CN104086514A - Paclitaxel derivatives and preparation method thereof - Google Patents

Paclitaxel derivatives and preparation method thereof Download PDF

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Publication number
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
ethyl acetate
alkyl
concentrated
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Inventor
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

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

D51-7059 and preparation method thereof
Technical field
The invention belongs to pharmaceutical chemistry field, relate in particular to a kind of D51-7059 and preparation method thereof.
Background technology
Taxol is as a kind of novel broad-spectrum anti-cancer drug, be used for the treatment of the malignant tumours such as advanced ovarian cancer, mammary cancer, nonsmall-cell lung cancer in have significant curative effect.And its poorly water-soluble, poor selectivity, the large grade of toxic side effect makes its curative effect and safety be subject to great impact.And the SB-T 101144 derivative that we synthesize has overcome these shortcomings to a certain extent, also there is good biological activity.
The structure of taxol:
Malignant tumour is that current serious affects human health, threatens one of principal disease of human life.Cancer together with mishap, forms world today's All Countries three large causes of death with cardiovascular and cerebrovascular diseases.Therefore, the World Health Organization (WHO) and hygiene department of national governments all classify capture cancer as a top priority as.The exploitation of PTS has in recent years had very large progress, and medicine is anticancer also more and more to come into one's own, and taxol has unique antitumour activity and mechanism of action because of it, and becomes the representative of PTS of new generation, is one of at present best cancer therapy drug.But invalid to a little cancers, easily produce multidrug resistance etc.Due to taxol, there are the untoward reactions such as anaphylaxis, poorly water-soluble, neurotoxicity, Cardiovascular Toxicity.Change its formulation and it is carried out to the direction that structural modification becomes more people's researchs, we are the C to Cabazitaxel for its shortcoming 7and C 10modify.
Summary of the invention
For the defect existing in above-mentioned prior art, technical problem to be solved by this invention is to provide a kind of D51-7059 and preparation method thereof, it is limited that described this D51-7059 and preparation method thereof will solve the effect of paclitaxel treatment cancer of the prior art, and the large technical problem of side effect.
The invention provides the compound that a kind of general formula (I) represents, its structural formula is as follows:
Wherein: R 1group is C 1-6alkyl, C 3-8cycloalkyl ,-(C=O)-(C 1-6alkyl) ,-CH 2-O-(C 1-6alkyl) or C 1-6alkyl alcohol;
R 2group is C 1-6alkyl, C 3-8cycloalkyl ,-(C=O)-(C 1-6alkyl) ,-CH 2-O-(C 1-6alkyl) or C 1-6alkyl alcohol;
R 3group is H, C 1-6alkyl, C 3-8cycloalkyl ,-(C=O)-(C 1-6alkyl) ,-CH 2-O-(C 1-6alkyl) or C 1-6alkyl alcohol;
R 4group is (C 1-6alkyl), C 1-6alkyl, C 3-8cycloalkyl ,-(C=O)-(C 1-6alkyl) ,-CH 2-O-(C 1-6alkyl) or C 1-6alkyl alcohol.
Further, wherein,
R 1group is C 1-6alkyl or C 3-8cycloalkyl;
R 2group is C 1-6alkyl, C 3-16cycloalkyl ,-(C=O)-(C 1-8alkyl) or-CH 2-O-(C 1-6alkyl);
R 3group is H, C 1-6alkyl, C 3-8cycloalkyl ,-(C=O)-(C 1-6alkyl) ,-CH 2-O-(C 1-6alkyl) or C 1-6alkyl alcohol;
R 4group is (C 1-6alkyl), C 1-6alkyl, C 3-8cycloalkyl ,-(C=O)-(C 1-6alkyl) ,-CH 2-O-(C 1-6alkyl) or C 1-6alkyl alcohol.
Further,
Wherein,
R 1group is-(C=O)-(C 1-8alkyl) ,-CH 2-O-(C 1-6alkyl) or C 1-6alkyl alcohol;
R 2group is C 1-6alkyl, C 3-8cycloalkyl ,-(C=O)-(C 1-8alkyl) or-CH 2-O-(C 1-6alkyl);
R 3group is H, C 1-6alkyl, C 3-8cycloalkyl ,-(C=O)-(C 1-6alkyl) ,-CH 2-O-(C 1-6alkyl) or C 1-6alkyl alcohol;
R 4group is (C 1-6alkyl), C 1-6alkyl, C 3-8cycloalkyl ,-(C=O)-(C 1-6alkyl) ,-CH 2-O-(C 1-6alkyl) or C 1-6alkyl alcohol.
Further, its structural formula is
The present invention also provides isomer, racemic modification, pharmacy acceptable salt, crystalline hydrate, solvate or their mixture of above-mentioned compound.
The present invention also provides a kind of pharmaceutical composition, the isomer of the above-claimed cpd that it comprises significant quantity, racemic modification, pharmacy acceptable salt, crystalline hydrate, solvate or their mixture, and contain one or more pharmaceutically acceptable carriers.
The present invention also provides above-mentioned a kind of pharmaceutical composition to prevent or treat the purposes in fibrosarcoma, liver cancer, lung cancer, leukemia, epidermoid carcinoma, mammary cancer, prostate cancer, lymphoma, cancer of the stomach, bone marrow cancer and carcinoma of the pancreas medicine in preparation.
The present invention also provides the purposes of above-claimed cpd in preparation prevention or treatment fibrosarcoma, liver cancer, lung cancer, leukemia, epidermoid carcinoma, mammary cancer, prostate cancer, lymphoma, cancer of the stomach, bone marrow cancer and carcinoma of the pancreas medicine.
The purposes of isomer, racemic modification, pharmacy acceptable salt, crystalline hydrate, solvate or their mixture that the present invention also provides above-claimed cpd in preparation prevention or treatment and fibrosarcoma, liver cancer, lung cancer, leukemia, epidermoid carcinoma, mammary cancer, prostate cancer, lymphoma, cancer of the stomach, bone marrow cancer and carcinoma of the pancreas medicine.
Hydrophobic group in compound of the present invention has better antitumour activity, can contribute to through hemato encephalic barrier.The synthetic compound of simultaneously the present invention is good compared with taxol aspect water-soluble, and also effective compared with taxol at some anticancer effect.
Embodiment
Synthesizing of embodiment 1 compound 56
Under argon shield; at 0 ℃ to compound 55 (3g; in pyridine 5.51mmol) (54ml) solution, drip TrocCl (2.49ml; 18.18mmol); room temperature reaction 1h; TLC detection reaction is complete; pyridine is removed in decompression, adds 80ml ethyl acetate, 50ml water; by ethyl acetate (50ml * 2), extract; with saturated sodium-chloride (50ml) washing, anhydrous sodium sulfate drying, concentrated; column chromatography (PE: EA=3: 1) obtain white solid compound 56 (3.96g, 81%).
Synthesizing of embodiment 2 compounds 58
By compound 56 (3g; 3.36mmol), compound 57 (3.24g), DCC, DMAP add in reaction flask successively; under argon shield, add 68mL toluene; after 85 ℃ of stirring reaction 2h, HPLC monitoring reacts completely; toluene is removed in decompression; add 80ml ethyl acetate; 50ml water, stirs 20min, removes by filter insolubles; by ethyl acetate (50ml * 2), extract; with saturated sodium-chloride (50ml) washing, anhydrous sodium sulfate drying, concentrated; column chromatography (PE: EA=3: 1) obtain compound 58 (3.70g, 92%).
Synthesizing of embodiment 3 compounds 59
To compound 58 (3.7g, in methyl alcohol 3.09mmol) (120ml) solution, add successively zinc powder (6.75g, 92.87mmol) and acetic acid, after 30 ℃ of reaction 5h, TLC detection reaction is complete, remove by filter zinc powder, methyl alcohol and acetic acid are removed in decompression, add 100ml ethyl acetate, 50ml water, with ethyl acetate (50ml * 2) extraction, with saturated sodium-chloride (50ml) washing, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 59 (2.53g, 90%).
Synthesizing of embodiment 4 compounds 60
Under argon shield, at-78 ℃, to compound 59 (100mg, in DMF 0.11mmol) (10ml) solution, slowly drip LiHMDS (0.5ml, DMF 0.54mmol) (2ml) solution, after stirring 1h, add MeI (3ml), after reaction 12h, naturally be warmed up to 0 ℃, intensification needs 5h, at 0 ℃, react again 4h, cool to-78 ℃, with saturated ammonium chloride solution (3ml) cancellation, DMF and MeI are removed in decompression, add 20ml ethyl acetate, 5ml water, by ethyl acetate (10ml * 2), extract, with saturated nacl aqueous solution (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound 60 (56.1ml, 54%).
Synthesizing of embodiment 5 compounds 61
To compound 60 (50mg, in methyl alcohol 0.052mmol) (1.3ml) solution, add tosic acid (11mg, 0.058mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, by ethyl acetate (10ml * 3), extract, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 61 (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.
Compound 61 synthetic routes:
Synthesizing of embodiment 6 compounds 63
Under argon shield, at 0 ℃, to compound 59 (100mg, toluene 0.11mmol) and DCE (1: 1) (5ml) slowly drip DIPEA (0.5ml in solution, 0.54mmol), the toluene of compound 62 and DCE (1: 1) be solution (5ml), be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete, cooling, with saturated ammonium chloride (3ml) cancellation, concentrated, add 20ml ethyl acetate, 5ml water, by ethyl acetate (10ml * 2), extract, with saturated sodium-chloride (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound 63 (31.0ml, 23%).
Synthesizing of embodiment 7 compounds 64
Under argon shield; at 0 ℃; to compound 63 (100mg; in THF 0.082mmol) (2ml) solution, drip TBAF (38.9mg; THF solution 0.180mmol); reaction 8h; TLC detection reaction is complete, saturated ammonium chloride solution (1ml) cancellation, and methyl alcohol is removed in decompression; by ethyl acetate (5ml * 3), extract; with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying, concentrated; column chromatography (PE: EA=3: 1) obtain white solid compound 64 (40.4mg, 50%).
Synthesizing of embodiment 8 compounds 1
To compound 64 (40.4mg, in methyl alcohol 0.041mmol) (1.3ml) solution, add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, by ethyl acetate (10ml * 3), extract, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 1 (23.6mg, 65%). 1H?NMR(400MHz，CDCl 3)：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.
The synthetic route of compound 1
Synthesizing of embodiment 9 compounds 65
Under argon shield; at 0 ℃; in DCM (5ml) solution of compound 59 (100mg, 0.11mmol), slowly drip DIPEA (0.5ml, 0.54mmol), MOMCl (0.041ml; 0.54mmol); be warming up to room temperature reaction 12h, TLC detection reaction is complete, cooling; with saturated ammonium chloride (3ml) cancellation; concentrated, add 5ml ethyl acetate, 5ml water; by ethyl acetate (5ml * 2), extract; with saturated sodium-chloride (5ml) washing, anhydrous sodium sulfate drying, concentrated; column chromatography (PE: EA=2: 1) obtain white solid compound 65 (89.9mg, 72%).
Synthesizing of embodiment 10 compounds 2
To compound 65 (89.9mg, in methyl alcohol 0.090mmol) (3ml) solution, add tosic acid (17.0mg, 0.099mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate (2ml) cancellation, methyl alcohol is removed in decompression, by ethyl acetate (10ml * 3), extract, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 2 (23.6mg, 65%).
1H?NMR(400MHz，CDCl 3)：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.
Synthesizing of compound 2
Synthesizing of embodiment 11 compounds 67
By compound 59 (100mg; 0.11mmol), compound 66 (47.8mg; 0.132mmol), DCC, DMAP add in reaction flask successively; under argon shield, add 5mL toluene; after 85 ℃ of stirring reaction 5h, HPLC monitoring reacts completely; toluene is removed in decompression, adds 5ml ethyl acetate, 5ml water; stir 20min; remove by filter insolubles, with ethyl acetate (5ml * 2) extraction, with saturated nacl aqueous solution (5ml) washing; anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain compound 67 (110.72mg, 63%).
Synthesizing of embodiment 12 compounds 68
Under argon shield; at 0 ℃; to compound 67 (100mg; in THF 0.063mmol) (2ml) solution, drip TBAF (69.2mg; THF solution 0.265mmol); reaction 8h; TLC detection reaction is complete, saturated ammonium chloride (1ml) cancellation, and methyl alcohol is removed in decompression; by ethyl acetate (5ml * 3), extract; with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying, concentrated; column chromatography (PE: EA=3: 1) obtain white solid compound 68 (41.7mg, 58%).
Synthesizing of embodiment 13 compounds 3
To compound 68 (41.7mg, in methyl alcohol 0.037mmol) (2ml) solution, add tosic acid (7.0mg, 0.041mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, by ethyl acetate (5ml * 3), extract, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 3 (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.
Synthesizing of compound 3
Synthetic the synthesizing with compound 63 of embodiment 14 compounds 70.
Synthetic the synthesizing with compound 1, compound 2 and compound 3 of embodiment 15 compounds 4.
Synthesizing of compound 4
Synthetic the synthesizing with compound 63 of embodiment 16 compounds 72.
Synthetic the synthesizing with compound 1, compound 2 and compound 3 of embodiment 17 compounds 5.
Synthesizing of compound 5
Embodiment 18
Compound 6
Under argon shield, at 0 ℃, to compound 59 (100mg, toluene 0.11mmol) and DCE (1: 1) (5ml) slowly drip DIPEA (0.5ml in solution, 0.54mmol), the toluene of compound a and DCE (1: 1) be solution (5ml), be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete, cooling, with saturated ammonium chloride (3ml) cancellation, concentrated, add 20ml ethyl acetate, 5ml water, by ethyl acetate (10ml * 2), extract, with saturated sodium-chloride (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound 72 (28.2mg, 24%).
Synthesizing of embodiment 19 compounds 73
Under argon shield; at 0 ℃; to compound 72 (100mg; in THF 0.094mmol) (2ml) solution, drip TBAF (38.9mg; THF solution 0.180mmol); reaction 8h; TLC detection reaction is complete; saturated ammonium chloride solution (1ml) cancellation, methyl alcohol is removed in decompression, with ethyl acetate (5ml * 3) extraction; with saturated nacl aqueous solution (5ml), wash; anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: the productive rate that 1) obtains white solid compound is 51%.
To by compound (40.4mg above, in methyl alcohol 0.041mmol) (1.3ml) solution, add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, by ethyl acetate (10ml * 3), extract, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 6 (23.7mg, 65.3%).Compound 6: 1h NMR (400MHz, CDCl 3): δ 8.08 (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.
Embodiment 20 compounds 7
Under argon shield, at 0 ℃, to compound 59 (100mg, toluene 0.11mmol) and DCE (1: 1) (5ml) slowly drip DIPEA (0.5ml in solution, 0.54mmol), the toluene of compound a and DCE (1: 1) be solution (5ml), be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete, cooling, with saturated ammonium chloride (3ml) cancellation, concentrated, add 20ml ethyl acetate, 5ml water, by ethyl acetate (10ml * 2), extract, with saturated sodium-chloride (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound 63 (31.0ml, 23%).
By compound 59 (100mg; 0.11mmol), compound 66 (47.8mg; 0.132mmol), DCC, DMAP add in reaction flask successively; under argon shield, add 5mL toluene; after 85 ℃ of stirring reaction 5h, HPLC monitoring reacts completely; toluene is removed in decompression, adds 5ml ethyl acetate, 5ml water; stir 20min; remove by filter insolubles, with ethyl acetate (5ml * 2) extraction, with saturated nacl aqueous solution (5ml) washing; anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain compound 67 (110.72mg, 63%).
Under argon shield; at 0 ℃; in THF (2ml) solution of compound 75 (0.082mmol), drip TBAF (38.9mg; THF solution 0.180mmol); reaction 8h; TLC detection reaction is complete; saturated ammonium chloride solution (1ml) cancellation; methyl alcohol is removed in decompression; with ethyl acetate (5ml * 3) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 76 (50.3%).
To compound 76 (40.4mg, in methyl alcohol 0.041mmol) (1.3ml) solution, add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, by ethyl acetate (10ml * 3), extract, with saturated nacl aqueous solution (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 7 (66%).
1H?NMR(400MHz，CDCl 3)：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.
Embodiment 21 compounds 8
Under argon shield, at 0 ℃, to compound 59 (100mg, toluene 0.11mmol) and DCE (1: 1) (5ml) slowly drip DIPEA (0.5ml in solution, 0.54mmol), the toluene of compound a and DCE (1: 1) be solution (5ml), be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete, cooling, with saturated ammonium chloride (3ml) cancellation, concentrated, add 20ml ethyl acetate, 5ml water, by ethyl acetate (10ml * 2), extract, with saturated sodium-chloride (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound 72 (23%).
Under argon shield, at 0 ℃, toluene and DCE (1: 1) to compound 72 (0.11mmol) (5ml) slowly drip DIPEA (0.5ml in solution, 0.54mmol), the toluene of compound b and DCE (1: 1) be solution (5ml), be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete, cooling, with saturated ammonium chloride (3ml) cancellation, concentrated, add 20ml ethyl acetate, 5ml water, by ethyl acetate (10ml * 2), extract, with saturated sodium-chloride (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound 77 (23%).
Under argon shield; at 0 ℃; in THF (2ml) solution of compound 77 (0.082mmol), drip TBAF (38.9mg; THF solution 0.180mmol); reaction 8h; TLC detection reaction is complete; saturated ammonium chloride solution (1ml) cancellation; methyl alcohol is removed in decompression; with ethyl acetate (5ml * 3) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 78 (50.3%).
In methyl alcohol (1.3ml) solution of compound 78 (0.041mmol), add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, with ethyl acetate (10ml * 3) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 8 (63%). 1H?NMR(400MHz，CDCl 3)：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.
Embodiment 22 compounds 9
Under argon shield, at 0 ℃, to compound 59 (100mg, toluene 0.11mmol) and DCE (1: 1) (5ml) slowly drip DIPEA (0.5ml in solution, 0.54mmol), the toluene of compound a and DCE (1: 1) be solution (5ml), be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete, cooling, with saturated ammonium chloride (3ml) cancellation, concentrated, add 20ml ethyl acetate, 5ml water, by ethyl acetate (10ml * 2), extract, with saturated sodium-chloride (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound 72 (23%).
Under argon shield, at 0 ℃, toluene and DCE (1: 1) to compound 72 (0.11mmol) (5ml) slowly drip DIPEA (0.5ml in solution, 0.54mmol), the toluene of compound b and DCE (1: 1) be solution (5ml), be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete, cooling, with saturated ammonium chloride (3ml) cancellation, concentrated, add 20ml ethyl acetate, 5ml water, by ethyl acetate (10ml * 2), extract, with saturated sodium-chloride (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound 79 (23%).
Under argon shield; at 0 ℃; in THF (2ml) solution of compound 79 (0.082mmol), drip TBAF (38.9mg; THF solution 0.180mmol); reaction 8h; TLC detection reaction is complete; saturated ammonium chloride solution (1ml) cancellation; methyl alcohol is removed in decompression; with ethyl acetate (5ml * 3) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 80 (50.3%).
In methyl alcohol (1.3ml) solution of compound 80 (0.041mmol), add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, with ethyl acetate (10ml * 3) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 9 (63%). 1H?NMR(400MHz，CDCl 3)：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.
Embodiment 23 compounds 10
Under argon shield, at 0 ℃, to compound 59 (100mg, toluene 0.11mmol) and DCE (1: 1) (5ml) slowly drip DIPEA (0.5ml in solution, 0.54mmol), the toluene of compound a and DCE (1: 1) be solution (5ml), be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete, cooling, with saturated ammonium chloride (3ml) cancellation, concentrated, add 20ml ethyl acetate, 5ml water, by ethyl acetate (10ml * 2), extract, with saturated sodium-chloride (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound (23%).
To compound (100mg above; 0.11mmol), compound (0.132mmol), DCC, DMAP add in reaction flask successively; under argon shield, add 5mL toluene; after 85 ℃ of stirring reaction 5h, HPLC monitoring reacts completely; toluene is removed in decompression; add 5ml ethyl acetate; 5ml water; stir 20min, remove by filter insolubles, with ethyl acetate (5ml * 2) extraction; with saturated nacl aqueous solution (5ml), wash; anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain compound (61%).
Under argon shield; at 0 ℃; to the THF solution that drips TBAF (0.180mmol) in THF (2ml) solution of compound 79 (0.082mmol); reaction 8h; TLC detection reaction is complete; saturated ammonium chloride solution (1ml) cancellation; methyl alcohol is removed in decompression; by ethyl acetate (5ml * 3), extract; with saturated nacl aqueous solution (5ml), wash; anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (50.3%).
In methyl alcohol (1.3ml) solution of compound upward (0.041mmol), add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, with ethyl acetate (10ml * 3) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 10 (62%).
1H?NMR(400MHz，CDCl 3)：：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.
Embodiment 24 compounds 11
Under argon shield; at 0 ℃; toluene and DCE (1: 1) to compound 59 (0.11mmol) (5ml) slowly drip DIPEA (0.5ml in solution; 0.54mmol), (5ml) solution of the toluene of compound a and DCE (1: 1); be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete; cooling; with saturated ammonium chloride (3ml) cancellation, concentrated, add 20ml ethyl acetate; 5ml water; with ethyl acetate (10ml * 2) extraction, with saturated sodium-chloride (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound (23%).
Under argon shield, at 0 ℃, the toluene of compound upward (0.11mmol) and DCE (1: 1) (5ml) slowly drip DIPEA (0.5ml in solution, 0.54mmol), the toluene of compound b and DCE (1: 1) be solution (5ml), be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete, cooling, with saturated ammonium chloride (3ml) cancellation, concentrated, add 20ml ethyl acetate, 5ml water, by ethyl acetate (10ml * 2), extract, with saturated sodium-chloride (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound 79 (23%).
Under argon shield; at 0 ℃; in THF (2ml) solution of compound upward (0.082mmol), drip TBAF (38.9mg; THF solution 0.180mmol); reaction 8h; TLC detection reaction is complete; saturated ammonium chloride solution (1ml) cancellation; methyl alcohol is removed in decompression; with ethyl acetate (5ml * 3) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (50.7%).
In methyl alcohol (1.3ml) solution of compound (0.041mmol), add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, with ethyl acetate (10ml * 3) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 11 (63%). 1H?NMR(400MHz，CDCl 3)：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.
Embodiment 25 compounds 12
Under argon shield; at 0 ℃; toluene and DCE (1: 1) to compound 59 (0.11mmol) (5ml) slowly drip DIPEA (0.5ml in solution; 0.54mmol), (5ml) solution of the toluene of compound a and DCE (1: 1); be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete; cooling; with saturated ammonium chloride (3ml) cancellation, concentrated, add 20ml ethyl acetate; 5ml water; with ethyl acetate (10ml * 2) extraction, with saturated sodium-chloride (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound (23%).
Under argon shield, at 0 ℃, the toluene of compound (0.11mmol) and DCE (1: 1) (5ml) slowly drip DIPEA (0.5ml in solution upward, 0.54mmol), the toluene of compound b and DCE (1: 1) be solution (5ml), be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete, cooling, with saturated ammonium chloride (3ml) cancellation, concentrated, add 20ml ethyl acetate, 5ml water, by ethyl acetate (10ml * 2), extract, with saturated sodium-chloride (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound (23%).
In methyl alcohol (1.3ml) solution of compound upward (0.041mmol), add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, with ethyl acetate (10ml * 3) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 12 (63%). 1H?NMR(400MHz，CDCl 3)：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.
Embodiment 26 compounds 13
Under argon shield; at 0 ℃; toluene and DCE (1: 1) to compound 59 (0.11mmol) (5ml) slowly drip DIPEA (0.5ml in solution; 0.54mmol), (5ml) solution of the toluene of compound a and DCE (1: 1); be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete; cooling; with saturated ammonium chloride (3ml) cancellation, concentrated, add 20ml ethyl acetate; 5ml water; with ethyl acetate (10ml * 2) extraction, with saturated sodium-chloride (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound (23%).
Compound above (0.11mmol), compound (0.132mmol), DCC, DMAP are added in reaction flask successively; under argon shield, add 5mL toluene; after 85 ℃ of stirring reaction 5h, HPLC monitoring reacts completely; toluene is removed in decompression; add 5ml ethyl acetate; 5ml water; stir 20min; remove by filter insolubles; with ethyl acetate (5ml * 2) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain compound (63.3%).
Under argon shield; at 0 ℃; in THF (2ml) solution of compound upward (0.082mmol), drip TBAF (38.9mg; THF solution 0.180mmol); reaction 8h; TLC detection reaction is complete; saturated ammonium chloride solution (1ml) cancellation; methyl alcohol is removed in decompression; with ethyl acetate (5ml * 3) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (50.3%).
In methyl alcohol (1.3ml) solution of compound (0.041mmol), add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, with ethyl acetate (10ml * 3) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 13 (61.3%).
1H?NMR(400MHz，CDCl 3)：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.
Embodiment 27 compounds 14
Under argon shield; at 0 ℃; toluene and DCE (1: 1) to compound 59 (0.11mmol) (5ml) slowly drip DIPEA (0.5ml in solution; 0.54mmol), (5ml) solution of the toluene of compound a and DCE (1: 1); be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete; cooling; with saturated ammonium chloride (3ml) cancellation, concentrated, add 20ml ethyl acetate; 5ml water; with ethyl acetate (10ml * 2) extraction, with saturated sodium-chloride (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound (23%).
Compound above (0.11mmol), compound (0.132mmol), DCC, DMAP are added in reaction flask successively; under argon shield, add 5mL toluene; after 85 ℃ of stirring reaction 5h, HPLC monitoring reacts completely; toluene is removed in decompression; add 5ml ethyl acetate; 5ml water; stir 20min; remove by filter insolubles; with ethyl acetate (5ml * 2) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain compound (63.3%).
Under argon shield; at 0 ℃; in THF (2ml) solution of compound upward (0.082mmol), drip TBAF (38.9mg; THF solution 0.180mmol); reaction 8h; TLC detection reaction is complete; saturated ammonium chloride solution (1ml) cancellation; methyl alcohol is removed in decompression; with ethyl acetate (5ml * 3) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (51.3%).
In methyl alcohol (1.3ml) solution of compound (0.041mmol), add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, with ethyl acetate (10ml * 3) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 13 (61.4%). 1H?NMR(400MHz，CDCl 3)：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.
Embodiment 28 compounds 15
Under argon shield; at 0 ℃; toluene and DCE (1: 1) to compound 59 (0.11mmol) (5ml) slowly drip DIPEA (0.5ml in solution; 0.54mmol), (5ml) solution of the toluene of compound a and DCE (1: 1); be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete; cooling; with saturated ammonium chloride (3ml) cancellation, concentrated, add 20ml ethyl acetate; 5ml water; with ethyl acetate (10ml * 2) extraction, with saturated sodium-chloride (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound (23%).
Under argon shield, at 0 ℃, the toluene of compound (0.11mmol) and DCE (1: 1) (5ml) slowly drip DIPEA (0.5ml in solution upward, 0.54mmol), the toluene of compound b and DCE (1: 1) be solution (5ml), be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete, cooling, with saturated ammonium chloride (3ml) cancellation, concentrated, add 20ml ethyl acetate, 5ml water, by ethyl acetate (10ml * 2), extract, with saturated sodium-chloride (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound (23%).
In methyl alcohol (1.3ml) solution of compound upward (0.041mmol), add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, with ethyl acetate (10ml * 3) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 15 (63%).
1H?NMR(400MHz，CDCl 3)：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.
Embodiment 29 compounds 16
By compound 59 (100mg; 0.11mmol), compound 66 (47.8mg; 0.132mmol), DCC, DMAP add in reaction flask successively; under argon shield, add 5mL toluene; after 85 ℃ of stirring reaction 5h, HPLC monitoring reacts completely; toluene is removed in decompression; add 5ml ethyl acetate, 5ml water, stirs 20min; remove by filter insolubles; with ethyl acetate (5ml * 2) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain compound (61.3%).
By compound above (0.11mmol), compound 66 (47.8mg; 0.132mmol), DCC, DMAP add in reaction flask successively; under argon shield, add 5mL toluene; after 85 ℃ of stirring reaction 5h, HPLC monitoring reacts completely; toluene is removed in decompression; add 5ml ethyl acetate; 5ml water; stir 20min, remove by filter insolubles, with ethyl acetate (5ml * 2) extraction; with saturated nacl aqueous solution (5ml), wash; anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain compound (63%).
Under argon shield; at 0 ℃, to the THF solution that drips TBAF (0.180mmol) in THF (2ml) solution of compound (0.082mmol), reaction 8h; TLC detection reaction is complete; saturated ammonium chloride solution (1ml) cancellation, methyl alcohol is removed in decompression, with ethyl acetate (5ml * 3) extraction; with saturated nacl aqueous solution (5ml), wash; anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (50.3%).
In methyl alcohol (1.3ml) solution of compound upward (0.041mmol), add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, with ethyl acetate (10ml * 3) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 16 (63%).
1H?NMR(400MHz，CDCl 3)：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.
Embodiment 30 compounds 17
Compound 59 (0.11mmol), compound (0.132mmol), DCC, DMAP are added in reaction flask successively; under argon shield, add 5mL toluene; after 85 ℃ of stirring reaction 5h, HPLC monitoring reacts completely; toluene is removed in decompression; add 5ml ethyl acetate; 5ml water; stir 20min; remove by filter insolubles; with ethyl acetate (5ml * 2) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain compound (63.7%).
In methyl alcohol (1.3ml) solution of compound upward (0.041mmol), add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, with ethyl acetate (10ml * 3) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 17 (63%). 1H?NMR(400MHz，CDCl 3)：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.
Embodiment 31 compounds 18
Under argon shield; at 0 ℃; toluene and DCE (1: 1) to compound (0.11mmol) (5ml) slowly drip DIPEA (0.5ml in solution; 0.54mmol), (5ml) solution of the toluene of compound a and DCE (1: 1); be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete; cooling; with saturated ammonium chloride (3ml) cancellation, concentrated, add 20ml ethyl acetate; 5ml water; with ethyl acetate (10ml * 2) extraction, with saturated sodium-chloride (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound (23.2%).
Under argon shield, at 0 ℃, the toluene of compound (0.11mmol) and DCE (1: 1) (5ml) slowly drip DIPEA (0.5ml in solution upward, 0.54mmol), the toluene of compound b and DCE (1: 1) be solution (5ml), be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete, cooling, with saturated ammonium chloride (3ml) cancellation, concentrated, add 20ml ethyl acetate, 5ml water, by ethyl acetate (10ml * 2), extract, with saturated sodium-chloride (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound (23.7%).
Under argon shield; at 0 ℃; to the THF solution that drips TBAF (0.180mmol) in THF (2ml) solution of compound 79 (0.082mmol); reaction 8h; TLC detection reaction is complete; saturated ammonium chloride solution (1ml) cancellation; methyl alcohol is removed in decompression; by ethyl acetate (5ml * 3), extract; with saturated nacl aqueous solution (5ml), wash; anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (50.3%).
In methyl alcohol (1.3ml) solution of compound upward (0.041mmol), add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, with ethyl acetate (10ml * 3) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 18 (63%).
1H?NMR(400MHz，CDCl 3)：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.
Embodiment 32 compounds 19
Under argon shield, at 0 ℃, to compound 59 (100mg, toluene 0.11mmol) and DCE (1: 1) (5ml) slowly drip DIPEA (0.5ml in solution, 0.54mmol), the toluene of compound a and DCE (1: 1) be solution (5ml), be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete, cooling, with saturated ammonium chloride (3ml) cancellation, concentrated, add 20ml ethyl acetate, 5ml water, by ethyl acetate (10ml * 2), extract, with saturated sodium-chloride (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound (23%).
Compound (0.11mmol), compound (0.132mmol), DCC, DMAP are added in reaction flask successively; under argon shield, add 5mL toluene; after 85 ℃ of stirring reaction 5h, HPLC monitoring reacts completely; toluene is removed in decompression; add 5ml ethyl acetate; 5ml water; stir 20min; remove by filter insolubles; with ethyl acetate (5ml * 2) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain compound (63%).
Under argon shield; at 0 ℃, to the THF solution that drips TBAF (0.180mmol) in THF (2ml) solution of compound (0.082mmol), reaction 8h; TLC detection reaction is complete; saturated ammonium chloride solution (1ml) cancellation, methyl alcohol is removed in decompression, with ethyl acetate (5ml * 3) extraction; with saturated nacl aqueous solution (5ml), wash; anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (50.3%).
In methyl alcohol (1.3ml) solution of compound upward (0.041mmol), add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, with ethyl acetate (10ml * 3) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 19 (63%). 1H?NMR(400MHz，CDCl 3)：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.
Embodiment 33 compounds 20
Under argon shield; at 0 ℃; toluene and DCE (1: 1) to compound (0.11mmol) (5ml) slowly drip DIPEA (0.5ml in solution; 0.54mmol), (5ml) solution of the toluene of compound a and DCE (1: 1); be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete; cooling; with saturated ammonium chloride (3ml) cancellation, concentrated, add 20ml ethyl acetate; 5ml water; with ethyl acetate (10ml * 2) extraction, with saturated sodium-chloride (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound (23%).
Under argon shield, at 0 ℃, the toluene of compound (0.11mmol) and DCE (1: 1) (5ml) slowly drip DIPEA (0.5ml in solution upward, 0.54mmol), the toluene of compound b and DCE (1: 1) be solution (5ml), be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete, cooling, with saturated ammonium chloride (3 ml) cancellation, concentrated, add 20ml ethyl acetate, 5ml water, by ethyl acetate (10ml * 2), extract, with saturated sodium-chloride (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound (24.2%).
Under argon shield; at 0 ℃; in THF (2ml) solution of compound upward (0.082mmol), drip the THF solution of TBAF (0.180mmol); reaction 8h; TLC detection reaction is complete; saturated ammonium chloride solution (1ml) cancellation; methyl alcohol is removed in decompression; by ethyl acetate (5ml * 3), extract; with saturated nacl aqueous solution (5ml), wash; anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (51.3%).
In methyl alcohol (1.3ml) solution of compound upward (0.041mmol), add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, with ethyl acetate (10ml * 3) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 20 (63%).
1H?NMR(400MHz，CDCl 3)：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.
Embodiment 34 compounds 21
Under argon shield; at 0 ℃; toluene and DCE (1: 1) to compound (0.11mmol) (5ml) slowly drip DIPEA (0.5ml in solution; 0.54mmol), (5ml) solution of the toluene of compound a and DCE (1: 1); be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete; cooling; with saturated ammonium chloride (3ml) cancellation, concentrated, add 20ml ethyl acetate; 5ml water; with ethyl acetate (10ml * 2) extraction, with saturated sodium-chloride (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound (23%).
Under argon shield, at 0 ℃, the toluene of compound (0.11mmol) and DCE (1: 1) (5ml) slowly drip DIPEA (0.5ml in solution upward, 0.54mmol), the toluene of compound b and DCE (1: 1) (5 ml) solution, be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete, cooling, with saturated ammonium chloride (3ml) cancellation, concentrated, add 20ml ethyl acetate, 5ml water, by ethyl acetate (10ml * 2), extract, with saturated sodium-chloride (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound (23.1%).
Under argon shield; at 0 ℃; to the THF solution that drips TBAF (0.180mmol) in THF (2ml) solution of compound 79 (0.082mmol); reaction 8h; TLC detection reaction is complete; saturated ammonium chloride solution (1ml) cancellation; methyl alcohol is removed in decompression; by ethyl acetate (5ml * 3), extract; with saturated nacl aqueous solution (5ml), wash; anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (50.6%).
In methyl alcohol (1.3ml) solution of compound upward (0.041mmol), add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, with ethyl acetate (10ml * 3) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 21 (63%). 1H?NMR(400MHz，CDCl 3)：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.
Embodiment 35 compounds 22
Under argon shield; at 0 ℃; toluene and DCE (1: 1) to compound (0.11mmol) (5ml) slowly drip DIPEA (0.5ml in solution; 0.54mmol), (5ml) solution of the toluene of compound a and DCE (1: 1); be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete; cooling; with saturated ammonium chloride (3ml) cancellation, concentrated, add 20ml ethyl acetate; 5ml water; with ethyl acetate (10ml * 2) extraction, with saturated sodium-chloride (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound (23%).
Compound (0.11mmol), compound (0.132mmol), DCC, DMAP are added in reaction flask successively; under argon shield, add 5mL toluene; after 85 ℃ of stirring reaction 5h, HPLC monitoring reacts completely; toluene is removed in decompression; add 5ml ethyl acetate; 5ml water; stir 20min; remove by filter insolubles; with ethyl acetate (5ml * 2) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain compound (63%).
Under argon shield; at 0 ℃, to the THF solution that drips TBAF (0.180mmol) in THF (2ml) solution of compound (0.082mmol), reaction 8h; TLC detection reaction is complete; saturated ammonium chloride solution (1ml) cancellation, methyl alcohol is removed in decompression, with ethyl acetate (5ml * 3) extraction; with saturated nacl aqueous solution (5ml), wash; anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (50.3%).
In methyl alcohol (1.3ml) solution of compound upward (0.041mmol), add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, with ethyl acetate (10ml * 3) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 22 (63%). 1H?NMR(400MHz，CDCl 3)：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.
Embodiment 36 compounds 23
Under argon shield; at 0 ℃; toluene and DCE (1: 1) to compound (0.11mmol) (5ml) slowly drip DIPEA (0.5ml in solution; 0.54mmol), (5ml) solution of the toluene of compound a and DCE (1: 1); be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete; cooling; with saturated ammonium chloride (3ml) cancellation, concentrated, add 20ml ethyl acetate; 5ml water; with ethyl acetate (10ml * 2) extraction, with saturated sodium-chloride (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound (23%).
Under argon shield, at 0 ℃, the toluene of compound (0.11mmol) and DCE (1: 1) (5ml) slowly drip DIPEA (0.5ml in solution upward, 0.54mmol), the toluene of compound b and DCE (1: 1) be solution (5ml), be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete, cooling, with saturated ammonium chloride (3 ml) cancellation, concentrated, add 20ml ethyl acetate, 5ml water, by ethyl acetate (10ml * 2), extract, with saturated sodium-chloride (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound (22.3%).
Under argon shield; at 0 ℃; to the THF solution that drips TBAF (0.180mmol) in THF (2ml) solution of compound 79 (0.082mmol); reaction 8h; TLC detection reaction is complete; saturated ammonium chloride solution (1ml) cancellation; methyl alcohol is removed in decompression; by ethyl acetate (5ml * 3), extract; with saturated nacl aqueous solution (5ml), wash; anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (50.3%).
In methyl alcohol (1.3ml) solution of compound upward (0.041mmol), add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, with ethyl acetate (10ml * 3) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 23 (63%). 1H?NMR(400MHz，CDCl 3)：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.
Embodiment 37 compounds 24
Under argon shield; at 0 ℃; toluene and DCE (1: 1) to compound (0.11mmol) (5ml) slowly drip DIPEA (0.5ml in solution; 0.54mmol), (5ml) solution of the toluene of compound a and DCE (1: 1); be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete; cooling; with saturated ammonium chloride (3ml) cancellation, concentrated, add 20ml ethyl acetate; 5ml water; with ethyl acetate (10ml * 2) extraction, with saturated sodium-chloride (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound (23%).
Under argon shield, at 0 ℃, the toluene of compound (0.11mmol) and DCE (1: 1) (5ml) slowly drip DIPEA (0.5ml in solution upward, 0.54mmol), the toluene of compound b and DCE (1: 1) be solution (5ml), be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete, cooling, with saturated ammonium chloride (3 ml) cancellation, concentrated, add 20ml ethyl acetate, 5ml water, by ethyl acetate (10ml * 2), extract, with saturated sodium-chloride (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound (23%).
Under argon shield; at 0 ℃; to the THF solution that drips TBAF (0.180mmol) in THF (2ml) solution of compound 79 (0.082mmol); reaction 8h; TLC detection reaction is complete; saturated ammonium chloride solution (1ml) cancellation; methyl alcohol is removed in decompression; by ethyl acetate (5ml * 3), extract; with saturated nacl aqueous solution (5ml), wash; anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (50.3%).
In methyl alcohol (1.3ml) solution of compound upward (0.041mmol), add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, with ethyl acetate (10ml * 3) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 24 (63%). 1H?NMR(400MHz，CDCl 3)：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.
Embodiment 38 compounds 25
Under argon shield; at 0 ℃; toluene and DCE (1: 1) to compound (0.11mmol) (5ml) slowly drip DIPEA (0.5ml in solution; 0.54mmol), (5ml) solution of the toluene of compound a and DCE (1: 1); be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete; cooling; with saturated ammonium chloride (3ml) cancellation, concentrated, add 20ml ethyl acetate; 5ml water; with ethyl acetate (10ml * 2) extraction, with saturated sodium-chloride (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound (23%).
Compound (0.11mmol), compound (0.132mmol), DCC, DMAP are added in reaction flask successively; under argon shield, add 5mL toluene; after 85 ℃ of stirring reaction 5h, HPLC monitoring reacts completely; toluene is removed in decompression; add 5ml ethyl acetate; 5ml water; stir 20min; remove by filter insolubles; with ethyl acetate (5ml * 2) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain compound (63%).
Under argon shield; at 0 ℃, to the THF solution that drips TBAF (0.180mmol) in THF (2ml) solution of compound (0.082mmol), reaction 8h; TLC detection reaction is complete; saturated ammonium chloride solution (1ml) cancellation, methyl alcohol is removed in decompression, with ethyl acetate (5ml * 3) extraction; with saturated nacl aqueous solution (5ml), wash; anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (50.3%).
In methyl alcohol (1.3ml) solution of compound upward (0.041mmol), add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, with ethyl acetate (10ml * 3) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 25 (63%).
1H?NMR(400MHz，CDCl 3)：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.
Embodiment 39 compounds 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 argon shield, at 0 ℃, to compound 59 (100mg, toluene 0.11mmol) and DCE (1: 1) (5ml) slowly drip DIPEA (0.5ml in solution, 0.54mmol), the toluene of compound a and DCE (1: 1) be solution (5ml), be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete, cooling, with saturated ammonium chloride (3ml) cancellation, concentrated, add 20ml ethyl acetate, 5ml water, by ethyl acetate (10ml * 2), extract, with saturated sodium-chloride (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound (21-26%).
Compound (0.11mmol), compound (0.132mmol), DCC, DMAP are added in reaction flask successively; under argon shield, add 5mL toluene; after 85 ℃ of stirring reaction 5h, HPLC monitoring reacts completely; toluene is removed in decompression; add 5ml ethyl acetate; 5ml water; stir 20min; remove by filter insolubles; with ethyl acetate (5ml * 2) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain compound (60-64%).
Under argon shield; at 0 ℃; to the THF solution that drips TBAF (0.180mmol) in THF (2ml) solution of compound 79 (0.082mmol); reaction 8h; TLC detection reaction is complete; saturated ammonium chloride solution (1ml) cancellation; methyl alcohol is removed in decompression; by ethyl acetate (5ml * 3), extract; with saturated nacl aqueous solution (5ml), wash; anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (49-54%).
In methyl alcohol (1.3ml) solution of compound upward (0.041mmol), add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, by ethyl acetate (10ml * 3), extract, with saturated nacl aqueous solution (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 26 (61-67%).
Embodiment 40 compounds 27
Under argon shield; at 0 ℃; toluene and DCE (1: 1) to compound (0.11mmol) (5ml) slowly drip DIPEA (0.5ml in solution; 0.54mmol), (5ml) solution of the toluene of compound a and DCE (1: 1); be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete; cooling; with saturated ammonium chloride (3ml) cancellation, concentrated, add 20ml ethyl acetate; 5ml water; with ethyl acetate (10ml * 2) extraction, with saturated sodium-chloride (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound (21-24%).
Under argon shield, at 0 ℃, the toluene of compound (0.11mmol) and DCE (1: 1) (5ml) slowly drip DIPEA (0.5ml in solution upward, 0.54mmol), the toluene of compound b and DCE (1: 1) be solution (5ml), be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete, cooling, with saturated ammonium chloride (3 ml) cancellation, concentrated, add 20ml ethyl acetate, 5ml water, by ethyl acetate (10ml * 2), extract, with saturated sodium-chloride (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound (21-25%).
Under argon shield; at 0 ℃; to the THF solution that drips TBAF (0.180mmol) in THF (2ml) solution of compound 79 (0.082mmol); reaction 8h; TLC detection reaction is complete; saturated ammonium chloride solution (1ml) cancellation; methyl alcohol is removed in decompression; by ethyl acetate (5ml * 3), extract; with saturated nacl aqueous solution (5ml), wash; anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (49.9-54.6%).
In methyl alcohol (1.3ml) solution of compound upward (0.041mmol), add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, by ethyl acetate (10ml * 3), extract, with saturated nacl aqueous solution (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 27 (61-65%).
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)，3.84-3.76(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.
Embodiment 41 compounds 28
Compound (0.11mmol), compound (0.132mmol), DCC, DM.AP are added in reaction flask successively; under argon shield, add 5mL toluene; after 85 ℃ of stirring reaction 5h, HPLC monitoring reacts completely; toluene is removed in decompression; add 5ml ethyl acetate; 5ml water; stir 20min; remove by filter insolubles; with ethyl acetate (5ml * 2) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain compound (60-64%).
Compound (0.11mmol), compound (0.132mmol), DCC, DMAP are added in reaction flask successively; under argon shield, add 5mL toluene; after 85 ℃ of stirring reaction 5h, HPLC monitoring reacts completely; toluene is removed in decompression; add 5ml ethyl acetate; 5ml water; stir 20min; remove by filter insolubles; with ethyl acetate (5ml * 2) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain compound (60-64%).
Under argon shield; at 0 ℃; to the THF solution that drips TBAF (0.180mmol) in THF (2ml) solution of compound 79 (0.082mmol); reaction 8h; TLC detection reaction is complete; saturated ammonium chloride solution (1ml) cancellation; methyl alcohol is removed in decompression; by ethyl acetate (5ml * 3), extract; with saturated nacl aqueous solution (5ml), wash; anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (49-54%).
In methyl alcohol (1.3ml) solution of compound upward (0.041mmol), add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, by ethyl acetate (10ml * 3), extract, with saturated nacl aqueous solution (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 28 (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，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.
Embodiment 42 compounds 29
Compound (0.11mmol), compound (0.132mmol), DCC, DMAP are added in reaction flask successively; under argon shield, add 5mL toluene; after 85 ℃ of stirring reaction 5h, HPLC monitoring reacts completely; toluene is removed in decompression; add 5ml ethyl acetate; 5ml water; stir 20min; remove by filter insolubles; with ethyl acetate (5ml * 2) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain compound (60-64%).
Compound (0.11mmol), compound (0.132mmol), DCC, DMAP are added in reaction flask successively; under argon shield, add 5mL toluene; after 85 ℃ of stirring reaction 5h, HPLC monitoring reacts completely; toluene is removed in decompression; add 5ml ethyl acetate; 5ml water; stir 20min; remove by filter insolubles; with ethyl acetate (5ml * 2) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain compound (60-64%).
Under argon shield; at 0 ℃; to the THF solution that drips TBAF (0.180mmol) in THF (2ml) solution of compound 79 (0.082mmol); reaction 8h; TLC detection reaction is complete; saturated ammonium chloride solution (1ml) cancellation; methyl alcohol is removed in decompression; by ethyl acetate (5ml * 3), extract; with saturated nacl aqueous solution (5ml), wash; anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (49-54%).
In methyl alcohol (1.3ml) solution of compound upward (0.041mmol), add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, by ethyl acetate (10ml * 3), extract, with saturated nacl aqueous solution (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 28 (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，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.
Embodiment 43 compounds 30
Compound (0.11mmol), compound (0.132mmol), DCC, DMAP are added in reaction flask successively; under argon shield, add 5mL toluene; after 85 ℃ of stirring reaction 5h, HPLC monitoring reacts completely; toluene is removed in decompression; add 5ml ethyl acetate; 5ml water; stir 20min; remove by filter insolubles; with ethyl acetate (5ml * 2) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain compound (60-64%).
Compound (0.11mmol), compound (0.132mmol), DCC, DMAP are added in reaction flask successively; under argon shield, add 5mL toluene; after 85 ℃ of stirring reaction 5h, HPLC monitoring reacts completely; toluene is removed in decompression; add 5ml ethyl acetate; 5ml water; stir 20min; remove by filter insolubles; with ethyl acetate (5ml * 2) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain compound (60-64%).
Under argon shield; at 0 ℃; to the THF solution that drips TBAF (0.180mmol) in THF (2ml) solution of compound 79 (0.082mmol); reaction 8h; TLC detection reaction is complete; saturated ammonium chloride solution (1ml) cancellation; methyl alcohol is removed in decompression; by ethyl acetate (5ml * 3), extract; with saturated nacl aqueous solution (5ml), wash; anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (49-54%).
In methyl alcohol (1.3ml) solution of compound upward (0.041mmol), add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, by ethyl acetate (10ml * 3), extract, with saturated nacl aqueous solution (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 30 (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，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.
Embodiment 44 compounds 31
Compound (0.11mmol), compound (0.132mmol), DCC, DMAP are added in reaction flask successively; under argon shield, add 5mL toluene; after 85 ℃ of stirring reaction 5h, HPLC monitoring reacts completely; toluene is removed in decompression; add 5ml ethyl acetate; 5ml water; stir 20min; remove by filter insolubles; with ethyl acetate (5ml * 2) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain compound (60-64%).
Compound (0.11mmol), compound (0.132mmol), DCC, DMAP are added in reaction flask successively; under argon shield, add 5mL toluene; after 85 ℃ of stirring reaction 5h, HPLC monitoring reacts completely; toluene is removed in decompression; add 5ml ethyl acetate; 5ml water; stir 20min; remove by filter insolubles; with ethyl acetate (5ml * 2) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain compound (60-64%).
Under argon shield; at 0 ℃; to the THF solution that drips TBAF (0.180mmol) in THF (2ml) solution of compound 79 (0.082mmol); reaction 8h; TLC detection reaction is complete; saturated ammonium chloride solution (1ml) cancellation; methyl alcohol is removed in decompression; by ethyl acetate (5ml * 3), extract; with saturated nacl aqueous solution (5ml), wash; anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (49-54%).
In methyl alcohol (1.3ml) solution of compound upward (0.041mmol), add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, by ethyl acetate (10ml * 3), extract, with saturated nacl aqueous solution (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 31 (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，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.
Embodiment 45 compounds 32
Compound (0.11mmol), compound (0.132mmol), DCC, DMAP are added in reaction flask successively; under argon shield, add 5mL toluene; after 85 ℃ of stirring reaction 5h, HPLC monitoring reacts completely; toluene is removed in decompression; add 5ml ethyl acetate; 5ml water; stir 20min; remove by filter insolubles; with ethyl acetate (5ml * 2) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain compound (60-64%).
Compound (0.11mmol), compound (0.132mmol), DCC, DMAP are added in reaction flask successively; under argon shield, add 5mL toluene; after 85 ℃ of stirring reaction 5h, HPLC monitoring reacts completely; toluene is removed in decompression; add 5ml ethyl acetate; 5ml water; stir 20min; remove by filter insolubles; with ethyl acetate (5ml * 2) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain compound (60-64%).
Under argon shield; at 0 ℃; to the THF solution that drips TBAF (0.180mmol) in THF (2ml) solution of compound 79 (0.082mmol); reaction 8h; TLC detection reaction is complete; saturated ammonium chloride solution (1ml) cancellation; methyl alcohol is removed in decompression; by ethyl acetate (5ml * 3), extract; with saturated nacl aqueous solution (5ml), wash; anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (49-54%).
In methyl alcohol (1.3ml) solution of compound upward (0.041mmol), add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, by ethyl acetate (10ml * 3), extract, with saturated nacl aqueous solution (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 32 (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，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.
Embodiment 46 compounds 33
Compound (0.11mmol), compound (0.132mmol), DCC, DMAP are added in reaction flask successively; under argon shield, add 5mL toluene; after 85 ℃ of stirring reaction 5h, HPLC monitoring reacts completely; toluene is removed in decompression; add 5ml ethyl acetate; 5ml water; stir 20min; remove by filter insolubles; with ethyl acetate (5ml * 2) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain compound (60-64%).
Under argon shield; at 0 ℃; to the THF solution that drips TBAF (0.180mmol) in THF (2ml) solution of compound 79 (0.082mmol); reaction 8h; TLC detection reaction is complete; saturated ammonium chloride solution (1ml) cancellation; methyl alcohol is removed in decompression; by ethyl acetate (5ml * 3), extract; with saturated nacl aqueous solution (5ml), wash; anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (49-54%).
In methyl alcohol (1.3ml) solution of compound upward (0.041mmol), add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, by ethyl acetate (10ml * 3), extract, with saturated nacl aqueous solution (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 33 (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，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.
Embodiment 47 compounds 34
Under argon shield; at 0 ℃; toluene and DCE (1: 1) to compound (0.11mmol) (5ml) slowly drip DIPEA (0.5ml in solution; 0.54mmol), (5ml) solution of the toluene of compound a and DCE (1: 1); be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete; cooling; with saturated ammonium chloride (3ml) cancellation, concentrated, add 20ml ethyl acetate; 5ml water; with ethyl acetate (10ml * 2) extraction, with saturated sodium-chloride (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound (21-24%).
Under argon shield; at 0 ℃; to the THF solution that drips TBAF (0.180mmol) in THF (2ml) solution of compound 79 (0.082mmol); reaction 8h; TLC detection reaction is complete; saturated ammonium chloride solution (1ml) cancellation; methyl alcohol is removed in decompression; by ethyl acetate (5ml * 3), extract; with saturated nacl aqueous solution (5ml), wash; anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (49.9-54.6%).
Under argon shield, at-78 ℃, to compound 59 (100mg, in DMF 0.11mmol) (10ml) solution, slowly drip LiHMDS (0.5ml, DMF 0.54mmol) (2ml) solution, after stirring 1h, add enpara (3ml), after reaction 12h, naturally be warmed up to 0 ℃, intensification needs 5h, at 0 ℃, react again 4h, cool to-78 ℃, with saturated ammonium chloride solution (3ml) cancellation, DMF and MeI are removed in decompression, add 20ml ethyl acetate, 5ml water, by ethyl acetate (10ml * 2), extract, with saturated nacl aqueous solution (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound 60 (56.1ml, 54%).
In methyl alcohol (1.3ml) solution of compound upward (0.041mmol), add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, by ethyl acetate (10ml * 3), extract, with saturated nacl aqueous solution (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 34 (61-65%).
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)，3.82-3.84(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.
Embodiment 48 compounds 35
Under argon shield, in 0 ℃ of pyridine to compound (5.51mmol) (54ml) solution, drip TrocCl (2.49ml, 18.18mmol); room temperature reaction 1h; TLC detection reaction is complete, and pyridine is removed in decompression, adds 80ml ethyl acetate; 50ml water; with ethyl acetate (50ml * 2) extraction, with saturated sodium-chloride (50ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (79-83%).
Compound (0.11mmol), compound (0.132mmol), DCC, DMAP are added in reaction flask successively; under argon shield, add 5mL toluene; after 85 ℃ of stirring reaction 5h, HPLC monitoring reacts completely; toluene is removed in decompression; add 5ml ethyl acetate; 5ml water; stir 20min; remove by filter insolubles; with ethyl acetate (5ml * 2) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain compound (60-64%).
In methyl alcohol (120ml) solution of compound (3.09mmol), add successively zinc powder (92.87mmol) and acetic acid, after 30 ℃ of reaction 5h, TLC detection reaction is complete, remove by filter zinc powder, methyl alcohol and acetic acid are removed in decompression, add 100ml ethyl acetate, 50ml water, with ethyl acetate (50ml * 2) extraction, with saturated sodium-chloride (50ml) washing, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (90%).
In methyl alcohol (1.3ml) solution of compound (0.052mmol), add tosic acid (0.058mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, with ethyl acetate (10ml * 3) extraction, with saturated nacl aqueous solution (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound
Under argon shield, at-78 ℃, to compound 59 (100mg, in DMF 0.11mmol) (10ml) solution, slowly drip LiHMDS (0.5ml, DMF 0.54mmol) (2ml) solution, after stirring 1h, add MeCl (3ml), after reaction 12h, naturally be warmed up to 0 ℃, intensification needs 5h, at 0 ℃, react again 4h, cool to-78 ℃, with saturated ammonium chloride solution (3ml) cancellation, DMF and MeI are removed in decompression, add 20ml ethyl acetate, 5ml water, by ethyl acetate (10ml * 2), extract, with saturated nacl aqueous solution (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=2: 1) obtain 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.
Embodiment 49 compounds 36
Under argon shield, in 0 ℃ of pyridine to compound (5.51mmol) (54ml) solution, drip TrocCl (2.49ml, 18.18mmol); room temperature reaction 1h; TLC detection reaction is complete, and pyridine is removed in decompression, adds 80ml ethyl acetate; 50ml water; with ethyl acetate (50ml * 2) extraction, with saturated sodium-chloride (50ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (79-83%).
Compound (0.11mmol), compound (0.132mmol), DCC, DMAP are added in reaction flask successively; under argon shield, add 5mL toluene; after 85 ℃ of stirring reaction 5h, HPLC monitoring reacts completely; toluene is removed in decompression; add 5ml ethyl acetate; 5ml water; stir 20min; remove by filter insolubles; with ethyl acetate (5ml * 2) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain compound (60-64%).
In methyl alcohol (120ml) solution of compound (3.09mmol), add successively zinc powder (92.87mmol) and acetic acid, after 30 ℃ of reaction 5h, TLC detection reaction is complete, remove by filter zinc powder, methyl alcohol and acetic acid are removed in decompression, add 100ml ethyl acetate, 50ml water, with ethyl acetate (50ml * 2) extraction, with saturated sodium-chloride (50ml) washing, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (90%).
In methyl alcohol (1.3ml) solution of compound (0.052mmol), add tosic acid (0.058mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, with ethyl acetate (10ml * 3) extraction, with saturated nacl aqueous solution (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound
Under argon shield, at-78 ℃, to compound 59 (100mg, in DMF 0.11mmol) (10ml) solution, slowly drip LiHMDS (0.5ml, DMF 0.54mmol) (2ml) solution, after stirring 1h, add MeCl (3ml), after reaction 12h, naturally be warmed up to 0 ℃, intensification needs 5h, at 0 ℃, react again 4h, cool to-78 ℃, with saturated ammonium chloride solution (3ml) cancellation, DMF and MeI are removed in decompression, add 20ml ethyl acetate, 5ml water, by ethyl acetate (10ml * 2), extract, with saturated nacl aqueous solution (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=2: 1) obtain 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.
Embodiment 50 compounds 37
Under argon shield, in 0 ℃ of pyridine to compound (5.51mmol) (54ml) solution, drip TrocCl (2.49ml, 18.18mmol); room temperature reaction 1h; TLC detection reaction is complete, and pyridine is removed in decompression, adds 80ml ethyl acetate; 50ml water; with ethyl acetate (50ml * 2) extraction, with saturated sodium-chloride (50ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (79-83%).
Compound (0.11mmol), compound (0.132mmol), DCC, DMAP are added in reaction flask successively; under argon shield, add 5mL toluene; after 85 ℃ of stirring reaction 5h, HPLC monitoring reacts completely; toluene is removed in decompression; add 5ml ethyl acetate; 5ml water; stir 20min; remove by filter insolubles; with ethyl acetate (5ml * 2) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain compound (60-64%).
In methyl alcohol (120ml) solution of compound (3.09mmol), add successively zinc powder (92.87mmol) and acetic acid, after 30 ℃ of reaction 5h, TLC detection reaction is complete, remove by filter zinc powder, methyl alcohol and acetic acid are removed in decompression, add 100ml ethyl acetate, 50ml water, with ethyl acetate (50ml * 2) extraction, with saturated sodium-chloride (50ml) washing, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (90%).
In methyl alcohol (1.3ml) solution of compound (0.052mmol), add tosic acid (0.058mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, with ethyl acetate (10ml * 3) extraction, with saturated nacl aqueous solution (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound
Under argon shield, at-78 ℃, to compound 59 (100mg, in DMF 0.11mmol) (10ml) solution, slowly drip LiHMDS (0.5ml, DMF 0.54mmol) (2ml) solution, after stirring 1h, add MeCl (3ml), after reaction 12h, naturally be warmed up to 0 ℃, intensification needs 5h, at 0 ℃, react again 4h, cool to-78 ℃, with saturated ammonium chloride solution (3ml) cancellation, DMF and MeI are removed in decompression, add 20ml ethyl acetate, 5ml water, by ethyl acetate (10ml * 2), extract, with saturated nacl aqueous solution (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=2: 1) obtain 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.
Embodiment 51 compounds 38
Under argon shield; at 0 ℃; toluene and DCE (1: 1) to compound (0.11mmol) (5ml) slowly drip DIPEA (0.5ml in solution; 0.54mmol), (5ml) solution of the toluene of compound a and DCE (1: 1); be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete; cooling; with saturated ammonium chloride (3ml) cancellation, concentrated, add 20ml ethyl acetate; 5ml water; with ethyl acetate (10ml * 2) extraction, with saturated sodium-chloride (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound (21-24%).
Under argon shield; at 0 ℃; to the THF solution that drips TBAF (0.180mmol) in THF (2ml) solution of compound 79 (0.082mmol); reaction 8h; TLC detection reaction is complete; saturated ammonium chloride solution (1ml) cancellation; methyl alcohol is removed in decompression; by ethyl acetate (5ml * 3), extract; with saturated nacl aqueous solution (5ml), wash; anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (49.9-54.6%).
In methyl alcohol (1.3ml) solution of compound upward (0.041mmol), add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, by ethyl acetate (10ml * 3), extract, with saturated nacl aqueous solution (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 38 (61-65%).
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，8H)，1.27(s，3H)，1.25(s，3H)ppm.
Embodiment 52 compounds 39
Under argon shield; at 0 ℃; toluene and DCE (1: 1) to compound (0.11mmol) (5ml) slowly drip DIPEA (0.5ml in solution; 0.54mmol), (5ml) solution of the toluene of compound a and DCE (1: 1); be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete; cooling; with saturated ammonium chloride (3ml) cancellation, concentrated, add 20ml ethyl acetate; 5ml water; with ethyl acetate (10ml * 2) extraction, with saturated sodium-chloride (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound (21-24%).
In methyl alcohol (1.3ml) solution of compound upward (0.041mmol), add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, by ethyl acetate (10ml * 3), extract, with saturated nacl aqueous solution (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 39 (61-65%).
Under argon shield; at 0 ℃; to the THF solution that drips TBAF (0.180mmol) in THF (2ml) solution of compound (0.082mmol); reaction 8h; TLC detection reaction is complete; saturated ammonium chloride solution (1ml) cancellation; methyl alcohol is removed in decompression; by ethyl acetate (5ml * 3), extract; with saturated nacl aqueous solution (5ml), wash; anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (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.
Embodiment 53 compounds 40
Compound (0.11mmol), compound (0.132mmol), DCC, DMAP are added in reaction flask successively; under argon shield, add 5mL toluene; after 85 ℃ of stirring reaction 5h, HPLC monitoring reacts completely; toluene is removed in decompression; add 5ml ethyl acetate; 5ml water; stir 20min; remove by filter insolubles; with ethyl acetate (5ml * 2) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain compound (60-64%).
In methyl alcohol (1.3ml) solution of compound upward (0.041mmol), add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, with ethyl acetate (10ml * 3) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (61-67%).
Under argon shield, at-78 ℃, to compound 59 (100mg, in DMF 0.11mmol) (10ml) solution, slowly drip LiHMDS (0.5ml, DMF 0.54mmol) (2ml) solution, after stirring 1h, add chloralkane (3ml), after reaction 12h, naturally be warmed up to 0 ℃, intensification needs 5h, at 0 ℃, react again 4h, cool to-78 ℃, with saturated ammonium chloride solution (3ml) cancellation, DMF and MeCl are removed in decompression, add 20ml ethyl acetate, 5ml water, by ethyl acetate (10ml * 2), extract, with saturated nacl aqueous solution (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=2: 1) obtain 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.
Embodiment 54 compounds 41
Compound (0.11mmol), compound (0.132mmol), DCC, DMAP are added in reaction flask successively; under argon shield, add 5mL toluene; after 85 ℃ of stirring reaction 5h, HPLC monitoring reacts completely; toluene is removed in decompression; add 5ml ethyl acetate; 5ml water; stir 20min; remove by filter insolubles; with ethyl acetate (5ml * 2) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain compound (60-64%).
In methyl alcohol (1.3ml) solution of compound upward (0.041mmol), add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, with ethyl acetate (10ml * 3) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (61-67%).
Under argon shield, at-78 ℃, to compound 59 (100mg, in DMF 0.11mmol) (10ml) solution, slowly drip LiHMDS (0.5ml, DMF 0.54mmol) (2ml) solution, after stirring 1h, add chloralkane (3ml), after reaction 12h, naturally be warmed up to 0 ℃, intensification needs 5h, at 0 ℃, react again 4h, cool to-78 ℃, with saturated ammonium chloride solution (3ml) cancellation, DMF and MeCl are removed in decompression, add 20ml ethyl acetate, 5ml water, by ethyl acetate (10ml * 2), extract, with saturated nacl aqueous solution (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound 42 (54%).
Under argon shield; at 0 ℃; to the THF solution that drips TBAF (0.180mmol) in THF (2ml) solution of compound 79 (0.082mmol); reaction 8h; TLC detection reaction is complete; saturated ammonium chloride solution (1ml) cancellation; methyl alcohol is removed in decompression; by ethyl acetate (5ml * 3), extract; with saturated nacl aqueous solution (5ml), wash; anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 41 (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)，3.82-3.84(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.
Embodiment 55 compounds 42
Compound (0.11mmol), compound (0.132mmol), DCC, DMAP are added in reaction flask successively; under argon shield, add 5mL toluene; after 85 ℃ of stirring reaction 5h, HPLC monitoring reacts completely; toluene is removed in decompression; add 5ml ethyl acetate; 5ml water; stir 20min; remove by filter insolubles; with ethyl acetate (5ml * 2) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain compound (60-64%).
In methyl alcohol (1.3ml) solution of compound upward (0.041mmol), add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, with ethyl acetate (10ml * 3) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (61-67%).
Under argon shield; at 0 ℃; to the THF solution that drips TBAF (0.180mmol) in THF (2ml) solution of compound 79 (0.082mmol); reaction 8h; TLC detection reaction is complete; saturated ammonium chloride solution (1ml) cancellation; methyl alcohol is removed in decompression; by ethyl acetate (5ml * 3), extract; with saturated nacl aqueous solution (5ml), wash; anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (49-54%).
Under argon shield, at-78 ℃, to compound 59 (100mg, in DMF 0.11mmol) (10ml) solution, slowly drip LiHMDS (0.5ml, DMF 0.54mmol) (2ml) solution, after stirring 1h, add chloralkane (3ml), after reaction 12h, naturally be warmed up to 0 ℃, intensification needs 5h, at 0 ℃, react again 4h, cool to-78 ℃, with saturated ammonium chloride solution (3ml) cancellation, DMF and MeCl are removed in decompression, add 20ml ethyl acetate, 5ml water, by ethyl acetate (10ml * 2), extract, with saturated nacl aqueous solution (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=2: 1) 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.
Embodiment 56 compounds 43
Compound (0.11mmol), compound (0.132mmol), DCC, DMAP are added in reaction flask successively; under argon shield, add 5mL toluene; after 85 ℃ of stirring reaction 5h, HPLC monitoring reacts completely; toluene is removed in decompression; add 5ml ethyl acetate; 5ml water; stir 20min; remove by filter insolubles; with ethyl acetate (5ml * 2) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain compound (60-64%).
In methyl alcohol (1.3ml) solution of compound upward (0.041mmol), add tosic acid (7.7 mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, by ethyl acetate (10ml * 3), extract, with saturated nacl aqueous solution (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (61-67%).
Under argon shield; at 0 ℃; to the THF solution that drips TBAF (0.180mmol) in THF (2ml) solution of compound 79 (0.082mmol); reaction 8h; TLC detection reaction is complete; saturated ammonium chloride solution (1ml) cancellation; methyl alcohol is removed in decompression; by ethyl acetate (5ml * 3), extract; with saturated nacl aqueous solution (5ml), wash; anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 43 (49-54%).
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)，3.81-3.76(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.
Embodiment 57 compounds 44
Compound (0.11mmol), compound (0.132mmol), DCC, DMAP are added in reaction flask successively; under argon shield, add 5mL toluene; after 85 ℃ of stirring reaction 5h, HPLC monitoring reacts completely; toluene is removed in decompression; add 5ml ethyl acetate; 5ml water; stir 20min; remove by filter insolubles; with ethyl acetate (5ml * 2) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain compound (60-64%).
In methyl alcohol (1.3ml) solution of compound upward (0.041mmol), add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, with ethyl acetate (10ml * 3) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (61-67%).
Under argon shield; at 0 ℃; to the THF solution that drips TBAF (0.180mmol) in THF (2ml) solution of compound 79 (0.082mmol); reaction 8h; TLC detection reaction is complete; saturated ammonium chloride solution (1ml) cancellation; methyl alcohol is removed in decompression; by ethyl acetate (5ml * 3), extract; with saturated nacl aqueous solution (5ml), wash; anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (49-54%).
Under argon shield, at-78 ℃, to compound 59 (100mg, in DMF 0.11mmol) (10ml) solution, slowly drip LiHMDS (0.5ml, DMF 0.54mmol) (2ml) solution, after stirring 1h, add MeCl (3ml), after reaction 12h, naturally be warmed up to 0 ℃, intensification needs 5h, at 0 ℃, react again 4h, cool to-78 ℃, with saturated ammonium chloride solution (3ml) cancellation, DMF and MeI are removed in decompression, add 20ml ethyl acetate, 5ml water, by ethyl acetate (10ml * 2), extract, with saturated nacl aqueous solution (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=2: 1) obtain 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.
Embodiment 58 compounds 45
Compound (0.11mmol), compound (0.132mmol), DCC, DMAP are added in reaction flask successively; under argon shield, add 5mL toluene; after 85 ℃ of stirring reaction 5h, HPLC monitoring reacts completely; toluene is removed in decompression; add 5ml ethyl acetate; 5ml water; stir 20min; remove by filter insolubles; with ethyl acetate (5ml * 2) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain compound (60-64%).
Under argon shield; at 0 ℃; to the THF solution that drips TBAF (0.180mmol) in THF (2ml) solution of compound 79 (0.082mmol); reaction 8h; TLC detection reaction is complete; saturated ammonium chloride solution (1ml) cancellation; methyl alcohol is removed in decompression; by ethyl acetate (5ml * 3), extract; with saturated nacl aqueous solution (5ml), wash; anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (49-54%).
In methyl alcohol (1.3ml) solution of compound upward (0.041mmol), add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, by ethyl acetate (10ml * 3), extract, with saturated nacl aqueous solution (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (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.
Embodiment 59 compounds 46
Under argon shield; at 0 ℃; toluene and DCE (1: 1) to compound (0.11mmol) (5ml) slowly drip DIPEA (0.5ml in solution; 0.54mmol), (5ml) solution of the toluene of compound a and DCE (1: 1); be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete; cooling; with saturated ammonium chloride (3ml) cancellation, concentrated, add 20ml ethyl acetate; 5ml water; with ethyl acetate (10ml * 2) extraction, with saturated sodium-chloride (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound (21-24%).
In methyl alcohol (1.3ml) solution of compound upward (0.041mmol), add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, by ethyl acetate (10ml * 3), extract, with saturated nacl aqueous solution (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 46 (61-65%).
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，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.
Embodiment 60 compounds 47
Under argon shield; at 0 ℃; toluene and DCE (1: 1) to compound (0.11mmol) (5ml) slowly drip DIPEA (0.5ml in solution; 0.54mmol), (5ml) solution of the toluene of compound a and DCE (1: 1); be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete; cooling; with saturated ammonium chloride (3ml) cancellation, concentrated, add 20ml ethyl acetate; 5ml water; with ethyl acetate (10ml * 2) extraction, with saturated sodium-chloride (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound (21-24%).
In methyl alcohol (1.3ml) solution of compound upward (0.041mmol), add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, by ethyl acetate (10ml * 3), extract, with saturated nacl aqueous solution (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 47 (61-65%).
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，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.
Embodiment 61 compounds 48
Under argon shield, in 0 ℃ of pyridine to compound (5.51mmol) (54ml) solution, drip TrocCl (2.49ml, 18.18mmol); room temperature reaction 1h; TLC detection reaction is complete, and pyridine is removed in decompression, adds 80ml ethyl acetate; 50ml water; with ethyl acetate (50ml * 2) extraction, with saturated sodium-chloride (50ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (79-83%).
Compound (3.36mmol), compound, DCC, DMAP are added in reaction flask successively, under argon shield, add 68mL toluene, after 85 ℃ of stirring reaction 2h, HPLC monitoring reacts completely, toluene is removed in decompression, add 80ml ethyl acetate, 50ml water, stir 20min, remove by filter insolubles, with ethyl acetate (50ml * 2) extraction, with saturated sodium-chloride (50ml) washing, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain compound (92%).
In methyl alcohol (120ml) solution of compound (3.09mmol), add successively zinc powder (92.87mmol) and acetic acid, after 30 ℃ of reaction 5h, TLC detection reaction is complete, remove by filter zinc powder, methyl alcohol and acetic acid are removed in decompression, add 100ml ethyl acetate, 50ml water, by ethyl acetate (50ml * 2), extract, with saturated sodium-chloride (50ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (87-93%).
Under argon shield, at-78 ℃, to compound 59 (100mg, in DMF 0.11mmol) (10ml) solution, slowly drip LiHMDS (0.5ml, DMF 0.54mmol) (2ml) solution, after stirring 1h, add MeI (3ml), after reaction 12h, naturally be warmed up to 0 ℃, intensification needs 5h, at 0 ℃, react again 4h, cool to-78 ℃, with saturated ammonium chloride solution (3ml) cancellation, DMF and MeI are removed in decompression, add 20ml ethyl acetate, 5ml water, by ethyl acetate (10ml * 2), extract, with saturated nacl aqueous solution (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound 60 (56.1ml, 54%).
Under argon shield; at 0 ℃; toluene and DCE (1: 1) to compound (0.11mmol) (5ml) slowly drip DIPEA (0.5ml in solution; 0.54mmol), (5ml) solution of the toluene of compound a and DCE (1: 1); be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete; cooling; with saturated ammonium chloride (3ml) cancellation, concentrated, add 20ml ethyl acetate; 5ml water; with ethyl acetate (10ml * 2) extraction, with saturated sodium-chloride (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound (21-24%).
In methyl alcohol (1.3ml) solution of compound upward (0.041mmol), add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, with ethyl acetate (10ml * 3) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (61-67%).
Under argon shield, at-78 ℃, to compound 59 (100mg, in DMF 0.11mmol) (10ml) solution, slowly drip LiHMDS (0.5ml, DMF 0.54mmol) (2ml) solution, after stirring 1h, add MeCl (3ml), after reaction 12h, naturally be warmed up to 0 ℃, intensification needs 5h, at 0 ℃, react again 4h, cool to-78 ℃, with saturated ammonium chloride solution (3ml) cancellation, DMF and MeI are removed in decompression, add 20ml ethyl acetate, 5ml water, by ethyl acetate (10ml * 2), extract, with saturated nacl aqueous solution (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound 60 (56.1ml, 54%).
Under argon shield; at 0 ℃; to the THF solution that drips TBAF (0.180mmol) in THF (2ml) solution of compound 79 (0.082mmol); reaction 8h; TLC detection reaction is complete; saturated ammonium chloride solution (1ml) cancellation; methyl alcohol is removed in decompression; by ethyl acetate (5ml * 3), extract; with saturated nacl aqueous solution (5ml), wash; anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 48 (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)，3.45(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.
Embodiment 62 compounds 49
Under argon shield, in 0 ℃ of pyridine to compound (5.51mmol) (54ml) solution, drip TrocCl (2.49ml, 18.18mmol); room temperature reaction 1h; TLC detection reaction is complete, and pyridine is removed in decompression, adds 80ml ethyl acetate; 50ml water; with ethyl acetate (50ml * 2) extraction, with saturated sodium-chloride (50ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (79-83%).
Compound (3.36mmol), compound, DCC, DMAP are added in reaction flask successively; under argon shield, add 68mL toluene; after 85 ℃ of stirring reaction 2h, HPLC monitoring reacts completely; toluene is removed in decompression; add 80ml ethyl acetate; 50ml water; stir 20min; remove by filter insolubles; with ethyl acetate (50ml * 2) extraction, with saturated sodium-chloride (50ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain compound (92%).
Under argon shield, at-78 ℃, to compound 59 (100mg, in DMF 0.11mmol) (10ml) solution, slowly drip LiHMDS (0.5ml, DMF 0.54mmol) (2ml) solution, after stirring 1h, add MeI (3ml), after reaction 12h, naturally be warmed up to 0 ℃, intensification needs 5h, at 0 ℃, react again 4h, cool to-78 ℃, with saturated ammonium chloride solution (3ml) cancellation, DMF and MeI are removed in decompression, add 20ml ethyl acetate, 5ml water, by ethyl acetate (10ml * 2), extract, with saturated nacl aqueous solution (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound 60 (56.1ml, 54%).
Under argon shield; at 0 ℃; toluene and DCE (1: 1) to compound (0.11mmol) (5ml) slowly drip DIPEA (0.5ml in solution; 0.54mmol), (5ml) solution of the toluene of compound a and DCE (1: 1); be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete; cooling; with saturated ammonium chloride (3ml) cancellation, concentrated, add 20ml ethyl acetate; 5ml water; with ethyl acetate (10ml * 2) extraction, with saturated sodium-chloride (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound (21-24%).
In methyl alcohol (1.3ml) solution of compound upward (0.041mmol), add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, with ethyl acetate (10ml * 3) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (61-67%).
Under argon shield, at-78 ℃, to compound 59 (100mg, in DMF 0.11mmol) (10ml) solution, slowly drip LiHMDS (0.5ml, DMF 0.54mmol) (2ml) solution, after stirring 1h, add MeCl (3ml), after reaction 12h, naturally be warmed up to 0 ℃, intensification needs 5h, at 0 ℃, react again 4h, cool to-78 ℃, with saturated ammonium chloride solution (3ml) cancellation, DMF and MeI are removed in decompression, add 20ml ethyl acetate, 5ml water, by ethyl acetate (10ml * 2), extract, with saturated nacl aqueous solution (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound 60 (56.1ml, 54%).
Under argon shield; at 0 ℃; to the THF solution that drips TBAF (0.180mmol) in THF (2ml) solution of compound 79 (0.082mmol); reaction 8h; TLC detection reaction is complete; saturated ammonium chloride solution (1ml) cancellation; methyl alcohol is removed in decompression; by ethyl acetate (5ml * 3), extract; with saturated nacl aqueous solution (5ml), wash; anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 49 (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)，3.45(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.
Embodiment 63 compounds 50
Under argon shield, in 0 ℃ of pyridine to compound (5.51mmol) (54ml) solution, drip TrocCl (2.49ml, 18.18mmol); room temperature reaction 1h; TLC detection reaction is complete, and pyridine is removed in decompression, adds 80ml ethyl acetate; 50ml water; with ethyl acetate (50ml * 2) extraction, with saturated sodium-chloride (50ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (79-83%).
Compound (3.36mmol), compound, DCC, DMAP are added in reaction flask successively, under argon shield, add 68mL toluene, after 85 ℃ of stirring reaction 2h, HPLC monitoring reacts completely, toluene is removed in decompression, add 80ml ethyl acetate, 50ml water, stir 20min, remove by filter insolubles, with ethyl acetate (50ml * 2) extraction, with saturated sodium-chloride (50ml) washing, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain compound (92%).
In methyl alcohol (120ml) solution of compound (3.09mmol), add successively zinc powder (92.87mmol) and acetic acid, after 30 ℃ of reaction 5h, TLC detection reaction is complete, remove by filter zinc powder, methyl alcohol and acetic acid are removed in decompression, add 100ml ethyl acetate, 50ml water, with ethyl acetate (50ml * 2) extraction, with saturated sodium-chloride (50ml) washing, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (90%).
Under argon shield; at 0 ℃; toluene and DCE (1: 1) to compound (0.11mmol) (5ml) slowly drip DIPEA (0.5ml in solution; 0.54mmol), (5ml) solution of the toluene of compound a and DCE (1: 1); be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete; cooling; with saturated ammonium chloride (3ml) cancellation, concentrated, add 20ml ethyl acetate; 5ml water; with ethyl acetate (10ml * 2) extraction, with saturated sodium-chloride (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound (21-24%).
In methyl alcohol (1.3ml) solution of compound upward (0.041mmol), add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, with ethyl acetate (10ml * 3) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (61-67%).
Under argon shield, at-78 ℃, to compound 59 (100mg, in DMF 0.11mmol) (10ml) solution, slowly drip LiHMDS (0.5ml, DMF 0.54mmol) (2ml) solution, after stirring 1h, add MeCl (3ml), after reaction 12h, naturally be warmed up to 0 ℃, intensification needs 5h, at 0 ℃, react again 4h, cool to-78 ℃, with saturated ammonium chloride solution (3ml) cancellation, DMF and MeI are removed in decompression, add 20ml ethyl acetate, 5ml water, by ethyl acetate (10ml * 2), extract, with saturated nacl aqueous solution (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound 60 (56.1ml, 54%).
Under argon shield; at 0 ℃; to the THF solution that drips TBAF (0.180mmol) in THF (2ml) solution of compound 79 (0.082mmol); reaction 8h; TLC detection reaction is complete; saturated ammonium chloride solution (1ml) cancellation; methyl alcohol is removed in decompression; by ethyl acetate (5ml * 3), extract; with saturated nacl aqueous solution (5ml), wash; anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 50 (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，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.
Embodiment 64 compounds 51
Under argon shield, at 0 ℃, toluene and DCE (1: 1) to compound (0.11mmol) (5ml) slowly drip DIPEA (0.5ml in solution, 0.54mmol), the toluene of compound a and DCE (1: 1) (5 ml) solution, be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete, cooling, with saturated ammonium chloride (3ml) cancellation, concentrated, add 20ml ethyl acetate, 5ml water, by ethyl acetate (10ml * 2), extract, with saturated sodium-chloride (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound (21-24%).
Under argon shield, at 0 ℃, the toluene of compound (0.11mmol) and DCE (1: 1) (5ml) slowly drip DIPEA (0.5ml in solution upward, 0.54mmol), the toluene of compound b and DCE (1: 1) be solution (5ml), be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete, cooling, with saturated ammonium chloride (3ml) cancellation, concentrated, add 20ml ethyl acetate, 5ml water, by ethyl acetate (10ml * 2), extract, with saturated sodium-chloride (5ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound (21-25%).
In methyl alcohol (1.3ml) solution of compound upward (0.041mmol), add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, with ethyl acetate (10ml * 3) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (61-65%).
Under argon shield; at 0 ℃; to the THF solution that drips TBAF (0.180mmol) in THF (2ml) solution of compound 79 (0.082mmol); reaction 8h; TLC detection reaction is complete; saturated ammonium chloride solution (1ml) cancellation; methyl alcohol is removed in decompression; by ethyl acetate (5ml * 3), extract; with saturated nacl aqueous solution (5ml), wash; anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 51 (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)，5.43-5.47(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.
Embodiment 65 compounds 52
Under argon shield, in 0 ℃ of pyridine to compound (5.51mmol) (54ml) solution, drip TrocCl (2.49ml, 18.18mmol); room temperature reaction 1h; TLC detection reaction is complete, and pyridine is removed in decompression, adds 80ml ethyl acetate; 50ml water; with ethyl acetate (50ml * 2) extraction, with saturated sodium-chloride (50ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (79-83%).
Compound (3.36mmol), compound, DCC, DMAP are added in reaction flask successively; under argon shield, add 68mL toluene; after 85 ℃ of stirring reaction 2h, HPLC monitoring reacts completely; toluene is removed in decompression; add 80ml ethyl acetate; 50ml water; stir 20min; remove by filter insolubles; with ethyl acetate (50ml * 2) extraction, with saturated sodium-chloride (50ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain compound (87-93%).
In methyl alcohol (120ml) solution of compound (3.09mmol), add successively zinc powder (92.87mmol) and acetic acid, after 30 ℃ of reaction 5h, TLC detection reaction is complete, remove by filter zinc powder, methyl alcohol and acetic acid are removed in decompression, add 100ml ethyl acetate, 50ml water, by ethyl acetate (50ml * 2), extract, with saturated sodium-chloride (50ml), wash, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound (89-91%).
Compound (3.36mmol), compound, DCC, DMAP are added in reaction flask successively; under argon shield, add 68mL toluene; after 85 ℃ of stirring reaction 2h, HPLC monitoring reacts completely; toluene is removed in decompression; add 80ml ethyl acetate; 50ml water; stir 20min; remove by filter insolubles; with ethyl acetate (50ml * 2) extraction, with saturated sodium-chloride (50ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=3: 1) obtain compound (87-93%).
In methyl alcohol (1.3ml) solution of compound (0.052mmol), add tosic acid (11mg, 0.058mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, with ethyl acetate (10ml * 3) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound
Under argon shield; at 0 ℃; to the THF solution that drips TBAF (0.180mmol) in THF (2ml) solution of compound 79 (0.082mmol); reaction 8h; TLC detection reaction is complete; saturated ammonium chloride solution (1ml) cancellation; methyl alcohol is removed in decompression; by ethyl acetate (5ml * 3), extract; with saturated nacl aqueous solution (5ml), wash; anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 52 (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)，3.82-3.84(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.
Embodiment 66 compounds 53
Under argon shield; at 0 ℃; toluene and DCE (1: 1) to compound (0.11mmol) (5ml) slowly drip DIPEA (0.5ml in solution; 0.54mmol), (5ml) solution of the toluene of compound a and DCE (1: 1); be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete; cooling; with saturated ammonium chloride (3ml) cancellation, concentrated, add 20ml ethyl acetate; 5ml water; with ethyl acetate (10ml * 2) extraction, with saturated sodium-chloride (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound (21-24%).
In methyl alcohol (1.3ml) solution of compound upward (0.041mmol), add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, with ethyl acetate (10ml * 3) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying, concentrated, obtain white solid compound (61-65%).
Under argon shield; at 0 ℃; to the THF solution that drips TBAF (0.180mmol) in THF (2ml) solution of compound 79 (0.082mmol); reaction 8h; TLC detection reaction is complete; saturated ammonium chloride solution (1ml) cancellation; methyl alcohol is removed in decompression; by ethyl acetate (5ml * 3), extract; with saturated nacl aqueous solution (5ml), wash; anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 53 (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.
Embodiment 67 compounds 54
Under argon shield; at 0 ℃; toluene and DCE (1: 1) to compound (0.11mmol) (5ml) slowly drip DIPEA (0.5ml in solution; 0.54mmol), (5ml) solution of the toluene of compound a and DCE (1: 1); be warming up to 50 ℃, reaction 12h, TLC detection reaction is complete; cooling; with saturated ammonium chloride (3ml) cancellation, concentrated, add 20ml ethyl acetate; 5ml water; with ethyl acetate (10ml * 2) extraction, with saturated sodium-chloride (5ml) washing, anhydrous sodium sulfate drying; concentrated, column chromatography (PE: EA=2: 1) obtain white solid compound (21-24%).
In methyl alcohol (1.3ml) solution of compound upward (0.041mmol), add tosic acid (7.7mg, 0.045mmol), stirring at room 1h, TLC detection reaction is complete, saturated sodium bicarbonate solution (2ml) cancellation, methyl alcohol is removed in decompression, with ethyl acetate (10ml * 3) extraction, with saturated nacl aqueous solution (5ml) washing, anhydrous sodium sulfate drying, concentrated, obtain white solid compound (61-65%).
Under argon shield; at 0 ℃; to the THF solution that drips TBAF (0.180mmol) in THF (2ml) solution of compound 79 (0.082mmol); reaction 8h; TLC detection reaction is complete; saturated ammonium chloride solution (1ml) cancellation; methyl alcohol is removed in decompression; by ethyl acetate (5ml * 3), extract; with saturated nacl aqueous solution (5ml), wash; anhydrous sodium sulfate drying, concentrated, column chromatography (PE: EA=3: 1) obtain white solid compound 54 (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)，3.47-3.52(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.
Embodiment 68 detection compound are tested tumor cell viability
1. experimental principle: the growth of compound anticancer detects by MTT method.The principle of mtt assay is, yellow Thiazolyl blue can permeate through cell membranes enter in cell, succinodehydrogenase in viable cell plastosome can make exogenous MTT be reduced to water-insoluble bluish voilet crystallization first a ceremonial jade-ladle, used in libation (Formazan) and be deposited in cell, and dead cell is without this function.First a ceremonial jade-ladle, used in libation in dimethyl sulfoxide (DMSO) (DMSO) energy dissolved cell, measures its absorbance value with enzyme-linked immunosorbent assay instrument at 570nm wavelength place, can indirectly reflect viable cell quantity.
2. experiment material: the cell using is HT1080 (human fibrosarcoma cell), Huh-7 (Bel7402), A549 (Lu-csf-1), Hela (human hela cell), HL60 (people's promyelocytic leukemia clone), A431 (cell of epidermoid carcinoma), MCF-7 (human breast carcinoma), DU145 (human benign prostatic cancer cells), U937 (lymphoma cell strain of human tissue cell), BEL-7402 (hepatocellular carcinoma), SGC-7901 (SGC-7901), K562 (human leukemia cell), PANC-1 (mankind's cancer of pancreas clones), BGC823 (gastric carcinoma cells), Molt-4 (people's acute lymphoblastic leukemia cell), with DMEM+10%FBS culture medium culturing or use 1640+10%FBS, cultivate respectively.
3. experimental technique and interpretation of result:
Experimental group: the medicine of 190 μ l cell suspension+10 μ l different concns (final concentration is 10-5～10-10M)
Blank group: 200 μ l PBS
Negative control group: 190 μ l cell suspension+10 μ l 2%DMSO (DMSO final concentration is 0.1%)
Positive controls: the compound of 190 μ l cell suspension+10 μ l different concns
A). cell is inoculated in 96 orifice plates, and inoculum size is 1500/hole, 190 μ l/ holes, the CO2 incubator overnight incubation of 37 ℃ 5%;
B). next day, every hole added 10 μ l different pharmaceuticals, and medicine final concentration is 10-5～10-10M, establishes three parallel holes; 37 ℃, 5% CO2 incubator are hatched 72 hours;
C). every hole adds the MTT of 20 μ l 5mg/ml, and the CO2 incubator of 37 ℃ 5% is hatched 4 hours;
D). abandon supernatant, every hole adds the DMSO of 100 μ l, vibration;
E) .570nm reading, calculates cell survival rate, according to result, calculates GI50, obtains following table.
Table 1
Table 2
Table 3
Table 4
Table 5
Table 6
Table 7
Table 8
Table 9
What in upper table, GI50 represented is the required drug level of cell 50% growth-inhibiting.
Result from upper table can be found out: the above-mentioned compound having in the effect that suppresses some cancer cells and taxol quite or more remarkable.
In sum, the D51-7059 that the present invention is synthetic, good compared with taxol aspect water-soluble, and also better at some anticancer effect.And hydrophobic group antitumour activity is better.
Foregoing is only the basic explanation of the present invention under conceiving, and according to any equivalent transformation that technical scheme of the present invention is done, all should belong to protection scope of the present invention.

Claims (9)

1. the compound that general formula (I) represents, its structural formula is as follows:
Wherein: R 1group is C 1-6alkyl, C 3-8cycloalkyl ,-(C=O)-(C 1-6alkyl) ,-CH 2-O-(C 1-6alkyl) or C 1-6alkyl alcohol;
R 2group is C 1-6alkyl, C 3-8cycloalkyl ,-(C=O)-(C 1-6alkyl) ,-CH 2-O-(C 1-6alkyl) or C 1-6alkyl alcohol;
R 3group is H, C 1-6alkyl, C 3-8cycloalkyl ,-(C=O)-(C 1-6alkyl) ,-CH 2-O-(C 1-6alkyl) or C 1-6alkyl alcohol;
R 4group is (C 1-6alkyl), C 1-6alkyl, C 3-8cycloalkyl ,-(C=O)-(C 1-6alkyl) ,-CH 2-O-(C 1-6alkyl) or C 1-6alkyl alcohol.
2. the compound that general formula according to claim 1 (I) represents, is characterized in that:
Wherein,
R 1group is C 1-6alkyl or C 3-8cycloalkyl;
R 2group is C 1-6alkyl, C 3-16cycloalkyl ,-(C=O)-(C 1-8alkyl) or-CH 2-O-(C 1-6alkyl);
R 3group is H, C 1-6alkyl, C 3-8cycloalkyl ,-(C=O)-(C 1-6alkyl) ,-CH 2-O-(C 1-6alkyl) or C 1-6alkyl alcohol;
R 4group is (C 1-6alkyl), C 1-6alkyl, C 3-8cycloalkyl ,-(C=O)-(C 1-6alkyl) ,-CH 2-O-(C 1-6alkyl) or C 1-6alkyl alcohol.
3. the compound that general formula according to claim 1 (I) represents, is characterized in that:
Wherein,
R 1group is-(C=O)-(C 1-8alkyl) ,-CH 2-O-(C 1-6alkyl) or C 1-6alkyl alcohol;
R 2group is C 1-6alkyl, C 3-8cycloalkyl ,-(C=O)-(C 1-8alkyl) or-CH 2-O-(C 1-6alkyl);
R 3group is H, C 1-6alkyl, C 3-8cycloalkyl ,-(C=O)-(C 1-6alkyl) ,-CH 2-O-(C 1-6alkyl) or C 1-6alkyl alcohol;
R 4group is (C 1-6alkyl), C 1-6alkyl, C 3-8cycloalkyl ,-(C=O)-(C 1-6alkyl) ,-CH 2-O-(C 1-6alkyl) or C 1-6alkyl alcohol.
4. the compound that general formula according to claim 1 (I) represents, is characterized in that: its structural formula is
5. the isomer of the compound described in claim 1～4, racemic modification, pharmacy acceptable salt, crystalline hydrate, solvate or their mixture.
6. a pharmaceutical composition, the isomer of compound, racemic modification, pharmacy acceptable salt, crystalline hydrate, solvate or their mixture described in any one claim of being selected from claim 1-4 that it comprises significant quantity, and contain one or more pharmaceutically acceptable carriers.
7. a kind of pharmaceutical composition claimed in claim 6 prevents or treats the purposes in fibrosarcoma, liver cancer, lung cancer, leukemia, epidermoid carcinoma, mammary cancer, prostate cancer, lymphoma, cancer of the stomach, bone marrow cancer and carcinoma of the pancreas medicine in preparation.
8. in claim 1-4, described in any one, compound prevents or treats the purposes in fibrosarcoma, liver cancer, lung cancer, leukemia, epidermoid carcinoma, mammary cancer, prostate cancer, lymphoma, cancer of the stomach, bone marrow cancer and carcinoma of the pancreas medicine in preparation.
9. the isomer of compound, racemic modification, pharmacy acceptable salt, crystalline hydrate, solvate or their the mixture purposes in preparation prevention or treatment and fibrosarcoma, liver cancer, lung cancer, leukemia, epidermoid carcinoma, mammary cancer, prostate cancer, lymphoma, cancer of the stomach, bone marrow cancer and carcinoma of the pancreas medicine described in any one in claim 1-4.
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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
CN115232092A (en) * 2022-05-19 2022-10-25 无锡紫杉药业有限公司 Preparation method of 10-acetyl docetaxel

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