmol of S1, the amount of lithium bis(trimethylsilyl)amide used is 200 mmol.

4. The method according to claim 1, characterized in that In step (3), S3 has the structural formula shown below: And / or, in step (3), the amount of S2 used is 83 mmol; And / or, in step (3), corresponding to 83 mmol of S2, the amount of lithium diisopropylamide used is 207 mmol; And / or, in step (3), corresponding to 83 mmol of S2, the amount of carbon tetrachloride used is 166 mmol.

5. The method according to claim 1, wherein In step (4), S4 has the structural formula shown below: And / or, in step (4), the amount of S3 used is 45.6 mmol; And / or, in step (4), corresponding to 45.6 mmol of S3, the amount of copper(II) trifluoromethanesulfonate used is 4.6 mmol; And / or, in step (4), corresponding to 45.6 mmol of S3, the amount of Ligand-DF1 used is 6.8 mmol; And / or, in step (4), the Ligand-DF1 has the structural formula shown below: And / or, in step (4), corresponding to 45.6 mmol of S3, the amount of cesium carbonate used is 137 mmol; And / or, in step (4), corresponding to 45.6 mmol of S3, the amount of trimethylsilylacetylene used is 456 mmol; And / or, in step (4), the organic solvent is trifluorotoluene or chlorobenzene.

6. The method according to claim 1, wherein In step (5), S5 has the structural formula shown below: And / or, in step (5), the amount of S4 used is 40 mmol; And / or, in step (5), corresponding to 40 mmol of S4, the amount of tetrabutylammonium fluoride used is 48 mmol; And / or, in step (5), corresponding to 40 mmol of S4, the amount of glacial acetic acid used is 40 mmol; And / or, in step (5), corresponding to 40 mmol of S4, the amount of 4-dimethylaminopyridine used is 80 mmol; And / or, in step (5), corresponding to 40 mmol of S4, the amount of di-tert-butyl dicarbonate used is 200 mmol; 7. The method according to claim 1, wherein In step (6), S6 has the structural formula shown below: And / or, in step (6), the amount of S5 used is 33 mmol; And / or, in step (6), corresponding to 33 mmol of S5, the amount of cesium fluoride used is 6.6 mmol; And / or, in step (6), corresponding to 33 mmol of S5, the amount of methanol used is 40 mmol.

8. The method according to claim 1, characterized in that, In step (7), S7 has the structural formula shown below: And / or, in step (7), the amount of S6 used is 28 mmol; And / or, in step (7), corresponding to 28 mmol of S6, the amount of N,O-dimethylhydroxylamine hydrochloride used is 34 mmol; And / or, in step (7), corresponding to 28 mmol of S6, the amount of the first batch of methylmagnesium chloride used is 70 mmol; And / or, in step (7), corresponding to 28 mmol of S6, the amount of the second batch of methylmagnesium chloride used is 78 mmol.

9. The method according to claim 1, characterized in that In step (8), S8 has the structural formula shown below: And / or, in step (8), the amount of S7 used is 23 mmol; And / or, in step (8), corresponding to 23 mmol of S7, the amount of ketone bromide used is 35 mmol.

10. The method according to claim 1, wherein In step (9), S9 has the structural formula shown below: And / or, in step (9), the amount of S8 used is 20 mmol; And / or, in step (9), corresponding to 20 mmol of S8, the amount of thiourea used is 28 mmol; And / or, in step (9), corresponding to 20 mmol of S8, the amount of sodium bicarbonate used is 20 mmol.

Images