CN104086514A - Paclitaxel derivatives and preparation method thereof - Google Patents

Paclitaxel derivatives and preparation method thereof Download PDF

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CN104086514A
CN104086514A CN201410276150.5A CN201410276150A CN104086514A CN 104086514 A CN104086514 A CN 104086514A CN 201410276150 A CN201410276150 A CN 201410276150A CN 104086514 A CN104086514 A CN 104086514A
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compound
solution
reaction
ethyl acetate
alkyl
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姚志艺
蒋晟
李彩红
王东升
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Shanghai Institute of Technology
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Shanghai Institute of Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems

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Abstract

The invention provides paclitaxel derivatives with a general structural formula (I) as described in the invention. The invention further provides application of the paclitaxel derivatives in preparation of drugs used for preventing or treating fibrosarcoma, liver cancer, lung cancer, leukemia, epidermoid carcinoma, breast cancer, prostatic cancer, lymphoma, stomach cancer, myeloma and pancreatic cancer. The derivatives synthesized in the invention have better water-solubility compared with paclitaxel and are superior to paclitaxel in the aspect of a plurality of anticancer effects.

Description

Taxol derivative and preparation method thereof
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a taxol derivative and a preparation method thereof.
Background
Paclitaxel is a novel broad-spectrum anti-tumor drug, and has significant curative effect on malignant tumors such as late ovarian cancer, breast cancer, non-small cell lung cancer and the like. And the treatment effect and safety of the traditional Chinese medicine composition are greatly influenced due to poor water solubility, poor selectivity, large toxic and side effects and the like. The new taxol derivative synthesized by the people overcomes the defects to a certain extent and has good biological activity.
Structure of paclitaxel:
malignant tumors are one of the major diseases that currently seriously affect human health and threaten human life. Cancer, together with cardiovascular and cerebrovascular diseases and accidents, constitutes three leading causes of death in all countries of the world today. Therefore, the World Health Organization (WHO) and the government health departments of all countries have cancer as a primary task. The development of new anticancer drugs has been greatly advanced in recent years, the anticancer drug has been paid more and more attention, and paclitaxel has unique anticancer activity and action mechanism, so that paclitaxel becomes a representative of new anticancer drugs of the new generation, and is one of the best anticancer drugs at present. But is not effective for some cancers and is easy to generate multidrug resistance. Paclitaxel has adverse reactions such as anaphylaxis, poor water solubility, neurotoxicity, cardiovascular toxicity and the like. Changing the dosage form and carrying out structural modification on the same become the direction of more researches, and the C of cabazitaxel is overcome7And C10The modification is carried out.
Disclosure of Invention
In view of the above-mentioned drawbacks of the prior art, the present invention provides a paclitaxel derivative and a preparation method thereof, and the paclitaxel derivative and the preparation method thereof are intended to solve the technical problems of limited effect and great side effect of paclitaxel in the prior art for treating cancer.
The invention provides a compound represented by a general formula (I), wherein the structural formula of the compound is as follows:
wherein: r1The radical being C1-6Alkyl radical, C3-8Cycloalkyl, - (C ═ O) - (C)1-6Alkyl), -CH2-O-(C1-6Alkyl), or C1-6An alkyl alcohol;
R2the radical being C1-6Alkyl radical, C3-8Cycloalkyl, - (C ═ O) - (C)1-6Alkyl), -CH2-O-(C1-6Alkyl), or C1-6An alkyl alcohol;
R3group H, C1-6Alkyl radical, C3-8Cycloalkyl, - (C ═ O) - (C)1-6Alkyl), -CH2-O-(C1-6Alkyl), or C1-6An alkyl alcohol;
R4the radical is(C1-6Alkyl group), C1-6Alkyl radical, C3-8Cycloalkyl, - (C ═ O) - (C)1-6Alkyl), -CH2-O-(C1-6Alkyl), or C1-6An alkyl alcohol.
Further, wherein,
R1the radical being C1-6Alkyl, or C3-8A cycloalkyl group;
R2the radical being C1-6Alkyl radical, C3-16Cycloalkyl, - (C ═ O) - (C)1-8Alkyl), or-CH2-O-(C1-6Alkyl groups);
R3group H, C1-6Alkyl radical, C3-8Cycloalkyl, - (C ═ O) - (C)1-6Alkyl), -CH2-O-(C1-6Alkyl), or C1-6An alkyl alcohol;
R4the radical is(C1-6Alkyl group), C1-6Alkyl radical, C3-8Cycloalkyl, - (C ═ O) - (C)1-6Alkyl), -CH2-O-(C1-6Alkyl), or C1-6An alkyl alcohol.
Further, in the above-mentioned case,
wherein,
R1the radical is- (C ═ O) - (C)1-8Alkyl), -CH2-O-(C1-6Alkyl), or C1-6An alkyl alcohol;
R2the radical being C1-6Alkyl radical, C3-8Cycloalkyl, - (C ═ O) - (C)1-8Alkyl), or-CH2-O-(C1-6Alkyl groups);
R3group H, C1-6Alkyl radical, C3-8Cycloalkyl, - (C ═ O) - (C)1-6Alkyl), -CH2-O-(C1-6Alkyl), or C1-6An alkyl alcohol;
R4the radical is(C1-6Alkyl group), C1-6Alkyl radical, C3-8Cycloalkyl, - (C ═ O) - (C)1-6Alkyl), -CH2-O-(C1-6Alkyl), or C1-6An alkyl alcohol.
Further, the structural formula is
The invention also provides an isomer, a racemate, a pharmaceutically acceptable salt, a crystalline hydrate, a solvate or a mixture thereof of the compound.
The invention also provides a pharmaceutical composition, which comprises an effective amount of isomers, racemes, pharmaceutically acceptable salts, crystal hydrates, solvates or mixtures thereof of the compounds, and one or more pharmaceutically acceptable carriers.
The invention also provides application of the pharmaceutical composition in preparing medicines for preventing or treating fibrosarcoma, liver cancer, lung cancer, leukemia, epidermoid carcinoma, breast cancer, prostatic cancer, lymphoma, gastric cancer, bone marrow cancer and pancreatic cancer.
The invention also provides application of the compound in preparing medicaments for preventing or treating fibrosarcoma, liver cancer, lung cancer, leukemia, epidermoid carcinoma, breast cancer, prostatic cancer, lymphoma, gastric cancer, bone marrow cancer and pancreatic cancer.
The invention also provides an application of the isomer, the racemate, the pharmaceutically acceptable salt, the crystal hydrate, the solvate or the mixture of the isomer, the racemate, the pharmaceutically acceptable salt, the crystal hydrate and the solvate of the compound in preparing medicaments for preventing or treating fibrosarcoma, liver cancer, lung cancer, leukemia, epidermoid carcinoma, breast cancer, prostatic cancer, lymphoma, gastric cancer, bone marrow cancer and pancreatic cancer.
The hydrophobic group in the compound has better anticancer activity and can help to pass through the blood brain barrier. Meanwhile, the compound synthesized by the invention has better water solubility than paclitaxel and better anticancer effect than paclitaxel.
Detailed Description
EXAMPLE 1 Synthesis of Compound 56
TrocCl (2.49ml, 18.18mmol) was added dropwise to a pyridine (54ml) solution of compound 55(3g, 5.51mmol) under argon atmosphere at 0 ℃ to react at room temperature for 1 hour, TLC checked for completion of the reaction, pyridine was removed under reduced pressure, 80ml ethyl acetate and 50ml water were added, extraction was performed with ethyl acetate (50ml × 2), washing was performed with saturated sodium chloride (50ml), dried over anhydrous sodium sulfate, concentrated, and column chromatography (PE: EA ═ 3: 1) gave compound 56(3.96g, 81%) as a white solid.
EXAMPLE 2 Synthesis of Compound 58
Compound 56(3g, 3.36mmol), compound 57(3.24g), DCC, DMAP were sequentially added to a reaction flask, 68mL of toluene was added under argon protection, the reaction was stirred at 85 ℃ for 2 hours and then HPLC monitored for completion of the reaction, toluene was removed under reduced pressure, 80mL of ethyl acetate and 50mL of water were added, stirring was carried out for 20min, insoluble matter was removed by filtration, extraction was carried out with ethyl acetate (50mL × 2), washing was carried out with saturated sodium chloride (50mL), drying was carried out with anhydrous sodium sulfate, concentration was carried out, and column chromatography was carried out (PE: EA ═ 3: 1) to obtain compound 58(3.70g, 92%).
EXAMPLE 3 Synthesis of Compound 59
To a solution of compound 58(3.7g, 3.09mmol) in methanol (120ml) were added zinc powder (6.75g, 92.87mmol) and acetic acid in this order, reacted at 30 ℃ for 5 hours and then the reaction was checked by TLC, the zinc powder was removed by filtration, the methanol and acetic acid were removed under reduced pressure, 100ml of ethyl acetate and 50ml of water were added, extracted with ethyl acetate (50ml × 2), washed with saturated sodium chloride (50ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain compound 59(2.53g, 90%) as a white solid.
EXAMPLE 4 Synthesis of Compound 60
Under the protection of argon, a solution of LiHMDS (0.5ml, 0.54mmol) in DMF (10ml) is slowly added dropwise to a solution of compound 59(100mg, 0.11mmol) in DMF (10ml), after stirring for 1h, MeI (3ml) is added, after 12h reaction, the temperature is naturally raised to 0 ℃, the temperature is raised to 5h, after 4h reaction at 0 ℃, the temperature is lowered to-78 ℃, the solution is quenched with saturated ammonium chloride solution (3ml), DMF and MeI are removed under reduced pressure, 20ml of ethyl acetate and 5ml of water are added, extraction is carried out with ethyl acetate (10 ml. times.2), washing is carried out with saturated sodium chloride solution (5ml), drying is carried out with anhydrous sodium sulfate, concentration is carried out, and column chromatography (PE: EA is 2: 1) is carried out to obtain 60(56.1ml, 54%) of a white solid compound.
EXAMPLE 5 Synthesis of Compound 61
To a solution of compound 60(50mg, 0.052mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (11mg, 0.058mmol), stirred at room temperature for 1h, TLC detected complete reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give compound 61 as a white solid (27.2mg, 62%).1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.80(d，J＝7.5Hz，1H)，3.45(s，1H)，3.30(s，3H)，2.36(s，3H)，2.24-2.29(m，2H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，4H)，1.36(s，9H)，1.27(s，3H)，1.25(s，3H)ppm.
Synthetic route to compound 61:
EXAMPLE 6 Synthesis of Compound 63
Under the protection of argon, DIPEA (0.5ml, 0.54mmol), compound 62 in toluene and DCE (1: 1) (5ml) was slowly added dropwise to a solution of compound 59(100mg, 0.11mmol) in toluene and DCE (1: 1) (5ml), the temperature was raised to 50 ℃, the reaction was 12h, TLC detected complete, cooled, quenched with saturated ammonium chloride (3ml), concentrated, added with 20ml ethyl acetate, 5ml water, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 2: 1) to give compound 63(31.0ml, 23%) as a white solid.
EXAMPLE 7 Synthesis of Compound 64
Under the protection of argon, a THF solution of TBAF (38.9mg, 0.180mmol) was added dropwise to a THF (2ml) solution of compound 63(100mg, 0.082mmol) at 0 ℃ for 8h, TLC detected complete reaction, quenched with saturated ammonium chloride solution (1ml), methanol was removed under reduced pressure, extracted with ethyl acetate (5ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give compound 64(40.4mg, 50%) as a white solid.
EXAMPLE 8 Synthesis of Compound 1
To a solution of compound 64(40.4mg, 0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected complete reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give compound 1 as a white solid (23.6mg, 65%).1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.81-3.76(m，5H)，3.55-3.72(m，4H)，3.45(s，1H)，2.24-2.29(m，2H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，4H)，1.36(s，9H)，1.27(s，3H)，1.25(s，3H)ppm.
Synthetic route to Compound 1
EXAMPLE 9 Synthesis of Compound 65
Compound 59(100mg, 0.11mmol) in DCM (5ml) was slowly added dropwise DIPEA (0.5ml, 0.54mmol), MOMCl (0.041ml, 0.54mmol) under argon at 0 ℃, warmed to room temperature for 12h, TLC detected for reaction completion, cooled, quenched with saturated ammonium chloride (3ml), concentrated, added with 5ml ethyl acetate, 5ml water, extracted with ethyl acetate (5ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 2: 1) to give compound 65(89.9mg, 72%) as a white solid.
EXAMPLE 10 Synthesis of Compound 2
To a solution of compound 65(89.9mg, 0.090mmol) in methanol (3ml) was added p-toluenesulfonic acid (17.0mg, 0.099mmol), stirred at room temperature for 1h, TLC detected for reaction completion, saturated sodium bicarbonate (2ml), quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give compound 2(23.6mg, 65%) as a white solid.
1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43-5.47(m，5H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.80(d，J＝7.5Hz，1H)，3.45(s，1H)，3.32(s，3H)，3.28(s，3H)，2.24-2.29(m，2H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，4H)，1.36(s，9H)，1.27(s，3H)，1.25(s，3H)ppm.
Synthesis of Compound 2
EXAMPLE 11 Synthesis of Compound 67
Compound 59(100mg, 0.11mmol), compound 66(47.8mg, 0.132mmol), DCC, DMAP were sequentially added to a reaction flask, 5mL of toluene was added under argon protection, the reaction was stirred at 85 ℃ for 5 hours and then monitored by HPLC for completion of the reaction, toluene was removed under reduced pressure, 5mL of ethyl acetate and 5mL of water were added, the mixture was stirred for 20min, insoluble matter was removed by filtration, extraction was performed with ethyl acetate (5mL × 2), washing was performed with a saturated sodium chloride solution (5mL), drying was performed with anhydrous sodium sulfate, concentration was performed, and column chromatography (PE: EA ═ 3: 1) gave compound 67(110.72mg, 63%).
EXAMPLE 12 Synthesis of Compound 68
Under the protection of argon, a THF solution of TBAF (69.2mg, 0.265mmol) was added dropwise to a THF (2ml) solution of compound 67(100mg, 0.063mmol) at 0 ℃ for 8h, TLC detected complete reaction, quenched with saturated ammonium chloride (1ml), methanol was removed under reduced pressure, extracted with ethyl acetate (5ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give compound 68(41.7mg, 58%) as a white solid.
EXAMPLE 13 Synthesis of Compound 3
To a solution of compound 68(41.7mg, 0.037mmol) in methanol (2ml) was added p-toluenesulfonic acid (7.0mg, 0.041mmol), stirred at room temperature for 1h, TLC detected for completion of the reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (5ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give compound 3 as a white solid (26.9mg, 71%).
1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.82-3.84(m，8H)，3.80(d，J＝7.5Hz，1H)，3.45(s，1H)，2.24-2.29(m，2H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，4H)，1.36(s，6H)，1.36(s，9H)，1.27(s，3H)，1.25(s，3H)ppm.
Synthesis of Compound 3
Example 14 Synthesis of Compound 70 and Synthesis of Compound 63.
Example 15 Synthesis of Compound 4 Synthesis of Compound 1, Compound 2 and Compound 3.
Synthesis of Compound 4
Example 16 Synthesis of Compound 72 was followed by Synthesis of Compound 63.
Example 17 Synthesis of Compound 5 Synthesis of Compound 1, Compound 2 and Compound 3.
Synthesis of Compound 5
Example 18
Compound 6
Under the protection of argon, DIPEA (0.5ml, 0.54mmol), compound a in toluene and DCE (1: 1) (5ml) was slowly added dropwise to a solution of compound 59(100mg, 0.11mmol) in toluene and DCE (1: 1) (5ml), the temperature was raised to 50 ℃, the reaction was 12h, TLC detected complete, cooled, quenched with saturated ammonium chloride (3ml), concentrated, added with 20ml ethyl acetate, 5ml water, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 2: 1) to give compound 72(28.2mg, 24%) as a white solid.
EXAMPLE 19 Synthesis of Compound 73
Under the protection of argon, a THF solution of TBAF (38.9mg, 0.180mmol) was added dropwise to a THF (2ml) solution of compound 72(100mg, 0.094mmol) at 0 ℃ for 8h, TLC detected complete reaction, quenched with saturated ammonium chloride solution (1ml), methanol was removed under reduced pressure, extracted with ethyl acetate (5ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give 51% yield of the compound as a white solid.
To a solution of the above compound (40.4mg, 0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected complete reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give compound 6(23.7mg, 65.3%) as a white solid. Compound 6:1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.81-3.76(m，5H)，3.28(s，3H)，3.45(s，1H)，2.24-2.29(m，2H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，4H)，1.36(s，9H)，1.27(s，3H)，1.25(s，3H)ppm.
EXAMPLE 20 Compound 7
Under the protection of argon, DIPEA (0.5ml, 0.54mmol), compound a in toluene and DCE (1: 1) (5ml) was slowly added dropwise to a solution of compound 59(100mg, 0.11mmol) in toluene and DCE (1: 1) (5ml), the temperature was raised to 50 ℃, the reaction was 12h, TLC detected complete, the reaction was cooled, quenched with saturated ammonium chloride (3ml), concentrated, 20ml ethyl acetate, 5ml water were added, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatography (PE: EA ═ 2: 1) gave compound 63 as a white solid (31.0ml, 23%).
Compound 59(100mg, 0.11mmol), compound 66(47.8mg, 0.132mmol), DCC, DMAP were sequentially added to a reaction flask, 5mL of toluene was added under argon protection, the reaction was stirred at 85 ℃ for 5 hours and then monitored by HPLC for completion of the reaction, toluene was removed under reduced pressure, 5mL of ethyl acetate and 5mL of water were added, the mixture was stirred for 20min, insoluble matter was removed by filtration, extraction was performed with ethyl acetate (5mL × 2), washing was performed with a saturated sodium chloride solution (5mL), drying was performed with anhydrous sodium sulfate, concentration was performed, and column chromatography (PE: EA ═ 3: 1) gave compound 67(110.72mg, 63%).
Under the protection of argon, a THF solution of TBAF (38.9mg, 0.180mmol) was added dropwise to a THF (2ml) solution of compound 75(0.082mmol) at 0 ℃ for 8h, the reaction was complete by TLC detection, and a saturated ammonium chloride solution (1ml) was quenched, methanol was removed under reduced pressure, extracted with ethyl acetate (5ml × 3), washed with a saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatography (PE: EA ═ 3: 1) gave compound 76 (50.3%) as a white solid.
To a solution of compound 76(40.4mg, 0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected complete reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give compound 7 (66%) as a white solid.
1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.82-3.84(m，4H)，3.81-3.76(m，5H)，3.45(s，1H)，2.24-2.29(m，2H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，4H)，1.36(s，3H)，1.36(s，9H)，1.27(s，3H)，1.25(s，3H)ppm.
EXAMPLE 21 Compound 8
Under the protection of argon, DIPEA (0.5ml, 0.54mmol), compound a in toluene and DCE (1: 1) (5ml) was slowly added dropwise to a solution of compound 59(100mg, 0.11mmol) in toluene and DCE (1: 1) (5ml), the temperature was raised to 50 ℃, the reaction was 12h, TLC detected complete, the reaction was cooled, quenched with saturated ammonium chloride (3ml), concentrated, added with 20ml ethyl acetate, 5ml water, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatography (PE: EA ═ 2: 1) gave compound 72 (23%) as a white solid.
Under the protection of argon, DIPEA (0.5ml, 0.54mmol), compound b in toluene and DCE (1: 1) (5ml) solution were slowly added dropwise to compound 72(0.11mmol) in toluene and DCE (1: 1) (5ml) solution at 0 ℃, the temperature was raised to 50 ℃, the reaction was 12h, TLC detection reaction was complete, cooling, quenching with saturated ammonium chloride (3ml), concentration, addition of 20ml ethyl acetate, 5ml water, extraction with ethyl acetate (10ml × 2), washing with saturated sodium chloride (5ml), drying over anhydrous sodium sulfate, concentration, column chromatography (PE: EA ═ 2: 1) gave compound 77 (23%) as a white solid.
Under the protection of argon, a THF solution of TBAF (38.9mg, 0.180mmol) was added dropwise to a THF (2ml) solution of compound 77(0.082mmol) at 0 ℃ for 8h, the reaction was complete by TLC detection, and a saturated ammonium chloride solution (1ml) was quenched, methanol was removed under reduced pressure, extracted with ethyl acetate (5ml × 3), washed with a saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatography (PE: EA ═ 3: 1) gave compound 78 (50.3%) as a white solid.
To a solution of compound 78(0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected complete reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give compound 8 (63%) as a white solid.1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.81-3.76(m，5H)，3.55-3.72(m，4H)，3.45(s，1H)，3.28(s，3H)，2.24-2.29(m，2H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，4H)，1.36(s，3H)1.36(s，9H)，1.27(s，3H)，1.25(s，3H)ppm.
EXAMPLE 22 Compound 9
Under the protection of argon, DIPEA (0.5ml, 0.54mmol), compound a in toluene and DCE (1: 1) (5ml) was slowly added dropwise to a solution of compound 59(100mg, 0.11mmol) in toluene and DCE (1: 1) (5ml), the temperature was raised to 50 ℃, the reaction was 12h, TLC detected complete, the reaction was cooled, quenched with saturated ammonium chloride (3ml), concentrated, added with 20ml ethyl acetate, 5ml water, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatography (PE: EA ═ 2: 1) gave compound 72 (23%) as a white solid.
Under the protection of argon, compound 72(0.11mmol) in toluene and DCE (1: 1) (5ml) was slowly added dropwise DIPEA (0.5ml, 0.54mmol), compound b in toluene and DCE (1: 1) (5ml) at 0 ℃, heated to 50 ℃, reacted for 12h, TLC detected reaction was complete, cooled, quenched with saturated ammonium chloride (3ml), concentrated, added with 20ml ethyl acetate, 5ml water, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 2: 1) to give compound 79 (23%) as a white solid.
Under the protection of argon, a THF solution of TBAF (38.9mg, 0.180mmol) was added dropwise to a THF (2ml) solution of compound 79(0.082mmol) at 0 ℃ for 8h, the reaction was complete by TLC detection, and a saturated ammonium chloride solution (1ml) was quenched, methanol was removed under reduced pressure, extracted with ethyl acetate (5ml × 3), washed with a saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatography (PE: EA ═ 3: 1) gave compound 80 (50.3%) as a white solid.
To a solution of compound 80(0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected complete reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give compound 9 (63%) as a white solid.1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.81-3.76(m，5H)，3.55-3.72(m，4H)，3.45(s，1H)，3.28(s，3H)，2.24-2.29(m，2H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，4H)，1.36(s，3H)1.36(s，9H)，1.27(s，3H)，1.25(s，3H)ppm.
EXAMPLE 23 Compound 10
Under the protection of argon, compound 59(100mg, 0.11mmol) in toluene and DCE (1: 1) (5ml) was slowly added dropwise DIPEA (0.5ml, 0.54mmol), compound a in toluene and DCE (1: 1) (5ml) at 0 ℃, heated to 50 ℃, reacted for 12h, TLC detected reaction was complete, cooled, quenched with saturated ammonium chloride (3ml), concentrated, added with 20ml ethyl acetate, 5ml water, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 2: 1) to give compound (23%) as a white solid.
The above compound (100mg, 0.11mmol), compound (0.132mmol), DCC, DMAP were sequentially added to a reaction flask, 5mL of toluene was added under argon protection, the reaction was stirred at 85 ℃ for 5 hours and then monitored by HPLC for completion of the reaction, toluene was removed under reduced pressure, 5mL of ethyl acetate and 5mL of water were added, the mixture was stirred for 20min, insoluble materials were removed by filtration, extracted with ethyl acetate (5mL × 2), washed with a saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain compound (61%).
Under the protection of argon, a THF solution of TBAF (0.180mmol) was added dropwise to a THF (2ml) solution of compound 79(0.082mmol) at 0 ℃ for 8h, the reaction was checked by TLC for completion, a saturated ammonium chloride solution (1ml) was quenched, methanol was removed under reduced pressure, extracted with ethyl acetate (5ml × 3), washed with a saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to give a white solid compound (50.3%).
To a solution of the above compound (0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected for completion of the reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give compound 10 (62%) as a white solid.
1H NMR(400MHz，CDCl3)：：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43(d，J＝10.0Hz，1H)，5.43-5.47(m，2H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.82-3.84(m，4H)，3.80(d，J＝7.5Hz，1H)，3.45(s，1H)，3.28(s，3H)，2.24-2.29(m，2H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，4H)，1.36(s，3H)，1.36(s，9H)，1.27(s，3H)，1.25(s，3H)ppm.
EXAMPLE 24 Compound 11
Under the protection of argon, compound 59(0.11mmol) in toluene and DCE (1: 1) (5ml) was slowly added dropwise DIPEA (0.5ml, 0.54mmol), compound a in toluene and DCE (1: 1) (5ml) at 0 ℃, heated to 50 ℃, reacted for 12h, TLC detected reaction was complete, cooled, quenched with saturated ammonium chloride (3ml), concentrated, added with 20ml ethyl acetate, 5ml water, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 2: 1) to give compound (23%) as a white solid.
Under the protection of argon, DIPEA (0.5ml, 0.54mmol), compound b in toluene and DCE (1: 1) (5ml) was slowly added dropwise to the above compound (0.11mmol) in toluene and DCE (1: 1) (5ml) at 0 ℃, the temperature was raised to 50 ℃, the reaction was 12h, the reaction was checked by TLC to be complete, the reaction was cooled, quenched with saturated ammonium chloride (3ml), concentrated, 20ml of ethyl acetate and 5ml of water were added, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatography (PE: EA ═ 2: 1) gave compound 79 (23%) as a white solid.
Under the protection of argon, a THF solution of TBAF (38.9mg, 0.180mmol) was added dropwise to a THF (2ml) solution of the above compound (0.082mmol) at 0 ℃ for 8h, the reaction was complete by TLC detection, and a saturated ammonium chloride solution (1ml) was quenched, methanol was removed under reduced pressure, extracted with ethyl acetate (5ml × 3), washed with a saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatography (PE: EA ═ 3: 1) gave a white solid compound (50.7%).
To a solution of compound (0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected complete reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give compound 11 (63%) as a white solid.1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43(d，J＝10.0Hz，1H)，5.43-5.47(m，2H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.80(d，J＝7.5Hz，1H)，3.55-3.72(m，4H)，3.45(s，1H)，3.30(s，3H)，3.28(s，3H)，2.24-2.29(m，2H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，4H)，1.36(s，9H)，1.27(s，3H)，1.25(s，3H)ppm.
EXAMPLE 25 Compound 12
Under the protection of argon, compound 59(0.11mmol) in toluene and DCE (1: 1) (5ml) was slowly added dropwise DIPEA (0.5ml, 0.54mmol), compound a in toluene and DCE (1: 1) (5ml) at 0 ℃, heated to 50 ℃, reacted for 12h, TLC detected reaction was complete, cooled, quenched with saturated ammonium chloride (3ml), concentrated, added with 20ml ethyl acetate, 5ml water, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 2: 1) to give compound (23%) as a white solid.
Under the protection of argon, DIPEA (0.5ml, 0.54mmol), toluene of compound b and DCE (1: 1) (5ml) solution were slowly added dropwise to the above compound (0.11mmol) in toluene and DCE (1: 1) (5ml) solution at 0 ℃, the temperature was raised to 50 ℃, the reaction was 12h, the TLC detection reaction was complete, the reaction was cooled, quenched with saturated ammonium chloride (3ml), concentrated, 20ml ethyl acetate, 5ml water were added, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatography (PE: EA ═ 2: 1) gave compound (23%) as a white solid.
To a solution of the above compound (0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC checked for completion of the reaction, and quenched with saturated sodium bicarbonate solution (2ml)Then, methanol was removed under reduced pressure, and the extract was extracted with ethyl acetate (10 ml. times.3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA: 3: 1) to give compound 12 (63%) as a white solid.1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43-5.47(m，2H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.80(d，J＝7.5Hz，1H)，3.45(s，1H)，3.32(s，3H)，2.24-2.29(m，2H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，4H)，1.36(s，9H)，1.27(s，3H)，1.25(s，3H)，1.10(s，3H)ppm.
EXAMPLE 26 Compound 13
Under the protection of argon, compound 59(0.11mmol) in toluene and DCE (1: 1) (5ml) was slowly added dropwise DIPEA (0.5ml, 0.54mmol), compound a in toluene and DCE (1: 1) (5ml) at 0 ℃, heated to 50 ℃, reacted for 12h, TLC detected reaction was complete, cooled, quenched with saturated ammonium chloride (3ml), concentrated, added with 20ml ethyl acetate, 5ml water, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 2: 1) to give compound (23%) as a white solid.
The above compound (0.11mmol), compound (0.132mmol), DCC, DMAP were sequentially added to a reaction flask, 5mL of toluene was added under argon protection, the reaction was stirred at 85 ℃ for 5 hours and then monitored by HPLC for completion of the reaction, toluene was removed under reduced pressure, 5mL of ethyl acetate and 5mL of water were added, the mixture was stirred for 20min, insoluble matter was removed by filtration, extracted with ethyl acetate (5mL × 2), washed with a saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain compound (63.3%).
Under the protection of argon, a THF solution of TBAF (38.9mg, 0.180mmol) was added dropwise to a THF (2ml) solution of the above compound (0.082mmol) at 0 ℃ for 8h, the reaction was complete by TLC detection, and a saturated ammonium chloride solution (1ml) was quenched, methanol was removed under reduced pressure, extracted with ethyl acetate (5ml × 3), washed with a saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatography (PE: EA ═ 3: 1) gave a white solid compound (50.3%).
To a solution of compound (0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected complete reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give compound 13 as a white solid (61.3%).
1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.82-3.84(m，4H)，3.80(d，J＝7.5Hz，1H)，3.45(s，1H)，2.24-2.29(m，2H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，4H)，1.36(s，3H)，1.36(s，9H)，1.27(s，3H)，1.25(s，3H)ppm.
EXAMPLE 27 Compound 14
Under the protection of argon, compound 59(0.11mmol) in toluene and DCE (1: 1) (5ml) was slowly added dropwise DIPEA (0.5ml, 0.54mmol), compound a in toluene and DCE (1: 1) (5ml) at 0 ℃, heated to 50 ℃, reacted for 12h, TLC detected reaction was complete, cooled, quenched with saturated ammonium chloride (3ml), concentrated, added with 20ml ethyl acetate, 5ml water, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 2: 1) to give compound (23%) as a white solid.
The above compound (0.11mmol), compound (0.132mmol), DCC, DMAP were sequentially added to a reaction flask, 5mL of toluene was added under argon protection, the reaction was stirred at 85 ℃ for 5 hours and then monitored by HPLC for completion of the reaction, toluene was removed under reduced pressure, 5mL of ethyl acetate and 5mL of water were added, the mixture was stirred for 20min, insoluble matter was removed by filtration, extracted with ethyl acetate (5mL × 2), washed with a saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain compound (63.3%).
Under the protection of argon, a THF solution of TBAF (38.9mg, 0.180mmol) was added dropwise to a THF (2ml) solution of the above compound (0.082mmol) at 0 ℃ for 8h, the reaction was complete by TLC detection, and a saturated ammonium chloride solution (1ml) was quenched, methanol was removed under reduced pressure, extracted with ethyl acetate (5ml × 3), washed with a saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatography (PE: EA ═ 3: 1) gave a white solid compound (51.3%).
To a solution of compound (0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected complete reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give compound 13 as a white solid (61.4%).1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.80(d，J＝7.5Hz，1H)，3.81-3.76(m，4H)，3.45(s，1H)，3.28(s，3H)，2.24-2.29(m，2H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，4H)，1.36(s，3H)1.36(s，9H)，1.27(s，3H)，1.25(s，3H)ppm.
EXAMPLE 28 Compound 15
Under the protection of argon, compound 59(0.11mmol) in toluene and DCE (1: 1) (5ml) was slowly added dropwise DIPEA (0.5ml, 0.54mmol), compound a in toluene and DCE (1: 1) (5ml) at 0 ℃, heated to 50 ℃, reacted for 12h, TLC detected reaction was complete, cooled, quenched with saturated ammonium chloride (3ml), concentrated, added with 20ml ethyl acetate, 5ml water, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 2: 1) to give compound (23%) as a white solid.
Under the protection of argon, DIPEA (0.5ml, 0.54mmol), toluene of compound b and DCE (1: 1) (5ml) solution were slowly added dropwise to the above compound (0.11mmol) in toluene and DCE (1: 1) (5ml) solution at 0 ℃, the temperature was raised to 50 ℃, the reaction was 12h, the TLC detection reaction was complete, the reaction was cooled, quenched with saturated ammonium chloride (3ml), concentrated, 20ml ethyl acetate, 5ml water were added, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatography (PE: EA ═ 2: 1) gave compound (23%) as a white solid.
To a solution of the above compound (0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected for completion of the reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give compound 15 (63%) as a white solid.
1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.81-3.76(m，4H)，3.80(d，J＝7.5Hz，1H)，3.55-3，72(m，4H)，3.47-3.52(m，2H)，3.45(s，1H)，3.32(s，3H)，2.24-2.29(m，2H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，4H)，1.36(s，9H)，1.27(s，3H)，1.25(s，3H)，1.10(s，3H)，ppm.
EXAMPLE 29 Compound 16
Compound 59(100mg, 0.11mmol), compound 66(47.8mg, 0.132mmol), DCC, DMAP were sequentially added to a reaction flask, 5mL of toluene was added under argon protection, the reaction was stirred at 85 ℃ for 5 hours and then monitored by HPLC for completion of the reaction, toluene was removed under reduced pressure, 5mL of ethyl acetate and 5mL of water were added, the mixture was stirred for 20min, insoluble matter was removed by filtration, extracted with ethyl acetate (5mL × 2), washed with a saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain compound (61.3%).
The above compound (0.11mmol), compound 66(47.8mg, 0.132mmol), DCC, and DMAP were sequentially added to a reaction flask, 5mL of toluene was added under argon protection, the reaction was stirred at 85 ℃ for 5 hours, then HPLC was used to monitor completion of the reaction, toluene was removed under reduced pressure, 5mL of ethyl acetate and 5mL of water were added, the mixture was stirred for 20min, insoluble matter was removed by filtration, extracted with ethyl acetate (5mL × 2), washed with saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain compound (63%).
Under the protection of argon, a THF solution of TBAF (0.180mmol) was added dropwise to a THF (2ml) solution of the compound (0.082mmol) at 0 ℃ for 8h, the reaction was checked by TLC for completion, a saturated ammonium chloride solution (1ml) was quenched, methanol was removed under reduced pressure, extracted with ethyl acetate (5ml × 3), washed with a saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to give the compound as a white solid (50.3%).
To a solution of the above compound (0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected for completion of the reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give compound 16 (63%) as a white solid.
1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.82-3.84(m，8H)，3.80(d，J＝7.5Hz，1H)，3.45(s，1H)，3.30(s，3H)，2.36(s，3H)，2.24-2.29(m，2H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，4H)，1.36(s，6H)，1.36(s，9H)，1.27(s，3H)，1.25(s，3H)ppm.
EXAMPLE 30 Compound 17
Compound 59(0.11mmol), compound (0.132mmol), DCC, DMAP were sequentially added to a reaction flask, 5mL of toluene was added under argon protection, the reaction was stirred at 85 ℃ for 5 hours and then monitored by HPLC for completion of the reaction, toluene was removed under reduced pressure, 5mL of ethyl acetate and 5mL of water were added, the mixture was stirred for 20min, insoluble matter was removed by filtration, extracted with ethyl acetate (5mL × 2), washed with a saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to give compound (63.7%).
To a solution of the above compound (0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected for completion of the reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give compound 17 (63%) as a white solid.1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.81-3.76(m，4H)，3.55-3.72(m，4H)，3.80(d，J＝7.5Hz，1H)，3.45(s，1H)，3.30(s，6H)，2.36(s，6H)，2.24-2.29(m，2H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，4H)，1.36(s，6H)，1.36(s，9H)，1.27(s，3H)，1.25(s，3H)ppm.
EXAMPLE 31 Compound 18
Under the protection of argon, DIPEA (0.5ml, 0.54mmol), toluene of compound a and DCE (1: 1) (5ml) solution were slowly added dropwise to the toluene and DCE (1: 1) (5ml) solution of compound (0.11mmol) at 0 ℃, the temperature was raised to 50 ℃, the reaction was 12h, the reaction was detected by TLC completely, the reaction was cooled, quenched with saturated ammonium chloride (3ml), concentrated, 20ml of ethyl acetate and 5ml of water were added, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatography (PE: EA ═ 2: 1) gave the compound as a white solid (23.2%).
Under the protection of argon, DIPEA (0.5ml, 0.54mmol), toluene of compound b and DCE (1: 1) (5ml) solution were slowly added dropwise to the above compound (0.11mmol) in toluene and DCE (1: 1) (5ml) solution at 0 ℃, the temperature was raised to 50 ℃, the reaction was 12h, the reaction was detected by TLC completely, cooled, quenched with saturated ammonium chloride (3ml), concentrated, added with 20ml of ethyl acetate, 5ml of water, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 2: 1) to obtain the compound (23.7%) as a white solid.
Under the protection of argon, a THF solution of TBAF (0.180mmol) was added dropwise to a THF (2ml) solution of compound 79(0.082mmol) at 0 ℃ for 8h, the reaction was checked by TLC for completion, a saturated ammonium chloride solution (1ml) was quenched, methanol was removed under reduced pressure, extracted with ethyl acetate (5ml × 3), washed with a saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to give a white solid compound (50.3%).
To a solution of the above compound (0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected for completion of the reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give compound 18 (63%) as a white solid.
1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.80(d，J＝7.5Hz，1H)，3.55-3.72(m，4H)，3.62(s，2H)3.45(s，1H)，3.32(s，1H)，2.24-2.29(m，2H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，4H)，1.36(s，3H)，1.36(s，9H)，1.27(s，3H)，1.25(s，3H)ppm.
EXAMPLE 32 Compound 19
Under the protection of argon, compound 59(100mg, 0.11mmol) in toluene and DCE (1: 1) (5ml) was slowly added dropwise DIPEA (0.5ml, 0.54mmol), compound a in toluene and DCE (1: 1) (5ml) at 0 ℃, heated to 50 ℃, reacted for 12h, TLC detected reaction was complete, cooled, quenched with saturated ammonium chloride (3ml), concentrated, added with 20ml ethyl acetate, 5ml water, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 2: 1) to give compound (23%) as a white solid.
The compound (0.11mmol), the compound (0.132mmol), DCC, DMAP were sequentially added to a reaction flask, 5mL of toluene was added under argon protection, the reaction was stirred at 85 ℃ for 5 hours and then monitored by HPLC for completion of the reaction, toluene was removed under reduced pressure, 5mL of ethyl acetate and 5mL of water were added, the mixture was stirred for 20min, insoluble matter was removed by filtration, extracted with ethyl acetate (5mL × 2), washed with a saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain the compound (63%).
Under the protection of argon, a THF solution of TBAF (0.180mmol) was added dropwise to a THF (2ml) solution of the compound (0.082mmol) at 0 ℃ for 8h, the reaction was checked by TLC for completion, a saturated ammonium chloride solution (1ml) was quenched, methanol was removed under reduced pressure, extracted with ethyl acetate (5ml × 3), washed with a saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to give the compound as a white solid (50.3%).
To a solution of the above compound (0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected for completion of the reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give compound 19 (63%) as a white solid.1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.82-3.84(m，4H)，3.80(d，J＝7.5Hz，1H)，3.55-3.72(m，4H)，3.45(s，1H)，3.30(s，3H)，2.24-2.29(m，2H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，4H)，1.36(s，3H)，1.36(s，9H)，1.27(s，3H)，1.25(s，3H)ppm.
EXAMPLE 33 Compound 20
Under the protection of argon, DIPEA (0.5ml, 0.54mmol), toluene of compound a and DCE (1: 1) (5ml) solution were slowly added dropwise to the toluene of compound (0.11mmol) and DCE (1: 1) (5ml) solution at 0 ℃, the temperature was raised to 50 ℃, the reaction was 12h, the TLC detection reaction was complete, cooled, quenched with saturated ammonium chloride (3ml), concentrated, added with 20ml ethyl acetate, 5ml water, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 2: 1) to obtain the compound (23%) as a white solid.
Under the protection of argon, DIPEA (0.5ml, 0.54mmol), toluene of compound b and DCE (1: 1) (5ml) solution were slowly added dropwise to the above compound (0.11mmol) in toluene and DCE (1: 1) (5ml) solution at 0 ℃, the temperature was raised to 50 ℃, the reaction was 12h, the reaction was detected by TLC completely, cooled, quenched with saturated ammonium chloride (3ml), concentrated, added with 20ml of ethyl acetate, 5ml of water, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 2: 1) to obtain the compound (24.2%) as a white solid.
Under the protection of argon, a THF solution of TBAF (0.180mmol) was added dropwise to a THF (2ml) solution of the above compound (0.082mmol) at 0 ℃ for 8h, the reaction was checked by TLC, the reaction was completed, a saturated ammonium chloride solution (1ml) was quenched, methanol was removed under reduced pressure, extracted with ethyl acetate (5ml × 3), washed with a saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain a white solid compound (51.3%).
To a solution of the above compound (0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected for completion of the reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give compound 20 (63%) as a white solid.
1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.80(d，J＝7.5Hz，1H)，3.55-3.72(m，8H)，3.45(s，1H)，2.24-2.29(m，2H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，4H)，1.36(s，3H)，1.36(s，9H)，1.27(s，3H)，1.25(s，3H)ppm.
EXAMPLE 34 Compound 21
Under the protection of argon, DIPEA (0.5ml, 0.54mmol), toluene of compound a and DCE (1: 1) (5ml) solution were slowly added dropwise to the toluene of compound (0.11mmol) and DCE (1: 1) (5ml) solution at 0 ℃, the temperature was raised to 50 ℃, the reaction was 12h, the TLC detection reaction was complete, cooled, quenched with saturated ammonium chloride (3ml), concentrated, added with 20ml ethyl acetate, 5ml water, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 2: 1) to obtain the compound (23%) as a white solid.
Under the protection of argon, DIPEA (0.5ml, 0.54mmol), toluene of compound b and DCE (1: 1) (5ml) solution were slowly added dropwise to the above compound (0.11mmol) in toluene and DCE (1: 1) (5ml) solution at 0 ℃, the temperature was raised to 50 ℃, the reaction was 12h, the reaction was detected by TLC completely, cooled, quenched with saturated ammonium chloride (3ml), concentrated, added with 20ml of ethyl acetate, 5ml of water, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 2: 1) to obtain the compound (23.1%) as a white solid.
Under the protection of argon, a THF solution of TBAF (0.180mmol) was added dropwise to a THF (2ml) solution of compound 79(0.082mmol) at 0 ℃ for 8h, the reaction was checked by TLC for completion, a saturated ammonium chloride solution (1ml) was quenched, methanol was removed under reduced pressure, extracted with ethyl acetate (5ml × 3), washed with a saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to give a white solid compound (50.6%).
To a solution of the above compound (0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected for completion of the reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give compound 21 (63%) as a white solid.1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.80(d，J＝7.5Hz，1H)，3.55-3.72(m，10H)，3.45(s，1H)，2.24-2.29(m，2H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，4H)，1.36(s，9H)，1.27(s，3H)，1.25(s，3H)，1.10(s，3H)ppm.
EXAMPLE 35 Compound 22
Under the protection of argon, DIPEA (0.5ml, 0.54mmol), toluene of compound a and DCE (1: 1) (5ml) solution were slowly added dropwise to the toluene of compound (0.11mmol) and DCE (1: 1) (5ml) solution at 0 ℃, the temperature was raised to 50 ℃, the reaction was 12h, the TLC detection reaction was complete, cooled, quenched with saturated ammonium chloride (3ml), concentrated, added with 20ml ethyl acetate, 5ml water, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 2: 1) to obtain the compound (23%) as a white solid.
The compound (0.11mmol), the compound (0.132mmol), DCC, DMAP were sequentially added to a reaction flask, 5mL of toluene was added under argon protection, the reaction was stirred at 85 ℃ for 5 hours and then monitored by HPLC for completion of the reaction, toluene was removed under reduced pressure, 5mL of ethyl acetate and 5mL of water were added, the mixture was stirred for 20min, insoluble matter was removed by filtration, extracted with ethyl acetate (5mL × 2), washed with a saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain the compound (63%).
Under the protection of argon, a THF solution of TBAF (0.180mmol) was added dropwise to a THF (2ml) solution of the compound (0.082mmol) at 0 ℃ for 8h, the reaction was checked by TLC for completion, a saturated ammonium chloride solution (1ml) was quenched, methanol was removed under reduced pressure, extracted with ethyl acetate (5ml × 3), washed with a saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to give the compound as a white solid (50.3%).
To a solution of the above compound (0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected for completion of the reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give compound 22 (63%) as a white solid.1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43-5.47(m，2H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.82-3.84(m，4H)，3.80(d，J＝7.5Hz，1H)，3.45(s，1H)，3.32(s，3H)，2.24-2.29(m，2H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，4H)，1.36(s，3H)，1.36(s，9H)，1.27(s，3H)，1.25(s，3H)ppm.
EXAMPLE 36 Compound 23
Under the protection of argon, DIPEA (0.5ml, 0.54mmol), toluene of compound a and DCE (1: 1) (5ml) solution were slowly added dropwise to the toluene of compound (0.11mmol) and DCE (1: 1) (5ml) solution at 0 ℃, the temperature was raised to 50 ℃, the reaction was 12h, the TLC detection reaction was complete, cooled, quenched with saturated ammonium chloride (3ml), concentrated, added with 20ml ethyl acetate, 5ml water, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 2: 1) to obtain the compound (23%) as a white solid.
Under the protection of argon, DIPEA (0.5ml, 0.54mmol), toluene of compound b and DCE (1: 1) (5ml) solution were slowly added dropwise to the above compound (0.11mmol) in toluene and DCE (1: 1) (5ml) solution at 0 ℃, the temperature was raised to 50 ℃, the reaction was 12h, the TLC detection reaction was complete, the reaction was cooled, quenched with saturated ammonium chloride (3ml), concentrated, 20ml ethyl acetate, 5ml water were added, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatography (PE: EA ═ 2: 1) gave compound (22.3%) as a white solid.
Under the protection of argon, a THF solution of TBAF (0.180mmol) was added dropwise to a THF (2ml) solution of compound 79(0.082mmol) at 0 ℃ for 8h, the reaction was checked by TLC for completion, a saturated ammonium chloride solution (1ml) was quenched, methanol was removed under reduced pressure, extracted with ethyl acetate (5ml × 3), washed with a saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to give a white solid compound (50.3%).
To a solution of the above compound (0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected for completion of the reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give compound 23 (63%) as a white solid.1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43-5.47(m，2H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.81-3.76(m，4H)，3.80(d，J＝7.5Hz，1H)，3.45(s，1H)，3.32(s，3H)，3.28(s，3H)，2.24-2.29(m，2H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，4H)，1.36(s，9H)，1.27(s，3H)，1.25(s，3H)ppm.
EXAMPLE 37 Compound 24
Under the protection of argon, DIPEA (0.5ml, 0.54mmol), toluene of compound a and DCE (1: 1) (5ml) solution were slowly added dropwise to the toluene of compound (0.11mmol) and DCE (1: 1) (5ml) solution at 0 ℃, the temperature was raised to 50 ℃, the reaction was 12h, the TLC detection reaction was complete, cooled, quenched with saturated ammonium chloride (3ml), concentrated, added with 20ml ethyl acetate, 5ml water, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 2: 1) to obtain the compound (23%) as a white solid.
Under the protection of argon, DIPEA (0.5ml, 0.54mmol), toluene of compound b and DCE (1: 1) (5ml) solution were slowly added dropwise to the above compound (0.11mmol) in toluene and DCE (1: 1) (5ml) solution at 0 ℃, the temperature was raised to 50 ℃, the reaction was 12h, the TLC detection reaction was complete, the reaction was cooled, quenched with saturated ammonium chloride (3ml), concentrated, 20ml ethyl acetate, 5ml water were added, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatography (PE: EA ═ 2: 1) gave compound (23%) as a white solid.
Under the protection of argon, a THF solution of TBAF (0.180mmol) was added dropwise to a THF (2ml) solution of compound 79(0.082mmol) at 0 ℃ for 8h, the reaction was checked by TLC for completion, a saturated ammonium chloride solution (1ml) was quenched, methanol was removed under reduced pressure, extracted with ethyl acetate (5ml × 3), washed with a saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to give a white solid compound (50.3%).
To a solution of the above compound (0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected for completion of the reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give compound 24 (63%) as a white solid.1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43-5.47(m，2H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.81-3.76(m，6H)，3.80(d，J＝7.5Hz，1H)，3.45(s，1H)，3.28(s，3H)，2.24-2.29(m，2H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，4H)，1.36(s，3H)，1.36(s，9H)，1.27(s，3H)，1.25(s，3H)ppm.
EXAMPLE 38 Compound 25
Under the protection of argon, DIPEA (0.5ml, 0.54mmol), toluene of compound a and DCE (1: 1) (5ml) solution were slowly added dropwise to the toluene of compound (0.11mmol) and DCE (1: 1) (5ml) solution at 0 ℃, the temperature was raised to 50 ℃, the reaction was 12h, the TLC detection reaction was complete, cooled, quenched with saturated ammonium chloride (3ml), concentrated, added with 20ml ethyl acetate, 5ml water, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 2: 1) to obtain the compound (23%) as a white solid.
The compound (0.11mmol), the compound (0.132mmol), DCC, DMAP were sequentially added to a reaction flask, 5mL of toluene was added under argon protection, the reaction was stirred at 85 ℃ for 5 hours and then monitored by HPLC for completion of the reaction, toluene was removed under reduced pressure, 5mL of ethyl acetate and 5mL of water were added, the mixture was stirred for 20min, insoluble matter was removed by filtration, extracted with ethyl acetate (5mL × 2), washed with a saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain the compound (63%).
Under the protection of argon, a THF solution of TBAF (0.180mmol) was added dropwise to a THF (2ml) solution of the compound (0.082mmol) at 0 ℃ for 8h, the reaction was checked by TLC for completion, a saturated ammonium chloride solution (1ml) was quenched, methanol was removed under reduced pressure, extracted with ethyl acetate (5ml × 3), washed with a saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to give the compound as a white solid (50.3%).
To a solution of the above compound (0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected for completion of the reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give compound 25 (63%) as a white solid.
1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.84-3.76(m，8H)，3.80(d，J＝7.5Hz，1H)，3.45(s，1H)，3.30(s，3H)，2.24-2.29(m，2H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，4H)，1.36(s，3H)，1.36(s，9H)，1.27(s，3H)，1.25(s，3H)ppm.
EXAMPLE 39 Compound 26
1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.84-3.76(m，10H)，3.80(d，J＝7.5Hz，1H)，3.45(s，1H)，3.28(s，3H)，2.24-2.29(m，2H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，4H)，1.36(s，3H)，1.36(s，9H)，1.27(s，3H)，1.25(s，3H)ppm.
Under the protection of argon, compound 59(100mg, 0.11mmol) in toluene and DCE (1: 1) (5ml) was slowly added dropwise DIPEA (0.5ml, 0.54mmol), compound a in toluene and DCE (1: 1) (5ml) at 0 ℃, heated to 50 ℃, reacted for 12h, TLC detected reaction was complete, cooled, quenched with saturated ammonium chloride (3ml), concentrated, added with 20ml ethyl acetate, 5ml water, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 2: 1) to obtain compound (21-26%) as a white solid.
The compound (0.11mmol), the compound (0.132mmol), DCC, DMAP were sequentially added to a reaction flask, 5mL of toluene was added under argon protection, the reaction was stirred at 85 ℃ for 5 hours and then monitored by HPLC for completion of the reaction, toluene was removed under reduced pressure, 5mL of ethyl acetate and 5mL of water were added, the mixture was stirred for 20min, insoluble matter was removed by filtration, extracted with ethyl acetate (5mL × 2), washed with a saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain the compound (60-64%).
Under the protection of argon, a THF solution of TBAF (0.180mmol) was added dropwise to a THF (2ml) solution of compound 79(0.082mmol) at 0 ℃ for 8h, the reaction was checked by TLC for completion, a saturated ammonium chloride solution (1ml) was quenched, methanol was removed under reduced pressure, extracted with ethyl acetate (5ml × 3), washed with a saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to give compound (49-54%) as a white solid.
To a solution of the above compound (0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected for completion of the reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give compound 26 (61-67%) as a white solid.
EXAMPLE 40 Compound 27
Under the protection of argon, DIPEA (0.5ml, 0.54mmol), toluene of compound a and DCE (1: 1) (5ml) solution were slowly added dropwise to the toluene and DCE (1: 1) (5ml) solution of compound (0.11mmol) at 0 ℃, the temperature was raised to 50 ℃, the reaction was 12h, the TLC detection reaction was complete, cooled, quenched with saturated ammonium chloride (3ml), concentrated, added with 20ml ethyl acetate, 5ml water, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 2: 1) to obtain the compound (21-24%) as a white solid.
Under the protection of argon, DIPEA (0.5ml, 0.54mmol), toluene of compound b and DCE (1: 1) (5ml) solution were slowly added dropwise to the above compound (0.11mmol) in toluene and DCE (1: 1) (5ml) solution at 0 ℃, the temperature was raised to 50 ℃, the reaction was 12h, the TLC detection reaction was complete, cooled, quenched with saturated ammonium chloride (3ml), concentrated, added with 20ml ethyl acetate, 5ml water, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatography (PE: EA ═ 2: 1) gave compound (21-25%) as a white solid.
Under the protection of argon, a THF solution of TBAF (0.180mmol) was added dropwise to a THF (2ml) solution of compound 79(0.082mmol) at 0 ℃ for 8h, the reaction was checked by TLC, the reaction was completed, a saturated ammonium chloride solution (1ml) was quenched, methanol was removed under reduced pressure, extraction was performed with ethyl acetate (5ml × 3), washing was performed with a saturated sodium chloride solution (5ml), drying was performed with anhydrous sodium sulfate, concentration was performed, and column chromatography (PE: EA ═ 3: 1) gave a white solid compound (49.9-54.6%).
To a solution of the above compound (0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected for completion of the reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give compound 27 (61-65%) as a white solid.
1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.84-3.76(m，10H)，3.80(d，J＝7.5Hz，1H)，3.45(s，1H)，3.28(s，3H)，2.24-2.29(m，2H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，4H)，1.36(s，3H)，1.36(s，9H)，1.27(s，3H)，1.25(s，3H)ppm.
EXAMPLE 41 Compound 28
The compound (0.11mmol), the compound (0.132mmol), DCC, and dm.ap were sequentially added to a reaction flask, 5mL of toluene was added under the protection of argon, the reaction was stirred at 85 ℃ for 5 hours and then monitored by HPLC for completion of the reaction, toluene was removed under reduced pressure, 5mL of ethyl acetate and 5mL of water were added, the mixture was stirred for 20min, insoluble matter was removed by filtration, extracted with ethyl acetate (5mL × 2), washed with a saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain the compound (60-64%).
The compound (0.11mmol), the compound (0.132mmol), DCC, DMAP were sequentially added to a reaction flask, 5mL of toluene was added under argon protection, the reaction was stirred at 85 ℃ for 5 hours and then monitored by HPLC for completion of the reaction, toluene was removed under reduced pressure, 5mL of ethyl acetate and 5mL of water were added, the reaction was stirred for 20min, insoluble matter was removed by filtration, extracted with ethyl acetate (5mL × 2), washed with a saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain the compound (60-64%).
Under the protection of argon, a THF solution of TBAF (0.180mmol) was added dropwise to a THF (2ml) solution of compound 79(0.082mmol) at 0 ℃ for 8h, the reaction was checked by TLC for completion, a saturated ammonium chloride solution (1ml) was quenched, methanol was removed under reduced pressure, extracted with ethyl acetate (5ml × 3), washed with a saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to give compound (49-54%) as a white solid.
To a solution of the above compound (0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected for completion of the reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give compound 28 (61-67%) as a white solid.
1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.84-3.76(m，8H)，3.80(d，J＝7.5Hz，1H)，3.45(s，1H)，3.28(s，6H)，2.24-2.29(m，2H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，4H)，1.36(s，6H)，1.36(s，9H)，1.27(s，3H)，1.25(s，3H)ppm.
EXAMPLE 42 Compound 29
The compound (0.11mmol), the compound (0.132mmol), DCC, DMAP were sequentially added to a reaction flask, 5mL of toluene was added under argon protection, the reaction was stirred at 85 ℃ for 5 hours and then monitored by HPLC for completion of the reaction, toluene was removed under reduced pressure, 5mL of ethyl acetate and 5mL of water were added, the mixture was stirred for 20min, insoluble matter was removed by filtration, extracted with ethyl acetate (5mL × 2), washed with a saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain the compound (60-64%).
The compound (0.11mmol), the compound (0.132mmol), DCC, DMAP were sequentially added to a reaction flask, 5mL of toluene was added under argon protection, the reaction was stirred at 85 ℃ for 5 hours and then monitored by HPLC for completion of the reaction, toluene was removed under reduced pressure, 5mL of ethyl acetate and 5mL of water were added, the reaction was stirred for 20min, insoluble matter was removed by filtration, extracted with ethyl acetate (5mL × 2), washed with a saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain the compound (60-64%).
Under the protection of argon, a THF solution of TBAF (0.180mmol) was added dropwise to a THF (2ml) solution of compound 79(0.082mmol) at 0 ℃ for 8h, the reaction was checked by TLC for completion, a saturated ammonium chloride solution (1ml) was quenched, methanol was removed under reduced pressure, extracted with ethyl acetate (5ml × 3), washed with a saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to give compound (49-54%) as a white solid.
To a solution of the above compound (0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected for completion of the reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give compound 28 (61-67%) as a white solid.
1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43(d，J＝10.0Hz，1H)，5.27(s，2H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.84-3.76(m，4H)，3.80(d，J＝7.5Hz，1H)，3.45(s，1H)，3.28(s，6H)，2.24-2.29(m，4H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，4H)，1.36(s，3H)，1.36(s，9H)，1.27(s，3H)，1.25(s，3H)ppm.
EXAMPLE 43 Compound 30
The compound (0.11mmol), the compound (0.132mmol), DCC, DMAP were sequentially added to a reaction flask, 5mL of toluene was added under argon protection, the reaction was stirred at 85 ℃ for 5 hours and then monitored by HPLC for completion of the reaction, toluene was removed under reduced pressure, 5mL of ethyl acetate and 5mL of water were added, the mixture was stirred for 20min, insoluble matter was removed by filtration, extracted with ethyl acetate (5mL × 2), washed with a saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain the compound (60-64%).
The compound (0.11mmol), the compound (0.132mmol), DCC, DMAP were sequentially added to a reaction flask, 5mL of toluene was added under argon protection, the reaction was stirred at 85 ℃ for 5 hours and then monitored by HPLC for completion of the reaction, toluene was removed under reduced pressure, 5mL of ethyl acetate and 5mL of water were added, the reaction was stirred for 20min, insoluble matter was removed by filtration, extracted with ethyl acetate (5mL × 2), washed with a saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain the compound (60-64%).
Under the protection of argon, a THF solution of TBAF (0.180mmol) was added dropwise to a THF (2ml) solution of compound 79(0.082mmol) at 0 ℃ for 8h, the reaction was checked by TLC for completion, a saturated ammonium chloride solution (1ml) was quenched, methanol was removed under reduced pressure, extracted with ethyl acetate (5ml × 3), washed with a saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to give compound (49-54%) as a white solid.
To a solution of the above compound (0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected for completion of the reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give compound 30 (61-67%) as a white solid.
1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.80(d，J＝7.5Hz，1H)，3.45(s，1H)，3.28(s，3H)，2.24-2.29(m，6H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，4H)，1.36(s，6H)，1.36(s，9H)，1.27(s，3H)，1.25(s，3H)ppm.
EXAMPLE 44 Compound 31
The compound (0.11mmol), the compound (0.132mmol), DCC, DMAP were sequentially added to a reaction flask, 5mL of toluene was added under argon protection, the reaction was stirred at 85 ℃ for 5 hours and then monitored by HPLC for completion of the reaction, toluene was removed under reduced pressure, 5mL of ethyl acetate and 5mL of water were added, the mixture was stirred for 20min, insoluble matter was removed by filtration, extracted with ethyl acetate (5mL × 2), washed with a saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain the compound (60-64%).
The compound (0.11mmol), the compound (0.132mmol), DCC, DMAP were sequentially added to a reaction flask, 5mL of toluene was added under argon protection, the reaction was stirred at 85 ℃ for 5 hours and then monitored by HPLC for completion of the reaction, toluene was removed under reduced pressure, 5mL of ethyl acetate and 5mL of water were added, the reaction was stirred for 20min, insoluble matter was removed by filtration, extracted with ethyl acetate (5mL × 2), washed with a saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain the compound (60-64%).
Under the protection of argon, a THF solution of TBAF (0.180mmol) was added dropwise to a THF (2ml) solution of compound 79(0.082mmol) at 0 ℃ for 8h, the reaction was checked by TLC for completion, a saturated ammonium chloride solution (1ml) was quenched, methanol was removed under reduced pressure, extracted with ethyl acetate (5ml × 3), washed with a saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to give compound (49-54%) as a white solid.
To a solution of the above compound (0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected for completion of the reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give compound 31 (61-67%) as a white solid.
1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.82-3.84(m，2H)，3.80(d，J＝7.5Hz，1H)，3.45(s，3H)，2.36(s，3H)，2.24-2.29(m，4H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，4H)，1.36(s，9H)，1.27(s，3H)，1.25(s，3H)ppm.
EXAMPLE 45 Compound 32
The compound (0.11mmol), the compound (0.132mmol), DCC, DMAP were sequentially added to a reaction flask, 5mL of toluene was added under argon protection, the reaction was stirred at 85 ℃ for 5 hours and then monitored by HPLC for completion of the reaction, toluene was removed under reduced pressure, 5mL of ethyl acetate and 5mL of water were added, the mixture was stirred for 20min, insoluble matter was removed by filtration, extracted with ethyl acetate (5mL × 2), washed with a saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain the compound (60-64%).
The compound (0.11mmol), the compound (0.132mmol), DCC, DMAP were sequentially added to a reaction flask, 5mL of toluene was added under argon protection, the reaction was stirred at 85 ℃ for 5 hours and then monitored by HPLC for completion of the reaction, toluene was removed under reduced pressure, 5mL of ethyl acetate and 5mL of water were added, the reaction was stirred for 20min, insoluble matter was removed by filtration, extracted with ethyl acetate (5mL × 2), washed with a saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain the compound (60-64%).
Under the protection of argon, a THF solution of TBAF (0.180mmol) was added dropwise to a THF (2ml) solution of compound 79(0.082mmol) at 0 ℃ for 8h, the reaction was checked by TLC for completion, a saturated ammonium chloride solution (1ml) was quenched, methanol was removed under reduced pressure, extracted with ethyl acetate (5ml × 3), washed with a saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to give compound (49-54%) as a white solid.
To a solution of the above compound (0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected for completion of the reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give compound 32 (61-67%) as a white solid.
1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.82-3.84(m，4H)，3.80(d，J＝7.5Hz，1H)，3.45(s，1H)，2.24-2.29(m，4H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，4H)，1.36(s，9H)，1.27(s，3H)，1.25(s，3H)ppm.
EXAMPLE 46 Compound 33
The compound (0.11mmol), the compound (0.132mmol), DCC, DMAP were sequentially added to a reaction flask, 5mL of toluene was added under argon protection, the reaction was stirred at 85 ℃ for 5 hours and then monitored by HPLC for completion of the reaction, toluene was removed under reduced pressure, 5mL of ethyl acetate and 5mL of water were added, the mixture was stirred for 20min, insoluble matter was removed by filtration, extracted with ethyl acetate (5mL × 2), washed with a saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain the compound (60-64%).
Under the protection of argon, a THF solution of TBAF (0.180mmol) was added dropwise to a THF (2ml) solution of compound 79(0.082mmol) at 0 ℃ for 8h, the reaction was checked by TLC for completion, a saturated ammonium chloride solution (1ml) was quenched, methanol was removed under reduced pressure, extracted with ethyl acetate (5ml × 3), washed with a saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to give compound (49-54%) as a white solid.
To a solution of the above compound (0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected for completion of the reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give compound 33 (61-67%) as a white solid.
1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.82-3.84(m，4H)，3.80(d，J＝7.5Hz，1H)，3.45(s，1H)，2.24-2.29(m，6H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，4H)，1.36(s，9H)，1.27(s，3H)，1.25(s，3H)ppm.
EXAMPLE 47 Compound 34
Under the protection of argon, DIPEA (0.5ml, 0.54mmol), toluene of compound a and DCE (1: 1) (5ml) solution were slowly added dropwise to the toluene and DCE (1: 1) (5ml) solution of compound (0.11mmol) at 0 ℃, the temperature was raised to 50 ℃, the reaction was 12h, the TLC detection reaction was complete, cooled, quenched with saturated ammonium chloride (3ml), concentrated, added with 20ml ethyl acetate, 5ml water, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 2: 1) to obtain the compound (21-24%) as a white solid.
Under the protection of argon, a THF solution of TBAF (0.180mmol) was added dropwise to a THF (2ml) solution of compound 79(0.082mmol) at 0 ℃ for 8h, the reaction was checked by TLC, the reaction was completed, a saturated ammonium chloride solution (1ml) was quenched, methanol was removed under reduced pressure, extracted with ethyl acetate (5ml × 3), washed with a saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to give a white solid compound (49.9-54.6%).
Under the protection of argon, a solution of LiHMDS (0.5ml, 0.54mmol) in DMF (10ml) is slowly added dropwise to a solution of compound 59(100mg, 0.11mmol) in DMF (10ml), after stirring for 1h, chloroalkane (3ml) is added, after 12h reaction, the temperature is naturally raised to 0 ℃, the temperature is raised to 5h, reaction is further carried out for 4h at 0 ℃, the temperature is lowered to-78 ℃, quenching is carried out with a saturated ammonium chloride solution (3ml), DMF and MeI are removed under reduced pressure, 20ml of ethyl acetate and 5ml of water are added, extraction is carried out with ethyl acetate (10 ml. times.2), washing is carried out with a saturated sodium chloride solution (5ml), drying is carried out with anhydrous sodium sulfate, concentration is carried out, and column chromatography (PE: EA is 2: 1) is carried out to obtain a white solid compound 60(56.1ml, 54%).
To a solution of the above compound (0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected for completion of the reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give compound 34 (61-65%) as a white solid.
1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.82-3.84(m，4H)，3.80(d，J＝7.5Hz，1H)，3.55-3.72(m，4H)，3.45(s，1H)，2.24-2.29(m，2H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，6H)，1.36(s，9H)，1.27(s，3H)，1.25(s，3H)ppm.
EXAMPLE 48 Compound 35
TrocCl (2.49ml, 18.18mmol) was added dropwise to a pyridine (54ml) solution of the compound (5.51mmol) at 0 ℃ under an argon atmosphere, the reaction was carried out at room temperature for 1 hour, the completion of the reaction was detected by TLC, pyridine was removed under reduced pressure, 80ml of ethyl acetate and 50ml of water were added, extraction was carried out with ethyl acetate (50ml × 2), washing was carried out with saturated sodium chloride (50ml), drying was carried out over anhydrous sodium sulfate, concentration was carried out, and column chromatography (PE: EA ═ 3: 1) was carried out to obtain a white solid compound (79-83%).
The compound (0.11mmol), the compound (0.132mmol), DCC, DMAP were sequentially added to a reaction flask, 5mL of toluene was added under argon protection, the reaction was stirred at 85 ℃ for 5 hours and then monitored by HPLC for completion of the reaction, toluene was removed under reduced pressure, 5mL of ethyl acetate and 5mL of water were added, the mixture was stirred for 20min, insoluble matter was removed by filtration, extracted with ethyl acetate (5mL × 2), washed with a saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain the compound (60-64%).
To a solution of the compound (3.09mmol) in methanol (120ml) were added zinc powder (92.87mmol) and acetic acid in this order, reacted at 30 ℃ for 5 hours and then the reaction was checked by TLC, the zinc powder was removed by filtration, the methanol and acetic acid were removed under reduced pressure, 100ml of ethyl acetate and 50ml of water were added, extracted with ethyl acetate (50ml × 2), washed with saturated sodium chloride (50ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain a white solid compound (90%).
Adding p-toluenesulfonic acid (0.058mmol) into a methanol (1.3ml) solution of the compound (0.052mmol), stirring at room temperature for 1h, detecting by TLC that the reaction is complete, quenching with a saturated sodium bicarbonate solution (2ml), removing methanol under reduced pressure, extracting with ethyl acetate (10 ml. times.3), washing with a saturated sodium chloride solution (5ml), drying over anhydrous sodium sulfate, concentrating, and performing column chromatography (PE: EA ═ 3: 1) to obtain a white solid compound
Under argon protection, a solution of LiHMDS (0.5ml, 0.54mmol) in DMF (10ml) was slowly added dropwise to a solution of compound 59(100mg, 0.11mmol) in DMF (10ml), after stirring for 1 hour, MeCl (3ml) was added, after 12 hours of reaction, the temperature was naturally raised to 0 ℃ and the temperature was raised to 5 hours, and the reaction was further carried out at 0 ℃ for 4 hours, and the temperature was lowered to-78 ℃, and the mixture was quenched with a saturated ammonium chloride solution (3ml), DMF and MeI were removed under reduced pressure, 20ml of ethyl acetate and 5ml of water were added, and the mixture was extracted with ethyl acetate (10 ml. times.2), washed with a saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA: 2: 1) to obtain a white solid compound 60(56.1ml, 54%).
1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，3H)，3.80(d，J＝7.5Hz，1H)，3.45(s，1H)，3.30(s，3H)，2.36(s，3H)，2.24-2.29(m，2H)，2.04(s，3H)，1.87(s，6H)，1.79-1.82(m，3H)，1.76(s，3H)，1.59-1.71(m，4H)，1.27(s，3H)，1.25(s，3H)，1.10(s，3H)ppm.
EXAMPLE 49 Compound 36
TrocCl (2.49ml, 18.18mmol) was added dropwise to a pyridine (54ml) solution of the compound (5.51mmol) at 0 ℃ under an argon atmosphere, the reaction was carried out at room temperature for 1 hour, the completion of the reaction was detected by TLC, pyridine was removed under reduced pressure, 80ml of ethyl acetate and 50ml of water were added, extraction was carried out with ethyl acetate (50ml × 2), washing was carried out with saturated sodium chloride (50ml), drying was carried out over anhydrous sodium sulfate, concentration was carried out, and column chromatography (PE: EA ═ 3: 1) was carried out to obtain a white solid compound (79-83%).
The compound (0.11mmol), the compound (0.132mmol), DCC, DMAP were sequentially added to a reaction flask, 5mL of toluene was added under argon protection, the reaction was stirred at 85 ℃ for 5 hours and then monitored by HPLC for completion of the reaction, toluene was removed under reduced pressure, 5mL of ethyl acetate and 5mL of water were added, the mixture was stirred for 20min, insoluble matter was removed by filtration, extracted with ethyl acetate (5mL × 2), washed with a saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain the compound (60-64%).
To a solution of the compound (3.09mmol) in methanol (120ml) were added zinc powder (92.87mmol) and acetic acid in this order, reacted at 30 ℃ for 5 hours and then the reaction was checked by TLC, the zinc powder was removed by filtration, the methanol and acetic acid were removed under reduced pressure, 100ml of ethyl acetate and 50ml of water were added, extracted with ethyl acetate (50ml × 2), washed with saturated sodium chloride (50ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain a white solid compound (90%).
Adding p-toluenesulfonic acid (0.058mmol) into a methanol (1.3ml) solution of the compound (0.052mmol), stirring at room temperature for 1h, detecting by TLC that the reaction is complete, quenching with a saturated sodium bicarbonate solution (2ml), removing methanol under reduced pressure, extracting with ethyl acetate (10 ml. times.3), washing with a saturated sodium chloride solution (5ml), drying over anhydrous sodium sulfate, concentrating, and performing column chromatography (PE: EA ═ 3: 1) to obtain a white solid compound
Under argon protection, a solution of LiHMDS (0.5ml, 0.54mmol) in DMF (10ml) was slowly added dropwise to a solution of compound 59(100mg, 0.11mmol) in DMF (10ml), after stirring for 1 hour, MeCl (3ml) was added, after 12 hours of reaction, the temperature was naturally raised to 0 ℃ and the temperature was raised to 5 hours, and the reaction was further carried out at 0 ℃ for 4 hours, and the temperature was lowered to-78 ℃, and the mixture was quenched with a saturated ammonium chloride solution (3ml), DMF and MeI were removed under reduced pressure, 20ml of ethyl acetate and 5ml of water were added, and the mixture was extracted with ethyl acetate (10 ml. times.2), washed with a saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA: 2: 1) to obtain a white solid compound 60(56.1ml, 54%).
1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.80(d，J＝7.5Hz，1H)，3.45(s，1H)，3.30(s，3H)，2.36(s，3H)，2.24-2.29(m，3H)，2.04(s，3H)，1.87(s，6H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，8H)，1.27(s，3H)，1.25(s，3H)ppm.
EXAMPLE 50 Compound 37
TrocCl (2.49ml, 18.18mmol) was added dropwise to a pyridine (54ml) solution of the compound (5.51mmol) at 0 ℃ under an argon atmosphere, the reaction was carried out at room temperature for 1 hour, the completion of the reaction was detected by TLC, pyridine was removed under reduced pressure, 80ml of ethyl acetate and 50ml of water were added, extraction was carried out with ethyl acetate (50ml × 2), washing was carried out with saturated sodium chloride (50ml), drying was carried out over anhydrous sodium sulfate, concentration was carried out, and column chromatography (PE: EA ═ 3: 1) was carried out to obtain a white solid compound (79-83%).
The compound (0.11mmol), the compound (0.132mmol), DCC, DMAP were sequentially added to a reaction flask, 5mL of toluene was added under argon protection, the reaction was stirred at 85 ℃ for 5 hours and then monitored by HPLC for completion of the reaction, toluene was removed under reduced pressure, 5mL of ethyl acetate and 5mL of water were added, the mixture was stirred for 20min, insoluble matter was removed by filtration, extracted with ethyl acetate (5mL × 2), washed with a saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain the compound (60-64%).
To a solution of the compound (3.09mmol) in methanol (120ml) were added zinc powder (92.87mmol) and acetic acid in this order, reacted at 30 ℃ for 5 hours and then the reaction was checked by TLC, the zinc powder was removed by filtration, the methanol and acetic acid were removed under reduced pressure, 100ml of ethyl acetate and 50ml of water were added, extracted with ethyl acetate (50ml × 2), washed with saturated sodium chloride (50ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain a white solid compound (90%).
Adding p-toluenesulfonic acid (0.058mmol) into a methanol (1.3ml) solution of the compound (0.052mmol), stirring at room temperature for 1h, detecting by TLC that the reaction is complete, quenching with a saturated sodium bicarbonate solution (2ml), removing methanol under reduced pressure, extracting with ethyl acetate (10 ml. times.3), washing with a saturated sodium chloride solution (5ml), drying over anhydrous sodium sulfate, concentrating, and performing column chromatography (PE: EA ═ 3: 1) to obtain a white solid compound
Under argon protection, a solution of LiHMDS (0.5ml, 0.54mmol) in DMF (10ml) was slowly added dropwise to a solution of compound 59(100mg, 0.11mmol) in DMF (10ml), after stirring for 1 hour, MeCl (3ml) was added, after 12 hours of reaction, the temperature was naturally raised to 0 ℃ and the temperature was raised to 5 hours, and the reaction was further carried out at 0 ℃ for 4 hours, and the temperature was lowered to-78 ℃, and the mixture was quenched with a saturated ammonium chloride solution (3ml), DMF and MeI were removed under reduced pressure, 20ml of ethyl acetate and 5ml of water were added, and the mixture was extracted with ethyl acetate (10 ml. times.2), washed with a saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA: 2: 1) to obtain a white solid compound 60(56.1ml, 54%).
1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.80(d，J＝7.5Hz，1H)，3.45(s，1H)，3.30(s，3H)，2.36(s，3H)，2.24-2.29(m，3H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，12H)，1.27(s，3H)，1.25(s，3H)ppm.
EXAMPLE 51 Compound 38
Under the protection of argon, DIPEA (0.5ml, 0.54mmol), toluene of compound a and DCE (1: 1) (5ml) solution were slowly added dropwise to the toluene and DCE (1: 1) (5ml) solution of compound (0.11mmol) at 0 ℃, the temperature was raised to 50 ℃, the reaction was 12h, the TLC detection reaction was complete, cooled, quenched with saturated ammonium chloride (3ml), concentrated, added with 20ml ethyl acetate, 5ml water, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 2: 1) to obtain the compound (21-24%) as a white solid.
Under the protection of argon, a THF solution of TBAF (0.180mmol) was added dropwise to a THF (2ml) solution of compound 79(0.082mmol) at 0 ℃ for 8h, the reaction was checked by TLC, the reaction was completed, a saturated ammonium chloride solution (1ml) was quenched, methanol was removed under reduced pressure, extracted with ethyl acetate (5ml × 3), washed with a saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to give a white solid compound (49.9-54.6%).
To a solution of the above compound (0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected for completion of the reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give compound 38 (61-65%) as a white solid.
1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.81-3.76(m，5H)，3.55-3.72(m，4H)，3.45(s，1H)，2.24-2.29(m，2H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，8H)，1.27(s，3H)，1.25(s，3H)ppm.
EXAMPLE 52 Compound 39
Under the protection of argon, DIPEA (0.5ml, 0.54mmol), toluene of compound a and DCE (1: 1) (5ml) solution were slowly added dropwise to the toluene and DCE (1: 1) (5ml) solution of compound (0.11mmol) at 0 ℃, the temperature was raised to 50 ℃, the reaction was 12h, the TLC detection reaction was complete, cooled, quenched with saturated ammonium chloride (3ml), concentrated, added with 20ml ethyl acetate, 5ml water, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 2: 1) to obtain the compound (21-24%) as a white solid.
To a solution of the above compound (0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected for completion of the reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give compound 39 (61-65%) as a white solid.
Under the protection of argon, a THF solution of TBAF (0.180mmol) was added dropwise to a THF (2ml) solution of the compound (0.082mmol) at 0 ℃ for 8h, the reaction was checked by TLC, a saturated ammonium chloride solution (1ml) was quenched, methanol was removed under reduced pressure, extracted with ethyl acetate (5ml × 3), washed with a saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give the compound as a white solid (49.9-54.6%).
1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.81-3.76(m，5H)，3.55-3.72(m，4H)，3.45(s，1H)，2.24-2.29(m，2H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，8H)，1.36(s，9H)，1.27(s，3H)，1.25(s，3H)ppm.
EXAMPLE 53 Compound 40
The compound (0.11mmol), the compound (0.132mmol), DCC, DMAP were sequentially added to a reaction flask, 5mL of toluene was added under argon protection, the reaction was stirred at 85 ℃ for 5 hours and then monitored by HPLC for completion of the reaction, toluene was removed under reduced pressure, 5mL of ethyl acetate and 5mL of water were added, the mixture was stirred for 20min, insoluble matter was removed by filtration, extracted with ethyl acetate (5mL × 2), washed with a saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain the compound (60-64%).
To a solution of the above compound (0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected for completion of the reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give the compound as a white solid (61-67%).
Under the protection of argon, a solution of LiHMDS (0.5ml, 0.54mmol) in DMF (10ml) is slowly added dropwise to a solution of compound 59(100mg, 0.11mmol) in DMF (10ml), after stirring for 1h, alkane chloride (3ml) is added, after 12h reaction, the temperature is naturally raised to 0 ℃, the temperature is raised to 5h, after 4h reaction at 0 ℃, the temperature is lowered to-78 ℃, the solution is quenched with saturated ammonium chloride solution (3ml), DMF and MeCl are removed under reduced pressure, 20ml ethyl acetate and 5ml water are added, extraction is carried out with ethyl acetate (10ml multiplied by 2), washing is carried out with saturated sodium chloride solution (5ml), drying is carried out with anhydrous sodium sulfate, concentration is carried out, and column chromatography (PE: EA equals to 2: 1) is carried out to obtain a white solid compound 40 (54%).
1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43-5.47(m，5H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.80(d，J＝7.5Hz，1H)，3.45(s，1H)，3.32(s，3H)，3.28(s，3H)，2.24-2.29(m，2H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，8H)，1.36(s，9H)，1.27(s，3H)，1.25(s，3H)ppm.
EXAMPLE 54 Compound 41
The compound (0.11mmol), the compound (0.132mmol), DCC, DMAP were sequentially added to a reaction flask, 5mL of toluene was added under argon protection, the reaction was stirred at 85 ℃ for 5 hours and then monitored by HPLC for completion of the reaction, toluene was removed under reduced pressure, 5mL of ethyl acetate and 5mL of water were added, the mixture was stirred for 20min, insoluble matter was removed by filtration, extracted with ethyl acetate (5mL × 2), washed with a saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain the compound (60-64%).
To a solution of the above compound (0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected for completion of the reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give the compound as a white solid (61-67%).
Under the protection of argon, a solution of LiHMDS (0.5ml, 0.54mmol) in DMF (10ml) is slowly added dropwise to a solution of compound 59(100mg, 0.11mmol) in DMF (10ml), after stirring for 1h, alkane chloride (3ml) is added, after 12h reaction, the temperature is naturally raised to 0 ℃, the temperature is raised to 5h, after 4h reaction at 0 ℃, the temperature is lowered to-78 ℃, the solution is quenched with saturated ammonium chloride solution (3ml), DMF and MeCl are removed under reduced pressure, 20ml ethyl acetate and 5ml water are added, extraction is carried out with ethyl acetate (10ml multiplied by 2), washing is carried out with saturated sodium chloride solution (5ml), drying is carried out with anhydrous sodium sulfate, concentration is carried out, and column chromatography (PE: EA equals to 2: 1) is carried out to obtain white solid compound 42 (54%).
Under the protection of argon, a THF solution of TBAF (0.180mmol) was added dropwise to a THF (2ml) solution of compound 79(0.082mmol) at 0 ℃ for 8h, the reaction was checked by TLC, saturated ammonium chloride solution (1ml) was quenched, methanol was removed under reduced pressure, extracted with ethyl acetate (5ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give compound 41 (49.9-54.6%) as a white solid.
1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.82-3.84(m，8H)，3.80(d，J＝7.5Hz，1H)，3.45(s，1H)，2.24-2.29(m，2H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，8H)，1.36(s，6H)，1.36(s，9H)，1.27(s，3H)，1.25(s，3H)ppm.
EXAMPLE 55 Compound 42
The compound (0.11mmol), the compound (0.132mmol), DCC, DMAP were sequentially added to a reaction flask, 5mL of toluene was added under argon protection, the reaction was stirred at 85 ℃ for 5 hours and then monitored by HPLC for completion of the reaction, toluene was removed under reduced pressure, 5mL of ethyl acetate and 5mL of water were added, the mixture was stirred for 20min, insoluble matter was removed by filtration, extracted with ethyl acetate (5mL × 2), washed with a saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain the compound (60-64%).
To a solution of the above compound (0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected for completion of the reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give the compound as a white solid (61-67%).
Under the protection of argon, a THF solution of TBAF (0.180mmol) was added dropwise to a THF (2ml) solution of compound 79(0.082mmol) at 0 ℃ for 8h, the reaction was checked by TLC for completion, a saturated ammonium chloride solution (1ml) was quenched, methanol was removed under reduced pressure, extracted with ethyl acetate (5ml × 3), washed with a saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to give compound (49-54%) as a white solid.
Under the protection of argon, a solution of LiHMDS (0.5ml, 0.54mmol) in DMF (10ml) is slowly added dropwise to a solution of compound 59(100mg, 0.11mmol) in DMF (10ml), after stirring for 1h, alkane chloride (3ml) is added, after 12h reaction, the temperature is naturally raised to 0 ℃, the temperature is raised to 5h, after 4h reaction at 0 ℃, the temperature is lowered to-78 ℃, the solution is quenched with saturated ammonium chloride solution (3ml), DMF and MeCl are removed under reduced pressure, 20ml ethyl acetate and 5ml water are added, extraction is carried out with ethyl acetate (10ml multiplied by 2), washing is carried out with saturated sodium chloride solution (5ml), drying is carried out with anhydrous sodium sulfate, concentration is carried out, and column chromatography (PE: EA is 2: 1) is carried out to obtain white solid compound 42 (54%).
1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.81-3.76(m，5H)，3.55-3.72(m，4H)，3.45(s，1H)，3.30(s，3H)，2.36(s，3H)，2.24-2.29(m，2H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，8H)，1.36(s，9H)，1.27(s，3H)，1.25(s，3H)ppm.
EXAMPLE 56 Compound 43
The compound (0.11mmol), the compound (0.132mmol), DCC, DMAP were sequentially added to a reaction flask, 5mL of toluene was added under argon protection, the reaction was stirred at 85 ℃ for 5 hours and then monitored by HPLC for completion of the reaction, toluene was removed under reduced pressure, 5mL of ethyl acetate and 5mL of water were added, the mixture was stirred for 20min, insoluble matter was removed by filtration, extracted with ethyl acetate (5mL × 2), washed with a saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain the compound (60-64%).
To a solution of the above compound (0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected for completion of the reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give the compound as a white solid (61-67%).
Under the protection of argon, a THF solution of TBAF (0.180mmol) was added dropwise to a THF (2ml) solution of compound 79(0.082mmol) at 0 ℃ for 8h, the reaction was checked by TLC for completion, a saturated ammonium chloride solution (1ml) was quenched, methanol was removed under reduced pressure, extracted with ethyl acetate (5ml × 3), washed with a saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to give compound 43 (49-54%) as a white solid.
1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.81-3.76(m，5H)，3.55-3.72(m，4H)，3.81-3.76(m，5H3.47-3.52(m，4H)，3.45(s，1H)，2.24-2.29(m，2H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，4H)，1.36(s，9H)，1.27(s，3H)，1.25(s，3H)，1.10(s，6H)ppm.
EXAMPLE 57 Compound 44
The compound (0.11mmol), the compound (0.132mmol), DCC, DMAP were sequentially added to a reaction flask, 5mL of toluene was added under argon protection, the reaction was stirred at 85 ℃ for 5 hours and then monitored by HPLC for completion of the reaction, toluene was removed under reduced pressure, 5mL of ethyl acetate and 5mL of water were added, the mixture was stirred for 20min, insoluble matter was removed by filtration, extracted with ethyl acetate (5mL × 2), washed with a saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain the compound (60-64%).
To a solution of the above compound (0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected for completion of the reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give the compound as a white solid (61-67%).
Under the protection of argon, a THF solution of TBAF (0.180mmol) was added dropwise to a THF (2ml) solution of compound 79(0.082mmol) at 0 ℃ for 8h, the reaction was checked by TLC for completion, a saturated ammonium chloride solution (1ml) was quenched, methanol was removed under reduced pressure, extracted with ethyl acetate (5ml × 3), washed with a saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to give compound (49-54%) as a white solid.
Under argon protection, a solution of LiHMDS (0.5ml, 0.54mmol) in DMF (10ml) was slowly added dropwise to a solution of compound 59(100mg, 0.11mmol) in DMF (10ml), after stirring for 1 hour, MeCl (3ml) was added, after 12 hours of reaction, the temperature was naturally raised to 0 ℃ and the temperature was raised to 5 hours, and the reaction was further carried out at 0 ℃ for 4 hours, and the temperature was lowered to-78 ℃, and the mixture was quenched with a saturated ammonium chloride solution (3ml), DMF and MeI were removed under reduced pressure, 20ml of ethyl acetate and 5ml of water were added, and the mixture was extracted with ethyl acetate (10 ml. times.2), washed with a saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA: 2: 1) to obtain a white solid compound 60(56.1ml, 54%).
1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，3H)，5.43-5.47(m，5H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.80(d，J＝7.5Hz，1H)，3.45(s，1H)，3.30(s，3H)，2.36(s，3H)，2.24-2.29(m，3H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，8H)，1.27(s，3H)，1.25(s，3H)ppm.
EXAMPLE 58 Compound 45
The compound (0.11mmol), the compound (0.132mmol), DCC, DMAP were sequentially added to a reaction flask, 5mL of toluene was added under argon protection, the reaction was stirred at 85 ℃ for 5 hours and then monitored by HPLC for completion of the reaction, toluene was removed under reduced pressure, 5mL of ethyl acetate and 5mL of water were added, the mixture was stirred for 20min, insoluble matter was removed by filtration, extracted with ethyl acetate (5mL × 2), washed with a saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain the compound (60-64%).
Under the protection of argon, a THF solution of TBAF (0.180mmol) was added dropwise to a THF (2ml) solution of compound 79(0.082mmol) at 0 ℃ for 8h, the reaction was checked by TLC for completion, a saturated ammonium chloride solution (1ml) was quenched, methanol was removed under reduced pressure, extracted with ethyl acetate (5ml × 3), washed with a saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to give compound (49-54%) as a white solid.
To a solution of the above compound (0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected for completion of the reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give the compound as a white solid (61-67%).1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，3H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.82-3.84(m，8H)，3.80(d，J＝7.5Hz，1H)，3.45(s，1H)，2.24-2.29(m，3H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，8H)，1.36(s，6H)，1.27(s，3H)，1.25(s，3H)ppm.
EXAMPLE 59 Compound 46
Under the protection of argon, DIPEA (0.5ml, 0.54mmol), toluene of compound a and DCE (1: 1) (5ml) solution were slowly added dropwise to the toluene and DCE (1: 1) (5ml) solution of compound (0.11mmol) at 0 ℃, the temperature was raised to 50 ℃, the reaction was 12h, the TLC detection reaction was complete, cooled, quenched with saturated ammonium chloride (3ml), concentrated, added with 20ml ethyl acetate, 5ml water, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 2: 1) to obtain the compound (21-24%) as a white solid.
To a solution of the above compound (0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected for completion of the reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give compound 46 (61-65%) as a white solid.
1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，3H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.81-3.76(m，5H)，3.55-3.72(m，4H)，3.45(s，1H)，3.32(s，3H)，3.28(s，3H)，2.24-2.29(m，2H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，2H)，1.76(s，3H)，1.59-1.71(m，8H)，1.27(s，3H)，1.25(s，3H)ppm.
EXAMPLE 60 Compound 47
Under the protection of argon, DIPEA (0.5ml, 0.54mmol), toluene of compound a and DCE (1: 1) (5ml) solution were slowly added dropwise to the toluene and DCE (1: 1) (5ml) solution of compound (0.11mmol) at 0 ℃, the temperature was raised to 50 ℃, the reaction was 12h, the TLC detection reaction was complete, cooled, quenched with saturated ammonium chloride (3ml), concentrated, added with 20ml ethyl acetate, 5ml water, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 2: 1) to obtain the compound (21-24%) as a white solid.
To a solution of the above compound (0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected for completion of the reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give compound 47 (61-65%) as a white solid.
1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，3H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.81-3.76(m，5H)，3.55-3.72(m，4H)，3.47-3.52(m，4H)，3.45(s，1H)，2.24-2.29(m，3H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，8H)，1.27(s，3H)，1.25(s，3H)ppm.
EXAMPLE 61 Compound 48
TrocCl (2.49ml, 18.18mmol) was added dropwise to a pyridine (54ml) solution of the compound (5.51mmol) at 0 ℃ under an argon atmosphere, the reaction was carried out at room temperature for 1 hour, the completion of the reaction was detected by TLC, pyridine was removed under reduced pressure, 80ml of ethyl acetate and 50ml of water were added, extraction was carried out with ethyl acetate (50ml × 2), washing was carried out with saturated sodium chloride (50ml), drying was carried out over anhydrous sodium sulfate, concentration was carried out, and column chromatography (PE: EA ═ 3: 1) was carried out to obtain a white solid compound (79-83%).
The compound (3.36mmol), the compound, DCC, and DMAP were sequentially added to a reaction flask, 68mL of toluene was added under the protection of argon, the reaction was stirred at 85 ℃ for 2 hours and then monitored by HPLC for completion of the reaction, toluene was removed under reduced pressure, 80mL of ethyl acetate and 50mL of water were added, the mixture was stirred for 20min, insoluble matter was removed by filtration, extracted with ethyl acetate (50mL × 2), washed with saturated sodium chloride (50mL), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain the compound (92%).
To a solution of the compound (3.09mmol) in methanol (120ml) were added zinc powder (92.87mmol) and acetic acid in this order, reacted at 30 ℃ for 5 hours, followed by detection of completion of the reaction by TLC, the zinc powder was removed by filtration, the methanol and acetic acid were removed under reduced pressure, 100ml of ethyl acetate and 50ml of water were added, extracted with ethyl acetate (50ml × 2), washed with saturated sodium chloride (50ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain a white solid compound (87-93%).
Under the protection of argon, a solution of LiHMDS (0.5ml, 0.54mmol) in DMF (10ml) is slowly added dropwise to a solution of compound 59(100mg, 0.11mmol) in DMF (10ml), MeI (3ml) is added after stirring for 1h, after 12h of reaction, the temperature is naturally raised to 0 ℃, the temperature is raised to 5h, the reaction is further carried out for 4h at 0 ℃, the temperature is lowered to-78 ℃, the solution is quenched with saturated ammonium chloride solution (3ml), DMF and MeI are removed under reduced pressure, 20ml of ethyl acetate and 5ml of water are added, the mixture is extracted with ethyl acetate (10 ml. times.2), the mixture is washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate and concentrated, and the white solid compound 60(56.1ml, 54%) is obtained by column chromatography (PE: EA is 2: 1).
Under the protection of argon, DIPEA (0.5ml, 0.54mmol), toluene of compound a and DCE (1: 1) (5ml) solution were slowly added dropwise to the toluene and DCE (1: 1) (5ml) solution of compound (0.11mmol) at 0 ℃, the temperature was raised to 50 ℃, the reaction was 12h, the TLC detection reaction was complete, cooled, quenched with saturated ammonium chloride (3ml), concentrated, added with 20ml ethyl acetate, 5ml water, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 2: 1) to obtain the compound (21-24%) as a white solid.
To a solution of the above compound (0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected for completion of the reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give the compound as a white solid (61-67%).
Under argon protection, a solution of LiHMDS (0.5ml, 0.54mmol) in DMF (10ml) was slowly added dropwise to a solution of compound 59(100mg, 0.11mmol) in DMF (10ml), after stirring for 1 hour, MeCl (3ml) was added, after 12 hours of reaction, the temperature was naturally raised to 0 ℃ and the temperature was raised to 5 hours, and the reaction was further carried out at 0 ℃ for 4 hours, and the temperature was lowered to-78 ℃, and the mixture was quenched with a saturated ammonium chloride solution (3ml), DMF and MeI were removed under reduced pressure, 20ml of ethyl acetate and 5ml of water were added, and the mixture was extracted with ethyl acetate (10 ml. times.2), washed with a saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA: 2: 1) to obtain a white solid compound 60(56.1ml, 54%).
Under the protection of argon, a THF solution of TBAF (0.180mmol) was added dropwise to a THF (2ml) solution of compound 79(0.082mmol) at 0 ℃ for 8h, the reaction was checked by TLC, the reaction was completed, a saturated ammonium chloride solution (1ml) was quenched, methanol was removed under reduced pressure, extraction was performed with ethyl acetate (5ml × 3), washing was performed with a saturated sodium chloride solution (5ml), drying was performed with anhydrous sodium sulfate, concentration was performed, and column chromatography (PE: EA ═ 3: 1) gave compound 48 (49.9-54.6%) as a white solid.
1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.81-3.76(m，9H)，3.45(s，1H)，2.36(s，3H)，2.24-2.29(m，3H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，8H)，1.27(s，3H)，1.25(s，3H)ppm.
EXAMPLE 62 Compound 49
TrocCl (2.49ml, 18.18mmol) was added dropwise to a pyridine (54ml) solution of the compound (5.51mmol) at 0 ℃ under an argon atmosphere, the reaction was carried out at room temperature for 1 hour, the completion of the reaction was detected by TLC, pyridine was removed under reduced pressure, 80ml of ethyl acetate and 50ml of water were added, extraction was carried out with ethyl acetate (50ml × 2), washing was carried out with saturated sodium chloride (50ml), drying was carried out over anhydrous sodium sulfate, concentration was carried out, and column chromatography (PE: EA ═ 3: 1) was carried out to obtain a white solid compound (79-83%).
The compound (3.36mmol), the compound, DCC, and DMAP were sequentially added to a reaction flask, 68mL of toluene was added under argon protection, the reaction was stirred at 85 ℃ for 2 hours, followed by HPLC monitoring for completion of the reaction, toluene was removed under reduced pressure, 80mL of ethyl acetate and 50mL of water were added, the mixture was stirred for 20min, insoluble materials were removed by filtration, extracted with ethyl acetate (50mL × 2), washed with saturated sodium chloride (50mL), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain the compound (92%).
Under the protection of argon, a solution of LiHMDS (0.5ml, 0.54mmol) in DMF (10ml) is slowly added dropwise to a solution of compound 59(100mg, 0.11mmol) in DMF (10ml), MeI (3ml) is added after stirring for 1h, after 12h of reaction, the temperature is naturally raised to 0 ℃, the temperature is raised to 5h, the reaction is further carried out for 4h at 0 ℃, the temperature is lowered to-78 ℃, the solution is quenched with saturated ammonium chloride solution (3ml), DMF and MeI are removed under reduced pressure, 20ml of ethyl acetate and 5ml of water are added, the mixture is extracted with ethyl acetate (10 ml. times.2), the mixture is washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate and concentrated, and the white solid compound 60(56.1ml, 54%) is obtained by column chromatography (PE: EA is 2: 1).
Under the protection of argon, DIPEA (0.5ml, 0.54mmol), toluene of compound a and DCE (1: 1) (5ml) solution were slowly added dropwise to the toluene and DCE (1: 1) (5ml) solution of compound (0.11mmol) at 0 ℃, the temperature was raised to 50 ℃, the reaction was 12h, the TLC detection reaction was complete, cooled, quenched with saturated ammonium chloride (3ml), concentrated, added with 20ml ethyl acetate, 5ml water, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 2: 1) to obtain the compound (21-24%) as a white solid.
To a solution of the above compound (0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected for completion of the reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give the compound as a white solid (61-67%).
Under argon protection, a solution of LiHMDS (0.5ml, 0.54mmol) in DMF (10ml) was slowly added dropwise to a solution of compound 59(100mg, 0.11mmol) in DMF (10ml), after stirring for 1 hour, MeCl (3ml) was added, after 12 hours of reaction, the temperature was naturally raised to 0 ℃ and the temperature was raised to 5 hours, and the reaction was further carried out at 0 ℃ for 4 hours, and the temperature was lowered to-78 ℃, and the mixture was quenched with a saturated ammonium chloride solution (3ml), DMF and MeI were removed under reduced pressure, 20ml of ethyl acetate and 5ml of water were added, and the mixture was extracted with ethyl acetate (10 ml. times.2), washed with a saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA: 2: 1) to obtain a white solid compound 60(56.1ml, 54%).
Under the protection of argon, a THF solution of TBAF (0.180mmol) was added dropwise to a THF (2ml) solution of compound 79(0.082mmol) at 0 ℃ for 8h, the reaction was checked by TLC, saturated ammonium chloride solution (1ml) was quenched, methanol was removed under reduced pressure, extracted with ethyl acetate (5ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give compound 49 (49.9-54.6%) as a white solid.
1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.81-3.76(m，9H)，3.45(s，1H)，2.36(s，3H)，2.24-2.29(m，3H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，8H)，1.27(s，3H)，1.25(s，3H)ppm.
EXAMPLE 63 Compound 50
TrocCl (2.49ml, 18.18mmol) was added dropwise to a pyridine (54ml) solution of the compound (5.51mmol) at 0 ℃ under an argon atmosphere, the reaction was carried out at room temperature for 1 hour, the completion of the reaction was detected by TLC, pyridine was removed under reduced pressure, 80ml of ethyl acetate and 50ml of water were added, extraction was carried out with ethyl acetate (50ml × 2), washing was carried out with saturated sodium chloride (50ml), drying was carried out over anhydrous sodium sulfate, concentration was carried out, and column chromatography (PE: EA ═ 3: 1) was carried out to obtain a white solid compound (79-83%).
The compound (3.36mmol), the compound, DCC, and DMAP were sequentially added to a reaction flask, 68mL of toluene was added under the protection of argon, the reaction was stirred at 85 ℃ for 2 hours and then monitored by HPLC for completion of the reaction, toluene was removed under reduced pressure, 80mL of ethyl acetate and 50mL of water were added, the mixture was stirred for 20min, insoluble matter was removed by filtration, extracted with ethyl acetate (50mL × 2), washed with saturated sodium chloride (50mL), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain the compound (92%).
To a solution of the compound (3.09mmol) in methanol (120ml) were added zinc powder (92.87mmol) and acetic acid in this order, reacted at 30 ℃ for 5 hours and then the reaction was checked by TLC, the zinc powder was removed by filtration, the methanol and acetic acid were removed under reduced pressure, 100ml of ethyl acetate and 50ml of water were added, extracted with ethyl acetate (50ml × 2), washed with saturated sodium chloride (50ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain a white solid compound (90%).
Under the protection of argon, DIPEA (0.5ml, 0.54mmol), toluene of compound a and DCE (1: 1) (5ml) solution were slowly added dropwise to the toluene and DCE (1: 1) (5ml) solution of compound (0.11mmol) at 0 ℃, the temperature was raised to 50 ℃, the reaction was 12h, the TLC detection reaction was complete, cooled, quenched with saturated ammonium chloride (3ml), concentrated, added with 20ml ethyl acetate, 5ml water, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 2: 1) to obtain the compound (21-24%) as a white solid.
To a solution of the above compound (0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected for completion of the reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give the compound as a white solid (61-67%).
Under argon protection, a solution of LiHMDS (0.5ml, 0.54mmol) in DMF (10ml) was slowly added dropwise to a solution of compound 59(100mg, 0.11mmol) in DMF (10ml), after stirring for 1 hour, MeCl (3ml) was added, after 12 hours of reaction, the temperature was naturally raised to 0 ℃ and the temperature was raised to 5 hours, and the reaction was further carried out at 0 ℃ for 4 hours, and the temperature was lowered to-78 ℃, and the mixture was quenched with a saturated ammonium chloride solution (3ml), DMF and MeI were removed under reduced pressure, 20ml of ethyl acetate and 5ml of water were added, and the mixture was extracted with ethyl acetate (10 ml. times.2), washed with a saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA: 2: 1) to obtain a white solid compound 60(56.1ml, 54%).
Under the protection of argon, a THF solution of TBAF (0.180mmol) was added dropwise to a THF (2ml) solution of compound 79(0.082mmol) at 0 ℃ for 8h, the reaction was checked by TLC, and a saturated ammonium chloride solution (1ml) was quenched, methanol was removed under reduced pressure, extracted with ethyl acetate (5ml × 3), washed with a saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to give compound 50 (49.9-54.6%) as a white solid.
1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.81-3.76(m，9H)，3.55-3.72(m，9H)，3.45(s，1H)，2.36(s，3H)，2.24-2.29(m，2H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，4H)，1.27(s，3H)，1.25(s，3H)ppm.
EXAMPLE 64 Compound 51
Under the protection of argon, DIPEA (0.5ml, 0.54mmol), toluene of compound a and DCE (1: 1) (5ml) solution were slowly added dropwise to the toluene and DCE (1: 1) (5ml) solution of compound (0.11mmol) at 0 ℃, the temperature was raised to 50 ℃, the reaction was 12h, the TLC detection reaction was complete, cooled, quenched with saturated ammonium chloride (3ml), concentrated, added with 20ml ethyl acetate, 5ml water, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 2: 1) to obtain the compound (21-24%) as a white solid.
Under the protection of argon, DIPEA (0.5ml, 0.54mmol), toluene of compound b and DCE (1: 1) (5ml) solution were slowly added dropwise to the above compound (0.11mmol) in toluene and DCE (1: 1) (5ml) solution at 0 ℃, the temperature was raised to 50 ℃, the reaction was 12h, the TLC detection reaction was complete, cooled, quenched with saturated ammonium chloride (3ml), concentrated, added with 20ml ethyl acetate, 5ml water, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatography (PE: EA ═ 2: 1) gave compound (21-25%) as a white solid.
To a solution of the above compound (0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC detected for completion of the reaction, saturated sodium bicarbonate solution (2ml) quenched, methanol removed under reduced pressure, extracted with ethyl acetate (10ml × 3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 3: 1) to give the compound as a white solid (61-65%).
Under the protection of argon, a THF solution of TBAF (0.180mmol) was added dropwise to a THF (2ml) solution of compound 79(0.082mmol) at 0 ℃ for 8h, the reaction was checked by TLC, the reaction was completed, a saturated ammonium chloride solution (1ml) was quenched, methanol was removed under reduced pressure, extraction was performed with ethyl acetate (5ml × 3), washing was performed with a saturated sodium chloride solution (5ml), drying was performed with anhydrous sodium sulfate, concentration was performed, and column chromatography (PE: EA ═ 3: 1) gave compound 51 (49.9-54.6%) as a white solid.
1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43-5.47(m，5H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.81-3.76(m，5H)，3.45(s，1H)，3.32(s，3H)，3.28(s，3H)，2.24-2.29(m，2H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，4H)，1.36(s，9H)，1.27(s，3H)，1.25(s，3H)ppm.
EXAMPLE 65 Compound 52
TrocCl (2.49ml, 18.18mmol) was added dropwise to a pyridine (54ml) solution of the compound (5.51mmol) at 0 ℃ under an argon atmosphere, the reaction was carried out at room temperature for 1 hour, the completion of the reaction was detected by TLC, pyridine was removed under reduced pressure, 80ml of ethyl acetate and 50ml of water were added, extraction was carried out with ethyl acetate (50ml × 2), washing was carried out with saturated sodium chloride (50ml), drying was carried out over anhydrous sodium sulfate, concentration was carried out, and column chromatography (PE: EA ═ 3: 1) was carried out to obtain a white solid compound (79-83%).
The compound (3.36mmol), the compound, DCC, and DMAP were sequentially added to a reaction flask, 68mL of toluene was added under argon protection, the reaction was stirred at 85 ℃ for 2 hours, followed by HPLC monitoring for completion of the reaction, toluene was removed under reduced pressure, 80mL of ethyl acetate and 50mL of water were added, the mixture was stirred for 20min, insoluble materials were removed by filtration, extracted with ethyl acetate (50mL × 2), washed with saturated sodium chloride (50mL), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain the compound (87-93%).
After zinc powder (92.87mmol) and acetic acid were added to a solution of compound (3.09mmol) in methanol (120ml) in this order, and reacted at 30 ℃ for 5 hours, the reaction was checked by TLC, the zinc powder was removed by filtration, methanol and acetic acid were removed under reduced pressure, 100ml of ethyl acetate and 50ml of water were added, extracted with ethyl acetate (50ml × 2), washed with saturated sodium chloride (50ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain a white solid compound (89-91%).
The compound (3.36mmol), the compound, DCC, and DMAP were sequentially added to a reaction flask, 68mL of toluene was added under argon protection, the reaction was stirred at 85 ℃ for 2 hours, followed by HPLC monitoring for completion of the reaction, toluene was removed under reduced pressure, 80mL of ethyl acetate and 50mL of water were added, the mixture was stirred for 20min, insoluble materials were removed by filtration, extracted with ethyl acetate (50mL × 2), washed with saturated sodium chloride (50mL), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain the compound (87-93%).
Adding p-toluenesulfonic acid (11mg, 0.058mmol) to a solution of compound (0.052mmol) in methanol (1.3ml), stirring at room temperature for 1h, detecting by TLC that the reaction was complete, quenching with saturated sodium bicarbonate solution (2ml), removing methanol under reduced pressure, extracting with ethyl acetate (10 ml. times.3), washing with saturated sodium chloride solution (5ml), drying over anhydrous sodium sulfate, concentrating, and performing column chromatography (PE: EA ═ 3: 1) to obtain a white solid compound
Under the protection of argon, a THF solution of TBAF (0.180mmol) was added dropwise to a THF (2ml) solution of compound 79(0.082mmol) at 0 ℃ for 8h, the reaction was checked by TLC, and a saturated ammonium chloride solution (1ml) was quenched, methanol was removed under reduced pressure, extracted with ethyl acetate (5ml × 3), washed with a saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to obtain compound 52 (49.9-54.6%) as a white solid.
1H NMR(400MHz，CDCl3)∶δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.82-3.84(m，8H)，3.81-3.76(m，5H)，3.45(s，1H)，2.24-2.29(m，2H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，4H)，1.36(s，6H)，1.27(s， 3H)，1.25(s，3H)ppm.
EXAMPLE 66 Compound 53
Under the protection of argon, DIPEA (0.5ml, 0.54mmol), toluene of compound a and DCE (1: 1) (5ml) solution were slowly added dropwise to the toluene and DCE (1: 1) (5ml) solution of compound (0.11mmol) at 0 ℃, the temperature was raised to 50 ℃, the reaction was 12h, the TLC detection reaction was complete, cooled, quenched with saturated ammonium chloride (3ml), concentrated, added with 20ml ethyl acetate, 5ml water, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 2: 1) to obtain the compound (21-24%) as a white solid.
To a solution of the above compound (0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC checked for completion of the reaction, and saturated sodium bicarbonate solution (2ml) was quenched, methanol was removed under reduced pressure, extracted with ethyl acetate (10 ml. times.3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, and concentrated to give the compound as a white solid (61-65%).
Under the protection of argon, a THF solution of TBAF (0.180mmol) was added dropwise to a THF (2ml) solution of compound 79(0.082mmol) at 0 ℃ for 8h, the reaction was checked by TLC for completion, a saturated ammonium chloride solution (1ml) was quenched, methanol was removed under reduced pressure, extracted with ethyl acetate (5ml × 3), washed with a saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to give compound 53 as a white solid (49.9-54.6%).
1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.81-3.76(m，9H)，3.55-3.72(m，4H)，3.45(s，1H)，3.32(s，3H)，3.28(s，3H)，2.24-2.29(m，2H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，4H)，1.27(s，3H)，1.25(s，3H)ppm.
EXAMPLE 67 Compound 54
Under the protection of argon, DIPEA (0.5ml, 0.54mmol), toluene of compound a and DCE (1: 1) (5ml) solution were slowly added dropwise to the toluene and DCE (1: 1) (5ml) solution of compound (0.11mmol) at 0 ℃, the temperature was raised to 50 ℃, the reaction was 12h, the TLC detection reaction was complete, cooled, quenched with saturated ammonium chloride (3ml), concentrated, added with 20ml ethyl acetate, 5ml water, extracted with ethyl acetate (10ml × 2), washed with saturated sodium chloride (5ml), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE: EA ═ 2: 1) to obtain the compound (21-24%) as a white solid.
To a solution of the above compound (0.041mmol) in methanol (1.3ml) was added p-toluenesulfonic acid (7.7mg, 0.045mmol), stirred at room temperature for 1h, TLC checked for completion of the reaction, and saturated sodium bicarbonate solution (2ml) was quenched, methanol was removed under reduced pressure, extracted with ethyl acetate (10 ml. times.3), washed with saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, and concentrated to give the compound as a white solid (61-65%).
Under the protection of argon, a THF solution of TBAF (0.180mmol) was added dropwise to a THF (2ml) solution of compound 79(0.082mmol) at 0 ℃ for 8h, the reaction was checked by TLC for completion, a saturated ammonium chloride solution (1ml) was quenched, methanol was removed under reduced pressure, extracted with ethyl acetate (5ml × 3), washed with a saturated sodium chloride solution (5ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA ═ 3: 1) to give compound 54 (49.9-54.6%) as a white solid.
1H NMR(400MHz，CDCl3)：δ8.08(d，J＝7.5Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.48(t，J＝7.5Hz，2H)，7.39-7.40(m，4H)，7.34-7.31(m，1H)，6.20(t，J＝9Hz，1H)，5.62(d，J＝7.5Hz，1H)，5.43(d，J＝10.0Hz，1H)，5.27(s，1H)，4.96(d，J＝10Hz，1H)，4.80(s，1H)，4.62(s，1H)，4.29(d，J＝8.5Hz，1H)，4.17(d，J＝8.5Hz，1H)，3.85(dd，J＝11.0Hz，J＝6.5Hz，1H)，3.81-3.76(m，9H)，3.55-3.72(m，4H)，3.47-3.52(m，4H)，3.45(s，1H)，2.24-2.29(m，2H)，2.04(s，3H)，1.87(s，3H)，1.79-1.82(m，1H)，1.76(s，3H)，1.59-1.71(m，4H)，1.36(s，9H)，1.27(s，3H)，1.25(s，3H)，1.10(s，6H)ppm.
EXAMPLE 68 test for the Activity of Compounds on cancer cells
1. The experimental principle is as follows: inhibition of cancer cell growth by compounds was measured by the MTT method. The principle of MTT method is that yellow thiazole blue can penetrate cell membrane to enter into cell, succinate dehydrogenase in mitochondria of living cell can reduce exogenous MTT to water-insoluble blue-purple crystalline Formazan (Formazan) and deposit in cell, while dead cell has no function. Dimethyl sulfoxide (DMSO) can dissolve formazan in cells, and its light absorption value is measured at 570nm wavelength by enzyme linked immunosorbent detector, which can indirectly reflect living cell number.
2. Experimental materials: the cell lines used were HT1080 (human fibrosarcoma cell), Huh-7 (human hepatoma cell line), A549 (human lung adenocarcinoma cell line), Hela (human cervical cancer cell), HL60 (human promyelocytic leukemia cell line), A431 (epidermoid carcinoma cell line), MCF-7 (human breast cancer), DU145 (human prostate cancer cell), U937 (lymphoma cell line of human tissue cells), BEL-7402 (hepatocellular carcinoma), SGC-7901 (human gastric cancer cell line), K562 (human leukemia cell line), PANC-1 (human pancreatic cancer cell line), BGC823 (human gastric cancer cell line), Molt-4 (human acute lymphoblastic leukemia cell line); culture was performed with DMEM + 10% FBS medium or 1640+ 10% FBS medium, respectively.
3. Experimental methods and analysis of results:
experimental groups: 190 μ l of cell suspension +10 μ l of different concentrations of drug (final concentration 10-5 ~ 10-10M)
Blank control group: 200 μ l PBS
Negative control group: 190. mu.l of cell suspension + 10. mu.l of 2% DMSO (final DMSO concentration: 0.1%)
Positive control group: 190. mu.l cell suspension + 10. mu.l of different concentrations of the compound
a) Inoculating the cells into a 96-well plate, wherein the inoculation amount is 1500/well and 190 mu l/well, and culturing overnight in a 37 ℃ 5% CO2 incubator;
b) adding 10 mul of different drugs into each hole every day, wherein the final concentration of the drugs is 10 < -5 > to 10 < -10 > M, and three parallel holes are formed; incubating in a 5% CO2 incubator at 37 ℃ for 72 hours;
c) add 20. mu.l of 5mg/ml MTT per well and incubate for 4 hours at 37 ℃ in 5% CO2 incubator;
d) discarding the supernatant, adding 100 μ l DMSO into each well, and oscillating;
e) 570nm readings, cell viability was calculated and GI50 was calculated from the results, as shown in the table below.
TABLE 1
TABLE 2
TABLE 3
TABLE 4
TABLE 5
TABLE 6
TABLE 7
TABLE 8
TABLE 9
GI50 in the above table represents the drug concentration required for 50% growth inhibition of cells.
From the results in the table above, it can be seen that: the effect of the compounds on inhibiting certain cancer cells is equivalent to or more remarkable than that of paclitaxel.
In conclusion, the synthesized taxol derivative has better water solubility than taxol and better anticancer effect. And hydrophobic groups have better anticancer activity.
The above description is only a basic description of the present invention, and any equivalent changes made according to the technical solution of the present invention should fall within the protection scope of the present invention.

Claims (9)

1. A compound represented by the general formula (I) having the following structural formula:
wherein: r1The radical being C1-6Alkyl radical, C3-8Cycloalkyl, - (C ═ O) - (C)1-6Alkyl), -CH2-O-(C1-6Alkyl), or C1-6An alkyl alcohol;
R2the radical being C1-6Alkyl radical, C3-8Cycloalkyl, - (C ═ O) - (C)1-6Alkyl), -CH2-O-(C1-6Alkyl), or C1-6An alkyl alcohol;
R3group H, C1-6Alkyl radical, C3-8Cycloalkyl, - (C ═ O) - (C)1-6Alkyl), -CH2-O-(C1-6Alkyl), or C1-6An alkyl alcohol;
R4the radical is(C1-6Alkyl group), C1-6Alkyl radical, C3-8Cycloalkyl, - (C ═ O) - (C)1-6Alkyl), -CH2-O-(C1-6Alkyl), or C1-6An alkyl alcohol.
2. The compound represented by the general formula (I) according to claim 1, characterized in that:
wherein,
R1the radical being C1-6Alkyl, or C3-8A cycloalkyl group;
R2the radical being C1-6Alkyl radical, C3-16Cycloalkyl, - (C ═ O) - (C)1-8Alkyl), or-CH2-O-(C1-6Alkyl groups);
R3group H, C1-6Alkyl radical, C3-8Cycloalkyl, - (C ═ O) - (C)1-6Alkyl), -CH2-O-(C1-6Alkyl), or C1-6An alkyl alcohol;
R4the radical is(C1-6Alkyl group), C1-6Alkyl radical, C3-8Cycloalkyl, - (C ═ O) - (C)1-6Alkyl), -CH2-O-(C1-6Alkyl), or C1-6An alkyl alcohol.
3. The compound represented by the general formula (I) according to claim 1, characterized in that:
wherein,
R1the radical is- (C ═ O) - (C)1-8Alkyl), -CH2-O-(C1-6Alkyl), or C1-6An alkyl alcohol;
R2the radical being C1-6Alkyl radical, C3-8Cycloalkyl, - (C ═ O) - (C)1-8Alkyl), or-CH2-O-(C1-6Alkyl groups);
R3group H, C1-6Alkyl radical, C3-8Cycloalkyl, - (C ═ O) - (C)1-6Alkyl), -CH2-O-(C1-6Alkyl), or C1-6An alkyl alcohol;
R4the radical is(C1-6Alkyl group), C1-6Alkyl radical, C3-8Cycloalkyl, - (C ═ O) - (C)1-6Alkyl), -CH2-O-(C1-6Alkyl), or C1-6An alkyl alcohol.
4. The compound represented by the general formula (I) according to claim 1, characterized in that: the structural formula is
5. An isomer, racemate, pharmaceutically acceptable salt, crystalline hydrate, solvate or mixture thereof of the compound according to claim 1 to 4.
6. A pharmaceutical composition comprising an effective amount of an isomer, racemate, pharmaceutically acceptable salt, crystalline hydrate, solvate or mixture thereof, selected from the compounds according to any one of claims 1 to 4, and one or more pharmaceutically acceptable carriers.
7. Use of a pharmaceutical composition according to claim 6 for the preparation of a medicament for the prevention or treatment of fibrosarcoma, liver cancer, lung cancer, leukemia, epidermoid carcinoma, breast cancer, prostate cancer, lymphoma, stomach cancer, bone marrow cancer and pancreatic cancer.
8. Use of a compound according to any one of claims 1 to 4 for the manufacture of a medicament for the prophylaxis or treatment of fibrosarcoma, liver cancer, lung cancer, leukemia, epidermoid carcinoma, breast cancer, prostate cancer, lymphoma, stomach cancer, bone marrow cancer and pancreatic cancer.
9. Use of an isomer, racemate, pharmaceutically acceptable salt, crystalline hydrate, solvate or mixture thereof of the compound according to any one of claims 1 to 4 for the preparation of a medicament for the prophylaxis or treatment of fibrosarcoma, liver cancer, lung cancer, leukemia, epidermoid carcinoma, breast cancer, prostate cancer, lymphoma, stomach cancer, bone marrow cancer and pancreatic cancer.
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CN113698369A (en) * 2021-08-31 2021-11-26 无锡紫杉药业有限公司 Method for removing specific single impurity in cabazitaxel
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Application publication date: 20141008