CN103087040B - Penicillide derivative, its preparation method and at pharmaceutical usage - Google Patents

Penicillide derivative, its preparation method and at pharmaceutical usage Download PDF

Info

Publication number
CN103087040B
CN103087040B CN201110340808.0A CN201110340808A CN103087040B CN 103087040 B CN103087040 B CN 103087040B CN 201110340808 A CN201110340808 A CN 201110340808A CN 103087040 B CN103087040 B CN 103087040B
Authority
CN
China
Prior art keywords
add
compound
concentrated
filters
single port
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CN201110340808.0A
Other languages
Chinese (zh)
Other versions
CN103087040A (en
Inventor
雷新胜
林国强
王逸平
方李松
张桥
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fudan University
Original Assignee
Fudan University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fudan University filed Critical Fudan University
Priority to CN201110340808.0A priority Critical patent/CN103087040B/en
Publication of CN103087040A publication Critical patent/CN103087040A/en
Application granted granted Critical
Publication of CN103087040B publication Critical patent/CN103087040B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention belongs to pharmaceutical synthesis field, be specifically related to new Penicillide derivative, its preparation method and the pharmaceutical composition containing this derivative and its purposes as therapeutical agent.Penicillide derivative of the present invention is for having the compound of general formula (I), and Penicillide derivative of the present invention can be used as effective constituent pharmaceutical compositions and especially prepares cholestery ester transfer protein inhibitors medicine; wherein: R 1be selected from (1R, 4S)-7-methyl bicyclic [2.2.1] heptane-7-carbonyl, 4-benzoyl bromide, 4-TRIFLUOROMETHYLBENZOYL, 3,5-bis-(trifluoromethyl) benzoyl; R 2be selected from hydrogen, methyl, p-methoxyphenyl; R 3be selected from hydrogen, methoxyl group.

Description

Penicillide derivative, its preparation method and at pharmaceutical usage
Technical field
The invention belongs to pharmaceutical synthesis field, be specifically related to new Penicillide derivative, its preparation method and the pharmaceutical composition containing this derivative and its purposes as therapeutical agent.
Background technology
Within 1974, from fungi plant, extract natural product Penicillide by people such as Japanese scientific research personnel Sassa, and confirm its basic structure (Tetrahedron Lett.1974,15 (45), 3941-3942.), and its absolute configuration is until just determine (Bioorg.Med.Chem.Lett.1993 by people such as Salituro in 1992,3 (2), 337-340.).Beyer Co., Ltd by carrying out derivatize to Penicillide, and confirms that its derivative has good cholesteryl ester transfer protein inhibit activities (the patent WO2004039453 of Beyer Co., Ltd; Bioorg.Med.Chem.Lett.2005,15 (15), 3611-3614.).Research and development problem about its derivative of natural product Penicillide has caused the concern of this area investigator.
Summary of the invention
The object of this invention is to provide new Penicillide derivative.
Penicillide derivative of the present invention is for having the compound of general formula (I):
Wherein:
R 1be selected from (1R, 4S)-7-methyl bicyclic [2.2.1] heptane-7-carbonyl, 4-benzoyl bromide, 4-TRIFLUOROMETHYLBENZOYL, 3,5-bis-(trifluoromethyl) benzoyl;
R 2be selected from hydrogen, methyl, p-methoxyphenyl;
R 3be selected from hydrogen, methoxyl group.
Concrete, compound of the present invention, has following chemical structural formula respectively:
A further object of the present invention is to provide the pharmaceutical usage of above-mentioned Penicillide derivative.Be specifically related to state Penicillide derivative in the pharmaceutical composition prepared containing this derivative and its purposes as therapeutical agent.
Pharmaceutical composition involved in the present invention, it contains above-mentioned Penicillide derivative and the pharmaceutical carriers for the treatment of effective dose.
The invention particularly relates to cholestery ester transfer protein inhibitors medicine, it contains above-mentioned Penicillide derivative and the pharmaceutical carriers for the treatment of effective dose.In other words, the invention provides the composition of the above-claimed cpd containing medicine effective dose, and described compound is preparing the purposes in cholestery ester transfer protein inhibitors medicine.
The invention provides the synthetic method of the above-mentioned Penicillide derivative as described in embodiment.
Embodiment
Be used for further describing the present invention below in conjunction with embodiment, but these embodiments not limit the scope of the invention.
Embodiment 1: prepare following compound,
1. step 1
Add NaH (5.8g, 144mmol) in the single port bottle of 250mL drying, THF (72mL) dissolves, drip compound 2, THF (36mL) solution of 3-Dihydroxy benzaldehyde (10.0g, 72mmol), room temperature reaction 1 hour.Slowly add THF (18mL) solution of cylite (12.3g, 72mmol) again, room temperature reaction 24 hours.Poured into by reaction solution in water (300mL), methylene dichloride (3x100mL) extracts, aqueous phase 1N hydrochloric acid adjust pH to 2 again, methylene dichloride (3x100mL) is used to extract again, 1N hydrochloric acid (2x100mL) is washed, and merges organic phase, anhydrous MgSO 4drying, filters, concentrated, column chromatography PE: EA=20: 1 (R f=0.42, PE: EA=10: 1), rear ethyl alcohol recrystallization obtains 10.7g compound 1, yield 65%.
1H-NMR(CDCl 3，300MHz)：δ11.12(s，1H，OH)，9.92(s，1H，CHO)，7.47-7.32(m，5H，Ar-H)，7.20(dd，J＝7.8，1.4Hz，1H，Ar-H)，7.13(d，J＝7.8Hz，1H，Ar-H)，6.90(t，J＝7.8Hz，1H，Ar-H)，5.20(s，2H，CH 2).MS(ESI)：229.1(M+H) +.
2. step 2
Add compound 1 (5.02g, 21.9mmol) in 250mL single port bottle, add methyl alcohol (200mL), under ice bath, add NaBH in batches 4(3.34g, 88.7mmol), more at room temperature react 4h.Concentrating under reduced pressure, is dissolved in 3N hydrochloric acid by the white solid obtained, and methylene dichloride (3x100mL) extracts, and merge organic phase, water (3x100mL) is washed, anhydrous Na 2sO 4drying, filters, and concentrates to obtain white solid 4.94g compound 2, yield 98%.
1H-NMR(CDCl 3，300MHz)：δ7.42-7.36(m，5H，Ar-H)，6.91-6.79(m，3H，Ar-H)，6.08(s，1H，OH)，5.11(s，2H，CH 2)，4.74(s，2H，CH 2)，2.33(br s，1H，OH).MS(ESI)：253.0(M+Na) +.
3. step 3
Add compound 2 (300mg, 1.3mmol) in the single port bottle of 100mL, then use dry methylene dichloride (5mL) to dissolve.Add tosic acid (24mg, 0.13mmol), after stirring 15min in cryosel bath, drip 3,4-dihydro-2H-pyrans (0.12mL, 1.37mmol), stopped reaction after 2h.Add triethylamine (1mL) cancellation reaction, organic phase saturated aqueous common salt (10mL) is washed, anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE: EA=20: 1 (R f=0.60, PE: EA=6: 1) 393mg compound 3 is obtained, yield 96%.
1H-NMR(CDCl 3，400MHz)：δ7.44-7.33(m，5H，Ar-H)，6.94(dd，J＝7.6，1.2Hz，1H，Ar-H)，6.87(dd，J＝7.8，1.2Hz，1H，Ar-H)，6.80(t，J＝7.8Hz，1H，Ar-H)，6.38(s，1HOH)，5.11(s，2H，CH 2)，4.86(d，J＝12Hz，1H，CH 2)，4.76(t，J＝3.8Hz，1H，CH)，4.63(d，J＝12Hz，1H，CH 2)，3.96-3.93(m，1H，CH 2)，3.58-3.55(m，1H，CH 2)，1.86-1.52(m，6H).MS(ESI)：337.2(M+Na) +.
4. step 4
5-amino-2-methyl phenol (1.00g, 8.13mmol) is added, NaHCO in the single port bottle of 100mL 3(2.05g, 24.4mmol), H 2o (33mL) and ethyl acetate (28mL), stirring at room temperature adds pivaloyl chloride (1.05mL, 8.54mmol), stopped reaction after 1h after dissolving.Organic phase 1N hydrochloric acid (1x30mL) is washed, anhydrous Na 2sO 4drying, filters, concentrated (R f=0.75, PE: EA=2: 1) 1.84g compound 4 is obtained, yield 97%.
1H-NMR(CDCl 3，400MHz)：δ8.57(s，1H)，7.89(s，1H)，7.38(s，1H)，6.99(d，J＝7.8Hz，1H，Ar-H)，6.39(d，J＝7.8Hz，1H，Ar-H)，2.19(s，3H，CH 3)，1.32(s，9H，t-Bu-H). 13C-NMR(CDCl 3，100MHz)：δ177.6，155.6，136.0，130.3，121.0，110.2，107.4，39.6，27.5(3C)，15.6.MS(ESI)：208.0(M+H) +.HRMS(APCI)：Calcd.for C 12H 18NO 2 +(M+H) +：208.1338，found：208.1349.
5. step 5
Compound 4 (1.00g, 4.83mmol) is added, K in 50mL single port bottle 2cO 3(1.67g, 12.1mmol), adds DMF (10mL), more at room temperature adds MeI (0.36mL, 5.8mmol), stopped reaction after 4h under argon shield.Add H 2o (10mL), extraction into ethyl acetate (3x20mL), water (2x50mL) is washed, anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE: EA=6: 1 (R f=0.69, PE: EA=4: 1) 1.00g compound 5 is obtained, yield 94%.
1H-NMR(CDCl 3，300MHz)：δ7.49(s，1H，Ar-H)，7.32(br s，1H，NH)，7.03(d，J＝8.1Hz，1H，Ar-H)，6.73-6.70(m，1H，Ar-H)，3.84(s，3H，OCH 3)，2.17(s，3H，CH 3)，1.32(s，9H，t-Bu-H).MS(ESI)：222.2(M+H) +.
6. step 6
Add compound 5 (500mg, 2.26mmol) in 50mL single port bottle, under argon shield, add dry THF (10mL), under cryosel bath, slowly drip n-buLi (4.5mL, 7.24mmol, 1.6M in THF).Dropwise rear stirring at room temperature 2h, then pass into CO 2gas 2h.Add H subsequently 2o (30mL), extraction into ethyl acetate (1x20mL), aqueous phase 1N HCl adjust pH to 1, then be extracted with ethyl acetate (4x30mL), merge organic phase, anhydrous Na 2sO 4drying, filters, concentrated (R f=0.24, PE: EA=4: 1) 540mg compound 6 is obtained, yield 90%.
1H-NMR(CDCl 3，300MHz)：δ11.72(s，1H，COOH)，8.63(d，J＝8.7Hz，1H，Ar-H)，7.40(d，J＝8.4Hz，1H，Ar-H)，3.92(s，3H，OCH 3)，2.32(s，3H，CH 3)，1.34(s，9H，t-Bu-H).MS(EI)：265.
7. step 7
Compound 6 (12.6g, 47.6mmol) is added, dissolve with methanol (50mL) in the single port bottle of 100mL, after slowly drip the vitriol oil (5.7mL) successively, trimethyl orthoformate (5.7mL, 52.4mmol), reflux, stopped reaction after 3 days, cooling, DCM dilutes (30mL), 1N hcl as extraction agent organic phase, aqueous phase 3N NaOH adjust pH to 13, rear DCM extraction (3x50mL), organic phase anhydrous Na 2sO 4drying, filters, concentrated (R f=0.64, PE: EA=3: 1) 7.41g compound 7 is obtained, yield 80%.
1H-NMR(CDCl 3，300MHz)：δ7.03(d，J＝8.4Hz，1H，Ar-H)，6.40(d，J＝8.7Hz，1H，Ar-H)，5.01(br s，2H，NH 2)，3.93(s，3H，OCH 3)，3.74(s，3H，OCH 3)，2.16(s，3H，CH 3).MS(ESI)：196.1(M+H) +.
8. step 8
Compound 7 (7.41g, 38.0mmol) is added, HBr (21mL), H in the single port bottle of 250mL 2o (82mL), is stirred to dissolving, drips NaNO under cryosel bath 2the aqueous solution of (2.86g, 41.4mmol), stirs 1h.Then slowly drip Hydrogen bromide (10mL) solution of CuBr (7.77g, 54.3mmol), be stirred to after not having bubble formation, oil bath 80 DEG C of reactions are spent the night.Stopped reaction, cooling, DCM (3x100mL) extracts, after merging organic phase, saturated NaHCO 3(1x100mL) wash, anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE: EA=100: 1 (R f=0.62, PE: EA=20: 1) 7.76g compound 8 is obtained, yield 79%.
1H-NMR(CDCl 3，300MHz)：δ7.23(d，J＝8.4Hz，1H，Ar-H)，7.09(d，J＝8.1Hz，1H，Ar-H)，3.96(s，3H，OCH 3)，3.79(s，3H，OCH 3)，2.26(s，3H，CH 3).MS(ESI)：259.0，261.1(M+H) +.
9. step 9
Add NBS (501mg, 2.81mmol) in the there-necked flask of 50mL, Diisopropyl azodicarboxylate (28mg, 0.18mmol), under argon shield, add the CCl of compound 8 (228mg, 0.88mmol) 4solution (10mL), is heated to backflow, reaction spend the night after stopped reaction, cooling, filters, concentrated, directly next step.50ml contains in the reaction flask of crude product and slowly drips the vitriol oil (5mL), stirring at room temperature, stopped reaction when TLC monitoring disappears to raw material, pours in frozen water (10mL) by reaction solution, ethyl acetate (3x20mL) extracts, saturated NaHCO 3(1x20mL) wash, water (1x30mL) is washed, anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE: EA=40: 1 (R f=0.17, PE: EA=50: 1) 208mg compound 9 is obtained, yield 87%.
1H-NMR(CDCl 3，300MHz)：δ10.30(s，1H，CHO)，7.78-7.74(m，1H，Ar-H)，7.49-7.46(m 1H，Ar-H)，3.99(s，3H，OCH 3)，3.98(s，3H，OCH 3).MS(ESI)：272.9，274.9(M+H) +.
10. step 10
Compound 3 (1.12g is added in 100mL single port bottle; 3.55mmol); compound 9 (0.808g, 2.96mmol), Cu (0.474g; 7.40mmol); CuO (0.592g, 7.40mmol), DMAP (1.08g; 8.88mmol), CH is added under argon shield 3cN (25mL), reheats to backflow, stopped reaction after reaction 17h, cooling, and DCM dilutes (20mL), filters, concentrated, column chromatography PE: EA=6: 1 (R f=0.11, PE: EA=10: 1) 1.10g compound 10 is obtained, yield 73%.
1H-NMR(CDCl 3，400MHz)：δ10.22(s，1H，CHO)，7.71(d，J＝4.7Hz，1H，Ar-H)，7.27-7.13(m，7H，Ar-H)，6.99(dd，J＝8.1，1.4Hz，1H，Ar-H)，6.43(d，J＝8.8Hz，1H，Ar-H)，5.02(s，2H，CH 2)，4.73(d，J＝12Hz，1H，CH 2)，4.67-4.66(m，1H，CH)，4.48(d，J＝12Hz，1H，CH 2)，3.99(s，3H，OCH 3)，3.94(s，3H，OCH 3)，3.83-3.76(m，1H，CH 2)，3.51-3.45(m，1H，CH 2)，1.65-1.43(m，6H).MS(ESI)：529.2(M+Na) +.
11. steps 11
Add compound 10 (1.01g, 2mmol) in the single port bottle of 100mL, tosic acid (2mg), after add Virahol (9mL) and H 2o (2mL), is heated to backflow and spends the night, stopped reaction, and cooling, adds H 2o (10mL), extraction into ethyl acetate (3x30mL), organic phase washing (1x30mL), anhydrous MgSO 4drying, filters, concentrated, column chromatography PE: EA=3: 1 (R f=0.14, PE: EA=3: 1) 720mg compound 11 is obtained, yield 88%.
1H-NMR(CDCl 3，400MHz)：δ10.20(s，1H，CHO)，7.73(d，J＝8.6Hz，1H，Ar-H)，7.26-7.14(m，6H，Ar-H)，7.07(d，J＝7.2Hz，1H，Ar-H)，6.99(d，J＝8.4Hz，1H，Ar-H)，6.43(d，J＝9.0Hz，1H，Ar-H)，5.02(s，2H，CH 2)，4.60(s，2H，CH 2)，3.98(s，3H，OCH 3)，3.94(s，3H，OCH 3)，2.74(br s，1H，OH). 13C-NMR(CDCl 3，100MHz)：δ187.7，165.5，161.9，160.7，150.5，140.2，136.3，135.3，131.6，128.3(2C)，127.8，126.8(2C)，126.7，123.4，121.3，117.5，114.0，110.0，70.5，64.7，60.5，52.9.MS(EI)：422.HRMS(ESI)：Calcd.for C 24H 22O 7Na +(M+Na) +：445.1263，found：445.1262.
12. steps 12
Compound 11 (655mg is added in the single port bottle of 100mL, 1.55mmol), (10mL) is dissolved with MeOH, add tosic acid (55mg, 0.32mmol), after stirring at room temperature 1h, add NaOH (722mg, 18.5mmol), be heated to backflow, reaction is spent the night.Stopped reaction, cooling, concentrating under reduced pressure removing MeOH, with 3N HCl adjust pH to 4, extraction into ethyl acetate (4x30mL), anhydrous Na 2sO 4drying, filters, concentrated, obtains 653mg compound 12 crude product.
MS(ESI)：407.0(M-H) -.
13. steps 13
The crude product (568mg, 1.39mmol) of compound 12 and triethylamine (1.55mL, 11.1mmol) are dissolved in dry CH 3in CN (10mL), be dissolved in dry CH by being slowly added drop-wise under above-mentioned obtained solution room temperature by the chloro-1-picoline (1.42g, 5.57mmol) of iodate-2- 3in the solution that CN (40mL) configures.After dropwising, heating reflux reaction 1h.Rear stopped reaction, cooling, concentrating under reduced pressure removing CH 3cN, adds H 2o (20mL), DCM extract (3x30mL), anhydrous Na 2sO 4drying, filters, concentrated, column chromatography DCM (R f=0.67, PE: EA=2: 1) obtain 261mg compound 13, two step and add up to yield 55%.
1H-NMR(CDCl 3，400MHz)：δ10.35(s，1H，CHO)，7.99(d，J＝8.6Hz，1H，Ar-H)，7.50-7.34(m，5H，Ar-H)，7.08-7.01(m，3H，Ar-H)，6.67(d，J＝7.1Hz，1H，Ar-H)，5.22(s，2H，CH 2)，5.18(s，2H，CH 2)，4.12(s，3H，OCH 3). 13C-NMR(CDCl 3，100MHz)：δ187.7，166.0，161.2，157.6，150.7，145.2，136.4，133.3，128.7(2C)，128.1，127.8，127.2(2C)，127.1，125.2，121.1，120.5，118.7，115.9，71.2，68.9，64.6.MS(ESI)：391.2(M+H) +.HRMS(ESI)：Calcd.for C 23H 18O 6Na +(M+Na) +：413.1001，found：413.0987.
14. steps 14
The preparation of neo-pentyl magnesium bromide: add Mg (1.045g in 50mL two-mouth bottle; 43.53mmol) He one iodine; dry diethyl ether solution (5mL) is added under argon shield; add the diethyl ether solution (1mL) of bromo neopentane (5mL); after question response causes; add the diethyl ether solution (10mL) of remaining bromo neopentane, 34 DEG C of reaction 12h.Cool for subsequent use after rear constant volume.
Compound 13 (136mg, 0.35mmol) is added, under argon shield in 100mL single port bottle; add dry THF (10mL), under ice bath, drip neo-pentyl magnesium bromide (0.53mL, 1.40mmol); naturally be warming up to stirring at room temperature 1h afterwards, add saturated NH 4cl cancellation is reacted, extraction into ethyl acetate (3x30mL), anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE: EA=5: 1 (R f=0.38, PE: EA=3: 1) 146mg compound 14 is obtained, yield 90%.
1H-NMR(CDCl 3，400MHz)：δ7.59(d，J＝8.6Hz，1H，Ar-H)，7.51-7.48(m，2H，Ar-H)，7.42-7.33(m，3H，Ar-H)，7.05-6.95(m，3H，Ar-H)，6.65(d，J＝7.3Hz，1H，Ar-H)，5.22(s，2H，CH 2)，5.19-5.16(m，1H，CH)，5.14(s，2H，CH 2)，3.98(s，3H，OCH 3)，1.87(d，J＝4.8Hz，1H，OH)，1.69-1.59(m，2H，CH 2)，1.03(s，9H，t-Bu-H). 13C-NMR(CDCl 3，100MHz)：δ167.3，154.1，152.0，150.6，146.3，137.6，136.7，131.0，128.6(2C)，128.0，127.8，127.2(2C)，124.5，121.3，119.4，118.0，116.0，71.4，69.0，66.5，62.7，52.2，30.7，30.1(3C).MS(ESI)：463.1(M+H) +.HRMS(ESI)：Calcd.forC 28H 29O 6 -(M-H) -：461.1964，found：461.1966.
15. steps 15
Add compound 14 (296mg, 0.64mmol) in 50mL single port bottle, DMSO adds IBX (358mg, 1.28mmol), stirred overnight at room temperature, stopped reaction, adds H after dissolving (10mL) 2o (100mL), DCM extract (4x40mL), washing (1x50mL), anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE: EA=4: 1 (R f=0.51, PE: EA=3: 1) 283mg compound 15 is obtained, yield 96%.
1H-NMR(CDCl 3，400MHz)：δ7.60(d，J＝8.6Hz，1H，Ar-H)，7.50-7.48(m，2H，Ar-H)，7.43-7.34(m，3H，Ar-H)，7.06-6.99(m，3H，Ar-H)，6.67(d，J＝7.2Hz，1H，Ar-H)，5.22(s，2H，CH 2)，5.16(s，2H，CH 2)，3.96(s，3H，OCH 3)，2.91(s，2H，CH 2)，1.01(s，9H，t-Bu-H). 13C-NMR(CDCl 3，100MHz)：δ202.2，166.3，156.5，154.9，150.7，145.7，136.5，133.8，133.7，128.7(2C)，128.1，127.8，127.2(2C)，124.9，121.3，120.8，118.5，116.0，71.3，68.9，63.8，54.8，31.6(3C)，29.8.MS(ESI)：461.0(M+H) +.HRMS(ESI)：Calcd.for C 28H 28O 6Na +(M+Na) +：483.1784，found：483.1777.
16. steps 16
In 50mL single port bottle, under argon shield, add (R)-Me-CBS (153 μ L, 0.153mmol), decompression removing toluene wherein, then add THF (7.7mL).Be cooled to-20 DEG C, add BH 3tHF (0.66mL, 0.66mmol, 1M in THF), the THF solution (7.7mL) of rear slow dropping compound 15 (237mg, 0.51mmol), 3h dropwises.Stopped reaction after-20 DEG C of reaction 4h, adds H 2o (3mL) cancellation is reacted, extraction into ethyl acetate (3x15mL), organic phase washing (1x20mL), anhydrous Na 2sO 4drying, filters, concentrated, and column chromatography PE: EA=5: 1 obtains 225mg compound 16, yield 95%, ee value 86%.(chiral column splitting condition: PC-2 post, UV 214nm, normal hexane: Virahol=50: 50,0.5mL/min)
[α] D 20＝+36°(C＝0.1，CHCl 3).
17. steps 17
Add compound 16 (42mg, 0.09mmol) in 50mL single port bottle, add palladium carbon (4mg) after dissolving with the mixing solutions of EtOH (3mL) and EA (7mL), pass into H 2, TLC monitoring disappears to raw material, filters, concentrated, column chromatography PE: EA=3: 1 (R f=0.47, PE: EA=2: 1) 29mg compound 17 is obtained, yield 85%.
1H-NMR(CDCl 3，400MHz)：δ7.53(d，J＝8.7Hz，1H，Ar-H)，7.03(d，J＝7.9Hz，1H，Ar-H)，6.97-6.93(m，1H，Ar-H)，6.83(d，J＝8.7Hz，1H，Ar-H)，6.82(s，1H，OH)，6.54(d，J＝7.5Hz，1H，Ar-H)，5.15-5.12(m，3H)，3.97(s，3H，OCH 3)，2.28(br s，1H，OH)，1.64-1.51(m，2H，CH 2)，1.01(s，9H，t-Bu-H). 13C-NMR(CDCl 3，100MHz)：δ167.8，153.7，150.8，147.9，143.4，138.1，130.9，126.1，124.9，120.2，119.2，117.6，117.3，69.1，66.4，62.4，52.3，30.7，30.0(3C).MS(ESI)：373.0(M+H) +.HRMS(ESI)：Calcd.for C 21H 24O 6Na +(M+Na) +：395.1471，found：395.1462，[α] D 20＝+23°(C＝0.1，CHCl 3).
18. steps 18
Compound a (500mg is added in 25mL single port bottle, 3.24mmol) with dry methylene dichloride (4mL), 1 DMF is added after at 0 DEG C, drip oxalyl chloride (0.34mL, 3.9mmol) again, after gas no longer produces, at room temperature continue stirring 30 minutes, concentrating under reduced pressure obtains acyl chlorides b again, with the THF constant volume of drying, participates in the next step directly.
Compound 17 (29mg is added in 25mL single port bottle, 0.078mmol) with dry THF (2mL), after add NaH (3.4mg, 0.086mmol), stirring at room temperature 1h, THF (2mL) solution of rear slow dropping acyl chlorides b (17mg, 0.10mmol), stopped reaction after spending the night, direct plate layer chromatography PE: EA=3: 1 (R f=0.42, PE: EA=3: 1) 23mg compound 18 is obtained, yield 58%.
1H-NMR(CDCl 3，400MHz)：δ7.61(d，J＝8.2Hz，1H，Ar-H)，7.09-7.07(m，2H，Ar-H)，7.00(d，J＝8.6Hz，1H，Ar-H)，6.96-6.92(m，1H，Ar-H)，5.18-5.11(m，3H)，3.98(s，3H，OCH 3)，2.33(s，2H)，1.97-1.84(m，5H)，1.70-1.55(m，2H，CH 2)，1.45(s，3H，CH 3)，1.34-1.32(m，4H)，1.03(s，9H，t-Bu-H). 13C-NMR(CDCl 3，100MHz)：δ175.3，167.1，153.9，151.2，148.4，142.3，138.3，131.1，127.6，127.2，124.5，124.2，119.6，118.3，69.1，66.4，63.0，58.6，52.3，42.0，30.7，30.1，29.4，27.8，17.1.HRMS(APCI)：Calcd.for C 30H 35O 7 -(M-H) -：507.2383，found：507.2375，[α] D 20＝+10.8°(C＝1.0，CHCl 3).
Embodiment 2: prepare following compound,
1. step 1
Embodiment 1 step 1 gained compound 1 (4.00g is added in 250mL single port bottle, 17.5mmol), after adding acetonitrile (90mL) dissolving, add ammonium acetate (137mg successively again, 1.75mmol), NBS (3.28g, 18.4mmol), reacts 4h under room temperature.Concentrating under reduced pressure removing acetonitrile, add water (100mL) dilution, and ethyl acetate (100mL) extracts, the anhydrous MgSO of organic phase 4drying, filters, concentrated, column chromatography PE: EA=20: 1 (R f=0.35, PE: DCM=2: 1), 4.59g compound 19 is obtained, yield 85%.
1H-NMR(CDCl 3，400MHz)：δ10.96(s，1H，OH)，9.86(s，1H，CHO)，7.46-7.35(m，5H，Ar-H)，7.33(d，J＝2.4Hz，1H，Ar-H)，7.23(d，J＝2.0Hz，1H，Ar-H)，5.16(s，2H，CH 2).MS(ESI)：329.0，331.1(M+Na) +.
2. step 2
Compound 19 (307mg is added in 50mL single port bottle, 1mmol), after adding DMF (1mL) dissolving, add N again, N-diisopropylethylamine (258mg, 2mmol), adds TERT-BUTYL DIMETHYL CHLORO SILANE (301mg after 10min, 2mmol), 1h is reacted under room temperature.(50mL) cancellation that adds water is reacted, and ethyl acetate (3x50mL) extracts, and after merging organic phase, washing, saturated common salt is washed, anhydrous MgSO 4drying, filters, concentrated, column chromatography PE: EA=100: 1 (R f=0.78, PE: EA=15: 1), 401mg compound 20 is obtained, yield 95%.
1H-NMR(CDCl 3，400MHz)：δ10.40(s，1H，CHO)，7.52(d，J＝2.4Hz，1H，Ar-H)，7.42-7.41(m，5H，Ar-H)，7.21(d，J＝2.4Hz，1H，Ar-H)，5.03(s，2H，CH 2)，0.92(s，9H，t-Bu-H)，0.07(s，6H，CH 3). 13C-NMR(CDCl 3，100MHz)：δ188.7，151.3，148.5，135.0，128.9，128.7(2C)，128.4(2C)，121.9，121.1，113.7，71.4，25.7(3C)，18.7，-4.3(2C).MS(ESI)：421.1，423.1(M+H) +.
3. step 3
In 50mL two-mouth bottle reflux, under argon shield, add compound 20 (2.21mg, 5.24mmol), Pd (dppf) Cl 2(58mg, 0.08mmol), anhydrous Isosorbide-5-Nitrae-dioxane (15mL), after zinc methide (5.2mL, 6.29mmol, 1.2m/L), reflux (110 DEG C), reaction 1h.1N hydrochloric acid (50mL) cancellation is reacted, and ethyl acetate (2x50mL) extracts, and after merging organic phase, washing, saturated common salt is washed, anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE: EA=40: 1 (R f=0.57, PE: EA=15: 1), 1.53g compound 21 is obtained, yield 82%.
1H-NMR(CDCl 3，400MHz)：δ10.46(s，1H，CHO)，7.44-7.35(m，5H，Ar-H)，7.21(d，J＝1.2Hz，1H，Ar-H)，6.94(d，J＝2.0Hz，1H，Ar-H)，5.05(s，2H，CH 2)，2.28(s，3H，CH 3)，0.94(s，9H，t-Bu-H)，0.08(s，6H，CH 3). 13C-NMR(CDCl 3，100MHz)：δ190.5，150.1，147.1，136.0，130.9，128.5(2C)，128.3，128.2(2C)，127.7，119.7，119.2，71.0，25.8(3C)，20.9，18.8，-4.3(2C).MS(ESI)：357.2(M+H) +.
4. step 4
Add compound 21 (891mg, 2.50mmol) in 50mL single port bottle, add methyl alcohol (25mL), under ice bath, add NaBH 4(378mg, 10.0mmol), more at room temperature react 4h.Concentrating under reduced pressure, is dissolved in 3N hydrochloric acid (50mL) by the white solid obtained, methylene dichloride (3x50mL) extracts, and merge organic phase, water (3x50mL) is washed, and saturated common salt is washed, anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE: EA=10: 1 (R f=0.41, PE: EA=10: 1), 812mg compound 22 is obtained, yield 91%.
1H-NMR(CDCl 3，400MHz)：δ7.42-7.30(m，5H，Ar-H)，6.75(s，1H，Ar-H)，6.68(s，1H，Ar-H)，5.02(s，2H，CH 2)，4.67(s，2H，CH 2)，2.26(s，3H，CH 3)，2.23(s，1H，OH)，0.94(s，9H，t-Bu-H)，0.06(s，6H，CH 3). 13C-NMR(CDCl 3，100MHz)：δ148.9，140.1，136.5，132.0，130.7，128.4(2C)，128.2(2C)，128.0，121.0，113.1，70.6，61.7，25.9(3C)，21.0，18.6，-4.0(2C).MS(ESI)：381.2(M+Na) +.
5. step 5
Add compound 22 (323mg, 0.90mmol) in 25mL single port bottle, add tetrahydrofuran (THF) (9mL), under ice bath, add tetrabutyl ammonium fluoride (471mg, 1.80mmol), under rear room temperature, react 0.5h.Add water (20mL) dilution, and ethyl acetate (3x20mL) extracts, and merges organic phase, washing, and saturated common salt is washed, anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE: EA=4: 1 (R f=0.26, PE: EA=4: 1), 206mg compound 23 is obtained, yield 94%.
1H-NMR(CDCl 3，400MHz)：δ7.43-7.37(m，5H，Ar-H)，6.73(s，1H，Ar-H)，6.70(s，1H，Ar-H)，5.91(s，1H，OH)，5.09(s，2H，CH 2)，4.70(s，2H，CH 2)，2.36(s，1H，OH)，2.28(s，3H，CH 3). 13C-NMR(CDCl 3，100MHz)：δ145.4，141.5，136.3，129.2，128.7(2C)，128.3，127.8(2C)，126.3，121.5，112.6，71.1，61.8，21.0.MS(ESI)：267.1(M+Na) +.
6. step 6
Compound 23 (892mg is added in 50mL single port bottle, 3.66mmol), dry methylene dichloride (20mL) is used to dissolve afterwards, add tosic acid (70mg, 0.37mmol) again, after stirring 15min in cryosel bath, drip 3,4-dihydro-2H-pyrans (0.35mL, 3.84mmol), reaction 1h.Stopped reaction, add triethylamine (1mL) cancellation reaction, organic phase saturated aqueous common salt (10mL) is washed, anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE: EA=20: 1 (R f=0.67, PE: EA=4: 1) 1.01g compound 24 is obtained, yield 84%.
1H-NMR(CDCl 3，400MHz)：δ7.44-7.34(m，5H，Ar-H)，6.74(s，1H，Ar-H)，6.71(s，1H，Ar-H)，6.23(s，1H，OH)，5.08(s，2H，CH 2)，4.82(d，J＝12Hz，1H，CH 2)，4.75(t，J＝3.3Hz，1H，CH)，4.58(d，J＝12Hz，1H，CH 2)，4.00-3.94(m，1H，CH 2)，3.59-3.56(m，1H，CH 2)，2.26(s，3H，CH 3)，1.88-1.53(m，6H).MS(ESI)：351.1(M+Na) +.
7. step 7
In 100mL two-mouth bottle reflux; add embodiment 1 step 9 gained compound 9 (1.11g, 4.08mmol), compound 24 (1.61g; 4.89mmol); Cu (0.653g, 10.2mmol), CuO (0.816g; 10.2mmol); DMAP (1.49g, 12.2mmol), adds CH under argon shield 3cN (30mL) post-heating is to backflow, and stopped reaction after reaction 12h, cooling, DCM dilutes (20mL), filters, concentrated, column chromatography PE: EA=6: 1 (R f=0.09, PE: EA=10: 1) 1.27g compound 25 is obtained, yield 60%.
1H-NMR(CDCl 3，400MHz)：δ10.22(s，1H，CHO)，7.76(d，J＝8.7Hz，1H，Ar-H)，7.28-7.16(m，5H，Ar-H)，6.94(s，1H，Ar-H)，6.83(s，1H，Ar-H)，6.46(d，J＝9.1Hz，1H，Ar-H)，5.00(s，2H，CH 2)，4.69(d，J＝12Hz，1H，CH 2)，4.68-4.67(m，1H，CH)，4.43(d，J＝12Hz，1H，CH 2)，3.99(s，3H，OCH 3)，3.95(s，3H，OCH 3)，3.83-3.76(m，1H，CH 2)，3.51-3.46(m，1H，CH 2)，2.36(s，3H，CH 3)，1.66-1.41(m，6H). 13C-NMR(CDCl 3，100MHz)：δ187.7，165.3，161.7，161.5，150.1，138.3，136.5，136.4，132,2，131.0，128.2(2C)，127.6，126.7(2C)，122.9，122.5，117.8，114.9，110.3，98.4，70.4，64.7，64.3，61.8，52.6，30.2，25.3，21.4，19.0.MS(ESI)：543.4(M+Na) +.HRMS(ESI)：Calcd.for C 30H 32O 8Na +(M+Na) +：543.1995，found：543.1968.
8. step 8
Add compound 25 (1.23g, 2.37mmol) in the single port bottle of 100mL, tosic acid (3mg), after add Virahol (10mL) and H 2o (3mL), heated overnight at reflux, stopped reaction, cooling, adds H 2o (10mL), extraction into ethyl acetate (3x30mL), organic phase is washed, and saturated common salt is washed, anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE: EA=3: 1 (R f=0.20, PE: EA=3: 1) 960mg compound 26 is obtained, yield 93%.
1H-NMR(CDCl 3，400MHz)：δ10.22(s，1H，CHO)，7.74(d，J＝9.0Hz，1H，Ar-H)，7.29-7.16(m，5H，Ar-H)，6.88(s，1H，Ar-H)，6.83(s，1H，Ar-H)，6.46(d，J＝9.0Hz，1H，Ar-H)，5.02(s，2H，CH 2)，4.56(s，2H，CH 2)，3.40(s，3H，OCH 3)，3.96(s，3H，OCH 3)，2.78(br s，1H，OH)，2.35(s，3H，CH 3). 13C-NMR(CDCl 3，100MHz)：δ187.7，165.6，161.9，160.9，150.2，138.0，136.8，136.3，134.6，131.6，128.3(2C)，127.7，126.7(2C)，123.3，121.9，117.4，114.7，109.9，70.5，64.7，60.7，52.9，21.4.MS(ESI)：459.3(M+Na) +.HRMS(ESI)：Calcd.for C 25H 24O 7Na +(M+Na) +：459.1420，found：459.1409.
9. step 9
Compound 26 (912mg is added in 50mL single port bottle, 2.09mmol), (12mL) is dissolved with MeOH, add tosic acid (80mg, 0.42mmol), after stirring at room temperature 1h, add NaOH (940mg, 23.5mmol), be heated to backflow, reaction is spent the night.Stopped reaction, cooling, concentrating under reduced pressure removing MeOH, with 3N HCl adjust pH to 3, extraction into ethyl acetate (4x30mL), anhydrous Na 2sO 4drying, filters, concentrated, obtains 837mg compound 27 crude product.
1H-NMR(DMSO，400MHz)：δ10.11(s，1H，CHO)，7.67(d，J＝8.8Hz，1H，Ar-H)，7.25-7.18(m，5H，Ar-H)，7.03(s，1H，Ar-H)，6.98(s，1H，Ar-H)，6.38(d，J＝8.8Hz，1H，Ar-H)，5.08(s，2H，CH 2)，4.37(s，2H，CH 2)，3.97(s，3H，OCH 3)，2.34(s，3H，CH 3).MS(ESI)：421.0(M-H) -.
10. step 10
The crude product (837mg, 1.98mmol) of compound 27 and triethylamine (2.2mL, 15.8mmol) are dissolved in dry CH 3in CN (20mL), be dissolved in dry CH by being slowly added drop-wise under above-mentioned obtained solution room temperature by the chloro-1-picoline (2.02g, 7.92mmol) of iodate-2- 3in the solution that CN (20mL) configures.After dropwising, heating reflux reaction spends the night.Stopped reaction, cooling, concentrating under reduced pressure removing CH 3cN, adds H 2o (20mL), DCM extract (3x30mL), anhydrous Na 2sO 4drying, filters, concentrated, column chromatography DCM (R f=0.80, PE: EA=2: 1) obtain 407mg compound 28, two step and add up to yield 51%.
1H-NMR(CDCl 3，400MHz)：δ10.35(d，J＝0.6Hz，1H，CHO)，7.98(d，J＝8.6Hz，1H，Ar-H)，7.51-7.35(m，5H，Ar-H)，7.03(dd，J＝8.6，0.6Hz，1H，Ar-H)，6.89(d，J＝1.5Hz，1H，Ar-H)，6.48(d，J＝1.2Hz，1H，Ar-H)，5.20(s，2H，CH 2)，5.13(s，2H，CH 2)，4.12(s，3H，OCH 3)，2.28(s，3H，CH 3). 13C-NMR(CDCl 3，100MHz)：δ187.8，166.1，161.2，158.0，150.4，143.2，136.5，135.3，133.3，128.7(2C)，128.1，127.32，127.27(2C)，127.0，121.5，120.6，118.7，116.6，71.3，69.0，64.7，21.2.MS(ESI)：427.0(M+Na) +.HRMS(ESI)：Calcd.for C 24H 20O 6Na +(M+Na) +：427.1158，found：427.1133.
11. steps 11
Compound 28 (262mg, 0.65mmol) is added, under argon shield in 25mL single port bottle; add dry THF (10mL), under ice bath, drip neo-pentyl magnesium bromide (1.5mL, 3.9mmol); naturally be warming up to stirring at room temperature 1h afterwards, add saturated NH 4cl cancellation is reacted, and EA extracts (3x30mL), anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE: EA=5: 1 (R f=0.44, PE: EA=3: 1) 305mg compound 29 is obtained, yield 98%.
1H-NMR(CDCl 3，400MHz)：δ7.57(d，J＝8.2Hz，1H，Ar-H)，7.51-7.49(m，2H，Ar-H)，7.42-7.31(m，3H，Ar-H)，6.94(d，J＝7.8Hz，1H，Ar-H)，6.85(s，1H，Ar-H)，6.44(s，1H，Ar-H)，5.19(s，2H，CH 2)，5.18-5.14(m，1H，CH)，5.08(s，2H，CH 2)，3.95(s，3H，OCH 3)，2.25(s，3H，CH 3)，2.12(br s，1H，OH)，1.68-1.53(m，2H，CH 2)，1.02(s，9H，t-Bu-H). 13C-NMR(CDCl 3，100MHz)：δ167.5，153.9，152.0，150.2，144.0，137.5，136.7，134.4，130.9，128.5(2C)，127.9，127.23，127.16(2C)，121.6，119.3，118.0，116.5，71.2，69.0，66.3，62.5，52.1，30.6，30.0(3C)，21.0.MS(ESI)：477.2(M+H) +.HRMS(APCI)：Calcd.for C 29H 33O 6 +(M+H) +：477.2277，found：477.2278.
12. steps 12
Add compound 29 (130mg, 0.27mmol) in 50mL single port bottle, DMSO dissolves (10mL), after add IBX (151mg, 0.54mmol), stirred overnight at room temperature, stopped reaction, add H 2o (10mL), DCM extract (4x20mL), organic phase washing (1x50mL), anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE: EA=7: 1 (R f=0.51, PE: EA=3: 1) 123mg compound 30 is obtained, yield 96%.
1H-NMR(CDCl 3，400MHz)：δ7.59(d，J＝8.6Hz，1H，Ar-H)，7.50-7.48(m，2H，Ar-H)，7.42-7.33(m，3H，Ar-H)，6.98(d，J＝8.6Hz，1H，Ar-H)，6.87(d，J＝1.2Hz，1H，Ar-H)，6.47(s，1H，Ar-H)，5.19(s，2H，CH 2)，5.11(s，2H，CH 2)，3.94(s，3H，OCH 3)，2.90(s，2H，CH 2)，2.26(s，3H，CH 3)，1.00(s，9H，t-Bu-H). 13C-NMR(CDCl 3，100MHz)：δ202.2，166.3，156.5，155.1，150.3，143.4，136.6，134.9，133.6，133.5，128.6(2C)，128.0，127.24，127.20(2C)，121.6，120.7，118.4，116.6，71.2，68.9，63.7，54.7，31.6，29.8(3C)，21.1.MS(ESI)：475.3(M+H) +.HRMS(APCI)：Calcd.forC 29H 31O 6 +(M+H) +：475.2121，found：475.2082.
13. steps 13
Under argon shield, in 50mL single port bottle, add (R)-Me-CBS (186 μ L, 0.186mmol), decompression removing toluene wherein, then add THF (9mL).Be cooled to-20 DEG C, add BH 3tHF (0.68mL, 0.68mmol, 1M in THF), the THF solution (9mL) of rear slow dropping compound 30 (294mg, 0.62mmol), 3h dropwises.Stopped reaction after-20 DEG C of reaction 4h, adds H 2o (3mL) cancellation is reacted, and EA extracts (3x15mL), and organic phase is washed, anhydrous Na 2sO 4drying, filters, concentrated, and column chromatography PE: EA=5: 1 obtains 250mg compound 31, yield 85%, ee value 88%.(chiral column splitting condition: PC-2 post, UV 214nm, normal hexane: Virahol=50: 50,0.5mL/min)
[α] D 20＝+7.3°(C＝4.4，CHCl 3).
14. steps 14
Add compound 31 (165mg, 0.35mmol) in 50mL single port bottle, add palladium carbon (17mg) after dissolving with the mixing solutions of EtOH (3mL) and EA (7mL), pass into H 2, TLC monitoring disappears to raw material, filters, concentrated, column chromatography PE: EA=3: 1 (R f=0.42, PE: EA=2: 1) 117mg compound 32 is obtained, yield 87%.
1H-NMR(CDCl 3，400MHz)：δ7.52(d，J＝8.7Hz，1H，Ar-H)，6.84(s，1H，Ar-H)，6.81(d，J＝8.7Hz，1H，Ar-H)，6.76(br s，1H，OH)，6.34(s，1H，Ar-H)，5.15-5.04(m，3H)，3.96(s，3H，OCH 3)，2.31(br s，1H，OH)，2.23(s，3H，CH 3)，1.64-1.50(m，2H，CH 2)，1.01(s，9H，t-Bu-H).MS(ESI)：387.0(M+H) +.，[α] D 20＝+9.7°(C＝3.2，CHCl 3)
15. steps 15
Compound 32 (161mg is added in 50mL single port bottle, 0.42mmol) with dry THF (10mL), after add NaH (18mg, 0.46mmol), stirring at room temperature 1h, THF (10mL) solution of rear slow dropping parabromobenzoyl chloride (101mg, 0.46mmol), stopped reaction after spending the night, direct column chromatography PE: EA=5: 1 (R f=0.25, PE: EA=3: 1) 219mg compound 33 is obtained, yield 92%.
1H-NMR(CDCl 3，400MHz)：δ8.13-8.10(m，2H，Ar-H)，7.69-7.66(m，2H，Ar-H)，7.57(d，J＝8.6Hz，1H，Ar-H)，7.07(s，1H，Ar-H)，6.94(d，J＝8.6Hz，1H，Ar-H)，6.81(s，1H，Ar-H)，5.15-5.11(m，3H)，3.95(s，3H，OCH 3)，2.32(s，3H，CH 3)，1.86(br s，1H，OH)，1.67-1.52(m，2H，CH 2)，1.01(s，9H，t-Bu-H). 13C-NMR(CDCl 3，100MHz)：δ167.0，164.7，153.9，151.1，145.7，141.9，138.1，134.5，132.0，131.7，131.0，129.2，128.0，127.8，127.2，124.8，119.5，118.2，69.0，66.4，62.9，52.2，30.7，30.0(3C)，20.6.HRMS(APCI)：Calcd.for C 29H 28BrO 7 -(M-H) -：567.1019，found：567.1037，[α] D 20＝-3.1°(C＝1.0，CHCl 3).
Embodiment 3: prepare following compound,
1. step 1
Embodiment 2 step 14 gained compound 32 (30mg is added in 25mL single port bottle, 0.078mmol) with dry THF (2mL), after add NaH (3.4mg, 0.086mmol), stirring at room temperature 1h, rear slow dropping is to THF (2mL) solution of trifluoromethyl benzoyl chloride (13 μ L, 0.086mmol), stopped reaction after spending the night, direct column chromatography PE: EA=5: 1 (R f=0.38, PE: EA=3: 1) 32mg compound 34 is obtained, yield 73%.
1H-NMR(CDCl 3，400MHz)：δ8.39-8.36(m，2H，Ar-H)，7.81-7.78(m，2H，Ar-H)，7.58(d，J＝8.6Hz，1H，Ar-H)，7.09(s，1H，Ar-H)，6.94(d，J＝8.2Hz，1H，Ar-H)，6.83(s，1H，Ar-H)，5.15-5.11(m，3H)，3.95(s，3H，OCH 3)，2.33(s，3H，CH 3)，1.91(br s，1H，OH)，1.67-1.51(m，2H，CH 2)，1.01(s，9H，t-Bu-H). 13C-NMR(CDCl 3，100MHz)：δ167.0，164.1，153.9，151.0，145.6，141.7，138.2，135.2(q，J＝32Hz)，134.5，132.1，131.0，130.6，128.1，127.2，125.7，124.8，124.7，119.4，118.1，68.9，66.3，62.8，52.2，30.6，30.0(3C)，20.6. 19F-NMR(CDCl 3，376MHz)：δ-63.6.HRMS(APCI)：Calcd.for C 30H 28F 3O 7 -(M-H) -：557.1787，found：557.1797，[α] D 20＝-8.4°(C＝1.0，CHCl 3).
Embodiment 4: prepare following compound,
1. step 1
Embodiment 2 step 14 gained compound 32 (30mg is added in 25mL single port bottle, 0.078mmol) with dry THF (2mL), after add NaH (3.4mg, 0.086mmol), stirring at room temperature 1h, rear slow dropping 3,5-bis-(trifluoromethyl) Benzoyl chloride (16 μ L, THF (2mL) solution 0.086mmol), stopped reaction after spending the night, direct column chromatography PE: EA=5: 1 (R f=0.45, PE: EA=3: 1) 42mg compound 35 is obtained, yield 86%.
1H-NMR(CDCl 3，400MHz)：δ8.70(s，2H，Ar-H)，8.16(s，1H，Ar-H)，7.61(d，J＝8.6Hz，1H，Ar-H)，7.09(s，1H，Ar-H)，6.94(d，J＝8.6Hz，1H，Ar-H)，6.86(s，1H，Ar-H)，5.16-5.12(m，3H)，3.95(s，3H，OCH 3)，2.34(s，3H，CH 3)，1.93(br s，1H，OH)，1.67-1.52(m，2H，CH 2)，1.01(s，9H，t-Bu-H). 13C-NMR(CDCl 3，100MHz)：δ166.9，162.7，153.9，150.9，145.5，141.3，138.4，134.6，132.5(q，J＝33Hz)，131.1，130.3，128.5，127.3，127.2，124.4，124.0，121.3，119.5，118.0，68.9，66.3，62.9，52.2，30.6，30.0(3C)，20.6. 19F-NMR(CDCl 3，376MHz)：δ-63.4.HRMS(APCI)：Calcd.forC 31H 27F 6O 7 -(M-H) -：625.1661，found：625.1649，[α] D 20＝-5.6°(C＝1.0，CHCl 3).
Embodiment 5: prepare following compound,
1. step 1
Embodiment 2 step 14 gained compound 32 (40mg is added in 25mL single port bottle, 0.10mmol) with dry THF (2mL), after add NaH (4.4mg, 0.11mmol), stirring at room temperature 1h, THF (2mL) solution of rear slow dropping embodiment 1 step 18 gained acyl chlorides b (22mg, 0.13mmol), stopped reaction after spending the night, direct plate layer chromatography PE: EA=3: 1 (R f=0.46, PE: EA=3: 1) 38mg compound 36 is obtained, yield 73%.
1H-NMR(CDCl 3，400MHz)：δ7.60(d，J＝8.6Hz，1H，Ar-H)，6.99(d，J＝8.6Hz，1H，Ar-H)，6.88(s，1H，Ar-H)，6.74(s，1H，Ar-H)，5.18-5.14(m，1H，CH)，5.07(s，2H，CH 2)，3.97(s，3H，OCH 3)，2.33(s，2H)，2.28(s，3H，CH 3)，1.98-1.84(m，5H)，1.70-1.55(m，2H，CH 2)，1.45(s，3H，CH 3)，1.34-1.32(m，4H)，1.02(s，9H，t-Bu-H). 13C-NMR(CDCl 3，100MHz)：δ175.4，167.2，153.8，151.3，146.1，141.8，138.1，134.2，131.1，127.6，127.1，124.7，119.7，118.3，69.1，66.3，62.9，58.6，52.2，41.9，30.7，30.1，29.3，27.7，20.5，17.1.HRMS(APCI)：Calcd.for C 31H 37O 7 -(M-H) -：521.2540，found：521.2551，[α] D 20＝+2.4°(C＝1.0，CHCl 3).
Embodiment 6: prepare following compound,
1. step 1
Embodiment 2 step 1 gained compound 19 (1.04g, 3.40mmol) is added in the two-mouth bottle of 50mL, to methoxyphenylboronic acid (620mg, 4.08mmol), Pd (PPh 3) 4(347mg, 0.34mmol), 2N K 2cO 3(3.4mL, 6.80mmol), methyl alcohol (15mL), 80 DEG C of reactions are spent the night.Reaction solution adds suction filtered through kieselguhr, extraction into ethyl acetate after thin up, and organic phase is washed, and saturated common salt is washed, anhydrous MgSO 4drying, filters, concentrated, column chromatography PE: EA=10: 1 (R f=0.16, PE: EA=10: 1) 950mg compound 37 is obtained, yield 84%.
1H-NMR(CDCl 3，400MHz)：δ11.00(s，1H，OH)，9.98(s，1H，CHO)，7.49-7.47(m，2H，Ar-H)，7.41-7.33(m，7H，Ar-H)，6.97-6.95(m，2H，Ar-H)，5.25(s，2H，CH 2)，3.85(s，3H，OCH 3). 13C-NMR(CDCl 3，100MHz)：δ196.5，159.1，151.1，147.3，136.4，132.8，132.0，128.6(2C)，128.1，127.6(2C)，127.4(2C)，122.9，121.0，119.7，114.3(2C)，71.5，55.3.MS(ESI)：335.2(M+H) +.HRMS(APCI)：Calcd.for C 21H 19O 4 +(M+H) +：335.1283，found：335.1262.
2. step 2
Add compound 37 (950mg, 2.84mmol) in 100mL single port bottle, add methyl alcohol (30mL), under ice bath, add NaBH 4after (216mg, 5.68mmol), under room temperature, react 1h.Concentrating under reduced pressure, is dissolved in 3N hydrochloric acid by the white solid obtained, extraction into ethyl acetate, and organic phase is washed, and saturated common salt is washed, anhydrous MgSO 4drying, filters, concentrated, column chromatography PE: EA=3: 1 (R f=0.21, PE: EA=3: 1), 822mg compound 38 is obtained, yield 86%.
1H-NMR(CDCl 3，400MHz)：δ7.45-7.44(m，7H，Ar-H)，7.08-7.07(m，2H，Ar-H)，6.96-6.94(m，2H，Ar-H)，6.10(s，1H，OH)，5.17(s，2H，CH 2)，4.79(s，2H，CH 2)，3.84(s，3H，OCH 3)，2.40(br s，1H，OH). 13C-NMR(CDCl 3，100MHz)：δ158.7，145.8，143.0，136.2，133.5，132.9，128.7(2C)，128.4，127.8(2C)，127.7(2C)，126.8，119.5，114.1(2C)，110.5，71.3，61.8，55.3.MS(ESI)：335.2(M-H) -.HRMS(APCI)：Calcd.for C 21H 19O 4 -(M-H) -：335.1284，found：335.1261.
3. step 3
Compound 38 (822mg is added in 50mL single port bottle, 2.45mmol), dry methylene dichloride (20mL) is used to dissolve afterwards, add tosic acid (48mg, 0.25mmol) again, after stirring 15min in cryosel bath, drip 3,4-dihydro-2H-pyrans (0.23mL, 2.52mmol), reaction 1h.Stopped reaction, add triethylamine (1mL) cancellation reaction, organic phase saturated common salt is washed, anhydrous MgSO 4drying, filters, concentrated, column chromatography PE: EA=7: 1 (R f=0.57, PE: EA=3: 1) 949mg compound 39 is obtained, yield 92%.
1H-NMR(CDCl 3，400MHz)：δ7.46-7.35(m，7H，Ar-H)，7.12(d，J＝1.6Hz，1H，Ar-H)，7.07(d，J＝2.0Hz，1H，Ar-H)，6.95-6.92(m，2H，Ar-H)，6.40(s，1H，OH)，5.17(s，2H，CH 2)，4.90(d，J＝12Hz，1H，CH 2)，4.79(t，J＝3.5Hz，1H，CH)，4.67(d，J＝12Hz，1H，CH 2)，4.01-3.95(m，1H，CH 2)，3.83(s，3H，OCH 3)，3.60-3.56(m，1H，CH 2)，1.89-1.54(m，6H). 13C-NMR(CDCl 3，100MHz)：δ158.6，146.2，143.6，136.5，133.7，132.6，128.6(2C)，128.2，127.8(2C)，127.7(2C)，124.0，120.3，114.0(2C)，111.0，98.2，71.3，64.9，62.5，55.3，30.5，25.3，19.5.MS(ESI)：443.2(M+Na) +.HRMS(APCI)：Calcd.for C 26H 27O 5 -(M-H) -：419.1859，found：419.1823.
4. step 4
In 50mL two-mouth bottle reflux; add embodiment 1 step 9 gained compound 9 (513mg, 1.88mmol), compound 39 (949mg; 2.25mmol); Cu (301mg, 4.70mmol), CuO (376mg; 4.70mmol); DMAP (688mg, 5.64mmol), adds CH under argon shield 3cN (20mL) post-heating is to backflow, and stopped reaction after reaction 12h, cooling, adds diatomite filtration, concentrated, column chromatography PE: EA=5: 1 (R f=0.32, PE: EA=5: 1) 793mg compound 40 is obtained, yield 69%.
1H-NMR(CDCl 3，400MHz)：δ10.23(s，1H，CHO)，7.74(d，J＝8.7Hz，1H，Ar-H)，7.50-7.47(m，2H，Ar-H)，7.31-7.16(m，7H，Ar-H)，7.00-6.97(m，2H，Ar-H)，6.53(d，J＝8.7Hz，1H，Ar-H)，5.08(s，2H，CH 2)，4.77(d，J＝12Hz，1H，CH 2)，4.71-4.70(m，1H，CH)，4.51(d，J＝12Hz，1H，CH 2)，4.00(s，3H，OCH 3)，3.96(s，3H，OCH 3)，3.86(s，3H，OCH 3)，3.84-3.78(m，1H，CH 2)，3.52-3.47(m，1H，CH 2)，1.64-1.42(m，6H). 13C-NMR(CDCl 3，100MHz)：δ187.8，165.3，161.7，161.3，159.3，150.5，139.6，139.4，136.3，132.9，132.8，131.1，128.3(2C)，128.1(2C)，127.7，126.8(2C)，123.1，120.3，117.9，114.2(2C)，112.6，110.4，98.5，70.6，64.8，64.4，61.8，55.3，52.7，30.2，25.3，19.1.MS(ESI)：635.1(M+Na) +.HRMS(ESI)：Calcd.for C 36H 37O 9 +(M+H) +：613.2438，found：613.2395.
5. step 5
Add compound 40 (993mg, 1.62mmol) in the single port bottle of 100mL, tosic acid (2mg), after add Virahol (8mL) and H 2o (2mL), heated overnight at reflux, stopped reaction, cooling, adds H 2o (10mL), extraction into ethyl acetate (3x30mL), organic phase is washed, and saturated common salt is washed, anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE: EA=3: 1 (R f=0.14, PE: EA=3: 1) 813mg compound 41 is obtained, yield 95%.
1H-NMR(CDCl 3，400MHz)：δ10.23(s，1H，CHO)，7.77(d，J＝9.1Hz，1H，Ar-H)，7.49-7.46(m，2H，Ar-H)，7.29-7.16(m，7H，Ar-H)，6.99-6.96(m，2H，Ar-H)，6.53(d，J＝9.1Hz，1H，Ar-H)，5.09(s，2H，CH 2)，4.65(d，J＝5.6Hz，2H，CH 2)，4.01(s，3H，OCH 3)，3.97(s，3H，OCH 3)，3.86(s，3H，OCH 3)，2.74(t，J＝6.5Hz，1H，OH). 13C-NMR(CDCl 3，100MHz)：δ187.7，165.5，161.9，160.8，159.4，150.7，139.7，139.2，136.2，135.2，132.7，131.6，128.4(2C)，128.1(2C)，127.9，126.9(2C)，123.5，119.8，117.5，114.2(2C)，112.5，110.1，70.7，64.8，61.0，55.3，52.9.MS(ESI)：528.7(M+H) +.HRMS(APCI)：Calcd.for C 31H 29O 8 +(M+H) +：529.1862，found：529.1850.
6. step 6
Compound 41 (797mg is added in 100mL single port bottle, 1.51mmol), (9mL) is dissolved with MeOH, add tosic acid (74mg, 0.39mmol), after stirring at room temperature 1h, add NaOH (846mg, 15.1mmol), be heated to backflow, reaction is spent the night.Stopped reaction, cooling, concentrating under reduced pressure removing MeOH, with 3N hydrochloric acid adjust pH to 3, extraction into ethyl acetate (4x30mL), anhydrous Na 2sO 4drying, filters, concentrated, obtains 778mg compound 42 crude product.
MS(ESI)：512.7(M-H) -.
7. step 7
The crude product (778mg, 1.51mmol) of compound 42 and triethylamine (1.7mL, 12.1mmol) are dissolved in dry CH 3in CN (30mL), be dissolved in dry CH by being slowly added drop-wise under above-mentioned obtained solution room temperature by the chloro-1-picoline (1.54g, 6.04mmol) of iodate-2- 3in the solution that CN (30mL) configures.After dropwising, heating reflux reaction spends the night.Stopped reaction, cooling, concentrating under reduced pressure removing CH 3cN, adds H 2o (20mL), DCM extract (3x30mL), anhydrous Na 2sO 4drying, filters, concentrated, column chromatography DCM (R f=0.58, PE: EA=2: 1) obtain 138mg compound 43, two step and add up to yield 18%.
1H-NMR(CDCl 3，400MHz)：δ10.37(s，1H，CHO)，8.02(d，J＝8.7Hz，1H，Ar-H)，7.54-7.51(m，2H，Ar-H)，7.45-7.36(m，5H，Ar-H)，7.23(d，J＝2.0Hz，1H，Ar-H)，7.08(dd，J＝8.7，0.8Hz，1H，Ar-H)，6.97-6.94(m，2H，Ar-H)，6.83(d，J＝2.0Hz，1H，Ar-H)，5.28(s，2H，CH 2)，5.23(s，2H，CH 2)，4.14(s，3H，OCH 3)，3.85(s，3H，OCH 3). 13C-NMR(CDCl 3，100MHz)：δ187.8，166.0，161.2，159.5，157.7，150.8，144.2，138.3，136.4，133.4，132.2，128.7(2C)，128.2，128.0(2C)，127.8，127.4(2C)，127.1，120.6，119.4，118.8，114.4，114.3(2C)，71.5，69.1，64.7，55.3.HRMS(APCI)：Calcd.forC 30H 25O 7 +(M+H) +：497.1600，found：497.1599.
8. step 8
Compound 43 (136mg, 0.27mmol) is added, under argon shield in 50mL single port bottle; add dry THF (10mL), under ice bath, drip neo-pentyl magnesium bromide (0.61mL, 1.6mmol); naturally be warming up to stirring at room temperature 1h afterwards, add saturated NH 4cl cancellation is reacted, extraction into ethyl acetate (3x30mL), anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE: EA=5: 1 (R f=0.30, PE: EA=3: 1) 119mg compound 44 is obtained, yield 77%.
1H-NMR(CDCl 3，400MHz)：δ7.60(d，J＝8.6Hz，1H，Ar-H)，7.54-7.51(m，2H，Ar-H)，7.43-7.34(m，5H，Ar-H)，7.19(d，J＝1.6Hz，1H，Ar-H)，6.99(d，J＝8.6Hz，1H，Ar-H)，6.95-6.92(m，2H，Ar-H)，6.80(d，J＝1.6Hz，1H，Ar-H)，5.27(s，2H，CH 2)，5.19-5.18(s，3H)，3.99(s，3H，OCH 3)，3.83(s，3H，OCH 3)，1.93(br s，1H，OH)，1.70-1.55(m，2H，CH 2)，1.03(s，9H，t-Bu-H). 13C-NMR(CDCl 3，100MHz)：δ167.3，159.3，154.0，152.0，150.6，145.2，137.6，137.5，136.6，132.3，131.0，128.6(2C)，128.0，127.9(2C)，127.8，127.3(2C)，119.5，119.3，118.0，114.4，114.2(2C)，71.5 69.2，66.4，62.6，55.3，52.2，30.7，30.0(3C).MS(ESI)：568.7(M+H) +.HRMS(APCI)：Calcd.forC 35H 37O 7 +(M+H) +：569.2539，found：569.2534.
9. step 9
Add compound 44 (108mg, 0.19mmol) in 50mL single port bottle, DMSO dissolves (10mL), after add IBX (106mg, 0.38mmol), stirred overnight at room temperature, stopped reaction, add H 2o (10mL), DCM extract (4x20mL), organic phase washing (1x50mL), anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE: EA=5: 1 (R f=0.53, PE: EA=3: 1) 104mg compound 45 is obtained, yield 96%.
1H-NMR(CDCl 3，400MHz)：δ7.61(d，J＝8.6Hz，1H，Ar-H)，7.53-7.51(m，2H，Ar-H)，7.44-7.36(m，5H，Ar-H)，7.21(d，J＝1.6Hz，1H，Ar-H)，7.03(d，J＝8.2Hz，1H，Ar-H)，6.96-6.93(m，2H，Ar-H)，6.82(d，J＝1.6Hz，1H，Ar-H)，5.27(s，2H，CH 2)，5.20(s，2H，CH 2)，3.96(s，3H，OCH 3)，3.84(s，3H，OCH 3)，2.91(s，2H，CH 2)，1.01(s，9H，t-Bu-H). 13C-NMR(CDCl 3，100MHz)：δ202.1，166.3，159.5，156.6，155.0，150.8，144.7，138.1，136.5，133.8，133.7，132.3，128.7(2C)，128.2，128.0(2C)，127.8，127.4(2C)，120.8，119.6，118.5，114.6，114.3(2C)，71.6，69.1，63.9，55.4，54.8，31.6，29.9(3C).HRMS(APCI)：Calcd.for C 35H 35O 7 +(M+H) +：567.2383，found：567.2350.
10. step 10
Under argon shield, in 50mL single port bottle, add (R)-Me-CBS (51 μ L, 0.051mmol), decompression removing toluene wherein, then add THF (2.5mL).Be cooled to-20 DEG C, add BH 3tHF (0.22mL, 0.22mmol, 1M in THF), the THF solution (2.5mL) of rear slow dropping compound 45 (94mg, 0.17mmol), 3h dropwises.Stopped reaction after-20 DEG C of reaction 4h, adds H 2o (3mL) cancellation is reacted, extraction into ethyl acetate (3x15mL), and organic phase is washed, anhydrous Na 2sO 4drying, filters, concentrated, and column chromatography PE: EA=5: 1 obtains 72mg compound 46, yield 74%.
[α] D 20＝+19°(C＝0.2，CHCl 3).
11. steps 11
Add compound 46 (68mg, 0.12mmol) in 50mL single port bottle, add palladium carbon (7mg) after dissolving with the mixing solutions of EtOH (3mL) and EA (7mL), pass into H 2, TLC monitoring disappears to raw material, filters, concentrated, column chromatography PE: EA=2: 1 (R f=0.24, PE: EA=2: 1) 53mg compound 47 is obtained, yield 93%, ee value 74%.(chiral column splitting condition: PC-2 post, UV 214nm, normal hexane: Virahol=20: 30,0.5mL/min)
1H-NMR(CDCl 3，400MHz)：δ7.55(d，J＝8.2Hz，1H，Ar-H)，7.42-7.39(m，2H，Ar-H)，7.21(d，J＝2.0Hz，1H，Ar-H)，6.95-6.92(m，2H，Ar-H)，6.87(d，J＝8.2Hz，1H，Ar-H)，6.81(br s，1H，OH)，6.71(d，J＝2.0Hz，1H，Ar-H)，5.17-5.14(m，3H)，3.98(s，3H，OCH 3)，3.83(s，3H，OCH 3)，2.24(br s，1H，OH)，1.66-1.52(m，2H，CH 2)，1.02(s，9H，t-Bu-H). 13C-NMR(CDCl 3，100MHz)：δ167.8，159.3，153.8，151.0，147.9，142.4，138.1，137.9，132.1，131.0，127.9(2C)，126.2，119.2，118.5，117.6，115.4，114.2(2C)，69.3，66.4，62.4，55.3，52.3，30.7，30.1(3C).MS(ESI)：478.9(M+H) +.HRMS(APCI)：Calcd.for C 28H 31O 7 +(M+H) +：479.2070，found：479.2066，[α] D 20＝+55°(C＝0.2，CHCl 3).
12. steps 12
Compound 47 (7mg is added in 25mL single port bottle, 0.015mmol) with dry THF (2mL), after add NaH (0.7mg, 0.017mmol), stirring at room temperature 1h, rear slow dropping is to THF (2mL) solution of trifluoromethyl benzoyl chloride (3 μ L, 0.017mmol), stopped reaction after spending the night, direct plate layer chromatography PE: EA=3: 1 (R f=0.24, PE: EA=3: 1) 9mg compound 48 is obtained, yield 90%.
1H-NMR(CDCl 3，400MHz)：δ8.42-8.39(m，2H，Ar-H)，7.83-7.80(m，2H，Ar-H)，7.61(d，J＝8.6Hz，1H，Ar-H)，7.47-7.44(m，3H，Ar-H)，7.18(d，J＝2.0Hz，1H，Ar-H)，7.00(d，J＝8.6Hz，1H，Ar-H)，6.98-6.95(m，2H，Ar-H)，5.22(s，2H，CH 2)，5.17-5.15(m，1H，CH)，3.97(s，3H，OCH 3)，3.85(s，3H，OCH 3)，1.86(br s，1H，OH)，1.68-1.53(m，2H，CH 2)，1.02(s，9H，t-Bu-H). 13C-NMR(CDCl 3，100MHz)：δ166.9，164.1，159.6，154.0，151.0，146.6，142.3，138.4，137.6，135.5，135.1，132.1，131.2，131.1，130.7，128.0，127.8，125.8，125.7，122.3，119.4，118.2，114.3，69.1，66.4，62.9，55.3，52.2，30.7，30.0(3C). 19F-NMR(CDCl 3，376MHz)：δ-63.6.HRMS(APCI)：Calcd.for C 36H 32F 3O 8 -(M-H) -：649.2050，found：649.2085，[α] D 20＝+4.9°(C＝1.0，CHCl 3).
Embodiment 7 prepares following compound,
1. step 1
Embodiment 6 step 11 gained compound 47 (22mg is added in 25mL single port bottle, 0.046mmol) with dry THF (2mL), after add NaH (2mg, 0.051mmol), stirring at room temperature 1h, rear slow dropping 3,5-bis-(trifluoromethyl) Benzoyl chloride (12 μ L, THF (2mL) solution 0.066mmol), stopped reaction after spending the night, direct plate layer chromatography PE: EA=3: 1 (R f=0.67, PE: EA=2: 1) 10mg compound 49 is obtained, yield 30%.
1H-NMR(CDCl 3，400MHz)：δ8.73(s，2H，Ar-H)，8.18(s，1H，Ar-H)，7.64(d，J＝8.6Hz，1H，Ar-H)，7.47-7.45(m，3H，Ar-H)，7.21(s，1H，Ar-H)，7.01-6.95(m，3H，Ar-H)，5.22(s，2H，CH 2)，5.18-5.15(m，1H，CH)，3.98(s，3H，OCH 3)，3.85(s，3H，OCH 3)，1.86(br s，1H，OH)，1.69-1.54(m，2H，CH 2)，1.02(s，9H，t-Bu-H). 13C-NMR(CDCl 3，100MHz)：δ166.8，162.7，159.6，154.1，150.8，146.5，141.9，138.6，137.7，135.5，132.8，132.4，131.2，131.04，131.00，130.4，128.0，127.9，126.1，124.0，122.1，120.8，119.7，118.1，114.4，69.1，66.4，63.0，55.3，52.2，30.7，30.0(3C). 19F-NMR(CDCl 3，376MHz)：δ-63.3.HRMS(APCI)：Calcd.for C 37H 31F 6O 8 -(M-H) -：717.1923，found：717.1916，[α] D 20＝+7.0°(C＝1.0，CHCl 3).
Embodiment 8: prepare following compound,
1. step 1
Embodiment 6 step 11 gained compound 47 (19mg is added in 25mL single port bottle, 0.040mmol) with dry THF (2mL), after add NaH (1.8mg, 0.044mmol), stirring at room temperature 1h, THF (2mL) solution of acyl chlorides b (9mg, 0.052mmol) in rear slow dropping embodiment 1 step 18, stopped reaction after spending the night, direct plate layer chromatography PE: EA=3: 1 (R f=0.37 PE: EA=3: 1) 18mg compound 50 is obtained, yield 72%.
1H-NMR(CDCl 3，400MHz)：δ7.63(d，J＝8.6Hz，1H，Ar-H)，7.43-7.40(m，2H，Ar-H)，7.20(s，1H，Ar-H)，7.08(s，1H，Ar-H)，7.04(d，J＝8.6Hz，1H，Ar-H)，6.95-6.93(m，2H，Ar-H)，5.19-5.16(m，3H)，3.99(s，3H，OCH 3)，3.83(s，3H，OCH 3)，2.35(s，2H)，2.00-1.85(m，5H)，1.71-1.56(m，2H，CH 2)，1.48(s，3H，CH 3)，1.35-1.33(m，4H)，1.03(s，9H，t-Bu-H). 13C-NMR(CDCl 3，100MHz)：δ191.0，175.3，167.1，159.5，153.9，151.3，147.2，142.4，138.3，137.4，131.4，131.2，128.0，127.6，125.3，122.4，118.4，114.3，69.3，66.4，63.0，58.6，55.3，52.3，42.0，30.7，30.1，29.4，27.8，17.2.HRMS(APCI)：Calcd.for C 37H 41O 8 -(M-H) -：613.2802，found：613.2816，[α] D 20＝+16.2°(C＝0.5，CHCl 3).
Embodiment 9: prepare following compound,
1. step 1
Embodiment 1 step 17 gained compound 17 (30mg is added in 25mL single port bottle, 0.081mmol) with dry THF (5mL), after add NaH (3.2mg, 0.081mmol) stirring at room temperature 1h, rear slowly dropping is to trifluorobenzoyl chloride (0.013mL, 0.089mmol), stopped reaction after 1h, adds H 2o (5mL), EA extract (3x10mL), organic phase anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE: EA=3: 1 (R f=0.54, PE: EA=3: 1) 24mg compound 51 is obtained, productive rate 55%.
1H-NMR(CDCl 3，400MHz)：δ8.39(d，2H，J＝8.2Hz，Ar-H)，7.81(d，2H，J＝8.2Hz，Ar-H)，7.60(d，1H，J＝8.6Hz，Ar-H)，7.30(d，1H，J＝8.2Hz，Ar-H)，7.16(t，1H，J＝7.8Hz，Ar-H)，7.04(d，1H，J＝7.4Hz，Ar-H)，6.96(d，1H，J＝8.6Hz，Ar-H)，5.17-5.15(m，3H)，3.96(s，3H，OCH 3)，1.86(d，1H，J＝4.3Hz，OH)，1.67-1.52(m，2H，CH 2)，1.02(s，9H，t-Bu-H). 13C-NMR(CDCl 3，100MHz)：δ162.6，159.8，149.7，146.6，143.7，138.0，134.2，127.8，126.8，126.4，123.5，121.5，120.1，115.2，113.9，108.0，64.6，62.1，58.6，48.0，26.4，25.8.HRMS(ESI)：Calcd.for C 29H 27F 3O 7Na +(M+Na) +：567.1607，found 567.1593.
Embodiment 10: prepare following compound,
1. step 1
Embodiment 1 step 17 gained compound 17 (29mg is added in 25mL single port bottle, 0.078mmol) with dry THF (5mL), after add NaH (3.4mg, 0.086mmol) stirring at room temperature 1h, rear slowly dropping 3,5-bis-(trifluoromethyl) Benzoyl chloride (0.016mL, 0.086mmol), stopped reaction after 1h, adds H 2o (5mL), EA extract (3x10mL), anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE: EA=10: 1 (R f=0.71, PE: EA=3: 1) 31mg compound 52 is obtained, productive rate 65%.
1H-NMR(CDCl 3，400MHz)：δ8.71(s，2H，Ar-H)，8.17(s，1H，Ar-H)，7.62(d，1H，J＝8.6Hz，Ar-H)，7.30-7.26(m，1H，Ar-H)，7.18(t，1H，J＝7.8Hz，Ar-H)，7.07(d，1H，J＝7.4Hz，Ar-H)，6.96(d，1H，J＝8.6Hz，Ar-H)，5.17-5.16(m，3H)，3.97(s，3H，OCH 3)，1.84(d，1H，J＝4.3Hz，OH)，1.68-1.53(m，2H，CH 2)，1.02(s，9H，t-Bu-H). 13C-NMR(CDCl 3，100MHz)：δ162.5，158.4，149.7，146.4，143.6，137.5，134.3，128.5，128.1，126.9，126.7，126.1，123.9，123.6，123.0，120.2，120.0，119.8，117.0，115.2，113.8，64.6，62.1，58.7，48.0，26.4，25.8.HRMS(ESI)：Calcd.for C 30H 26F 6O 7Na +(M+Na) +：635.1480，found 635.1473.
Embodiment 11: prepare following compound,
1. step 1
H is added in the single port bottle of 100mL 2o (14mL), HBr (3.5mL), after add 2-amino-5 tolyl acid (1g, 6.62mmol) make it dissolve.NaNO is dripped under cryosel bath 2the aqueous solution (2mL) of (0.498g, 7.22mmol), stirs 1h, slowly drips the HBr solution (5mL) of CuBr (1.35g, 9.47mmol).Be stirred to not regeneration bubble, oil bath heats 80 DEG C, and reaction is spent the night, and second day is stopped reaction early, and cooling is filtered, washing (R f=0.33, PE: EA=2: 1) 1.325g compound 53 is obtained, productive rate 93%.
1H-NMR(CDCl 3，300MHz)：δ7.81(s，1H，Ar-H)，7.57(d，1H，J＝8.1Hz，Ar-H)，7.20(dd，1H，J＝8.1，1.5Hz，Ar-H)，2.36(s，3H，CH 3).
2. step 2
Compound 53 (1.228g, 5.99mmol) is added successively, methyl alcohol (7.04mL) vitriol oil (0.71mL), reflux 7h in 50mL single port bottle.Stopped reaction, cooling, adds saturated NaHCO 3solution adjust pH to 7, EA extracted organic phase (3x30mL), washing (1x30mL), anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE: EA=100: 1 (R f=0.89, PE: EA=2: 1) 1.348g compound 54 is obtained, productive rate 98%.
1H-NMR(CDCl 3，300MHz)：δ7.60(s，1H，Ar-H)，7.52(d，1H，J＝8.1Hz，Ar-H)，7.21(d，1H，J＝7.8Hz，Ar-H)，3.92(s，3H，OCH 3)，2.33(s，3H，CH 3).
3. step 3
Add NBS (3.26g, 18.3mmoL) successively in 50mL single port bottle, AIBN (0.143g, 0.873mmol), under argon shield, add the CCl of compound 54 4(20mL) solution, reflux 2h, NBS (1.71g, 9.6mmol) and AIBN (0.143g, 0.873mmol), reflux 2h are added in rear cooling.Stopped reaction, cooling, filters, concentrated.Add the vitriol oil (8mL), stirring at room temperature, TCL follows the tracks of reaction and disappears to raw material, pours in frozen water (30mL), EA extracted organic phase (3x30mL), saturated NaHCO 3wash (1x30mL), washing (1x30mL), anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE: EA=30: 1 (R f=0.55, PE: EA=5: 1) 1.131g compound 55 is obtained, yield 53%.
1H-NMR(CDCl 3，300MHz)：δ10.02(s，1H，CHO)，8.29(d，1H，J＝1.5Hz，Ar-H)，7.87(d，1H，J＝8.4Hz，Ar-H)，7.83(dd，1H，J＝8.4，1.5Hz，Ar-H)，3.98(s，3H，OCH 3).MS(EI)：244，242.
4. step 4
Embodiment 1 step 3 gained compound 3 (1.258g, 4.01mmol) is added, compound 55 (0.811g, 3.34mmol), CuBr (0.239g, 1.67mmol), Cs in 100mL single port bottle 2cO 3(2.178g, 6.68mmol), after add NMP (10mL), 2,2,6,6-tetramethyl--3,5-heptadione (0.069mL, 0.334mmol), degassed 0.5h, post-heating to 80 DEG C, reaction 2h after stopped reaction, cooling, add H 2o (1x30mL), with 3N HCl adjust pH to 4, EA extracts (3x30mL) organic phase, washing (1x50mL), saturated NH 4cl washes (1x30mL), anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE: EA=15: 1 (R f=0.12, PE: EA=20: 1) 1.14g compound 56 is obtained, yield 72%.
1H-NMR(CDCl 3，400MHz)：δ9.92(s，1H，CHO)，8.40(d，1H，J＝1.57Hz，Ar-H)，7.84-7.81(m，1H，Ar-H)，7.27-7.15(m，5H，Ar-H)，7.08-7.06(m，2H，Ar-H)，7.01(d，1H，J＝7.8Hz，Ar-H)，6.77(d，1H，J＝9.0Hz，Ar-H)，5.01(s，2H，OCH 2)，4.78(d，1H，J＝12Hz，OCH 2)，4.64(s，1H，OCH)，4.53(d，1H，J＝12Hz，OCH 2)，3.94(s，3H，COOCH 3)，3.76-3.45(m，2H，OCH 2)，1.61-1.40(m，6H，CH 2). 13C-NMR(CDCl 3，100MHz)：δ190.1，165.3，162.7，150.3，140.9，136.3，134.9，133.3，132.9，130.0，128.3，127.7，126.7，126.3，122.1，120.1，115.9，114.2，98.3，70.6，64.3，61.8，52.3，30.2，25.3.MS(ESI)：499.4(M+Na) +.HRMS(ESI)：Calcd.for C 28H 28O 7Na +(M+Na) +：499.1733，found：499.1711.
5. step 5
Add compound 56 (1.12g, 2.35mmol) successively in the single port bottle of 100mL, PTSA (3mg), add Virahol (10mL) and H 2o (2.6mL), heated overnight at reflux, second day is stopped reaction early, and cooling, adds H 2o (10mL), EA extract (3x30mL), H 2o washes (1x30mL), anhydrous MgSO 4drying, filters, concentrated, column chromatography PE: EA=3: 1 (R f=0.14, PE: EA=3: 1) 0.871g compound 57 is obtained, yield 95%.
1H-NMR(CDCl 3，300MHz)：δ9.92(s，1H，CHO)，8.41(s，1H，Ar-H)，7.85(d，1H，J＝8.7Hz，Ar-H)，7.24-7.02(m，8H，Ar-H)，6.79(d，1H，J＝8.7Hz，Ar-H)，5.04(s，2H，OCH 2)，4.58(s，2H，OCH 2)，3.96(s，3H，COOCH 3)，2.09(s，1H，OH).HRMS(ESI)：Calcd.for C 23H 20O 6Na +(M+Na) +：415.1158，found：415.1154.
6. step 6
Compound 57 (0.871g is added in the single port bottle of 100mL, 2.22mmol), (13mL) is dissolved with MeOH, add PTSA (0.19g 1.11mmol), stirring at room temperature 1h, adds NaOH (0.977g, 24.42mmol), reflux, reaction is spent the night.Second day is stopped reaction early, and cooling, rotary evaporation goes out MeOH, and with 3N HCl adjust pH to 4, EA extracts (4x30mL), anhydrous Na 2sO 4drying, filters, concentrated, obtains compound 58 crude product 0.775g.
1H-NMR(DMSO-d 6，300MHz)：δ13.21(s，1H，COOH)，9.94(s，1H，CHO)，8.35(d，1H，J＝1.8Hz，Ar-H)，7.95-7.91(m，1H，Ar-H)，7.33-6.99(m，8H，Ar-H)，6.71(d，1H，J＝8.4Hz，Ar-H)，5.08(s，2H，OCH 2)，4.47(s，2H，OCH 2).MS(ESI)：377.1(M-H) -.
7. step 7
The crude product (0.775g, 2.65mmol) of compound 58 and triethylamine (2.28mL, 16.4mmol) are dissolved in dry CH 3in CN (20mL), be dissolved in dry CH by being slowly added drop-wise under above-mentioned obtained solution room temperature by the chloro-1-picoline (2.091g, 8.2mmol) of iodate-2- 3in the solution that CN (53mL) configures.After dropwising, heating reflux reaction 1h.Rear stopped reaction, cooling, screws out CH 3cN, adds H 2o (20mL), DCM extract (3x30mL), anhydrous Na 2sO 4drying, filters, concentrated, column chromatography DCM (R f=0.67, PE: EA=2: 1) obtain 0.549g compound 59, two step yield and add up to 69%.
1H-NMR(CDCl 3，400MHz)：δ10.02(s，1H，CHO)，8.13(d，1H，J＝2Hz，Ar-H)，8.07(dd，1H，J＝8.2，2Hz，Ar-H)，7.52-7.36(m，6H，Ar-H)，7.11-7.04(m，2H，Ar-H)，6.79(dd，1H，J＝7.4，2Hz，Ar-H)，5.24(s，2H，OCH 2)，5.13(s，2H，OCH 2). 13C-NMR(CDCl 3，100MHz)：δ189.7，168.6，156.6，150.7，145.1，136.4，134.5，134.3，131.1，128.7，128.2，127.9，127.5，127.3，125.2，124.5，121.2，115.9，71.3，69.2.HRMS(ESI)：Calcd.for C 22H 15O 5 -(M-H) -：359.0920，found：359.0914.
8. step 8
Compound 59 (0.15g is added in 100mL single port bottle; 0.385mmol); under argon shield; add dry THF (10mL); the above-mentioned neo-pentyl magnesium bromide (0.9mL prepared is dripped under ice bath; 2.308mmol), be naturally warming up to stirring at room temperature 1h afterwards, add saturated NH 4cl cancellation is reacted, and EA extracts (3x30mL), anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE: EA=3: 1 (R f=0.13, DCM) obtain 0.173g compound 60, yield 97%.
1H-NMR(CDCl 3，400MHz)：δ7.57-7.49(m，4H，Ar-H)，7.43-7.38(m，2H，Ar-H)，7.36-7.31(m，1H，Ar-H)，7.20(d，1H，J＝8.2Hz，Ar-H)，7.07-6.97(m，2H，Ar-H)，6.67(dd，1H，J＝7.4，1.2Hz，Ar-H)，5.23(s，2H，OCH 2)，5.10(s，2H，OCH 2)，4.90-4.86(m，1H，OCH)，1.75-1.54(m，2H，CH 2)，1.00(s，9H，t-Bu-H). 13C-NMR(CDCl 3，100MHz)：δ170.0，151.1，150.6，146.0，145.0，136.7，131.2，128.7，128.1，128.0，127.3，126.3，126.1，124.5，123.4，121.3，116.0，71.5，71.4，69.4，53.2，30.6，30.2.MS(EI)：432，414，361，341，324，293，268，203，147，91，65，57，41.HRMS(ESI)：Calcd.for C 27H 27O 5 -(M-H) -：431.1859，found：431.1858.
9. step 9
Compound 60 (0.056g is added in 100mL single port bottle, 0.13mmol), DMSO dissolves (10mL), after add IBX (0.073g, 0.26mmol), stirred overnight at room temperature, second day is stopped reaction early, and add H2O (10mL), DCM extracts (4x20mL), washing (1x50mL), anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE: EA=4: 1 (R f=0.5, PE: EA=3: 1) 0.157g compound 61 is obtained, yield 91%.
1H-NMR(CDCl 3，400MHz)：δ8.17(s，1H，Ar-H)，8.12(d，1H，J＝8.2Hz，Ar-H)，7.51-7.28(m，6H，Ar-H)，7.10-7.02(m，2H，Ar-H)，6.69(d，1H，J＝7.0Hz，Ar-H)，5.24(s，2H，OCH 2)，5.11(s，2H，OCH 2)，2.86(s，2H，COCH 2)，1.07(s，9H，t-Bu-H). 13C-NMR(CDCl 3，100MHz)：δ198.0，169.1，155.3，150.6，145.3，136.6，136.5，133.8，129.3，128.7，128.1，127.9，127.3，126.6，125.0，123.7，121.2，115.8，71.2，69.2，50.1，31.5，29.3.MS(EI)：430，359，339，309，268，253，212，147，139，91，65.HRMS(EI)：Calcd.for C 27H 26O 5：430.1780，found：430.1776.
10. step 10
Under argon shield, in 25mL single port bottle, add (R)-Me-CBS (0.11mL, 0.112mmol), after add THF (5mL).Be cooled to-20 DEG C, add BH 3(0.37mL, 0.374mmol, 1M in THF), the THF solution (7mL) of rear slow dropping compound 61 (0.161g, 0.374mmol), 3h dropwises.Stopped reaction after-20 DEG C of reaction 4h, adds H 2o (5mL) cancellation is reacted, and EA extracts (3x20mL) organic phase, washing (1x20mL), anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE: EA=3: 1 (R f=0.13, PE: EA=5: 1) 0.095g compound 62 is obtained, yield 59%, transformation efficiency 80%, ee value 95.5%.(chiral column splitting condition: Chiralcel AD-H post, normal hexane: Virahol=4: 1,0.7mL/min, retention time: t=23.19, t=30.22)
11. steps 11
Add compound 62 (0.095g, 0.22mmol) in 100mL single port bottle, add palladium carbon (10mg) after dissolving with the mixing solutions of EtOH (3mL) and EA (7mL), pass into H 2, after TLC monitoring to raw material disappears, filter, concentrated, obtain 78mg compound 63, quantitative yield.
1H-NMR(CDCl 3，400MHz)：δ7.52-7.49(m，2H，Ar-H)，7.12-7.09(m，1H，Ar-H)，7.07-7.04(m，1H，Ar-H)，6.99-6.94(m，1H，Ar-H)，6.75(br s，1H，Ar-OH)，6.57(dd，1H，J＝7.6，1.4Hz，Ar-H)，5.06(s，2H，OCH 2)，4.87(dd，1H，J＝8.8，2.9Hz，OCH)，1.73-1.50(m，2H，CH 2)，1.00(s，9H，t-Bu-H). 13C-NMR(CDCl 3，100MHz)：δ170.3，150.0，147.7，145.6，143.2，131.2，126.3，126.2，126.1，124.8，122.9，120.2，117.3，71.4，69.3，53.1，30.6，30.1.HRMS(ESI)：Calcd.for C 20H 21O 5 -(M-H) -：341.1389，found：341.1415.
12. steps 12
Compound 63 (21mg is added in 25mL single port bottle, 0.061mmol) with dry THF (5mL), after add NaH (2mg, 0.077mmol) stirring at room temperature 1h, rear slowly dropping is to trifluorobenzoyl chloride (0.01mL, 0.068mmol), stopped reaction after 1h, adds H 2o (5mL), EA extract (3x10mL), anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE: EA=3: 1 (R f=0.76, PE: EA=3: 1) 19mg compound 64 is obtained, productive rate 61%.
1H-NMR(CDCl 3，400MHz)：δ8.40(d，2H，J＝7.9Hz，Ar-H)，7.81(d，2H，J＝7.9Hz，Ar-H)，7.54-7.50(m，2H，Ar-H)，7.32-7.29(d，1H，J＝7.5Hz，Ar-H)，7.19-7.15(m，2H，Ar-H)，7.06(d，1H，J＝7.1Hz，Ar-H)，5.15(s，2H，OCH 2)，4.89-4.86(m，1H，CH)，1.78(d，1H，J＝3.6Hz，OH)，1.73-1.51(m，2H，CH 2)，1.00(s，9H，t-Bu-H). 13C-NMR(CDCl 3，100MHz)：δ165.2，159.9，145.7，143.5，141.3，137.9，127.0，126.5，123.5，121.8，121.5，120.2，120.0，119.0，67.1，64.9，48.9，26.3，25.8.HRMS(ESI)：Calcd.for C 29H 26F 3O 7 -(M-H) -：513.1525，found：513.1547.
Embodiment 12: prepare following compound,
1. step 1
Compound 63 (26mg is added in 25mL single port bottle, 0.076mmol) with dry THF (5mL), after add NaH (2.3mg, 0.096mmol) stirring at room temperature 1h, rear slowly dropping 3,5-bis-(trifluoromethyl) Benzoyl chloride (0.015mL, 0.084mmol), stopped reaction after 1h, adds H 2o (5mL), EA extract (3x10mL), anhydrous Na 2sO 4drying, filters, concentrated, column chromatography DCM (R f=0.22, PE: EA=3: 1) obtain 16mg compound 65, productive rate 34%, reclaim raw material 8mg, transformation efficiency 52%.
1H-NMR(CDCl 3，400MHz)：δ8.72(s，2H，Ar-H)，8.17(s，1H，Ar-H)，7.55-7.52(m，2H，Ar-H)，7.31(d，1H，J＝7.8Hz，Ar-H)，7.21-7.16(m，2H，Ar-H)，7.09(d，1H，J＝7.4Hz，Ar-H)，5.15(s，2H，OCH 2)，4.89(d，1H，J＝8.2Hz，CH)，1.78(d，1H，J＝3.1Hz，OH)，1.77-1.52(m，2H，CH 2)，1.00(s，9H，t-Bu-H). 13C-NMR(CDCl 3，100MHz)：δ169.4，162.7，149.9，147.7，145.8，141.8，132.8，132.5，131.3，131.1，130.4，128.2，127.9，127.3，126.1，124.4，124.3.124.1，123.2，121.4，71.4，69.2，53.3，30.6，30.1.HRMS(ESI)：Calcd.for C 29H 24F 6O 6Na +(M+Na) +：605.1375，found：605.1359.
Embodiment 13: target compound suppresses CETP active testing
Experimental technique:
1. dissolve all testing compounds with DMSO, concentration is about 500 μMs,
2. according to the form below preparation feedback system, hatches 4 hours in 37 DEG C,
Mixture 1
Table 1
3. add 8 μ L LDL and 0.5 μ L [ 3h] LDL, supply reaction system to 600 μ L with TSE buffered soln,
Hatch 16 hours for 4.37 DEG C,
5. add 34.24 μ L LDL precipitation agent dextran sulfate/MgCl 2, final concentration is respectively 0.027% and 27mM.Mixing, leaves standstill 10 minutes,
Centrifugal 30 minutes of 6.1000g/min, leaves standstill 10 minutes after taking out,
7. often pipe is drawn 300 μ L supernatant liquors and is carried out scintillation counting.
Experimental result:
ado not record effective inhibiting rate.

Claims (1)

  1. The preparation method of 1.Penicillide derivative, is characterized in that, prepares compound 18 by following synthetic route and step:
    Step 1:
    Add NaH 144mmol in dry single port bottle, THF dissolves, and drips the THF solution of compound 2,3-Dihydroxy benzaldehyde 72mmol, room temperature reaction 1 hour, then the THF solution slowly adding cylite 72mmol, room temperature reaction 24 hours; Again reaction solution is poured into water, dichloromethane extraction, aqueous phase 1N hydrochloric acid adjust pH to 2, then uses dichloromethane extraction, the pickling of 1N salt, merge organic phase, anhydrous MgSO 4drying, filters, concentrated, column chromatography PE:EA=20:1, R f=0.42, PE:EA=10:1, rear ethyl alcohol recrystallization obtains compound 1;
    Step 2:
    Add compound 1 21.9mmol in single port bottle, add methyl alcohol, under ice bath, add NaBH in batches 488.7mmol, more at room temperature react 4h; Concentrating under reduced pressure, is dissolved in 3N hydrochloric acid by the white solid obtained, dichloromethane extraction, merges organic phase, washing, anhydrous Na 2sO 4drying, filters, and concentrates to obtain compound 2;
    Step 3:
    Add compound 2 1.3mmol in single port bottle, then dissolve with dry methylene dichloride, add tosic acid 0.13mmol, drip 3,4-dihydro-2H-pyrans 1.37mmol after stirring in cryosel bath, stopped reaction after 2h; Add triethylamine cancellation reaction, organic phase saturated common salt is washed, anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE:EA=20:1, R f=0.60, PE:EA=6:1, obtains compound 3;
    Step 4:
    5-amino-2-methyl phenol 8.13mmol is added, NaHCO in single port bottle 324.4mmol, H 2o and ethyl acetate, stirring at room temperature adds pivaloyl chloride 8.54mmol, stopped reaction after 1h after dissolving; The pickling of organic phase 1N salt, anhydrous Na 2sO 4drying, filters, concentrated, R f=0.75, PE:EA=2:1, obtains compound 4;
    Step 5:
    Compound 4 4.83mmol is added, K in single port bottle 2cO 312.1mmol, adds DMF under argon shield, more at room temperature adds MeI 5.8mmol, and stopped reaction after 4h, adds H 2o, extraction into ethyl acetate, washing, anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE:EA=6:1, R f=0.69, PE:EA=4:1, obtains compound 5;
    Step 6:
    Add compound 5 2.26mmol in single port bottle, add dry THF under argon shield, slowly drip n-buLi under cryosel bath, 7.24mmol, 1.6M in THF, dropwises rear stirring at room temperature 2h, then passes into CO 2gas 2h, adds H subsequently 2o, extraction into ethyl acetate, aqueous phase 1N HCl adjust pH to 1, then be extracted with ethyl acetate, merge organic phase, anhydrous Na 2sO 4drying, filters, concentrated, R f=0.24, PE:EA=4:1, obtains compound 6;
    Step 7:
    Compound 6 47.6mmol is added in single port bottle, dissolve with methanol, after slowly drip the vitriol oil successively, trimethyl orthoformate 52.4mmol, reflux, stopped reaction after 3 days, cooling, DCM dilutes, 1N hcl as extraction agent organic phase, aqueous phase 3NNaOH adjust pH to 13, rear DCM extraction, organic phase anhydrous Na 2sO 4drying, filters, concentrated, R f=0.64, PE:EA=3:1, obtains compound 7;
    Step 8:
    Compound 7 38.0mmol is added, HBr, H in single port bottle 2o, is stirred to dissolving, drips NaNO under cryosel bath 2the aqueous solution of 41.4mmol, stir 1h, then slowly drip CuBr, the hydrobromic acid solution of 54.3mmol, be stirred to after not having bubble formation, oil bath 80 DEG C of reactions are spent the night, stopped reaction, cooling, and DCM extracts, after merging organic phase, saturated NaHCO 3wash, anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE:EA=100:1, R f=0.62, PE:EA=20:1, obtains compound 8;
    Step 9:
    Add NBS in there-necked flask, 2.81mmol, Diisopropyl azodicarboxylate, 0.18mmol, under argon shield, add the CCl of compound 80.88mmol 4solution, is heated to backflow, reaction spend the night after stopped reaction, cooling, filters, concentrated, directly next step; L contains in the reaction flask of crude product and slowly drips the vitriol oil, stirring at room temperature, and stopped reaction when TLC monitoring disappears to raw material, pours into reaction solution in frozen water, extraction into ethyl acetate, saturated NaHCO 3wash, washing, anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE:EA=40:1, R f=0.17, PE:EA=50:1, obtains compound 9;
    Step 10:
    Add compound 3 3.55mmol in single port bottle, compound 9 2.96mmol, Cu, 7.40mmol, CuO, 7.40mmol, DMAP, 8.88mmol, add CH under argon shield 3cN, reheats to backflow, stopped reaction after reaction 17h, cooling, and DCM dilutes, and filters, concentrated, column chromatography PE:EA=6:1, R f=0.11, PE:EA=10:1, obtains compound 10;
    Step 11:
    Add compound 10,2mmol in single port bottle, tosic acid, after add Virahol and H 2o, is heated to backflow and spends the night, stopped reaction, and cooling, adds H 2o, extraction into ethyl acetate, organic phase is washed, anhydrous MgSO 4drying, filters, concentrated, column chromatography PE:EA=3:1, R f=0.14, PE:EA=3:1, obtains compound 11;
    Step 12:
    Add compound 11,1.55mmol in single port bottle, dissolve with MeOH, add tosic acid, 0.32mmol, after stirring at room temperature 1h, add NaOH, 18.5mmol, be heated to backflow, reaction is spent the night, stopped reaction, cooling, concentrating under reduced pressure removing MeOH, with 3N HCl adjust pH to 4, extraction into ethyl acetate, anhydrous Na 2sO 4drying, filters, concentrated, obtains compound 12 crude product;
    Step 13:
    By the crude product of compound 12,1.39mmol and triethylamine, 11.1mmol is dissolved in dry CH 3in CN, will slowly be added drop-wise to by the chloro-1-picoline of iodate-2-under above-mentioned obtained solution room temperature, 5.57mmol be dissolved in dry CH 3in the solution that CN configures, after dropwising, heating reflux reaction 1h, rear stopped reaction, cooling, concentrating under reduced pressure removing CH 3cN, adds H 2o, DCM extract, anhydrous Na 2sO 4drying, filters, concentrated, column chromatography DCM, R f=0.67, PE:EA=2:1, obtains compound 13;
    Step 14:
    Prepare neo-pentyl magnesium bromide: in two-mouth bottle, add Mg, a 43.53mmol and iodine, under argon shield, add dry diethyl ether solution, add the diethyl ether solution of bromo neopentane, question response adds the diethyl ether solution of remaining bromo neopentane after causing, 34 DEG C of reaction 12h, cool for subsequent use after rear constant volume;
    Add compound 13,0.35mmol in single port bottle, under argon shield, add dry THF, drip neo-pentyl magnesium bromide under ice bath, 1.40mmol, be naturally warming up to stirring at room temperature 1h afterwards, add saturated NH 4cl cancellation is reacted, extraction into ethyl acetate, anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE:EA=5:1, R f=0.38, PE:EA=3:1, obtains compound 14;
    Step 15:
    After adding compound 14,0.64mmol, DMSO dissolving in single port bottle, add IBX 1.28mmol, stirred overnight at room temperature, stopped reaction, add H 2o, DCM extract, washing, anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE:EA=4:1, R f=0.51, PE:EA=3:1, obtains compound 15;
    Step 16:
    In single port bottle, under argon shield, add (R)-Me-CBS, 0.153mmol, decompression removing toluene wherein, then add THF, be cooled to-20 DEG C, add BH 3tHF, 0.66mmol, 1M in THF, the THF solution of rear slow dropping compound 150.51mmol, 3h dropwises, and stopped reaction after-20 DEG C of reaction 4h, adds H 2o cancellation is reacted, extraction into ethyl acetate, and organic phase is washed, anhydrous Na 2sO 4drying, filters, and concentrated, column chromatography PE:EA=5:1 obtains compound 16;
    Step 17:
    Add compound 16 0.09mmol in single port bottle, add palladium carbon after dissolving with the mixing solutions of EtOH and EA, pass into H 2, TLC monitoring disappears to raw material, filters, concentrated, column chromatography PE:EA=3:1, R f=0.47, PE:EA=2:1, obtains compound 17;
    Step 18:
    Add compound a in single port bottle, 3.24mmol and dry methylene dichloride, add 1 DMF, then drip oxalyl chloride after at 0 DEG C, 3.9mmol, after gas no longer produces, at room temperature continues stirring 30 minutes, concentrating under reduced pressure obtains acyl chlorides b again, with the THF constant volume of drying, participates in the next step directly;
    Add compound 17,0.078mmol and dry THF in single port bottle, after add NaH, 0.086mmol, stirring at room temperature 1h, the THF solution of rear slow dropping acyl chlorides b, 0.10mmol, stopped reaction after spending the night, direct plate layer chromatography PE:EA=3:1, R f=0.42, PE:EA=3:1, obtains compound 18;
    Or,
    Compound 33 is prepared by following synthetic route and step
    Step 1:
    Add the above-mentioned step 1 gained compound 1,17.5mmol preparing compound 18 in single port bottle, after adding acetonitrile dissolving, then add ammonium acetate successively, 1.75mmol, NBS, 18.4mmol, react 4h under room temperature, concentrating under reduced pressure removing acetonitrile, thin up, extraction into ethyl acetate, the anhydrous MgSO of organic phase 4drying, filters, concentrated, column chromatography PE:EA=20:1, R f=0.35, PE:DCM=2:1, obtains compound 19;
    Step 2:
    Add compound 19,1mmol in single port bottle, after adding DMF dissolving, then add DIPEA, 2mmol, adds TERT-BUTYL DIMETHYL CHLORO SILANE, 2mmol, reacts 1h under room temperature, and the cancellation that adds water is reacted, extraction into ethyl acetate, after merging organic phase, washing, saturated common salt is washed, anhydrous MgSO 4drying, filters, concentrated, column chromatography PE:EA=100:1, R f=0.78, PE:EA=15:1, obtains compound 20;
    Step 3:
    In two-mouth bottle reflux, under argon shield, add compound 20,5.24mmol, Pd (dppf) Cl 2, 0.08mmol, anhydrous Isosorbide-5-Nitrae-dioxane, zinc methide, after 6.29mmol, reflux, the reaction of reaction 1h, 1N hydrochloric acid, extraction into ethyl acetate, after merging organic phase, washing, saturated common salt is washed, anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE:EA=40:1, R f=0.57, PE:EA=15:1, obtains compound 21;
    Step 4:
    Add compound 21,2.50mmol in single port bottle, add methyl alcohol, under ice bath, add NaBH 4, 10.0mmol, more at room temperature react 4h, concentrating under reduced pressure, the white solid obtained is dissolved in 3N hydrochloric acid, dichloromethane extraction, merges organic phase, washing, saturated common salt is washed, anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE:EA=10:1, R f=0.41, PE:EA=10:1, obtains compound 22;
    Step 5
    Add compound 22,0.90mmol in single port bottle, add tetrahydrofuran (THF), add tetrabutyl ammonium fluoride, 1.80mmol under ice bath, react 0.5h, thin up, extraction into ethyl acetate under rear room temperature, merge organic phase, washing, saturated common salt is washed, anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE:EA=4:1, R f=0.26, PE:EA=4:1, obtains compound 23;
    Step 6:
    Add compound 23,3.66mmol in single port bottle, rear dry methylene dichloride dissolves, add tosic acid again, 0.37mmol, after stirring in cryosel bath, drip 3,4-dihydro-2H-pyrans, 3.84mmol, reaction 1h, stopped reaction, add triethylamine cancellation reaction, organic phase saturated common salt is washed, anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE:EA=20:1, R f=0.67, PE:EA=4:1, obtains compound 24;
    Step 7:
    Add the above-mentioned step 9 gained compound 9,4.08mmol, compound 244.89mmol preparing compound 18 in two-mouth bottle reflux, Cu, 10.2mmol, CuO, 10.2mmol, DMAP, 12.2mmol, add CH under argon shield 3cN post-heating is to backflow, and stopped reaction after reaction 12h, cooling, DCM dilutes, and filters, concentrated, column chromatography PE:EA=6:1, R f=0.09, PE:EA=10:1, obtains compound 25:
    Step 8:
    Add compound 25,2.37mmol in single port bottle, tosic acid, after add Virahol and H 2o, heated overnight at reflux, stopped reaction, cooling, adds H 2o, extraction into ethyl acetate, organic phase is washed, and saturated common salt is washed, anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE:EA=3:1, R f=0.20, PE:EA=3:1, obtains compound 26;
    Step 9:
    Add compound 26,2.09mmol in single port bottle, dissolve with MeOH, add tosic acid, 0.42mmol, after stirring at room temperature 1h, add NaOH, 23.5mmol, be heated to backflow, reaction is spent the night, stopped reaction, cooling, concentrating under reduced pressure removing MeOH, with 3N HCl adjust pH to 3, extraction into ethyl acetate, anhydrous Na 2sO 4drying, filters, concentrated, obtains compound 27 crude product;
    Step 10:
    By the crude product g of compound 27,1.98mmol and triethylamine, 15.8mmol is dissolved in dry CH 3in CN, be dissolved in dry CH by being slowly added drop-wise under above-mentioned obtained solution room temperature by iodate-2-chloro-1-picoline 7.92mmol 3in the solution that CN configures, after dropwising, heating reflux reaction spends the night, stopped reaction, cooling, concentrating under reduced pressure removing CH 3cN, adds H 2o, DCM extract, anhydrous Na 2sO 4drying, filters, concentrated, column chromatography DCM, R f=0.80, PE:EA=2:1, obtains compound 28;
    Step 11:
    Add compound 28,0.65mmol in single port bottle, under argon shield, add dry THF, drip neo-pentyl magnesium bromide under ice bath, 3.9mmol, be naturally warming up to stirring at room temperature 1h afterwards, add saturated NH 4cl cancellation is reacted, and EA extracts, anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE:EA=5:1, R f=0.44, PE:EA=3:1, obtains compound 29;
    Step 12:
    Add in single port bottle compound 29,0.27mmol, DMSO dissolve, after add IBX, 0.54mmol, stirred overnight at room temperature, stopped reaction, add H 2o, DCM extract, and organic phase is washed, anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE:EA=7:1, R f=0.51, PE:EA=3:1, obtains compound 30;
    Step 13:
    Under argon shield, in single port bottle, add (R)-Me-CBS, 0.186mmol, decompression removing toluene wherein, then add THF, be cooled to-20 DEG C, add BH 3tHF, 0.68mmol, 1M in THF, the THF solution of rear slow dropping compound 30,0.62mmol, 3h dropwises, and stopped reaction after-20 DEG C of reaction 4h, adds H 2o cancellation is reacted, and EA extracts, and organic phase is washed, anhydrous Na 2sO 4drying, filters, and concentrated, column chromatography PE:EA=5:1 obtains compound 31;
    Step 14:
    Add compound 31,0.35mmol in single port bottle, add palladium carbon after dissolving with the mixing solutions of EtOH and EA, pass into H 2, TLC monitoring disappears to raw material, filters, concentrated, column chromatography PE:EA=3:1, R f=0.42, PE:EA=2:1, obtains compound 32;
    Step 15:
    Add compound 32,0.42mmol and dry THF in single port bottle, after add NaH, 0.46mmol, stirring at room temperature 1h, rear slow dropping parabromobenzoyl chloride, the THF solution of 0.46mmol, stopped reaction after spending the night, direct column chromatography PE:EA=5:1, R f=0.25, PE:EA=3:1, obtains compound 33;
    Or,
    Compound 34 is prepared by following synthetic route and step
    The above-mentioned step step 14 gained compound 32 preparing compound 33 is added in single port bottle, 0.078mmol and dry THF, after add NaH, 0.086mmol, stirring at room temperature 1h, rear slow dropping is to trifluoromethyl benzoyl chloride, the THF solution of 0.086mmol, stopped reaction after spending the night, direct column chromatography PE:EA=5:1, R f=0.38, PE:EA=3:1, obtains g compound 34;
    Or,
    Compound 35 is prepared by following synthetic route and step
    Above-mentioned gained compound 320.078mmol and dry THF is added in single port bottle, after add NaH, 0.086mmol, stirring at room temperature 1h, rear slow dropping 3,5-bis-(trifluoromethyl) Benzoyl chloride, the THF solution of 0.086mmol, stopped reaction after spending the night, direct column chromatography PE:EA=5:1, R f=0.45, PE:EA=3:1, obtains compound 35;
    Or,
    Compound 36 is prepared by following synthetic route and step,
    Add gained compound 32,0.10mmol and dry THF in single port bottle, after add NaH, 0.11mmol, stirring at room temperature 1h, rear slow dropping gained acyl chlorides b, the THF solution of 0.13mmol, stopped reaction after spending the night, direct plate layer chromatography PE:EA=3:1, R f=0.46, PE:EA=3:1, obtains compound 36;
    Or,
    Compound 48 is prepared by following synthetic route and step,
    Step 1:
    Gained compound 19 3.40mmol is added in two-mouth bottle, to methoxyphenylboronic acid, 4.08mmolPd (PPh 3) 4, 0.34mmol, 2N K 2cO 3, 6.80mmol, methyl alcohol, 80 DEG C of reactions are spent the night, and reaction solution adds suction filtered through kieselguhr, extraction into ethyl acetate after thin up, and organic phase is washed, and saturated common salt is washed, anhydrous MgSO 4drying, filters, concentrated, column chromatography PE:EA=10:1, R f=0.16, PE:EA=10:1, obtains compound 37;
    Step 2:
    Add compound 37,2.84mmol in single port bottle, add methyl alcohol, under ice bath, add NaBH 4, after 5.68mmol, react 1h, concentrating under reduced pressure under room temperature, the white solid obtained is dissolved in 3N hydrochloric acid, extraction into ethyl acetate, organic phase is washed, and saturated common salt is washed, anhydrous MgSO 4drying, filters, concentrated, column chromatography PE:EA=3:1, R f=0.21, PE:EA=3:1, obtains compound 38;
    Step 3:
    Add compound 38,2.45mmol in single port bottle, rear dry methylene dichloride dissolves, add tosic acid 0.25mmol again, after stirring in cryosel bath, drip 3,4-dihydro-2H-pyrans, 2.52mmol, reaction 1h, stopped reaction, adds triethylamine cancellation reaction, organic phase saturated common salt is washed, anhydrous MgSO 4drying, filters, concentrated, column chromatography PE:EA=7:1, R f=0.57, PE:EA=3:1, obtains compound 39;
    Step 4:
    In two-mouth bottle reflux, add gained compound 9 1.88mmol, compound 39,2.25mmol, Cu 4.70mmol, CuO, 4.70mmol, DMAP, 5.64mmol, add CH under argon shield 3cN post-heating is to backflow, and stopped reaction after reaction 12h, cooling, adds diatomite filtration, concentrated, column chromatography PE:EA=5:1, R f=0.32, PE:EA=5:1, obtains compound 40;
    Step 5:
    Add compound 40 1.62mmol in single port bottle, tosic acid, after add Virahol and H 2o, heated overnight at reflux, stopped reaction, cooling, adds H 2o, extraction into ethyl acetate, organic phase is washed, and saturated common salt is washed, anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE:EA=3:1, R f=0.14, PE:EA=3:1, obtains compound 41;
    Step 6:
    Add compound 41,1.51mmol in L single port bottle, dissolve with MeOH, add tosic acid, 0.39mmol, after stirring at room temperature 1h, add NaOH, 15.1mmol, be heated to backflow, reaction is spent the night, stopped reaction, cooling, concentrating under reduced pressure removing MeOH, with 3N hydrochloric acid adjust pH to 3, extraction into ethyl acetate, anhydrous Na 2sO 4drying, filters, concentrated, obtains compound 42 crude product;
    Step 7:
    By the crude product 1.51mmol of compound 42 and triethylamine, 12.1mmol is dissolved in dry CH 3in CN, will slowly be added drop-wise to by the chloro-1-picoline of iodate-2-under above-mentioned obtained solution room temperature, 6.04mmol be dissolved in dry CH 3in the solution that CN configures, after dropwising, heating reflux reaction spends the night, stopped reaction, cooling, concentrating under reduced pressure removing CH 3cN, adds H 2o, DCM extract, anhydrous Na 2sO 4drying, filters, concentrated, column chromatography DCM, R f=0.58, PE:EA=2:1, obtains compound 43;
    Step 8:
    Under adding compound 43 0.27mmol argon shield in single port bottle, add dry THF, under ice bath, drip neo-pentyl magnesium bromide 1.6mmol, be naturally warming up to stirring at room temperature 1h afterwards, add saturated NH 4cl cancellation is reacted, extraction into ethyl acetate, anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE:EA=5:1, R f=0.30, PE:EA=3:1 obtains compound 44;
    Step 9:
    Add in single port bottle compound 44,0.19mmol, DMSO dissolve, after add IBX, 0.38mmol, stirred overnight at room temperature, stopped reaction, add H 2o, DCM extract, and organic phase is washed, anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE:EA=5:1, R f=0.53, PE:EA=3:1, obtains compound 45;
    Step 10:
    Under argon shield, in single port bottle, add (R)-Me-CBS, 0.051mmol, decompression removing toluene wherein, then add THF, be cooled to-20 DEG C, add BH 3tHF, 0.22mmol, 1M in THF, the THF solution of rear slow dropping compound 45,0.17mmol, 3h dropwises, and stopped reaction after-20 DEG C of reaction 4h, adds H 2o cancellation is reacted, extraction into ethyl acetate, and organic phase is washed, anhydrous Na 2sO 4drying, filters, and concentrated, column chromatography PE:EA=5:1 obtains compound 46;
    Step 11:
    Add compound 46,0.12mmol in single port bottle, add palladium carbon after dissolving with the mixing solutions of EtOH and EA, pass into H 2, TLC monitoring disappears to raw material, filters, concentrated, column chromatography PE:EA=2:1, R f=0.24, PE:EA=2:1, obtains compound 47;
    Step 12:
    Add compound 47,0.015mmol and dry THF in single port bottle, after add NaH, 0.017mmol, stirring at room temperature 1h, rear slow dropping to trifluoromethyl benzoyl chloride, the THF solution of 0.017mmol, stopped reaction after spending the night, direct plate layer chromatography PE:EA=3:1, R f=0.24, PE:EA=3:1, obtains compound 48;
    Or,
    Compound 49 is prepared by following synthetic route and step,
    Add gained compound 47,0.046mmol and dry THF in single port bottle, after add NaH, 0.051mmol, stirring at room temperature 1h, rear slow dropping 3,5-bis-(trifluoromethyl) Benzoyl chloride, the THF solution of 0.066mmol, stopped reaction after spending the night, direct plate layer chromatography PE:EA=3:1, R f=0.67, PE:EA=2:1, obtains compound 49;
    Or,
    Compound 50 is prepared by following synthetic route and step,
    Add gained compound 47,0.040mmol and dry THF in single port bottle, after add NaH, 0.044mmol, stirring at room temperature 1h, the THF solution of the acyl chlorides b described in rear slow dropping, 0.052mmol, stopped reaction after spending the night, direct plate layer chromatography PE:EA=3:1, R f=0.37PE:EA=3:1, obtains compound 50;
    Or,
    Compound 51 is prepared by following synthetic route and step,
    Add gained compound 17,0.081mmol and dry THF in single port bottle, after add NaH, 0.081mmol stirring at room temperature 1h, rear slow dropping is to trifluorobenzoyl chloride, and stopped reaction after 0.089mmol, 1h, adds H 2o, EA extract, organic phase anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE:EA=3:1, R f=0.54, PE:EA=3:1, obtains compound 51;
    Or,
    Compound 52 is prepared by following synthetic route and step,
    Add gained compound 17 0.078mmol and dry THF in single port bottle, after add NaH, 0.086mmol stirring at room temperature 1h, rear slow dropping 3,5-bis-(trifluoromethyl) Benzoyl chloride, stopped reaction after 0.086mmol, 1h, adds H 2o, EA extract, anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE:EA=10:1, R f=0.71, PE:EA=3:1, obtains compound 52;
    Or,
    Compound 64 is prepared by following synthetic route and step,
    Step 1:
    H is added in single port bottle 2o, HBr, after add 2-amino-5 tolyl acid, 6.62mmol make it dissolve, cryosel bath under drip NaNO 2, the aqueous solution of 7.22mmol, stir 1h, slowly drip CuBr, the HBr solution of 9.47mmol, be stirred to not regeneration bubble, oil bath heats 80 DEG C, and reaction is spent the night, and second day is stopped reaction early, and cooling is filtered, washing, R f=0.33, PE:EA=2:1, obtains compound 53;
    Step 2:
    Add compound 53 5.99mmol in single port bottle successively, methyl alcohol, the vitriol oil, reflux 7h, stopped reaction, cooling, adds saturated NaHCO 3solution adjust pH to 7, EA extracted organic phase, washing, anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE:EA=100:1, R f=0.89, PE:EA=2:1, obtains compound 54;
    Step 3:
    Add NBS successively in single port bottle, 18.3mmoL, AIBN, 0.873mmol, under argon shield, add the CCl of compound 54 4solution, reflux 2h, NBS is added in rear cooling, 9.6mmol and AIBN, 0.873mmol reflux 2h, stopped reaction, cooling, filters, concentrated.Add the vitriol oil, stirring at room temperature, TCL follows the tracks of reaction and disappears to raw material, pours in frozen water, EA extracted organic phase, saturated NaHCO 3wash, washing, anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE:EA=30:1, R f=0.55, PE:EA=5:1, obtains compound 55;
    Step 4:
    Gained compound 3 4.01mmol is added, compound 55,3.34mmol, CuBr, 1.67mmol, Cs in single port bottle 2cO 3, 6.68mmol, after add NMP, 2,2,6,6-tetramethyl--3,5-heptadione, 0.334mmol, degassed 0.5h, post-heating to 80 DEG C, reaction 2h after stopped reaction, cooling, add H 2o, by 3N HCl adjust pH to 4, EA extracted organic phase, washing, saturated NH 4cl washes, anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE:EA=15:1, R f=0.12, PE:EA=20:1, obtains compound 56;
    Step 5:
    Add compound 56,2.35mmol, PTSA successively in single port bottle, add Virahol and H 2o, heated overnight at reflux, second day is stopped reaction early, and cooling, adds H 2o, EA extract, H 2o washes, anhydrous MgSO 4drying, filters, concentrated, column chromatography PE:EA=3:1, R f=0.14, PE:EA=3:1, obtains compound 57;
    Step 6:
    Add compound 57 2.22mmol in single port bottle, dissolve with MeOH, add PTSA 1.11mmol, stirring at room temperature 1h, add NaOH, 24.42mmol, reflux, reaction is spent the night.Second day is stopped reaction early, cooling, and rotary evaporation goes out MeOH, and with 3N HCl adjust pH to 4, EA extracts, anhydrous Na 2sO 4drying, filters, concentrated, obtains compound 58 crude product;
    Step 7:
    By the crude product of compound 58,2.65mmol and triethylamine, 16.4mmol is dissolved in dry CH 3in CN, will slowly be added drop-wise to by the chloro-1-picoline of iodate-2-under above-mentioned obtained solution room temperature, 8.2mmol be dissolved in dry CH 3in the solution that CN configures, after dropwising, heating reflux reaction 1h, rear stopped reaction, cooling, screws out CH 3cN, adds H 2o, DCM extract, anhydrous Na 2sO 4drying, filters, concentrated, column chromatography DCM, R f=0.67, PE:EA=2:1, obtains compound 59;
    Step 8:
    Add compound 59,0.385mmol in single port bottle, under argon shield, add dry THF, drip the neo-pentyl magnesium bromide of preparation under ice bath, 2.308mmol, be naturally warming up to stirring at room temperature 1h afterwards, add saturated NH 4cl cancellation is reacted, and EA extracts, anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE:EA=3:1, R f=0.13, DCM, obtains compound 60;
    Step 9:
    Add compound 60,0.13mmol, DMSO in single port bottle to dissolve, after add IBX, 0.26mmol, stirred overnight at room temperature, second day early stopped reaction, adds H 2o, DCM extract, washing, anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE:EA=4:1, R f=0.5, PE:EA=3:1, obtains compound 61;
    Step 10:
    Under argon shield, in single port bottle, add (R)-Me-CBS, 0.112mmol, after add THF, be cooled to-20 DEG C, add BH 3, 0.374mmol, 1M in THF, the THF solution of rear slow dropping compound 61,0.374mmol, 3h dropwises, and stopped reaction after-20 DEG C of reaction 4h, adds H 2o cancellation is reacted, EA extracted organic phase, washing, anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE:EA=3:1, R f=0.13, PE:EA=5:1, obtains compound 62;
    Step 11:
    Add compound 62 0.22mmol in single port bottle, add palladium carbon after dissolving with the mixing solutions of EtOH and EA, pass into H 2, after TLC monitoring to raw material disappears, filter, concentrated, obtain compound 63;
    Step 12:
    Add compound 63 0.061mmol and dry THF in single port bottle, after add NaHg, 0.077mmol stirring at room temperature 1h, rear slow dropping is to trifluorobenzoyl chloride, and stopped reaction after 0.068mmol, 1h, adds H 2o, EA extract, anhydrous Na 2sO 4drying, filters, concentrated, column chromatography PE:EA=3:1, R f=0.76, PE:EA=3:1, obtains compound 64;
    Or,
    Compound 65 is prepared by following synthetic route and step,
    Add compound 63 0.076mmol and dry THF in single port bottle, after add NaH, 0.096mmol stirring at room temperature 1h, rear slow dropping 3,5-bis-(trifluoromethyl) Benzoyl chloride, stopped reaction after 0.084mmol, 1h, adds H 2o, EA extract, anhydrous Na 2sO 4drying, filters, concentrated, column chromatography DCM, R f=0.22, PE:EA=3:1, obtains compound 65.
CN201110340808.0A 2011-11-01 2011-11-01 Penicillide derivative, its preparation method and at pharmaceutical usage Expired - Fee Related CN103087040B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201110340808.0A CN103087040B (en) 2011-11-01 2011-11-01 Penicillide derivative, its preparation method and at pharmaceutical usage

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201110340808.0A CN103087040B (en) 2011-11-01 2011-11-01 Penicillide derivative, its preparation method and at pharmaceutical usage

Publications (2)

Publication Number Publication Date
CN103087040A CN103087040A (en) 2013-05-08
CN103087040B true CN103087040B (en) 2015-10-28

Family

ID=48200221

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201110340808.0A Expired - Fee Related CN103087040B (en) 2011-11-01 2011-11-01 Penicillide derivative, its preparation method and at pharmaceutical usage

Country Status (1)

Country Link
CN (1) CN103087040B (en)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5089487A (en) * 1989-06-13 1992-02-18 Bayer Aktiengesellschaft Circulation-active dibenzo[1,5]dioxocin-5-ones
CN101298448A (en) * 2008-06-27 2008-11-05 扬州慧清医药科技开发有限公司 Synthetic method of 2-benzyloxy-3-ethyl-4-methyl-5-chloro-6-[(tetrahydro-2H-pyrrole-2-oxyl)methyl ] phenol

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10250687A1 (en) * 2002-10-31 2004-05-13 Bayer Ag 7H-Dibenzo (b, g) (1,5) dioxocin-5-one derivatives and their use

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5089487A (en) * 1989-06-13 1992-02-18 Bayer Aktiengesellschaft Circulation-active dibenzo[1,5]dioxocin-5-ones
CN101298448A (en) * 2008-06-27 2008-11-05 扬州慧清医药科技开发有限公司 Synthetic method of 2-benzyloxy-3-ethyl-4-methyl-5-chloro-6-[(tetrahydro-2H-pyrrole-2-oxyl)methyl ] phenol

Also Published As

Publication number Publication date
CN103087040A (en) 2013-05-08

Similar Documents

Publication Publication Date Title
JPS58501723A (en) Production method of cyanoheterocyclic compound
CN111592533B (en) 1,2, 4-oxadiazole bipyridyl substituted benzamide compound and preparation method and application thereof
CN101970401A (en) Leukotriene b4 inhibitors
CN103087040B (en) Penicillide derivative, its preparation method and at pharmaceutical usage
JP2752630B2 (en) New benzoic acid derivative and method for producing the same
Gupton et al. The application of (Z)-3-aryl-3-haloenoic acids to the synthesis of (Z)-5-benzylidene-4-arylpyrrol-2 (5H)-ones
JPS63280070A (en) Benzazepine derivative
CA2709863A1 (en) Azetidine derivatives, their preparation and their application in therapy
JP5166872B2 (en) Vitamin D-like compound
JPS6078972A (en) Ester compound
CN1234690C (en) Nicotinic acid ester of resveratrol and its synthetic method
CN110483391B (en) Five-component synthesis method of nicotinamide amide derivative
CN101279972A (en) Benzoxazole herbicides and preparation thereof
CN112691099B (en) Application of organic compound in preparation of medicine for treating colon cancer
CN115353514B (en) Fluoro-pyridopyrimidinone compounds and synthesis method thereof
CN110590747A (en) Compound, preparation method, pharmaceutical composition and application thereof
CN112624966B (en) Synthetic method of 2-aminomethyl-4-methyl-5-pyridine carboxylic acid
CN102617463A (en) Quinoline derivative and quinazoline derivative and preparation method thereof
JP3432880B2 (en) Preparation of optically active azaspiro compounds
JP2937387B2 (en) Process for producing 5-substituted 2-amino-3-cyanopyrazines
WO2019184772A1 (en) Gibberellin-like compound, preparation method thereof, pharmaceutical composition, uses and intermediate thereof
JPS58192874A (en) Novel spiroisoxazoline derivative
JP2003261474A (en) Cyclic acetylene compound and method for producing the same
JPS58140086A (en) 4-(trans-5-alkyl-1, 3-dioxa-2-yl)benzoic acid derivative
JP2003073381A (en) Optically active fulgide compound

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20151028

Termination date: 20181101