CN111909051A - N- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-butyl-2-yl ] -phenylalaninol derivative and preparation method and application thereof - Google Patents

N- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-butyl-2-yl ] -phenylalaninol derivative and preparation method and application thereof Download PDF

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CN111909051A
CN111909051A CN202010788680.3A CN202010788680A CN111909051A CN 111909051 A CN111909051 A CN 111909051A CN 202010788680 A CN202010788680 A CN 202010788680A CN 111909051 A CN111909051 A CN 111909051A
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徐必学
曾晓萍
黄维杰
况安香
邵晓霜
梁光义
刘锟
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Key Laboratory of Natural Product Chemistry of Guizhou Academy of Sciences
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Abstract

The invention discloses an N- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-butyl-2-yl]-phenylalaninol derivatives, which are compounds represented by general formula I and pharmaceutically acceptable salts or hydrates thereof, wherein R is1And R3Independently selected from hydrogen, fluorine, chlorine, bromine, -NO2、‑NH2、‑NHR、‑NRR′、‑NHCOR、‑N HCO(CH2)nCOOH、‑OH、‑OCOR、‑OR、‑O(CH2)nNRR′、‑O(CH2)nCOOR、‑O(CH2)nCOOH; the R is2Is an aromatic ring containing a substituent; the R is4is-OH, -O (CO) R, -OR; r and R' are independently selected from C1‑C6Alkyl radical, C3‑C7Cycloalkyl radical, C2‑C7An alkylene group; and n is an integer of 1 to 4. The invention also discloses a preparation method of the derivative. The derivative can be used for preparing medicines for treating viral infection, especially anti-HBV medicines and anti-HIV medicines. The invention is not easy to be hydrolyzed by enzyme, has better metabolic stability and obviously prolongs elimination half-life.

Description

N- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-butyl-2-yl ] -phenylalaninol derivative and preparation method and application thereof
Technical Field
The invention relates to the technical field of equisetum vulgare linn derivative pharmaceutical chemistry, in particular to an N- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-butyl-2-yl ] -phenylalaninol derivative, and a preparation method and application thereof.
Background
Hepatitis B ("Hepatitis B" for short) is a potentially life-threatening liver disease caused by Hepatitis B Virus (HBV) infection, and is also a major cause of chronic Hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) worldwide. New data from the 19 th world health organization at 7 th and 19 th 2019 shows that in 2015, 2.57 million people worldwide have chronic hepatitis b infection (defined as positive for hepatitis b surface antigen), and in 2017, 110 million new infected people exist. The main goals of hepatitis b treatment include three points: firstly, inhibiting viruses; ② the incidence of liver complications is reduced; and increasing long-term survival rate. The current clinical drugs for treating hepatitis b are mainly: interferon immunomodulators and nucleoside analogs. To date, no effective drug has been found for eliminating HBV and ultimately curing hepatitis B. Therefore, it is important to find and develop a therapeutic agent for hepatitis B having a novel chemical structure, particularly a novel mechanism of action.
In order to develop a novel high-efficiency and low-toxicity medicament for treating hepatitis B, the inventor designs and synthesizes a series of N- (N-benzoyl-L-phenylalanyl) -phenylalanine dipeptide derivatives (namely MTS derivatives) with novel structures by taking a compound N- (N-benzoyl-L-phenylalanyl) -O-acetyl-L-phenylalaninol (MTS) with anti-hepatitis B virus activity as a lead compound, and applies for obtaining an authorized invention patent (patent number: ZL 200610201016.4). The inventor finds that the MTS derivative is easily hydrolyzed and metabolized in vivo, has poor metabolic stability and short elimination half-life in further research.
Disclosure of Invention
The invention aims to provide an N- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-butyl-2-yl ] -phenylalaninol derivative, and a preparation method and application thereof. The invention can be used for preparing medicaments for treating viral infection, in particular anti-hepatitis B virus medicaments and anti-human immunodeficiency virus medicaments. The N- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-butyl-2-yl ] -phenylalaninol derivative provided by the invention is not easy to be hydrolyzed by enzyme, has better metabolic stability and obviously prolonged elimination half-life.
The technical scheme of the invention is as follows: n- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-butyl-2-yl ] -phenylalaninol derivative is a compound shown as the following general formula I and pharmaceutically acceptable salt or hydrate thereof,
Figure BDA0002622973250000021
the R is1And R3Independently selected from hydrogen, fluorine, chlorine, bromine, -NO2、-NH2、-NHR、-NRR′、-NHCOR、-N HCO(CH2)nCOOH、-OH、-OCOR、-OR、-O(CH2)nNRR′、-O(CH2)nCOOR and-O (CH)2)nA single or a combination of two or more of COOH;
the R is2Is an aromatic ring containing a substituent;
the R is4is-OH, -O (CO) R, -OR;
the R and R' are selected from the same or different C1-C6Straight or branched alkyl, C3-C7Cycloalkyl radical, C2-C7An alkylene group;
and n is an integer of 1 to 4.
In the aforementioned N- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-but-2-yl ] -phenylalaninol derivative, the aromatic ring is a benzene ring, a pyridine ring, a furan ring or a thiophene ring.
In the aforementioned N- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-but-2-yl ] -phenylalaninol derivative, the substituent on the aromatic ring is mono-substituted or poly-substituted.
N- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-but-2-yl ] as described above]-phenylalaninol derivatives in which the substituents on the aromatic ring are chosen from hydrogen, fluorine, chlorine, bromine, iodine, -CN, -NO2、-NH2、-OH、-S H、-COOH、-OR、-SR、-NHR、-NRR′、C1-C6An alkyl group.
In the aforementioned N- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-but-2-yl ] -phenylalaninol derivative, the alkyl group and the cycloalkyl group are optionally substituted with 1 to 2 substituents selected from the group consisting of a hydroxyl group, a nitro group, a haloalkyl group, a cyano group, and a trifluoromethyl group.
In the aforementioned N- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-but-2-yl ] -phenylalaninol derivative, the derivative is any one selected from T01-T140,
Figure BDA0002622973250000031
Figure BDA0002622973250000041
Figure BDA0002622973250000051
Figure BDA0002622973250000061
Figure BDA0002622973250000071
Figure BDA0002622973250000081
n- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-but-2-yl ] as described above]Process for the preparation of phenylalaninol derivatives, carried out according to the following synthetic route, with R1Substituted L-phenylalaninol (SM1) is used as a starting material, the starting material is reacted with trityl chloromethane in the presence of tertiary amine to obtain an intermediate M1, then M1 is subjected to Swern oxidation to obtain an intermediate M2, M2 is reacted with trifluoromethyl trimethylsilane in the presence of tetrabutylammonium fluoride (TBAF) to obtain an intermediate M3, M3 is subjected to acid catalysis to remove trityl protecting group to obtain an intermediate M4, M4 is reacted with N-Boc to obtain an intermediate M5, M5 is subjected to Dess-Martin oxidation to obtain an intermediate M6, M6 is further subjected to R-Martin oxidation to obtain an intermediate M6, and M6 and R are further subjected to tertiary amine oxidation3Coupling substituted L-phenylalaninol (SM2) to obtain an intermediate M7, opening ring of M7 under the action of lithium aluminum hydride to obtain an intermediate M8, removing Boc protecting group from M8 to obtain an intermediate M9, and reacting M9 with arylformic acid to obtain a Target Molecule (TM) with a structure shown as a general formula I:
Figure BDA0002622973250000091
in the aforementioned preparation method of the N- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-but-2-yl ] -phenylalaninol derivative, the reaction reagents and conditions are as follows: (a) tertiary amines such as trityl chloromethane, N, N-diisopropylethylamine (D IPEA) and triethylamine; (b) oxalyl chloride, dimethyl sulfoxide, DIPEA or triethylamine, dichloromethane; (c) trifluoromethyl trimethylsilane, tetrabutylammonium fluoride (TBAF), N-dimethylformamide (D MF); (d) concentrated hydrochloric acid or p-toluenesulfonic acid or trifluoroacetic acid, methanol, etc.; (e) di-tert-butyl dicarbonate, water-soluble carbonates such as potassium carbonate or sodium carbonate, tetrahydrofuran-water; (f) Dess-Martin reagent, dichloromethane; (g) refluxing the solvent such as toluene or tetrahydrofuran; (h) lithium aluminum hydride, tetrahydrofuran or toluene; (i) hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid and the like, dichloromethane; (j) condensing agents such as N-methylmorpholine, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) or dicyclohexylcarbodiimide (DC C), and methylene chloride.
In the aforementioned method for producing N- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-but-2-yl ] -phenylalaninol derivatives, the free phenolic hydroxyl group and alcoholic hydroxyl group are differently substituted to obtain the objective compounds as defined above.
The N- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-butyl-2-yl ] -phenylalaninol derivative is applied to the preparation of medicaments for treating viral infection.
In the application of the N- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-butyl-2-yl ] -phenylalaninol derivative in preparing the medicament for treating the viral infection, the N- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-butyl-2-yl ] -phenylalaninol derivative is used as an active ingredient, and one or more pharmaceutically acceptable carriers or excipients are added to prepare the medicinal preparation for treating the viral infection.
In the application of the N- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-butyl-2-yl ] -phenylalaninol derivative in preparing the medicament for treating the viral infection, the excipient is a pharmaceutically acceptable diluent and an auxiliary agent.
In the application of the N- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-butyl-2-yl ] -phenylalaninol derivative in preparing the medicaments for treating viral infection, the excipient comprises a binding agent, a lubricating agent, a disintegrating agent, a cosolvent, a diluting agent, a stabilizing agent, a suspending agent and a flavoring agent for oral preparations; preservatives, cosolvents and stabilizers for injection preparations; matrix for external preparation, diluent, lubricant, and antiseptic.
In the application of the N- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-butyl-2-yl ] -phenylalaninol derivative in preparing the medicament for treating the viral infection, the active ingredients also comprise other active ingredients of the medicament for treating the viral infection.
In the application of the N- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-butyl-2-yl ] -phenylalaninol derivative in preparing the medicaments for treating viral infection, the medicinal preparation is a clinically acceptable oral preparation, injection preparation or external preparation, and the oral preparation is tablets, capsules, oral liquid or suspension and the like; the injection preparation is solution, suspension or powder injection and the like; the external preparation is ointment or solution.
In the application of the N- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-butyl-2-yl ] -phenylalaninol derivative in preparing the medicament for treating viral infection, the anti-viral infection medicament is an anti-hepatitis B virus medicament or an anti-human immunodeficiency virus medicament.
In the present invention, the pharmaceutical preparation may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically) and, if certain drugs are unstable under gastric conditions, it may be formulated as enteric coated tablets.
Academic definitions and explanations
"hydroxy" means an-OH group.
"nitro" means-NO2A group.
"cyano" means a-CN group.
"haloalkyl" means a halogen-substituted alkyl group, which is substituted with the same or different halogen atoms, as set forth in: -CH2Cl、-CCl3、-CH2CF3And the like.
Aryl-substituted formic acids such as "arylcarboxylic acid" benzoic acid, 4-chlorobenzoic acid, 3-bromobenzoic acid, 3-iodobenzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, 4-fluorobenzoic acid, 4-methoxybenzoic acid, 4-nitrobenzoic acid, 3-nitrobenzoic acid, 4-trifluoromethylbenzoic acid, 4-methylbenzoic acid, 3-methylbenzoic acid, 2-nitrobenzoic acid, 3-trifluoromethylbenzoic acid, 3, 4-dimethoxybenzoic acid, 3,4, 5-trimethoxybenzoic acid, 3,4, 5-trimethylbenzoic acid, and 2-furancarboxylic acid.
Compared with the prior art, the invention replaces easily hydrolyzed amido bond in the MTS derivative by different bioisosteres, screens different bioisostere replacement groups, and finally obtains the N- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-butyl-2-yl ] -phenylalaninol derivative after replacing one amide (peptide) bond in the MTS derivative by a trifluoromethyl methylamino structural unit, wherein the N- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-butyl-2-yl ] -phenylalaninol derivative is not easily hydrolyzed by enzyme, has better metabolic stability and obviously prolongs the elimination half-life period; the N- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-butyl-2-yl ] -phenylalaninol derivative can be used for preparing medicaments for treating viral infection, in particular for preparing anti-hepatitis B virus medicaments and anti-human immunodeficiency virus medicaments.
Detailed Description
The present invention is further illustrated by the following examples, which are intended to be purely exemplary and are not intended to be limiting.
Example 1N- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-but-2-yl ] -phenylalaninol derivatives.
The N- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-butyl-2-yl ] -phenylalaninol derivative is any one of T01-T140,
Figure BDA0002622973250000111
Figure BDA0002622973250000121
Figure BDA0002622973250000131
Figure BDA0002622973250000141
Figure BDA0002622973250000151
Figure BDA0002622973250000161
Figure BDA0002622973250000171
example 2 preparation of N- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-but-2-yl ] -phenylalaninol derivatives
Synthetic preparation of (I) key intermediate
1. Synthetic preparation of intermediate M01
Figure BDA0002622973250000172
Reaction reagents and conditions: TrCl, Et3N,CH2Cl2,0℃。
Taking L-phenylalaninol (5.0g,331mmol) to a 250mL reaction bottle, adding 60mL anhydrous CH under the protection of argon2Cl2Dissolving completely, adding Et3N (9.2mL,66.2 mmol). While stirring in an ice-water bath, anhydrous CH containing triphenylchloromethane (9.22g,33.1mmol) was slowly added dropwise2Cl2The solution (40mL) was added dropwise and stirred at 0 ℃ for 3h until the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography to give 12.47g of a colorless oil with a yield of 95.9%. ESI-MS M/z 416.4[ M + Na ]]+；1H NMR (500MHz,CDCl3):7.59-7.53(m,6H),7.31-7.08(m,12H),6.96-6.90(m,2H),3.10 (dd,J＝10.8,2.7Hz,1H),2.92(dd,J＝10.9,4.1Hz,1H),2.84-2.77(m,1H),2.50(dd, J＝13.1,9.6Hz,1H),2.27(dd,J＝13.1,4.8Hz,1H)。
2. Synthetic preparation of intermediate M02
Figure BDA0002622973250000181
Reaction reagents and conditions: Dess-Martin reagent, CH2Cl2,RT。
M01(3.8g,9.7mmol) was placed in a 100mL reaction flask with 60mL anhydrous CH2Cl2Dissolving completely, adding Dess-Martin reagent (4.9g,11.6mmol), stirring at room temperature for 2h under the protection of argon gas until the reaction is complete, dispersing the reaction solution with ethyl acetate and water, extracting, and sequentially adding saturated NaHCO into the obtained organic layer3Saturated NaCl wash, anhydrous MgSO4Drying, and recovering solvent under reduced pressure to dryness to obtain crude M02 as white solid 2.7 g. ESI-MS M/z 414.1[ M + Na ]]+；1H NMR(500MHz,CDCl3): 8.85(d,J＝2.2Hz,1H),7.39-7.14(m,20H),3.58-3.53(m,1H),2.80-2.71(m,2H)。
3. Synthetic preparation of intermediate M03
Figure BDA0002622973250000182
Reaction reagents and conditions: TMSCF3,TBAF,DMF,-50℃。
The crude M02(5.2g,13.3mmol) was taken in a 250mL reaction flask, dissolved completely in 40mL anhydrous DMF, TBAF (4.06mL,15.9mmol) was added, and TMSCF was added with stirring at-50 deg.C3(2.92mL,19.9mmol), stirring until the reaction is complete, dispersing the reaction mixture in ethyl acetate and water, extracting, washing the organic layer with water and saturated NaCl, and removing anhydrous MgSO4Drying, recovering the solvent under reduced pressure to dryness, 6.14g crude M03 as yellow oil. ESI-MS M/z 484.4[ M + Na ]]+；1H NMR (500MHz,CDCl3):7.59-7.52(m,6H),7.36-7.29(m,6H),7.27-7.21(m,5H), 7.16-7.10(m,3H),6.67-6.60(m,2H),3.66(qd,J＝7.9,2.2Hz,1H),2.97-2.90(m, 1H),2.51(dd,J＝13.7,3.5Hz,1H),2.39(dd,J＝13.8,10.3Hz,1H)。
4. Synthetic preparation of intermediate M04
Figure BDA0002622973250000183
Reaction reagents and conditions: concentrated hydrochloric acid, MeOH,0 ℃.
Taking M03(6.1g,13.3mmol) crude product in a 250mL reaction bottle, dissolving the crude product completely with 40mL MeOH, placing the reaction system in an ice water bath, slowly dropwise adding concentrated hydrochloric acid (1.1mLg,13.3mmol), stirring for 30min till the reaction is complete, dispersing the reaction solution with ethyl acetate and water, adding K2CO3Adjusting pH to 10-11, extracting, sequentially washing the obtained organic layer with water and saturated NaCl, and removing anhydrous MgSO4Drying, recovering solvent under reduced pressure to dryness, and purifying the obtained crude product by silica gel column chromatography to obtain 2.0g of pure M04 as white solid with total yield of 68.5% in three steps. ESI-MS M/z 220.1[ M + H ]]+；1H NMR(600MHz,CDCl3):7.40-7.35(m, 2H),7.33-7.28(m,1H),7.26-7.23(m,2H),3.73(qd,J＝7.8,1.4Hz,1H),3.56(ddd, J＝9.3,6.0,1.3Hz,1H),2.92(dd,J＝13.7,5.9Hz,1H),2.73(dd,J＝13.7,9.2Hz, 1H)。
5. Synthetic preparation of intermediate M05
Figure BDA0002622973250000191
Reaction reagents and conditions: (Boc)2O,K2CO3,THF,H2O,RT。
M04(50mg,0.23mmol) was taken in a 10mL reaction flask, dissolved with 2mL tetrahydrofuran and 1mL water with stirring, and K was added successively2CO3(63mg,0.46mmol)、(Boc)2O (100mg,0.46 mmol), stirring at room temperature until the reaction is complete, dispersing the reaction solution with ethyl acetate and water, extracting, washing the obtained organic layer with water and saturated NaCl, and anhydrous MgSO4Drying, recovering solvent under reduced pressure to dryness, and purifying the crude product by silica gel column chromatography to obtain 55mg of pure M05 as white solid with yield of 75.3%. ESI-MS M/z 342.1[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.36-7.33(m,2H),7.30-7.24(m,3H), 5.06-5.00(m,2H),3.97-3.91(m,1H),3.90-3.84(m,1H),3.16(dd,J＝13.7,8.0Hz, 1H),3.03(dd,J＝13.8,7.7Hz,1H),1.46(s,9H)。
6. Synthetic preparation of intermediate M06
Figure BDA0002622973250000192
Reaction reagents and conditions: Dess-Martin reagent, CH2Cl2,RT。
Referring to the preparation method of M02, crude M06 was prepared as a yellow solid from M05. ESI-MS M/z 358.1[ M + H ]2O+Na]+。
7. Synthetic preparation of intermediate M07
Figure BDA0002622973250000193
Reaction reagents and conditions: toluene, reflux.
Taking M06(3.9g) crude product and L-phenylalaninol (2.8g,18.3mmol) to a 100mL reaction bottle, adding 50mL anhydrous toluene, refluxing and stirring for 48h till the reaction is complete, recovering the solvent under reduced pressure, and purifying the residue by silica gel column chromatography to obtain 4.5g of a white solid M07 sample with the yield of 81.2% in two steps. ESI-MS M/z 473.1 [ M + Na ]]+；1H NMR(600MHz,CDCl3):7.36-7.30(m,4H),7.29-7.20(m,6H),4.69 (d,J＝9.8Hz,1H),4.19-4.08(m,2H),3.87-3.75(m,1H),3.58(t,J＝8.3Hz,1H), 3.31(d,J＝14.5Hz,1H),3.22-3.16(m,1H),3.04(dd,J＝13.7,6.2Hz,1H),2.81-2.68 (m,2H),1.36(s,9H)。
8. Synthetic preparation of intermediate M08
Figure BDA0002622973250000201
Reaction reagents and conditions: LiAlH4,THF,-78℃。
M07(3.0g,6.6mmol) was reacted in 50mLIn a bottle, under the protection of argon, dissolving a substrate by 20mL of anhydrous THF, cooling and stirring at-78 ℃ for 5min, slowly adding lithium aluminum hydride (13.1mL and 13.1mmol), keeping the temperature at-78 ℃ and stirring for 5min, slowly returning to room temperature from-78 ℃, detecting by TLC until the reaction is complete, and slowly dropwise adding saturated NH into the reaction system4Stirring Cl solution 10mL for 5min, dispersing the reaction solution with ethyl acetate and water, extracting, washing the obtained organic layer with water and saturated NaCl, and anhydrous MgSO4Drying, recovering solvent under reduced pressure to dryness to obtain crude M08 as white solid 2.8 g. ESI-MS M/z 475.1[ M + Na ]]+。
9. Synthetic preparation of intermediate M09
Figure BDA0002622973250000202
Reaction reagents and conditions: trifluoroacetic acid, CH2Cl2,0℃。
The crude M08(2.8g) was placed in a 25mL reaction flask and 5mL anhydrous CH was added2Cl2Dissolving, adding 5mL of trifluoroacetic acid under the protection of argon, stirring in an ice water bath for 3h until the reaction is complete, dispersing the reaction solution by using ethyl acetate and water, and adding K2CO3Adjusting pH to 10-11, extracting, washing the obtained organic layer with water, saturated NaCl, anhydrous MgSO4Drying, recovering solvent under reduced pressure to dryness, and purifying the obtained crude product by silica gel column chromatography to obtain 1.6 g white solid M09 sample with total yield of 71.4% in two steps. ESI-MS M/z 353.1[ M + H ]]+；1H NMR (600MHz,CDCl3):7.34-7.29(m,4H),7.27-7.19(m,4H),7.17(d,J＝7.0Hz,2H), 3.64(dd,J＝11.8,3.0Hz,1H),3.55-3.47(m,1H),3.40(dd,J＝11.8,6.1Hz,1H), 3.36-3.31(m,1H),3.17-3.10(m,1H),2.92(dd,J＝13.6,3.0Hz,1H),2.77(dd,J＝ 13.7,6.7Hz,2H),2.67(dd,J＝13.6,7.7Hz,2H),2.40(dd,J＝13.7,11.3Hz,1H)。
10. Synthetic preparation of intermediate M10
Figure BDA0002622973250000211
Reaction reagents and conditions:Boc(O)2,NaHCO3,H2O,RT。
taking L-casamino alcohol (14.4g, 86.3mmol) and adding water 100mL, sodium bicarbonate (14.4g, 172mmol) and di-tert-butyl dicarbonate Boc (O) into a 250mL reaction bottle in sequence2(39.5mL, 172mmol) and stirred at room temperature for 8h until the reaction was complete. Dispersing the reaction solution with ethyl acetate and water, extracting, washing the obtained organic layer with 1.0mol/L hydrochloric acid, distilled water and saturated NaCl solution in sequence, and removing anhydrous MgSO4Drying, recovering the organic solvent under reduced pressure to dryness, and purifying the residue by silica gel column chromatography to obtain 16.33g of M10 sample as colorless oil with a yield of 70.8%. ESI-MS M/z 290.0[ M + Na ]]+；1H NMR(499MHz,CDCl3):7.00(d,J＝ 7.9Hz,2H),6.73(d,J＝7.9Hz,2H),3.85-3.75(m,1H),3.65-3.58(m,1H),3.50(dd, J＝11.4,5.4Hz,1H),2.72(d,J＝7.1Hz,2H),1.41(s,9H)。
11. Synthetic preparation of intermediate M11
Figure BDA0002622973250000212
Reaction reagents and conditions: BnBr, K2CO3,DMF.RT。
M10(3.2g,12mmol) was placed in a 100mL reaction flask and anhydrous DMF50mL, K was added sequentially2CO3(2.6g,19mmol), benzyl bromide (BnBr,1.6mL,13.7mmol) was injected under argon and stirred at room temperature for 8h until the reaction was complete. Dispersing the reaction solution with ethyl acetate and water, extracting, washing the obtained organic layer with water, saturated NaCl solution, anhydrous MgSO4Drying, and recovering the organic solvent under reduced pressure to dryness to obtain crude M11, 5.11g of white oily compound, yield: 87.0 percent. ESI-MS M/z 380.1[ M + Na ]]+。
12. Synthetic preparation of intermediate M12
Figure BDA0002622973250000213
Reaction reagents and conditions: HCl, MeOH, CH2Cl2,RT。
The crude M11(4.45g) was placed in a 100mL reaction flask and CH was added2Cl2(22mL) the argon was dissolved and replaced. 11mL of concentrated hydrochloric acid is put into a beaker, MeOH (11mL) is slowly added, stirring is carried out, the prepared hydrochloric acid is slowly injected into a reaction bottle, and stirring is carried out at room temperature for 6 hours until the reaction is completed. Using K as reaction solution2CO3Adjusting pH to 9-10, adding ethyl acetate and water, extracting, washing the obtained organic layer with water, saturated NaCl solution, and anhydrous MgSO4Drying, recovering the organic solvent under reduced pressure to dryness, and purifying the obtained residue by silica gel column chromatography to obtain M12 as a white solid powder compound 2.49g, yield: 78.4 percent. ESI-MS M/z 258.1[ M + Na ]]+；1H NMR(600MHz,DMSO-d6):7.44(d,J＝7.0Hz,2H),7.39(t,J＝7.5 Hz,2H),7.36-7.30(m,1H),7.19(d,J＝8.2Hz,2H),6.98(d,J＝8.6Hz,2H),5.08(s, 2H),3.50(dd,J＝11.5,3.5Hz,1H),3.36(dd,J＝11.5,6.0Hz,1H),3.29-3.22(m,1H), 2.83(dd,J＝13.5,2.5Hz,1H),2.74(dd,J＝13.7,8.9Hz,1H)。
13. Synthetic preparation of intermediate M13
Figure BDA0002622973250000221
Reaction reagents and conditions: toluene, reflux.
Referring to the preparation method of M07, M13 is prepared by taking M06 and M12 as raw materials. ESI-MS M/z 579.2[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.42(d,J＝7.1Hz,2H),7.38(t,J＝ 7.5Hz,2H),7.34-7.26(m,3H),7.23-7.17(m,3H),7.09(d,J＝8.6Hz,2H),6.90(d, J＝8.2Hz,2H),5.03(s,2H),4.68-4.63(m,1H),3.75-3.67(m,1H),3.56-3.47(m,1H), 3.28-3.19(m,1H),3.11(d,J＝9.0Hz,1H),2.96-2.89(m,1H),2.72-2.64(m,2H), 1.32(s,9H)。
14. Synthetic preparation of intermediate M14
Figure BDA0002622973250000222
Reaction reagents and conditions: THF, LiAlH4,-78℃。
Referring to the preparation method of M08, M13 is used as a raw material to prepare M14. ESI-MS M/z 581.2 [ M + Na ]]+；1H NMR(600MHz,CDCl3):7.43(d,J＝7.2Hz,2H),7.38(t,J＝7.6Hz, 2H),7.34-7.27(m,3H),7.25-7.16(m,3H),7.01(d,J＝7.7Hz,2H),6.89(d,J＝8.0Hz, 2H),5.05(s,2H),4.84-4.70(m,1H),3.57(d,J＝11.6Hz,1H),3.41-3.29(m,2H), 2.85(dd,J＝14.3,5.4Hz,1H),2.73-2.51(m,4H),1.34(s,9H)。
15. Synthetic preparation of intermediate M15
Figure BDA0002622973250000231
Reaction reagents and conditions: HCl, MeOH, CH2Cl2,RT。
Referring to the preparation method of M12, M15 was prepared from M14 with yield: 69.5 percent. ESI-MS M/z 459.2[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.45-7.41(m,2H), 7.41-7.35(m,2H),7.34-7.29(m,3H),7.25-7.14(m,3H),7.12(d,J＝8.6Hz,2H), 6.93(d,J＝8.6Hz,2H),5.05(s,2H),3.69-3.61(m,3H),3.41-3.33(m,2H),3.11-3.05 (m,2H),2.70(dd,J＝7.0,3.4Hz,1H),2.64(dd,J＝13.8,7.6Hz,1H),2.53-2.45(m, 1H)。
16. Synthetic preparation of intermediate M16
Figure BDA0002622973250000232
Reaction reagents and conditions: h2,10％Pd(OH)2/C,MeOH,RT。
Taking M15(0.70g,1.53mmol) in a 10mL reaction bottle, adding MeOH (2mL), stirring at room temperature until the sample is completely dissolved, and adding 10% Pd (OH) under the protection of argon2C (0.11mg, 78.3. mu. mol), replaced with hydrogen and stirred at room temperature for 24h until the reaction was complete. The reaction solution was filtered, the filtrate was concentrated to dryness under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 530mg of M16 as a white solid powder, yield: 94.2 percent. ESI-MS M/z 369.2[ M + Na ]]+；1H NMR(600MHz,CD3OD):7.36(t,J＝7.5Hz,2H), 7.32-7.23(m,3H),7.02(d,J＝8.5Hz,2H),6.74(d,J＝8.3Hz,2H),3.85-3.76(m,1H), 3.73-3.66(m,1H),3.61(dd,J＝11.1,3.4Hz,1H),3.41(dd,J＝11.1,6.8Hz,1H), 3.07-2.94(m,2H),2.83-2.74(m,1H),2.68(dd,J＝13.8,7.0Hz,1H),2.58(dd,J＝ 13.7,7.3Hz,1H)。
17. Synthetic preparation of intermediate M17
Figure BDA0002622973250000233
Reaction reagents and conditions: TrCl, Et3N,CH2Cl2,0℃。
Referring to the preparation method of M01, M17 was prepared from L-casamino alcohol as a raw material. ESI-MS M/z 416.4[ M + H ]]+；1H NMR(600MHz,CDCl3-d):7.59-7.51(m,6H),7.30-7.24(m, 6H),7.18(t,J＝7.3Hz,3H),6.74(d,J＝8.5Hz,2H),6.60(d,J＝8.4Hz,2H),3.12(dd, J＝10.9,2.6Hz,1H),2.94(dd,J＝10.9,4.2Hz,1H),2.80-2.72(m,1H),2.40(dd,J＝ 13.3,9.7Hz,1H),2.16(dd,J＝13.3,4.7Hz,1H)。
18. Synthetic preparation of intermediate M18
Figure BDA0002622973250000241
Reaction reagents and conditions: BnBr, K2CO3,DMF,0℃。
Referring to the preparation method of M11, M17 is used as a raw material to prepare M18. ESI-MS M/z 522.2[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.44-7.39(m,6H),7.25-7.21(m,2H), 7.21-7.16(m,2H),7.13-7.08(m,7H),7.04-7.00(m,3H),6.70(d,J＝8.7Hz,2H), 6.65(d,J＝8.7Hz,2H),4.82(s,2H),2.97(dd,J＝10.9,2.7Hz,1H),2.76(dd,J＝10.8, 4.2Hz,1H),2.65-2.58(m,1H),2.30(dd,J＝13.3,9.4Hz,1H),2.10(dd,J＝13.3,4.8 Hz,1H)。
19. Synthetic preparation of intermediate M19
Figure BDA0002622973250000242
Reaction reagents and conditions: oxalyl chloride, DMSO, Et3N,CH2Cl2,-78℃。
Anhydrous CH added under the protection of argon2Cl2(100mL) and oxalyl chloride (5.9mL,69.3mmol) in a 500mL reaction flask, stirring at-78 deg.C, slowly adding DMSO (7.4mL,103.9mmol), M18(17.3g,34.6mmol) in that order2Cl2Stirring the solution for 15min, and adding Et3N (19.2mL, 138.5mmol) and stirred at-78 deg.C for 2h until the reaction was complete. Quenching reaction with water, recovering solvent under reduced pressure, dispersing residue with ethyl acetate and water, extracting, washing organic phase with water and saturated NaCl, and removing anhydrous MgSO4Drying, and concentrating under reduced pressure to dryness to obtain M19 as pale yellow oil 17.2 g. It was used in the next reaction without further purification. ESI-MS M/z 520.0[ M + Na ]]+；1H NMR(600MHz,CDCl3): 8.97(d,J＝4.9Hz,1H),7.56-7.25(m,20H),7.24-7.17(m,2H),7.09-6.98(m,2H), 5.15(s,2H),3.70-3.57(m,1H),2.89-2.73(m,2H)。
20. Synthetic preparation of intermediate M20
Figure BDA0002622973250000251
Reaction reagents and conditions: TMSCF3,TBAF,DMF,-50℃。
Referring to the preparation method of M03, M19 is used as a raw material to prepare M20. ESI-MS M/z 590.2 [ M + Na ]]+；1H NMR(600MHz,CDCl3):7.57-7.52(m,6H),7.38-7.29(m,11H), 7.24-7.20(m,3H),6.75(d,J＝8.7Hz,2H),6.56(d,J＝8.7Hz,2H),4.95(s,2H), 3.73-3.65(m,1H),2.93-2.87(m,1H),2.44(dd,J＝14.0,3.5Hz,1H),2.33(dd,J＝ 14.0,10.2Hz,1H)。
21. Synthetic preparation of intermediate M21
Figure BDA0002622973250000252
Reaction reagents and conditions: concentrated hydrochloric acid, MeOH,0 ℃.
Referring to the preparation method of M03, M20 is used as a raw material to prepare M21. ESI-MS M/z 348.0 [ M + Na ]]+,326.0[M+H]+；1H NMR(600MHz,CDCl3):7.43(d,J＝7.1Hz,2H), 7.39(t,J＝7.6Hz,2H),7.33(t,J＝7.2Hz,1H),7.12(d,J＝8.6Hz,2H),6.94(d,J＝ 8.6Hz,2H),5.05(s,2H),3.71-3.63(m,1H),3.51-3.43(m,1H),2.81(dd,J＝13.8,6.0 Hz,1H),2.63(dd,J＝13.8,9.2Hz,1H)。
22. Synthetic preparation of intermediate M22
Figure BDA0002622973250000253
Reaction reagents and conditions: (Boc)2O,NaHCO3,MeOH,RT。
Referring to the preparation method of M10, M21 is used as a raw material to prepare M22. ESI-MS M/z 448.1[ M + Na ]]+。
23. Synthetic preparation of intermediate M23
Figure BDA0002622973250000254
Reaction reagents and conditions: Dess-Martin reagent, CH2Cl2,RT。
Referring to the preparation method of M06, M22 is used as a raw material to prepare M23. ESI-MS M/z 424.1 [ M + H ]]+,464.1[M+H2O+Na]+,478.1[M+MeOH+Na]+。
24. Synthetic preparation of intermediate M24
Figure BDA0002622973250000261
Reaction reagents and conditions: toluene, reflux.
Referring to the preparation method of M07, M23 and L-phenylalaninol are used as raw materials to prepare M24. ESI-MS M/z 448.1[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.41(d,J＝7.2Hz,2H), 7.37(t,J＝7.5Hz,2H),7.33-7.26(m,3H),7.21(d,J＝7.3Hz,1H),7.17(d,J＝7.2Hz, 2H),7.10(d,J＝8.2Hz,2H),6.90(d,J＝8.5Hz,2H),5.03(s,2H),4.68-4.57(m,1H), 4.16-3.99(m,2H),3.82-3.71(m,1H),3.56-3.50(m,1H),3.23-3.10(m,2H),2.98(dd, J＝13.6,6.2Hz,1H),2.72(dd,J＝13.6,7.7Hz,1H),2.67-2.59(m,1H),1.33(s,9H)。
25. Synthetic preparation of intermediate M25
Figure BDA0002622973250000262
Reaction reagents and conditions: LiAlH4,THF,-78℃。
Referring to the preparation method of M08, M24 is used as a raw material to prepare M25. ESI-MS M/z 581.3[ M + Na ]]+。
26. Synthetic preparation of intermediate M26
Figure BDA0002622973250000263
Reaction reagents and conditions: trifluoroacetic acid, CH2Cl2,0℃。
Referring to the preparation method of M09, M25 is used as a raw material to prepare M26. ESI-MS M/z 459.2[ M + H ]]+,481.2[M+Na]+；1H NMR(600MHz,CDCl3):7.47(d,J＝7.1Hz,2H), 7.45-7.32(m,8H),6.96-6.89(m,4H),5.08(s,2H),3.67(dd,J＝11.1,3.5Hz,1H), 3.51(dd,J＝11.1,3.1Hz,1H),3.47-3.42(m,1H),3.03-2.98(m,1H),2.97-2.84(m, 3H),2.43(dd,J＝13.5,4.9Hz,1H),2.04(dd,J＝13.6,9.7Hz,1H)。
27. Synthetic preparation of intermediate M27
Figure BDA0002622973250000271
Reaction reagents and conditions: h2,Pd(OH)2/C,MeOH,RT。
Reference is made to the preparation of M16 above, toM26 is used as a raw material to prepare M27. ESI-MS M/z 391.0 [ M + Na ]]+；1H NMR(600MHz,CD3OD):7.26(t,J＝7.6Hz,2H),7.20-7.12(m,3H), 7.02(d,J＝8.5Hz,2H),6.75(d,J＝8.5Hz,2H),3.56-3.47(m,2H),3.36(dd,J＝11.3, 6.2Hz,1H),3.29(p,J＝1.7Hz,2H),3.02-2.95(m,1H),2.85-2.78(m,1H),2.70(dd, J＝13.6,7.3Hz,1H),2.64(dd,J＝13.6,6.9Hz,1H),2.52(dd,J＝14.0,10.2Hz,1H)。
Synthesis preparation of (II) target compound
1. Preparation of target Compound T01
Figure BDA0002622973250000272
Reaction reagents and conditions: NMM, EDCI, CH2Cl2,RT。
M09(70mg,0.2mmol) and 4-chlorobenzoic acid (78mg,0.5mmol) were placed in a 25mL reaction flask and 5mL of anhydrous CH was added under protection of argon2Cl2And NMM (0.09mL,0.8mmol), stirring at room temperature until completely dissolved, adding EDCI (95mg,0.5mmol), stirring at room temperature for reaction for 4h, detecting by TLC until completely reacted, dispersing the reaction solution with ethyl acetate and water, extracting, and sequentially dissolving the obtained organic layer with 1 mol/L hydrochloric acid and saturated NaHCO3Saturated NaCl wash, anhydrous MgSO4Drying, recovering solvent under reduced pressure to dryness, and purifying the obtained crude product by silica gel column chromatography to obtain white solid T01 sample 60mg with yield 61.9%. ESI-MS M/z 513.2[ M + Na ]]+；1H NMR(400MHz,CDCl3):7.54(d,J＝8.5Hz,2H), 7.34-7.17(m,10H),7.10(d,J＝7.0Hz,2H),6.69(d,J＝8.8Hz,1H),4.85-4.71(m, 1H),3.58-3.47(m,3H),3.31(dd,J＝11.3,5.3Hz,1H),3.12-3.04(m,1H),3.01(dd, J＝14.2,5.5Hz,1H),2.80(dd,J＝14.1,9.8Hz,1H),2.69(d,J＝7.0Hz,2H)；19F NMR(565MHz,CDCl3):-70.00。
2. Preparation of target Compound T02
By referring to the preparation method of T01, 2-nitrobenzoic acid was used in place of 4-chlorobenzoic acid to prepare T02. ESI-MS M/z 524.2[ M + Na ]]+；1H NMR(400MHz,CDCl3):7.95(dd,J＝7.6,1.7Hz, 1H),7.52-7.43(m,2H),7.35-7.19(m,7H),7.17-7.11(m,2H),6.92-6.85(m,2H), 4.89-4.81(m,1H),3.62-3.52(m,2H),3.27(dd,J＝11.3,5.2Hz,1H),3.16-3.07(m, 1H),2.96(dd,J＝14.1,4.9Hz,1H),2.75-2.65(m,3H)；19F NMR(565MHz,CDCl3) :-70.01。
3. Preparation of target Compound T03
By referring to the preparation method of T01, 4-chlorobenzoic acid was replaced with 3, 5-dinitrobenzoic acid to prepare T03. ESI-MS M/z 763.2[ M + Na ]]+；1H NMR(600MHz,CDCl3):9.28(t,J＝2.2Hz, 1H),9.15(d,J＝2.1Hz,2H),9.12(t,J＝2.1Hz,1H),8.78(d,J＝2.1Hz,2H), 7.41-7.26(m,5H),7.26-7.19(m,5H),7.07(d,J＝8.8Hz,1H),4.85-4.77(m,1H), 4.64(dd,J＝11.3,3.7Hz,1H),4.12(dd,J＝11.3,3.9Hz,1H),3.74-3.67(m,1H), 3.51-3.45(m,1H),3.10(dd,J＝14.1,5.1Hz,1H),2.95(dd,J＝13.7,7.7Hz,1H),2.90 (dd,J＝13.7,6.9Hz,1H),2.76(dd,J＝14.1,10.5Hz,1H)；19F NMR(565MHz, CDCl3):-70.56(d,J＝7.9Hz)。
4. Preparation of target Compound T04
By referring to the preparation method of T01, 4-fluorobenzoic acid was used instead of 4-chlorobenzoic acid to prepare T04. ESI-MS M/z 497.1[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.69-7.62(m,2H), 7.37-7.11(m,10H),7.07-7.01(m,2H),6.71(d,J＝8.8Hz,1H),4.87-4.79(m,1H), 3.61-3.53(m,2H),3.35(dd,J＝11.2,5.4Hz,1H),3.13-3.08(m,1H),3.04(dd,J＝ 14.2,5.5Hz,1H),2.85(dd,J＝14.2,9.8Hz,1H),2.72(d,J＝7.0Hz,2H)；19F NMR (565MHz,CDCl3):-69.94,-107.71。
5. Preparation of target Compound T05
By referring to the above T01 preparation method, 4-chlorobenzoic acid was replaced with 2-chlorobenzoic acid to prepare T05. ESI-MS M/z 513.2[ M + Na ]]+；1H NMR(400MHz,CDCl3):7.54(d,J＝8.5Hz,2H), 7.34-7.17(m,10H),7.10(d,J＝7.0Hz,2H),6.69(d,J＝8.8Hz,1H),4.85-4.71(m, 1H),3.58-3.47(m,3H),3.31(dd,J＝11.3,5.3Hz,1H),3.12-3.04(m,1H),3.01(dd, J＝14.2,5.5Hz,1H),2.80(dd,J＝14.1,9.8Hz,1H),2.69(d,J＝7.0Hz,2H)；19F NMR(565MHz,CDCl3):-70.00。
6. Preparation of target Compound T06
By referring to the above T01 preparation method, 4-methylbenzoic acid was used in place of 4-chlorobenzoic acid to prepare T06. ESI-MS M/z 493.2[ M + Na ]]+；1H NMR(400MHz,CDCl3):7.51(d,J＝7.8Hz,2H), 7.31-7.16(m,8H),7.12(d,J＝7.6Hz,2H),7.08(d,J＝7.3Hz,3H),6.68(d,J＝8.7Hz, 1H),4.88-4.75(m,1H),3.59-3.46(m,3H),3.29(dd,J＝11.3,5.5Hz,1H),3.10-2.94 (m,3H),2.83(dd,J＝14.1,9.8Hz,1H),2.66(d,J＝7.1Hz,3H),2.33(s,3H)；19F NMR(565MHz,CDCl3):-69.78。
7. Preparation of target Compound T07
By referring to the above T01 preparation method, 4-methoxybenzoic acid was used instead of 4-chlorobenzoic acid to prepare T07. ESI-MS M/z 509.2[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.34-7.23(m,8H),7.14 (d,J＝6.6Hz,2H),6.85(d,J＝1.1Hz,2H),6.55(d,J＝8.6Hz,1H),4.85-4.77(m, 1H),3.87(s,3H),3.85(s,6H),3.61-3.55(m,2H),3.36(dd,J＝11.3,5.3Hz,1H), 3.13-3.08(m,1H),3.06(dd,J＝14.2,5.5Hz,1H),2.86(dd,J＝14.2,9.8Hz,1H),2.72 (d,J＝7.0Hz,2H)；19F NMR(565MHz,CDCl3):-70.06。
8. Preparation of target Compound T08
By referring to the above T01 preparation method, 4-chlorobenzoic acid was replaced with 3-trifluoromethylbenzoic acid to prepare T08. ESI-MS M/z 547.2[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.90(s,1H),7.81 (d,J＝7.8Hz,1H),7.72(d,J＝7.8Hz,1H),7.50(t,J＝7.8Hz,1H),7.38-7.22(m,8H), 7.18-7.13(m,2H),6.90(d,J＝8.8Hz,1H),4.89-4.81(m,1H),3.63-3.55(m,2H), 3.37(dd,J＝11.2,5.4Hz,1H),3.16-3.10(m,1H),3.06(dd,J＝14.1,5.2Hz,1H),2.84 (dd,J＝14.1,9.9Hz,1H),2.74(d,J＝7.0Hz,2H)；19F NMR(565MHz,CDCl3): -62.75,-70.12。
9. Preparation of target Compound T09
By referring to the above T01 preparation method, 4-chlorobenzoic acid was replaced with 3-trimethylbenzoic acid to prepare T09. ESI-MS M/z 493.2[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.47(s,1H),7.42(d,J＝ 7.4Hz,1H),7.35-7.21(m,10H),7.12(d,J＝7.5Hz,2H),6.59(d,J＝8.8Hz,1H), 4.89-4.82(m,1H),3.60-3.51(m,2H),3.35(dd,J＝11.3,5.5Hz,1H),3.11-3.07(m, 1H),3.04(dd,J＝14.2,5.8Hz,1H),2.88(dd,J＝14.2,9.6Hz,1H),2.70(d,J＝7.0Hz, 2H),2.36(s,3H)；19F NMR(565MHz,CDCl3):-69.72(d,J＝8.1Hz)。
10. Preparation of target Compound T10
By referring to the above T01 preparation method, 4-chlorobenzoic acid was replaced with 3-iodobenzoic acid to prepare T10. ESI-MS M/z 605.2[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.97(s,1H),7.79(d,J＝ 8.1Hz,1H),7.56(d,J＝8.0Hz,1H),7.34-7.21(m,8H),7.14(d,J＝7.1Hz,2H),7.09 (t,J＝7.8Hz,1H),6.75(d,J＝8.8Hz,1H),4.84-4.78(m,1H),3.62-3.53(m,2H), 3.37(dd,J＝11.2,5.4Hz,1H),3.14-3.08(m,1H),3.04(dd,J＝14.1,5.4Hz,1H),2.83 (dd,J＝14.1,9.9Hz,1H),2.78-2.66(m,2H)；19F NMR(565MHz,CDCl3):-69.96。
11. Preparation of target Compound T11
By referring to the above T01 preparation method, 4-chlorobenzoic acid was replaced with 3, 4-dimethoxybenzoic acid to prepare T11. ESI-MS M/z 539.2[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.34-7.23(m, 9H),7.19(dd,J＝8.3,2.1Hz,1H),7.12(d,J＝7.0Hz,2H),6.83(d,J＝8.4Hz,1H), 6.53(d,J＝8.7Hz,1H),4.88-4.80(m,1H),3.92(s,3H),3.88(s,3H),3.60-3.52(m, 2H),3.34(dd,J＝11.3,5.4Hz,1H),3.11-3.06(m,1H),3.04(dd,J＝14.3,5.9Hz,1H), 2.87(dd,J＝14.2,9.6Hz,1H),2.71(d,J＝7.1Hz,2H)；19F NMR(565MHz,CDCl3) :-69.89。
12. Preparation of target Compound T12
By referring to the above preparation method of T01, 4-nitrobenzoic acid was used in place of 4-chlorobenzoic acid to prepare T12. ESI-MS M/z 524.3[ M + Na ]]+；1H NMR(600MHz,CDCl3):8.19(d,J＝8.7Hz,2H), 7.76(d,J＝8.8Hz,2H),7.36-7.20(m,7H),7.16(d,J＝6.9Hz,2H),7.02(d,J＝8.8Hz, 1H),4.88-4.80(m,1H),3.64-3.56(m,2H),3.38(dd,J＝11.4,5.3Hz,1H),3.17-3.11 (m,1H),3.07(dd,J＝14.1,4.9Hz,1H),2.81(dd,J＝14.1,10.1Hz,1H),2.75(d,J＝ 7.0Hz,2H)；19F NMR(565MHz,CDCl3):-70.23。
13. Preparation of target Compound T13
By referring to the preparation method of T01, 4-acetoxybenzoic acid was used instead of 4-chlorobenzoic acid to prepare T13. ESI-MS M/z 537.3[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.67(d,J＝8.3Hz, 2H),7.33-7.28(m,5H),7.26-7.22(m,3H),7.15-7.09(m,4H),6.68(d,J＝8.8Hz,1H), 4.86-4.81(m,1H),3.59-3.52(m,2H),3.34(dd,J＝11.2,5.4Hz,1H),3.13-3.06(m, 1H),3.03(dd,J＝14.2,5.5Hz,1H),2.84(dd,J＝14.2,9.8Hz,1H),2.76-2.67(m,2H), 2.33(s,3H)；19F NMR(565MHz,CDCl3):-69.89(d,J＝4.5Hz)。
14. Preparation of target Compound T14
By referring to the preparation method of T01, 3,4, 5-trimethoxybenzoic acid is used to replace 4-chlorobenzoic acid to prepare T14. ESI-MS M/z 569.3[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.34-7.23(m, 8H),7.14(d,J＝6.6Hz,2H),6.85(d,J＝1.1Hz,2H),6.55(d,J＝8.6Hz,1H), 4.85-4.77(m,1H),3.87(s,3H),3.85(s,6H),3.61-3.55(m,2H),3.36(dd,J＝11.3,5.3 Hz,1H),3.13-3.08(m,1H),3.06(dd,J＝14.2,5.5Hz,1H),2.86(dd,J＝14.2,9.8Hz, 1H),2.72(d,J＝7.0Hz,2H)；19F NMR(565MHz,CDCl3):-70.06。
15. Preparation of target Compound T15
By referring to the above T01 preparation method, 4-methylthiobenzoic acid was used instead of 4-chlorobenzoic acid to prepare T15. ESI-MS M/z 525.2[ M + Na ]]+；1H NMR(400MHz,CDCl3):7.57(d,J＝8.5Hz,2H), 7.31-7.18(m,10H),7.14(d,J＝6.9Hz,2H),4.74-4.68(m,1H),3.61-3.53(m,1H), 3.49(dd,J＝11.2,3.6Hz,1H),3.32(dd,J＝11.2,5.3Hz,1H),3.13-3.02(m,1H),3.00 (dd,J＝14.1,4.5Hz,1H),2.84(dd,J＝14.0,10.7Hz,1H),2.79-2.65(m,2H),2.49(s, 3H)；19F NMR(565MHz,CDCl3):-70.83。
16. Preparation of target Compound T16
Referring to the preparation method of T01, 3-fluorobenzoic acid is used to replace 4-chlorobenzoic acid,to obtain T16. ESI-MS M/z 497.1[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.44-7.21(m,11H), 7.20-7.12(m,3H),6.78(d,J＝8.8Hz,1H),4.86-4.80(m,1H),3.62-3.54(m,2H), 3.36(dd,J＝11.4,5.4Hz,1H),3.15-3.08(m,1H),3.04(dd,J＝14.2,5.3Hz,1H),2.83 (dd,J＝14.1,9.9Hz,1H),2.77-2.68(m,2H)；19F NMR(565MHz,CDCl3):-69.99 (d,J＝8.2Hz),-111.65(td,J＝8.8,5.9Hz)。
17. Preparation of target Compound T17
By referring to the above T01 preparation method, 4-chlorobenzoic acid was replaced by 3, 4-diacetoxybenzoic acid to prepare T17. ESI-MS M/z 595.2[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.59(dd,J＝8.4, 2.1Hz,1H),7.50(d,J＝2.1Hz,1H),7.34-7.19(m,9H),7.15(d,J＝6.9Hz,2H), 4.87-4.80(m,1H),3.59-3.48(m,2H),3.37-3.31(m,1H),3.11-3.05(m,1H),3.02(dd, J＝14.1,4.8Hz,1H),2.79(dd,J＝14.1,10.1Hz,1H),2.77-2.72(m,2H),2.32(s,6H)；19F NMR(565MHz,CDCl3):-70.58。
18. Preparation of target Compound T18
By referring to the above T01 preparation method, 4-hydroxybenzoic acid was used in place of 4-chlorobenzoic acid to prepare T18. ESI-MS M/z 473.4[ M + H ]]+；1H NMR(600MHz,CD3OD):7.65-7.59(m,2H), 7.37-7.30(m,6H),7.29-7.22(m,4H),6.87-6.82(m,2H),4.72-4.65(m,1H), 3.75-3.67(m,1H),3.54(dd,J＝11.1,4.2Hz,1H),3.44(dd,J＝11.1,5.3Hz,1H), 3.19-3.13(m,1H),3.13(dd,J＝13.9,3.8Hz,1H),2.97(dd,J＝14.0,11.2Hz,1H), 2.85(dd,J＝13.5,7.2Hz,1H),2.77(dd,J＝13.6,6.8Hz,1H)；19F NMR(565MHz, CD3OD):-72.63。
19. Preparation of target Compound T19
By referring to the above T01 preparation method, 4-chlorobenzoic acid was replaced with 3, 4-dihydroxybenzoic acid to prepare T19. ESI-MS M/z 511.2[ M + Na ]]+；1H NMR(600MHz,CD3OD):7.30-7.24(m, 6H),7.23-7.15(m,4H),7.15(d,J＝2.2Hz,1H),7.08(dd,J＝8.3,2.2Hz,1H),6.77(d, J＝8.3Hz,1H),4.63-4.57(m,1H),3.67-3.62(m,1H),3.48(dd,J＝11.1,4.2Hz,1H), 3.38(dd,J＝11.0,5.2Hz,1H),3.12-3.07(m,1H),3.05(dd,J＝14.0,3.9Hz,1H),2.90 (dd,J＝14.0,11.2Hz,1H),2.79(dd,J＝13.6,7.1Hz,1H),2.71(dd,J＝13.6,6.8Hz, 1H)；19F NMR(565MHz,CD3OD):-71.96。
20. Preparation of target Compound T20
By referring to the above T01 preparation method, 4-chlorobenzoic acid was replaced with 3-bromobenzoic acid to prepare T20. ESI-MS M/z 557.2[ M + Na ]]+；1H NMR(400MHz,CDCl3):7.77(t,J＝1.9Hz,1H), 7.59-7.53(m,2H),7.31-7.19(m,9H),7.14(d,J＝7.0Hz,2H),4.74-4.67(m,1H), 3.62-3.53(m,1H),3.50(dd,J＝11.2,3.4Hz,1H),3.33(dd,J＝11.2,5.3Hz,1H), 3.12-3.04(m,1H),3.00(dd,J＝14.0,4.5Hz,1H),2.82(dd,J＝14.0,10.8Hz,1H), 2.77-2.68(m,2H)；19F NMR(565MHz,CDCl3):-70.23。
21. Preparation of target Compound T21
By referring to the above T01 preparation method, 4-aminobenzoic acid was substituted for 4-chlorobenzoic acid to prepare T21. ESI-MS M/z 594.5[ M + Na ]]+；1H NMR(600MHz,CD3OD):7.50-7.46(m,2H), 7.30-7.23(m,6H),7.22-7.14(m,4H),6.65-6.61(m,2H),4.65-4.59(m,1H), 3.67-3.60(m,1H),3.47(dd,J＝11.1,4.2Hz,1H),3.37(dd,J＝11.1,5.3Hz,2H), 3.12-3.06(m,1H),3.04(dd,J＝14.0,4.0Hz,1H),2.91(dd,J＝14.0,11.2Hz,1H), 2.78(dd,J＝13.6,7.2Hz,1H),2.71(dd,J＝13.6,6.8Hz,1H)；19F NMR(565MHz, CD3OD):-71.96。
22. Preparation of target Compound T22
By referring to the above T01 preparation method, 4-chlorobenzoic acid was replaced with 4-acetamidobenzoic acid to prepare T22. ESI-MS M/z 578.3[ M + Na ]]+；1H NMR(600MHz,DMSO-d6):10.19(s,1H), 8.25(d,J＝8.6Hz,1H),7.65(d,J＝8.6Hz,2H),7.60(d,J＝8.5Hz,2H),7.32-7.18(m, 9H),7.14(t,J＝7.1Hz,1H),4.49-4.41(m,1H),3.93(dd,J＝11.2,4.3Hz,1H),3.80 (dd,J＝11.3,5.8Hz,1H),3.71-3.63(m,1H),3.23-3.16(m,1H),3.10(dd,J＝14.0,3.2 Hz,1H),2.96-2.88(m,1H),2.75(dd,J＝13.6,6.3Hz,1H),2.68(dd,J＝13.7,7.5Hz, 1H),2.57(t,J＝6.3Hz,1H),2.06(s,3H),1.85(s,3H)；19F NMR(565MHz, DMSO-d6):-69.88(d,J＝8.0Hz)。
23. Preparation of target Compound T23
By referring to the above T01 preparation method, 4-diethylaminobenzoic acid was used in place of 4-chlorobenzoic acid to prepare T23. ESI-MS M/z 528.3[ M + H ]]+；1H NMR(600MHz,CDCl3):7.57-7.51(m,2H), 7.35-7.21(m,10H),7.10(d,J＝7.3Hz,2H),6.55-6.50(m,2H),6.35(d,J＝8.8Hz, 1H),4.88-4.81(m,1H),3.55(dd,J＝11.3,3.3Hz,1H),3.52-3.46(m,1H),3.31(dd, J＝11.4,5.7Hz,1H),3.19(q,J＝7.1Hz,2H),3.06-3.03(m,1H),3.01(dd,J＝14.3, 6.5Hz,2H),2.88(dd,J＝14.1,9.2Hz,1H),2.67(d,J＝7.0Hz,2H),1.27(t,J＝7.2Hz, 3H)；19F NMR(565MHz,CDCl3):-69.64(d,J＝8.1Hz)。
24. Preparation of target Compound T24
By referring to the above T01 preparation method, 4-chlorobenzoic acid was replaced with 4-ethylaminobenzoic acid to prepare T24. ESI-MS M/z 522.2[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.59(d,J＝8.9Hz,2H), 7.36-7.20(m,10H),7.11(d,J＝7.4Hz,2H),6.60(d,J＝8.5Hz,2H),6.37-6.32(m, 1H),4.90-4.83(m,0H),3.56(dd,J＝11.3,3.4Hz,1H),3.50(qd,J＝8.2,2.7Hz,1H), 3.39(q,4H),3.32(dd,J＝11.4,5.7Hz,1H),3.08-3.04(m,1H),3.02(dd,J＝14.1,6.5 Hz,1H),2.90(dd,J＝14.2,9.2Hz,1H),2.67(d,J＝7.0Hz,2H),1.19(t,J＝7.1Hz, 6H)；19F NMR(565MHz,CDCl3):-69.60。
25. Preparation of target Compound T25
By referring to the above T01 preparation method, furan carboxylic acid was used instead of 4-chlorobenzoic acid to prepare T25. ESI-MS M/z 469.4[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.44-7.41(m,1H), 7.32-7.25(m,4H),7.25-7.17(m,5H),7.11-7.06(m,2H),7.05(d,J＝3.5Hz,1H), 6.69-6.61(m,1H),6.48-6.43(m,1H),4.81-4.73(m,1H),3.54(dd,J＝11.3,3.4Hz, 1H),3.50-3.42(m,1H),3.32(dd,J＝11.4,5.6Hz,1H),3.08-3.00(m,1H),2.98(dd, J＝14.1,6.1Hz,1H),2.83(dd,J＝14.2,9.4Hz,1H),2.71-2.59(m,2H)；19F NMR (565MHz,CDCl3):-69.52。
26. Preparation of target Compound T26
Referring to the preparation method of T01, T26 is prepared by using M15 and benzoic acid as raw materials. ESI-MS M/z 585.2[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.65-7.57(m,2H),7.49-7.41(m, 3H),7.41-7.33(m,4H),7.32(d,J＝7.3Hz,1H),7.28(t,J＝7.5Hz,2H),7.22(d,J＝ 7.5Hz,3H),7.00(d,J＝8.2Hz,2H),6.88(d,J＝8.4Hz,2H),6.62(d,J＝8.8Hz,1H), 5.03(s,2H),4.86-4.78(m,1H),3.58-3.49(m,2H),3.30(dd,J＝11.2,5.4Hz,1H), 3.07-2.97(m,2H),2.83(dd,J＝14.1,9.7Hz,1H),2.67-2.54(m,2H)；19F NMR(565 MHz,CDCl3):-69.73。
27. Preparation of target Compound T27
Figure BDA0002622973250000341
Reaction reagents and conditions: h2,Pd/C,CH3COOH,MeOH,RT。
Compound T26(40mg, 71.1. mu. mol) was placed in a 10mL reaction flask, MeOH (2mL) was added to dissolve the sample, glacial acetic acid (8.0. mu.L, 142.2. mu. mol), 10% Pd/C (5.0mg, 4.4. mu. mol) were added, the mixture was replaced with hydrogen, and the mixture was stirred at room temperature for 24h until the reaction was complete. The reaction solution was filtered, the filtrate was concentrated under reduced pressure to dryness, and the residue was purified by silica gel column chromatography to obtain 27mg of T27 as a white solid compound with a yield: 80.4 percent. ESI-MS M/z 495.1[ M + Na ]]+；1H NMR(600MHz,DMSO-d6):9.23-9.14(m,1H),8.39(t,J＝ 7.4Hz,1H),7.75-7.66(m,2H),7.50(t,J＝7.3Hz,1H),7.43(t,J＝7.5Hz,2H), 7.30-7.20(m,4H),7.14(t,J＝7.1Hz,1H),6.99(d,J＝4.7Hz,2H),6.72-6.63(m,2H), 4.70-4.59(m,1H),4.52-4.41(m,1H),3.73-3.61(m,1H),3.43(s,1H),3.35-3.28(m, 1H),3.28-3.21(m,1H),3.15-3.06(m,1H),3.00-2.86(m,2H)；19F NMR(565MHz, DMSO-d6):-70.04。
28. Preparation of target Compound T28
Figure BDA0002622973250000342
Reaction reagents and conditions: CH (CH)3I,K2CO3,DMF.RT。
Taking compound T27(60mg,0.12mmol) and placing in a 25mL reaction flask, adding DMF (0.6mL) to dissolve, adding K2CO3(52.6mg,0.38mmol), argon shield, and methyl iodide (CH) injected3I, 20. mu.L, 0.25mmol), stirring the reaction at room temperature for 24h until the reaction is complete. Dispersing the reaction solution with ethyl acetate and water, extracting, washing the obtained organic layer with water, saturated NaCl solution, anhydrous MgSO4Drying, recovering the organic solvent under reduced pressure to dryness, and purifying the obtained residue by silica gel column chromatography to obtain T28 white solid 38mg, yield: 61.5 percent. ESI-MS M/z 509.1[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.65-7.56(m, 2H),7.48-7.40(m,1H),7.34(t,J＝7.8Hz,2H),7.29-7.24(m,2H),7.23-7.18(m,3H), 7.00(d,J＝8.6Hz,2H),6.80(d,J＝8.7Hz,2H),6.69(d,J＝8.6Hz,1H),4.85-4.77(m, 1H),3.77(s,3H),3.57-3.48(m,2H),3.29(dd,J＝11.2,5.4Hz,1H),3.04-2.97(m, 2H),2.83(dd,J＝14.2,9.8Hz,1H),2.66-2.56(m,2H)；13CNMR(151MHz,CDCl3) :167.89,158.32,137.13,134.00,131.73,130.15,129.80,129.08,128.75,128.74, 128.60,126.95,126.92,113.98,63.32,59.77(q,J＝25.8Hz),59.73,55.27,50.76, 37.85,36.12；19F NMR(565MHz,CDCl3):-69.79。
29. Preparation of target Compound T29
By referring to the above T28 preparation method, iodoethane was used instead of iodomethane to prepare T29. ESI-MS M/z 523.2[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.61(d,J＝7.6Hz,2H),7.45(t,J＝7.4 Hz,1H),7.35(t,J＝7.7Hz,2H),7.30-7.24(m,2H),7.21(d,J＝7.2Hz,3H),6.99(d, J＝8.2Hz,2H),6.79(d,J＝8.2Hz,2H),6.66(d,J＝8.8Hz,1H),4.85-4.77(m,1H), 3.99(q,J＝7.0Hz,2H),3.57-3.48(m,2H),3.29(dd,J＝11.2,5.4Hz,1H),3.04-2.97 (m,2H),2.82(dd,J＝14.2,9.8Hz,1H),2.65-2.56(m,2H),1.40(t,J＝7.0Hz,3H)；19F NMR(565MHz,CDCl3):-69.78。
30. Preparation of target Compound T30
By referring to the above T28 preparation method, methyl iodide was replaced with 1-bromo-3-methyl-2-butene to prepare T30. ESI-MS M/z 563.2[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.61(d,J＝8.3Hz,2H), 7.44(t,J＝7.4Hz,1H),7.35(t,J＝7.7Hz,2H),7.26(d,J＝6.9Hz,2H),7.21(d,J＝ 7.3Hz,3H),6.99(d,J＝8.5Hz,2H),6.82(d,J＝8.6Hz,2H),6.68(d,J＝8.8Hz,1H), 5.51-5.45(m,1H),4.85-4.78(m,1H),4.47(d,J＝6.8Hz,2H),3.57-3.48(m,2H), 3.29(dd,J＝11.2,5.4Hz,1H),3.04-2.97(m,2H),2.83(dd,J＝14.1,9.8Hz,1H), 2.65-2.55(m,2H),1.79(s,3H),1.73(s,3H)；19F NMR(565MHz,CDCl3):-69.78。
31. Preparation of target Compound T31
Referring to the above T28 preparation method, dimethylamino chloroethane hydrochloride was used instead of methyl iodide to prepare T31. ESI-MS M/z 566.2[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.67-7.60(m,2H), 7.48-7.40(m,2H),7.38-7.32(m,2H),7.30-7.24(m,2H),7.24-7.18(m,2H),6.99(d, J＝8.6Hz,2H),6.82(d,J＝8.6Hz,2H),6.73(d,J＝9.5Hz,1H),4.87-4.75(m,1H), 4.04(t,J＝5.7Hz,2H),3.58-3.48(m,2H),3.29(dd,J＝11.2,5.5Hz,1H),3.04-2.98 (m,2H),2.83(dd,J＝14.1,9.8Hz,1H),2.73(t,J＝6.0Hz,2H),2.65-2.56(m,2H), 2.34(s,6H)；19F NMR(565MHz,CDCl3):-69.89。
32. Preparation of target Compound T32
Referring to the preparation method of T01, the T32 is prepared by taking M16 and 4-methylbenzoic acid as raw materials. ESI-MS M/z 599.2[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.52(d,J＝8.1Hz,2H), 7.42(d,J＝7.3Hz,2H),7.40-7.35(m,2H),7.31(t,J＝7.3Hz,1H),7.30-7.24(m,2H), 7.24-7.17(m,3H),7.15(d,J＝7.9Hz,2H),6.99(d,J＝8.5Hz,2H),6.87(d,J＝8.5Hz, 2H),6.58(d,J＝8.9Hz,1H),5.03(s,2H),4.85-4.77(m,1H),3.56-3.48(m,2H),3.29 (dd,J＝11.2,5.4Hz,1H),3.05-2.95(m,2H),2.83(dd,J＝14.2,9.6Hz,1H), 2.65-2.56(m,2H),2.34(s,3H)；19F NMR(565MHz,CDCl3):-69.71。
33. Preparation of target Compound T33
Referring to the preparation method of T27, T32 is used as a raw material to prepare T33. ESI-MS M/z 509.1[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.53(d,J＝7.8Hz,2H),7.28(t,J＝7.9Hz, 2H),7.22(d,J＝7.4Hz,3H),7.18(d,J＝7.8Hz,2H),6.92(d,J＝7.9Hz,2H),6.72(d, J＝7.9Hz,2H),6.50(d,J＝8.8Hz,1H),4.86-4.76(m,1H),3.58-3.45(m,2H),3.29 (dd,J＝11.2,5.5Hz,1H),3.07-2.94(m,2H),2.84(dd,J＝14.2,9.5Hz,1H),2.58(d, J＝7.0Hz,2H),2.36(s,3H)；19F NMR(565MHz,CDCl3):-69.68。
34. Preparation of target Compound T34
Referring to the preparation method of T28, T33 and methyl iodide are used as raw materials to prepare T34. ESI-MS M/z 523.0[ M + Na ]]+；HNMR(600MHz,CDCl3):7.52(d,J＝8.1Hz,2H),7.31-7.26(m, 2H),7.21(d,J＝7.3Hz,3H),7.15(d,J＝7.9Hz,2H),7.04-6.95(m,2H),6.86-6.75(m, 2H),6.58(d,J＝8.4Hz,1H),4.84-4.77(m,1H),3.78(s,3H),3.56-3.47(m,2H),3.29 (dd,J＝11.2,5.4Hz,1H),3.05-2.95(m,2H),2.83(dd,J＝14.2,9.6Hz,1H), 2.65-2.56(m,2H),2.35(s,3H)；19F NMR(565MHz,CDCl3):-69.75。
35. Preparation of target Compound T35
Referring to the preparation method of T28, T33 and iodoethane are used as raw materials to prepare T39. ESI-MS M/z 537.2[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.52(d,J＝8.1Hz,2H),7.30-7.24(m, 2H),7.21(d,J＝7.4Hz,3H),7.14(d,J＝7.8Hz,2H),6.98(d,J＝8.5Hz,2H),6.79(d, J＝8.5Hz,2H),6.59(d,J＝8.8Hz,1H),4.84-4.77(m,1H),3.99(q,J＝6.9Hz,2H), 3.56-3.46(m,2H),3.29(dd,J＝11.3,5.4Hz,1H),3.03-2.96(m,2H),2.82(dd,J＝ 14.2,9.7Hz,1H),2.65-2.55(m,2H),2.34(s,3H),1.40(t,J＝7.0Hz,3H)；19F NMR (565MHz,CDCl3):-69.77。
36. Preparation of target Compound T36
Referring to the preparation method of T28, T33 and 1-bromo-3-methyl-2-butene are used as raw materials to prepare T36. ESI-MS M/z 557.3[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.53(d,J＝8.1Hz,2H), 7.32-7.24(m,2H),7.22(d,J＝7.5Hz,3H),7.16(d,J＝7.9Hz,2H),6.99(d,J＝8.5Hz, 2H),6.82(d,J＝8.6Hz,2H),6.54(d,J＝8.8Hz,1H),5.48(t,J＝6.7Hz,1H), 4.85-4.77(m,1H),4.48(d,J＝6.7Hz,2H),3.56-3.48(m,2H),3.29(dd,J＝11.3,5.4 Hz,1H),3.05-2.96(m,2H),2.83(dd,J＝14.2,9.6Hz,1H),2.65-2.56(m,2H),2.35(s, 3H),1.79(s,3H),1.74(s,3H)；19F NMR(565MHz,CDCl3):-69.73。
37. Preparation of target Compound T37
Referring to the preparation method of T28, T33 and dimethylamino chloroethane hydrochloride are used as raw materials to prepare T37. ESI-MS M/z 580.3[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.53(d,J＝7.8 Hz,2H),7.26(d,J＝4.5Hz,2H),7.23-7.18(m,3H),7.18-7.09(m,2H),6.99(d,J＝ 8.5Hz,2H),6.81(d,J＝7.0Hz,2H),4.84-4.77(m,1H),4.02(t,J＝5.6Hz,2H), 3.57-3.45(m,2H),3.28(dd,J＝11.2,5.5Hz,1H),3.03-2.96(m,2H),2.82(dd,J＝ 14.2,9.7Hz,1H),2.71(t,J＝5.7Hz,3H),2.65-2.55(m,2H),2.34(s,3H),2.32(s, 6H)；19F NMR(565MHz,CDCl3):-69.89。
38. Preparation of target Compound T38
Referring to the preparation method of T01, M16 and 4-fluorobenzoic acid are used as raw materials to prepare T38. ESI-MS M/z 603.0[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.69-7.60(m,2H),7.43 (d,J＝7.5Hz,2H),7.38(t,J＝7.5Hz,2H),7.35-7.25(m,3H),7.21(d,J＝7.4Hz,3H), 7.07-6.99(m,4H),6.89(d,J＝8.2Hz,2H),6.57(d,J＝8.8Hz,1H),5.04(s,2H), 4.84-4.76(m,1H),3.59-3.46(m,2H),3.31(dd,J＝11.3,5.4Hz,1H),3.10-2.95(m, 2H),2.81(dd,J＝14.2,9.7Hz,1H),2.68-2.56(m,2H)；19F NMR(565MHz,CDCl3) :-107.69,-69.84。
39. Preparation of target Compound T39
Referring to the preparation method of T27, T38 is used as a raw material to prepare T39. ESI-MS M/z 513.0 [ M + Na ]]+；1H NMR(600MHz,CD3OD):7.71-7.63(m,2H),7.30-7.20(m,4H), 7.20-7.13(m,1H),7.15-7.05(m,2H),7.00(d,J＝8.5Hz,2H),6.71(d,J＝8.4Hz,2H), 4.63-4.56(m,1H),3.69-3.59(m,1H),3.47(dd,J＝11.1,4.1Hz,1H),3.39-3.34(m, 1H),3.12-2.99(m,2H),2.87(dd,J＝14.0,11.3Hz,1H),2.68(dd,J＝13.8,7.0Hz, 1H),2.60(dd,J＝13.7,6.9Hz,1H)；19F NMR(565MHz,CD3OD):-110.63,-71.87。
40. Preparation of target Compound T40
Referring to the preparation method of T28, T39 and methyl iodide are used as raw materials to prepare T40. ESI-MS M/z 527.2[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.65-7.56(m,2H),7.30-7.24(m, 2H),7.24-7.18(m,3H),7.00(t,J＝8.7Hz,4H),6.81(d,J＝8.5Hz,2H),6.68(d,J＝8.8Hz,1H),4.83-4.76(m,1H),3.78(s,3H),3.57-3.46(m,2H),3.30(dd,J＝11.2,5.4 Hz,1H),3.05-2.97(m,2H),2.81(dd,J＝14.2,9.8Hz,1H),2.67-2.58(m,2H)；19F NMR(565MHz,CDCl3):-107.76,-69.91。
41. Preparation of target Compound T41
Referring to the preparation method of T28, T39 and iodoethane are used as raw materials to prepare T41. ESI-MS M/z 541.2[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.63-7.57(m,2H),7.30-7.23(m,2H), 7.23-7.16(m,3H),7.03-6.95(m,4H),6.80(d,J＝8.6Hz,2H),6.72(d,J＝8.8Hz,1H), 4.83-4.76(m,1H),4.00(q,J＝7.0Hz,2H),3.58-3.45(m,2H),3.30(dd,J＝11.2,5.4 Hz,1H),3.05-2.95(m,2H),2.81(dd,J＝14.2,9.8Hz,1H),2.66-2.55(m,2H),1.40(t, J＝7.0Hz,3H)；19F NMR(565MHz,CDCl3):-107.79,-69.92。
42. Preparation of target Compound T42
Referring to the preparation method of T28, T39 and 1-bromo-3-methyl-2-butene are used as raw materials to prepare T42. ESI-MS M/z 581.0[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.67-7.59(m,2H),7.28 (t,J＝7.6Hz,2H),7.24-7.19(m,3H),7.06-6.97(m,4H),6.83(d,J＝8.6Hz,2H), 6.60(d,J＝8.8Hz,1H),5.49(t,J＝6.1Hz,1H),4.84-4.75(m,1H),4.48(d,J＝6.8Hz, 2H),3.57-3.49(m,2H),3.31(dd,J＝11.6,5.3Hz,1H),3.07-2.97(m,2H),2.81(dd, J＝14.2,9.8Hz,1H),2.67-2.54(m,2H),1.79(s,3H),1.74(s,3H)；19F NMR(565 MHz,CDCl3):-107.72,-69.87。
43. Preparation of target Compound T43
Referring to the preparation method of T28, T43 is prepared by using T39 and isopropyl iodide as raw materials. ESI-MS M/z 555.0[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.66-7.58(m,2H),7.29-7.24(m, 2H),7.20(d,J＝7.4Hz,3H),7.04-6.96(m,4H),6.80(d,J＝8.2Hz,2H),6.70(d,J＝ 8.8Hz,1H),4.83-4.75(m,1H),4.58-4.44(m,1H),3.59-3.45(m,2H),3.31(dd,J＝ 11.2,5.4Hz,1H),3.09-2.92(m,2H),2.81(dd,J＝14.1,9.8Hz,1H),2.66-2.56(m, 2H)；19F NMR(565MHz,CDCl3):-107.80,-69.93。
44. Preparation of target Compound T44
Referring to the preparation method of T28, T44 is prepared by using T39 and n-propyl iodide as raw materials. ESI-MS M/z 555.2[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.67-7.61(m,2H),7.32-7.27(m, 2H),7.24(dd,J＝7.6,5.8Hz,3H),7.06-6.97(m,4H),6.84(d,J＝8.6Hz,2H), 4.87-4.78(m,1H),3.92(t,J＝6.6Hz,2H),3.61-3.52(m,2H),3.33(dd,J＝11.4,5.3 Hz,1H),3.09-3.01(m,2H),2.85(dd,J＝14.2,9.8Hz,1H),2.66(d,J＝7.0Hz,2H), 1.88-1.77(m,2H),1.07(t,J＝7.4Hz,3H)；19F NMR(565MHz,CDCl3):-107.81, -69.94。
45. Preparation of target Compound T45
Referring to the preparation method of T28, T45 is prepared by taking T39 and n-butyl iodide as raw materials. ESI-MS M/z 569.0[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.68-7.62(m,2H),7.33-7.27(m, 2H),7.27-7.20(m,3H),7.06-6.98(m,4H),6.84(d,J＝8.5Hz,2H),6.77(d,J＝8.8Hz, 1H),4.87-4.80(m,1H),3.96(t,J＝6.5Hz,2H),3.63-3.51(m,2H),3.34(dd,J＝11.2, 5.4Hz,1H),3.11-3.00(m,2H),2.85(dd,J＝14.2,9.8Hz,1H),2.66(d,J＝7.0Hz, 2H),1.83-1.75(m,2H),1.57-1.47(m,2H),1.01(t,J＝6.4Hz,3H)；19F NMR(565 MHz,CDCl3):-107.80,-69.93。
46. Preparation of target Compound T46
Referring to the preparation method of T01, the T46 is prepared by taking M16 and 4-trifluoromethylbenzoic acid as raw materials. ESI-MS M/z 653.2[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.73(d,J＝8.1Hz,2H), 7.63(d,J＝8.2Hz,2H),7.48(d,J＝7.1Hz,2H),7.43(t,J＝7.5Hz,2H),7.40-7.35(m, 1H),7.31(d,J＝7.1Hz,2H),7.27(d,J＝8.8Hz,2H),7.11-7.05(m,2H),6.96(t,J＝ 8.7Hz,3H),5.10(s,2H),4.91-4.84(m,1H),3.66-3.56(m,2H),3.38(dd,J＝11.2,5.3 Hz,1H),3.15-3.05(m,2H),2.85(dd,J＝14.2,10.1Hz,1H),2.75-2.66(m,2H)；19F NMR(565MHz,CDCl3):-70.03,-62.99。
47. Preparation of target Compound T47
Referring to the preparation method of T27, T46 is used as a raw material to prepare T47. ESI-MS M/z 563.0 [ M + Na ]]+；1H NMR(600MHz,CD3OD):7.75(d,J＝8.1Hz,2H),7.72-7.66(m,2H), 7.24(d,J＝4.0Hz,4H),7.20-7.13(m,1H),7.05-6.98(m,2H),6.78-6.69(m,2H), 4.67-4.59(m,1H),3.72-3.64(m,1H),3.50(dd,J＝11.0,4.1Hz,1H),3.38(dd,J＝ 11.1,5.2Hz,1H),3.15-3.01(m,2H),2.87(dd,J＝14.0,11.4Hz,1H),2.70(dd,J＝ 13.8,7.1Hz,1H),2.61(dd,J＝13.8,6.9Hz,1H)；19F NMR(565MHz,CD3OD): -71.82,-64.37。
48. Preparation of target Compound T48
Referring to the preparation method of T28, T47 and methyl iodide are used as raw materials to prepare T48. ESI-MS M/z 557.2[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.65(d,J＝8.1Hz,2H),7.53(d,J＝ 8.1Hz,2H),7.25(t,J＝7.3Hz,2H),7.23-7.16(m,3H),7.02(d,J＝8.6Hz,3H),6.82 (d,J＝8.6Hz,2H),4.85-4.76(m,1H),3.77(s,3H),3.62-3.49(m,2H),3.31(dd,J＝ 11.2,5.4Hz,1H),3.08-2.99(m,2H),2.80(dd,J＝14.2,10.1Hz,1H),2.69-2.59(m, 2H)；19F NMR(565MHz,CDCl3):-70.08,-63.03。
49. Preparation of target Compound T49
Referring to the preparation method of T28, T47 and iodoethane are used as raw materials to prepare T49. ESI-MS M/z 591.2[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.67(d,J＝8.1Hz,2H),7.57(d,J＝ 8.1Hz,2H),7.29-7.24(m,2H),7.20(t,J＝8.1Hz,3H),7.05-6.98(m,2H),6.90(d, J＝8.8Hz,1H),6.84-6.77(m,2H),4.86-4.76(m,1H),4.00(q,J＝6.9Hz,2H), 3.67-3.46(m,2H),3.32(dd,J＝11.2,5.3Hz,1H),3.10-2.99(m,2H),2.79(dd,J＝ 14.2,10.0Hz,1H),2.69-2.58(m,2H),1.40(t,J＝7.0Hz,3H)；19F NMR(565MHz, CDCl3):-70.05,-63.02。
50. Preparation of target Compound T50
See the above-mentioned system of T28The preparation method takes T47 and 1-bromo-3-methyl-2-butene as raw materials to prepare T50. ESI-MS M/z 631.2[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.65(d,J＝8.1Hz,2H), 7.53(d,J＝8.2Hz,2H),7.25(t,J＝7.4Hz,2H),7.19(t,J＝7.8Hz,2H),7.04-6.99(m, 3H),6.83(d,J＝8.1Hz,2H),5.48(t,J＝6.9Hz,1H),4.85-4.77(m,1H),4.48(d,J＝ 6.8Hz,2H),3.64-3.49(m,2H),3.32(dd,J＝11.2,5.4Hz,1H),3.10-2.98(m,2H), 2.80(dd,J＝14.2,10.1Hz,1H),2.70-2.58(m,2H),1.79(s,3H),1.73(s,3H)；19F NMR(565MHz,CDCl3):-70.09,-63.02。
51. Preparation of target Compound T51
Referring to the preparation method of T01, M16 and 4-nitrobenzoic acid were used as raw materials to prepare T51 as a white solid 100mg with yield: 72.6 percent. ESI-MS M/z 540.3[ M + Na ]]+；1H NMR(600MHz, CD3OD):8.24(d,J＝8.8Hz,2H),7.78(d,J＝8.6Hz,2H),7.36-7.19(m,4H), 7.22-7.08(m,1H),7.02(d,J＝8.5Hz,2H),6.71(d,J＝8.3Hz,2H),4.66-4.56(m,1H), 3.73-3.65(m,1H),3.50(dd,J＝11.0,4.1Hz,1H),3.38(dd,J＝11.0,5.4Hz,1H), 3.14-3.01(m,2H),2.87(dd,J＝14.1,11.4Hz,1H),2.69(dd,J＝13.7,7.0Hz,1H), 2.61(dd,J＝13.7,6.9Hz,1H)；19F NMR(565MHz,CD3OD):-71.86。
52. Preparation of target Compound T52
Referring to the preparation method of T01, T52 was prepared from M16 and 4-chlorobenzoic acid. ESI-MS M/z 529.3[ M + Na ]]+；1H NMR(600MHz,CD3OD):7.62(d,J＝8.4Hz,2H), 7.42(d,J＝8.5Hz,2H),7.30-7.23(m,4H),7.22-7.13(m,1H),6.99(d,J＝8.2Hz,2H), 6.72(d,J＝8.3Hz,2H),4.70-4.55(m,1H),3.81-3.69(m,1H),3.52(dd,J＝10.9,3.6 Hz,1H),3.40(dd,J＝11.3,5.4Hz,1H),3.15-3.03(m,2H),2.97-2.88(m,1H),2.71 (dd,J＝13.7,7.3Hz,1H),2.65(dd,J＝13.3,6.5Hz,1H)；19F NMR(565MHz, CD3OD):-71.35。
53. Preparation of target Compound T53
Referring to the preparation method of T01, T53 was prepared from M16 and 3-iodobenzoic acid. ESI-MS M/z 621.3[ M + Na ]]+；1H NMR(600MHz,CD3OD):7.95(s,1H),7.82(d, J＝6.9Hz,1H),7.61(d,J＝6.9Hz,1H),7.30-7.22(m,4H),7.23-7.09(m,2H), 7.03-6.94(m,2H),6.77-6.66(m,2H),4.69-4.57(m,1H),3.81-3.71(m,1H), 3.57-3.47(m,1H),3.44-3.37(m,1H),3.14-3.06(m,2H),2.97-2.88(m,1H),2.70(dd, J＝16.5,5.1Hz,1H),2.65(dd,J＝12.8,4.9Hz,1H)；19F NMR(565MHz,CD3OD): -71.31。
54. Preparation of target Compound T54
Referring to the preparation method of T01, M16 and 3-bromobenzoic acid are used as raw materials to prepare T54. ESI-MS M/z 573.3[ M + Na ]]+；1H NMR(600MHz,CD3OD):7.75(s,1H),7.63(d, J＝7.5Hz,1H),7.57(d,J＝7.9Hz,1H),7.36-7.12(m,6H),7.08-6.90(m,2H), 6.76-6.56(m,2H),4.65-4.49(m,1H),3.74-3.60(m,1H),3.48(dd,J＝11.0,3.9Hz, 1H),3.37(dd,J＝11.4,5.4Hz,1H),3.17-2.98(m,2H),2.92-2.79(m,1H),2.69(dd, J＝13.5,6.7Hz,1H),2.61(dd,J＝13.6,6.9Hz,1H)；19F NMR(565MHz,CD3OD): -71.88。
55. Preparation of target Compound T55
Referring to the preparation method of T01, T55 is prepared by taking M16 and furoic acid as raw materials. ESI-MS M/z 485.1[ M + Na ]]+；1H NMR(600MHz,CD3OD):7.53(d,J＝2.0Hz,1H), 7.22-7.13(m,4H),7.12-7.05(m,2H),6.99-6.95(m,2H),6.72-6.65(m,2H), 6.48-6.39(m,1H),4.60-4.53(m,1H),3.61-3.53(m,2H),3.48-3.40(m,1H), 3.37-3.31(m,1H),3.07-2.96(m,2H),2.65(dd,J＝13.8,7.2Hz,1H),2.57(dd,J＝ 13.8,6.9Hz,1H)；19F NMR(565MHz,CD3OD):-67.35。
56. Preparation of target Compound T56
Referring to the preparation method of T01, T56 is prepared by using M26 and benzoic acid as raw materials. ESI-MS M/z 585.3[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.64(d,J＝7.3Hz,2H),7.46(t, J＝7.4Hz,1H),7.41-7.33(m,6H),7.32-7.24(m,4H),7.20(d,J＝7.3Hz,1H),7.13(d, J＝8.5Hz,2H),7.09(d,J＝7.2Hz,2H),6.89(d,J＝8.6Hz,2H),6.57(d,J＝8.8Hz, 1H),5.00(s,2H),4.77(dt,J＝8.7,4.5Hz,1H),3.56-3.48(m,2H),3.30(dd,J＝11.2, 5.5Hz,1H),3.04(dt,J＝10.1,5.1Hz,1H),2.94(dd,J＝14.2,5.8Hz,1H),2.78(dd, J＝14.2,9.6Hz,1H),2.67(d,J＝7.0Hz,2H)；19F NMR(565MHz,CDCl3):-69.74。
57. Preparation of target Compound T57
Referring to the preparation method of T27, T56 is used as a raw material to prepare T57. ESI-MS M/z 495.2 [ M + Na ]]+；1H NMR(600MHz,CD3OD):7.67-7.62(m,2H),7.53-7.45(m,1H),7.40 (t,J＝7.7Hz,2H),7.26(t,J＝7.5Hz,2H),7.22-7.14(m,3H),7.07(d,J＝8.5Hz,2H), 6.69(d,J＝8.5Hz,2H),4.59-4.52(m,1H),3.67-3.59(m,1H),3.47(dd,J＝11.1,4.2 Hz,1H),3.37(dd,1H),3.09-3.03(m,1H),2.98(dd,J＝14.1,4.3Hz,1H),2.79(dd, J＝14.2,11.0Hz,1H),2.75(dd,J＝13.5,7.2Hz,1H),2.68(dd,J＝13.6,6.7Hz,1H)；19F NMR(565MHz,CD3OD):-71.89。
58. Preparation of target Compound T58
Referring to the preparation method of T28, T58ESI-MS M/z 544.2[ M + H ] is prepared by using T57 and dimethylamino chloroethane hydrochloride as raw materials]+,566.2[M+Na]+；1H NMR(600MHz,CD3OD): 7.65(dd,J＝8.0,1.3Hz,2H),7.53-7.46(m,1H),7.40(t,J＝7.7Hz,2H),7.27(t,J＝ 7.5Hz,2H),7.19(dd,J＝7.9,2.7Hz,5H),6.87(d,J＝8.7Hz,2H),4.61-4.54(m,1H), 4.13(t,J＝5.3Hz,2H),3.69-3.61(m,1H),3.48(dd,J＝11.1,4.1Hz,1H),3.38(dd, J＝11.1,5.3Hz,1H),3.35(s,1H),3.13-3.00(m,4H),2.84(dd,J＝14.0,11.2Hz,1H), 2.78(dd,J＝13.6,7.2Hz,1H),2.70(dd,J＝13.6,6.8Hz,1H),2.56(s,6H)；19F NMR (565MHz,CD3OD):-71.97。
59. Preparation of target Compound T59
Referring to the preparation method of T28, T57 and diethylaminoethyl chloride hydrochloride are used as raw materials to prepare T59. ESI-MS M/z 572.3[ M + H ]]+；1H NMR(600MHz,CDCl3):7.70(d,J＝7.0 Hz,2H),7.52(t,J＝7.4Hz,1H),7.43(t,J＝7.7Hz,2H),7.35-7.29(m,3H),7.28-7.22 (m,1H),7.20-7.12(m,4H),6.86(d,J＝8.6Hz,2H),6.63(d,J＝8.8Hz,1H), 4.85-4.77(m,1H),4.10-4.01(m,2H),3.62-3.53(m,2H),3.35(dd,J＝11.3,5.6Hz, 1H),3.13-3.05(m,1H),3.02-2.96(m,1H),2.92(d,J＝12.5Hz,2H),2.83(dd,J＝ 14.3,9.5Hz,1H),2.75-2.65(m,6H),1.11(t,J＝7.2Hz,6H)；19F NMR(565MHz, CDCl3):-69.79。
60. Preparation of target Compound T60
Referring to the preparation method of T28, T60 is prepared by using T57 and isopropyl iodide as raw materials. ESI-MS M/z 515.2[ M + H ]]+,537.2[M+Na]+；1H NMR(600MHz,CDCl3):7.66(d,J＝7.3 Hz,2H),7.50(t,J＝7.5Hz,1H),7.41(t,J＝7.6Hz,2H),7.33-7.27(m,3H),7.24(t, J＝7.4Hz,1H),7.16-7.09(m,4H),6.84(d,J＝8.6Hz,2H),6.51(d,J＝8.7Hz,1H), 4.83-4.76(m,1H),4.51(hept,J＝6.0Hz,1H),3.59-3.52(m,2H),3.34(dt,J＝10.5, 4.7Hz,1H),3.11-3.04(m,1H),2.97(dd,J＝14.3,6.1Hz,1H),2.80(dd,J＝14.3,9.4 Hz,1H),2.70(d,J＝7.0Hz,2H),1.32(d,J＝6.1Hz,6H)；19F NMR(565MHz, CDCl3):-69.70。
61. Preparation of target Compound T61
Referring to the preparation method of T28, T57 and methyl iodide are used as raw materials to prepare T61. ESI-MS M/z 509.0[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.64(d,J＝7.6Hz,2H),7.47(t,J＝7.4Hz,1H),7.37(t,J＝7.6Hz,2H),7.30-7.24(m,2H),7.21(t,J＝7.3Hz,1H),7.13 (d,J＝8.1Hz,2H),7.08(d,J＝7.4Hz,2H),6.81(d,J＝8.0Hz,2H),6.59(d,J＝8.8 Hz,1H),4.81-4.72(m,1H),3.75(s,3H),3.57-3.46(m,2H),3.31(dd,J＝11.3,5.5Hz, 1H),3.09-2.99(m,1H),2.94(dd,J＝14.3,5.9Hz,1H),2.78(dd,J＝14.2,9.5Hz,1H), 2.67(d,J＝6.9Hz,2H)；19F NMR(565MHz,CDCl3):-69.72。
62. Preparation of target Compound T62
Referring to the preparation method of T28, T57 and iodoethane are used as raw materials to prepare T62. ESI-MS M/z 501.2[ M + H ]]+,523.2[M+Na]+；1H NMR(600MHz,CDCl3):7.64(d,J＝7.0Hz, 2H),7.47(t,J＝7.4Hz,1H),7.38(t,J＝7.7Hz,2H),7.27(d,J＝7.5Hz,3H), 7.24-7.19(m,1H),7.12(d,J＝8.6Hz,2H),7.09(d,J＝6.9Hz,2H),6.81(d,J＝8.6Hz, 2H),6.52(d,J＝8.8Hz,1H),4.80-4.73(m,1H),3.97(q,J＝6.9Hz,2H),3.57-3.47(m, 2H),3.31(dd,J＝11.5,5.5Hz,1H),3.07-3.00(m,1H),2.94(dd,J＝14.2,6.0Hz,1H), 2.78(dd,J＝14.2,9.4Hz,1H),2.66(d,J＝7.0Hz,2H),1.38(t,J＝7.0Hz,3H)；19F NMR(565MHz,CDCl3):-69.70。
63. Preparation of target Compound T63
Referring to the preparation method of T28, T57 and 1-bromo-3-methyl-2-butene are used as raw materials to prepare T63. ESI-MS M/z 563.3[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.67(d,J＝7.2Hz,2H), 7.50(t,J＝7.4Hz,1H),7.41(t,J＝7.7Hz,2H),7.33-7.27(m,3H),7.26-7.21(m,1H), 7.15(d,J＝8.6Hz,2H),7.12(d,J＝7.0Hz,2H),6.86(d,J＝8.6Hz,2H),6.57(d,J＝ 8.9Hz,1H),5.49(ddd,J＝6.8,4.9,3.0Hz,1H),4.83-4.76(m,1H),4.48(d,J＝6.8Hz, 2H),3.58-3.52(m,2H),3.34(dd,J＝11.4,5.6Hz,1H),3.11-3.04(m,1H),2.97(dd, J＝14.3,6.0Hz,1H),2.81(dd,J＝14.2,9.4Hz,1H),2.70(d,J＝7.0Hz,2H),1.80(s, 3H),1.74(s,3H)；19F NMR(565MHz,CDCl3):-69.70。
64. Preparation of target Compound T64
Figure BDA0002622973250000431
Reaction reagents and conditions: acetic anhydride, pyridine, 0 ℃.
T57(100mg, 211.6. mu. mol) was added to a 10mL reaction flask, pyridine (1mL) was added under argon at 0 deg.C, acetic anhydride (1mL) was added, and stirring was continued at 0 deg.C for 4h until the reaction was complete. Dispersing the reaction solution with ethyl acetate and water, extracting, washing the obtained organic layer with water and saturated NaCl, and removing anhydrous MgSO4Drying, recovering solvent under reduced pressure to dryness, and purifying the obtained product by silica gel column chromatography to obtain T60 white solid powder 95mg with yield 80.7%. ESI-MS M/z 557.3[ M + H ]]+,579.2[M+Na]+；1H NMR(600MHz,CDCl3): 7.61(dd,J＝8.3,1.4Hz,2H),7.50-7.44(m,1H),7.39(t,J＝7.7Hz,2H),7.30(t,J＝ 7.5Hz,2H),7.25-7.20(m,3H),7.16-7.11(m,2H),7.00(d,J＝8.5Hz,2H),6.51(d, J＝9.0Hz,1H),4.77-4.71(m,1H),4.08(dd,J＝11.4,3.8Hz,1H),3.78(dd,J＝11.3, 5.4Hz,1H),3.61(d,J＝8.9Hz,1H),3.25(qt,J＝6.3,3.6Hz,1H),2.97(dd,J＝14.3, 4.9Hz,1H),2.79(dd,J＝13.7,6.8Hz,1H),2.72(dd,J＝14.3,10.1Hz,1H),2.65(dd, J＝13.7,7.4Hz,1H),2.26(s,3H),1.87(s,3H)；19F NMR(565MHz,CDCl3): -69.99。
65. Preparation of target Compound T65
Referring to the preparation method of T01, the T65 is prepared by taking M25 and 4-nitrobenzoic acid as raw materials. ESI-MS M/z 630.3[ M + Na ]]+；1H NMR(600MHz,CDCl3):8.18(d,J＝8.7Hz,2H), 7.76(d,J＝8.7Hz,2H),7.39(d,J＝7.2Hz,2H),7.35(t,J＝7.4Hz,2H),7.32-7.28(m, 3H),7.23(t,J＝7.4Hz,1H),7.12(t,J＝8.2Hz,4H),6.89(dd,J＝13.3,8.7Hz,3H), 5.01(s,2H),4.80-4.73(m,1H),3.61-3.53(m,2H),3.35(dd,J＝11.1,5.3Hz,1H), 3.14-3.07(m,1H),2.98(dd,J＝14.2,5.1Hz,1H),2.79-2.67(m,3H)；19F NMR(565 MHz,CDCl3):-70.14。
66. Preparation of target Compound T66
Referring to the preparation method of T01, M27 and p-nitrobenzoic acid are used as raw materials to prepare T66. ESI-MS M/z 540.2[ M + Na ]]+；1H NMR(600MHz,CD3OD):8.25(d,J＝8.8Hz,1H), 7.81(d,J＝8.8Hz,1H),7.31-7.23(m,3H),7.22-7.14(m,5H),7.06(d,J＝8.5Hz,2H), 6.68(d,J＝8.5Hz,2H),4.59-4.51(m,1H),3.71-3.61(m,2H),3.49(dd,J＝11.1,4.0 Hz,1H),3.37(dd,J＝11.1,5.4Hz,1H),3.10-3.05(m,1H),3.00(dd,J＝14.0,4.3Hz, 1H),2.80-2.73(m,2H),2.69(dd,J＝13.6,6.8Hz,1H)；19F NMR(565MHz,CD3OD) :-71.88。
67. Preparation of target Compound T67
Referring to the preparation method of T28, T66 and methyl iodide are used as raw materials to prepare T67. ESI-MS M/z 554.2[ M + Na ]]+；1H NMR(600MHz,CDCl3):8.19-8.10(m,2H),7.79-7.71(m,2H), 7.29(t,J＝7.5Hz,2H),7.23(t,J＝7.3Hz,1H),7.14-6.98(m,5H),6.79(d,J＝8.5Hz, 2H),4.79-4.72(m,1H),3.74(s,3H),3.56(dd,J＝11.2,3.3Hz,2H),3.34(dd,J＝11.3, 5.4Hz,1H),3.14-3.06(m,1H),2.97(dd,J＝14.3,5.0Hz,1H),2.77-2.70(m,3H)；19F NMR(565MHz,CDCl3):-70.18。
68. Preparation of target Compound T68
Referring to the preparation method of T28, T66 and dimethylamino chloroethane hydrochloride are used as raw materials to prepare T68. ESI-MS M/z 612.2[ M + Na ]]+；1H NMR(600MHz,CDCl3):8.10(d,J＝8.7 Hz,2H),7.77(d,J＝8.7Hz,2H),7.27(dd,J＝8.2,6.9Hz,2H),7.21(t,J＝7.4Hz, 1H),7.14-7.07(m,4H),6.78(d,J＝8.7Hz,2H),4.78-4.71(m,1H),3.97(t,J＝5.6Hz, 2H),3.59-3.51(m,2H),3.31(dd,J＝11.2,5.6Hz,1H),3.12-3.04(m,1H),2.95(dd, J＝14.0,4.6Hz,1H),2.76(dd,J＝14.3,10.3Hz,1H),2.73-2.67(m,4H),2.29(s,6H)；19F NMR(565MHz,CDCl3):-70.45。
69. Preparation of target Compound T69
Referring to the preparation method of T28, T66 and diethylaminochloromethane hydrochloride were used as raw materials to prepare T69. ESI-MS M/z 639.2[ M + Na ]]+；1H NMR(600MHz,CDCl3):8.11(d,J＝7.7 Hz,2H),7.76(d,J＝8.8Hz,2H),7.26(t,J＝7.5Hz,2H),7.19(t,J＝7.4Hz,1H), 7.13-7.06(m,4H),6.75(d,J＝8.5Hz,2H),4.76-4.69(m,1H),3.98(t,J＝5.4Hz,2H), 3.57-3.50(m,2H),3.30(dd,J＝11.1,5.5Hz,1H),3.09-3.04(m,1H),2.93(dd,J＝ 14.2,4.8Hz,1H),2.85(t,J＝6.1Hz,2H),2.73(dd,J＝14.2,10.2Hz,1H),2.69(d,J＝ 7.0Hz,2H),2.63(q,J＝7.1Hz,4H),1.04(t,J＝7.2Hz,6H)；19F NMR(565MHz, CDCl3):-70.38(d,J＝4.1Hz)。
70. Preparation of target Compound T70
Referring to the preparation method of T28, T66 and 1-bromo-3-methyl-2-butene are used as raw materials to prepare T70. ESI-MS M/z 608.2[ M + Na ]]+；1H NMR(600MHz,CDCl3):8.18(d,J＝8.4Hz,2H), 7.77(d,J＝8.6Hz,2H),7.29(t,J＝7.5Hz,2H),7.23(t,J＝7.4Hz,1H),7.14-7.08(m, 4H),6.94(d,J＝8.6Hz,1H),6.81(d,J＝8.6Hz,2H),5.45(tt,J＝6.7,1.6Hz,1H), 4.80-4.71(m,1H),4.44(d,J＝6.8Hz,2H),3.56(dd,J＝11.1,3.3Hz,2H),3.35(dd, J＝11.2,5.4Hz,1H),3.14-3.07(m,1H),2.97(dd,J＝14.3,5.1Hz,1H),2.78-2.67(m, 3H),1.77(s,3H),1.71(s,3H)；19F NMR(565MHz,CDCl3):-70.13。
71. Preparation of target Compound T71
Referring to the preparation method of T01, M25 and 4-fluorobenzoic acid are used as raw materials to prepare T71. ESI-MS M/z 581.3[ M + H ]]+,603.3[M+Na]+；1H NMR(600MHz,CDCl3):7.62(dd, J＝8.6,5.3Hz,2H),7.39(d,J＝7.2Hz,2H),7.35(t,J＝7.5Hz,2H),7.33-7.23(m, 3H),7.21(t,J＝7.3Hz,1H),7.13-7.07(m,4H),7.01(t,J＝8.5Hz,2H),6.87(d,J＝ 8.4Hz,2H),6.62(d,J＝8.8Hz,1H),4.99(s,2H),4.79-4.71(m,1H),3.56-3.47(m, 2H),3.35-3.27(m,1H),3.08-3.01(m,1H),2.94(dd,J＝14.3,5.6Hz,1H),2.75(dd, J＝14.2,9.6Hz,1H),2.67(d,J＝6.9Hz,2H)；19F NMR(565MHz,CDCl3):-69.87, -107.69。
72. Preparation of target Compound T72
Referring to the preparation method of T27, T71 is used as a raw material to prepare T72. ESI-MS M/z 513.3 [ M + Na ]]+；1H NMR(600MHz,CD3OD):7.70(dd,J＝8.7,5.4Hz,2H),7.26(t,J＝ 7.5Hz,2H),7.20-7.15(m,3H),7.13(t,J＝8.7Hz,2H),7.05(d,J＝8.5Hz,2H),6.68 (d,J＝8.5Hz,2H),4.57-4.50(m,1H),3.66-3.58(m,1H),3.46(dd,J＝11.0,4.1Hz, 1H),3.39-3.35(m,1H),3.09-3.03(m,1H),2.97(dd,J＝14.0,4.3Hz,1H),2.83-2.71 (m,2H),2.68(dd,J＝13.6,6.8Hz,1H)；19F NMR(565MHz,CD3OD):-71.89,-110.68。
73. Preparation of target Compound T73
Referring to the preparation method of T28, T72 and methyl iodide are used as raw materials to prepare T73. ESI-MS M/z 527.3[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.67-7.58(m,2H),7.27(t,J＝7.4Hz, 2H),7.21(t,J＝7.3Hz,1H),7.14-7.06(m,4H),7.03(t,J＝8.6Hz,2H),6.81(d,J＝ 8.7Hz,2H),6.58(d,J＝8.8Hz,1H),4.79-4.70(m,1H),3.75(s,3H),3.57-3.45(m, 2H),3.35-3.28(m,1H),3.09-3.00(m,1H),2.94(dd,J＝14.3,5.7Hz,1H),2.76(dd, J＝14.2,9.6Hz,1H),2.68(d,J＝7.0Hz,2H)；19F NMR(565MHz,CDCl3):-69.84, -107.69。
74. Preparation of target Compound T74
According to the preparation method of the T28, the T72 and iodoethane are used as raw materials to prepare the productT74。ESI-MS m/z: 541.3[M+Na]+；1H NMR(600MHz,CDCl3):7.69-7.60(m,2H),7.30-7.26(m,2H), 7.21(t,J＝7.3Hz,1H),7.15-7.07(m,4H),7.03(t,J＝8.6Hz,2H),6.80(d,J＝8.7Hz, 2H),6.55(t,J＝8.3Hz,1H),4.78-4.71(m,1H),3.97(q,J＝7.0Hz,2H),3.53(dt,J＝ 11.7,3.9Hz,2H),3.31(dt,J＝11.5,5.9Hz,1H),3.05(qd,J＝6.9,3.5Hz,1H),2.94 (dd,J＝14.2,5.9Hz,1H),2.76(dd,J＝14.3,9.6Hz,1H),2.68(d,J＝7.0Hz,2H), 1.42-1.34(m,3H)；19F NMR(565MHz,CDCl3):-69.83,-107.71。
75. Preparation of target Compound T75
Referring to the preparation method of T28, T72 and iodopropane are used as raw materials to prepare T75. ESI-MS M/z 533.3[ M + H ]]+,555.5[M+Na]+；1H NMR(600MHz,CDCl3):7.64(dd,J＝8.7,5.3 Hz,2H),7.27(t,J＝7.5Hz,2H),7.21(t,J＝7.3Hz,1H),7.13-7.06(m,4H),7.03(t, J＝8.6Hz,2H),6.81(s,2H),6.56(d,J＝8.7Hz,1H),4.80-4.69(m,1H),3.86(t,J＝ 6.6Hz,2H),3.57-3.48(m,2H),3.31(dt,J＝11.6,6.0Hz,1H),3.07-3.01(m,1H), 2.94(dd,J＝14.3,5.8Hz,1H),2.76(dd,J＝14.3,9.5Hz,1H),2.67(d,J＝7.0Hz,2H), 2.48(dd,J＝6.6,4.4Hz,1H),1.77(h,J＝7.1Hz,2H),1.01(t,J＝7.4Hz,3H)；19F NMR(565MHz,CDCl3):-69.82,-107.72。
76. Preparation of target Compound T76
Referring to the preparation method of T28, T76 is prepared by taking T72 and iodon-butane as raw materials. ESI-MS M/z 547.5[ M + H ]]+,569.3[M+Na]+；1H NMR(600MHz,CDCl3):7.64(dd,J＝8.6, 5.3Hz,2H),7.27(t,J＝7.7Hz,2H),7.21(t,J＝7.3Hz,1H),7.13-7.07(m,4H),7.04 (t,J＝8.6Hz,2H),6.80(d,J＝8.4Hz,2H),6.54(d,J＝8.7Hz,1H),4.78-4.69(m,1H), 3.90(t,J＝6.6Hz,2H),3.59-3.47(m,2H),3.31(dt,J＝11.4,5.7Hz,1H),3.09-3.01 (m,1H),2.94(dd,J＝14.3,5.8Hz,1H),2.76(dd,J＝14.3,9.5Hz,1H),2.67(d,J＝7.0 Hz,2H),1.78-1.70(m,2H),1.46(h,J＝7.4Hz,2H),0.95(t,J＝7.4Hz,3H)；19F NMR (565MHz,CDCl3):-69.81,-107.71。
77. Preparation of target Compound T77
Referring to the preparation method of T28, T77 is prepared by using T72 and isopropyl iodide as raw materials. ESI-MS M/z 533.5[ M + H ]]+,555.3[M+Na]+；1H NMR(600MHz,CDCl3):7.67-7.60(m, 2H),7.27(t,J＝7.5Hz,2H),7.21(t,J＝7.3Hz,1H),7.13-7.07(m,4H),7.07-7.00(m, 2H),6.80(d,J＝8.5Hz,2H),6.59-6.46(m,1H),4.78-4.71(m,1H),4.48(hept,J＝6.1 Hz,1H),3.58-3.48(m,2H),3.31(dt,J＝11.4,5.7Hz,1H),3.09-3.01(m,1H), 2.99-2.90(m,1H),2.76(dd,J＝14.3,9.5Hz,1H),2.68(d,J＝7.0Hz,2H),1.29(d,J＝ 6.0Hz,6H)；19F NMR(565MHz,CDCl3):-69.84(d,J＝7.5Hz),-107.72(d,J＝9.3 Hz)。
78. Preparation of target Compound T78
Referring to the preparation method of T28, T72 and iodoisobutane are used as raw materials to prepare T78. ESI-MS M/z 569.5[ M + Na ]]+；1H NMR(400MHz,CDCl3):7.72-7.57(m,2H),7.28(dd,J＝ 6.9,1.5Hz,2H),7.24-7.18(m,1H),7.09(dd,J＝7.7,5.0Hz,4H),7.07-7.00(m,2H), 6.81(d,J＝8.3Hz,2H),6.55(d,J＝8.7Hz,1H),4.79-4.67(m,1H),3.66(d,J＝6.6Hz, 2H),3.59-3.45(m,2H),3.38-3.26(m,1H),3.09-3.01(m,1H),2.94(dd,J＝14.3,5.8 Hz,1H),2.76(dd,J＝14.3,9.6Hz,1H),2.67(d,J＝7.0Hz,2H),2.47(t,J＝5.6Hz, 1H),2.04(dp,J＝13.3,6.5Hz,1H),1.00(dd,J＝6.7,1.4Hz,6H)；19F NMR(565 MHz,CDCl3):-69.80,-107.70。
79. Preparation of target Compound T79
Referring to the preparation method of T28, T72 and 1-bromo-3-methyl-2-butene are used as raw materials to prepare T79. ESI-MS M/z 581.3[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.69-7.60(m,2H),7.27 (t,J＝7.7Hz,2H),7.21(t,J＝7.3Hz,1H),7.13-7.07(m,4H),7.07-7.01(m,2H),6.83 (d,J＝8.1Hz,2H),6.61-6.43(m,1H),5.46(t,J＝6.8Hz,1H),4.79-4.71(m,1H), 4.45(d,J＝6.9Hz,2H),3.59-3.47(m,2H),3.36-3.28(m,1H),3.10-3.01(m,1H), 2.94(dd,J＝14.2,5.8Hz,1H),2.76(dd,J＝14.3,9.5Hz,1H),2.68(d,J＝7.0Hz,2H), 1.77(s,3H),1.71(s,3H)；19F NMR(565MHz,CDCl3):-69.81,-107.70。
80. Preparation of target Compound T80
Referring to the preparation method of T28, T72 and dimethylamino chloroethane hydrochloride are used as raw materials to prepare T80. ESI-MS M/z 562.5[ M + H ]]+,584.5[M+Na]+；1H NMR(600MHz,CDCl3): 7.66(dd,J＝8.4,5.3Hz,2H),7.26(t,J＝7.2Hz,3H),7.20(t,J＝7.3Hz,1H), 7.13-7.07(m,4H),7.04-6.89(m,3H),6.81-6.75(m,2H),4.77-4.70(m,1H),4.03(d, J＝4.7Hz,2H),3.56-3.47(m,2H),3.29(dd,J＝11.2,5.5Hz,1H),3.09-3.02(m,1H), 2.92(dd,J＝14.2,5.1Hz,1H),2.84-2.74(m,3H),2.68(d,J＝6.9Hz,2H),2.37(t,J＝ 1.6Hz,6H)；19F NMR(565MHz,CDCl3):-70.22,-107.94。
81. Preparation of target Compound T81
Referring to the preparation method of T28, T72 and diethylaminoethyl chloride hydrochloride are used as raw materials to prepare T81. ESI-MS M/z 590.5[ M + H ]]+,612.5[M+Na]+；1H NMR(600MHz,CDCl3): 7.74(dd,J＝8.6,5.5Hz,2H),7.27(t,J＝7.6Hz,2H),7.21(t,J＝7.4Hz,1H),7.16(d, J＝8.4Hz,2H),7.13(d,J＝7.4Hz,2H),7.03-6.97(m,2H),6.75(dt,J＝8.4,1.9Hz, 2H),4.79-4.71(m,1H),4.25-4.15(m,2H),3.59-3.50(m,2H),3.30(dd,J＝11.3,5.7 Hz,1H),3.18(t,J＝5.4Hz,2H),3.12-3.04(m,1H),3.03-2.84(m,6H),2.71(t,J＝6.3 Hz,2H),1.23(t,J＝7.2Hz,6H)；19F NMR(565MHz,CDCl3):-70.52,-108.16。
82. Preparation of target Compound T82
Referring to the preparation method of T01, the T82 is prepared by taking M25 and 4-methoxybenzoic acid as raw materials. ESI-MS M/z 585.3[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.65(d,J＝8.8Hz,2H), 7.43(d,J＝7.1Hz,2H),7.39(t,J＝7.4Hz,2H),7.36-7.29(m,3H),7.23(t,J＝7.4Hz, 1H),7.16(d,J＝8.5Hz,2H),7.12(d,J＝6.8Hz,2H),6.92(d,J＝8.6Hz,2H),6.90(d, J＝8.8Hz,2H),6.47(d,J＝8.8Hz,1H),5.04(s,2H),4.83-4.76(m,1H),3.85(s,3H), 3.58-3.49(m,2H),3.33(dd,J＝11.3,5.5Hz,1H),3.11-3.03(m,1H),2.97(dd,J＝ 14.3,5.9Hz,1H),2.81(dd,J＝14.3,9.4Hz,1H),2.69(d,J＝7.0Hz,2H)；19F NMR (565MHz,CDCl3):-69.71。
83. Preparation of target Compound T83
Referring to the preparation method of T27, T82 is used as a raw material to prepare T83. ESI-MS M/z 525.2[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.63(d,J＝8.8Hz,2H),7.30-7.27(m,2H), 7.21(t,J＝7.3Hz,1H),7.11-7.07(m,2H),7.05(d,J＝8.5Hz,2H),6.88(d,J＝8.8Hz, 2H),6.69(d,J＝8.5Hz,2H),6.47(d,J＝9.0Hz,1H),4.80-4.73(m,1H),3.82(s,3H), 3.55(dd,J＝11.3,3.4Hz,1H),3.47(dt,J＝9.2,6.7Hz,1H),3.33(dd,J＝11.2,5.6Hz, 1H),3.07-3.00(m,1H),2.91(dd,J＝14.1,5.9Hz,1H),2.74(dd,J＝14.2,9.4Hz,1H), 2.67(d,J＝7.0Hz,2H)；19F NMR(565MHz,CDCl3):-69.72。
84. Preparation of target Compound T84
Referring to the preparation method of T28, T83 and iodoethane are used as raw materials to prepare T84. ESI-MS M/z 553.2[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.61(d,J＝8.8Hz,2H),7.27-7.23(m, 2H),7.20(t,J＝7.4Hz,1H),7.11(d,J＝8.3Hz,2H),7.08(d,J＝7.0Hz,2H), 6.88-6.82(m,2H),6.82-6.77(m,2H),6.57-6.44(m,1H),4.80-4.69(m,1H),3.96(q, J＝7.0Hz,2H),3.82-3.79(m,3H),3.55-3.46(m,2H),3.29(dd,J＝11.3,5.5Hz,1H), 3.06-2.99(m,1H),2.93(dd,J＝14.2,6.1Hz,1H),2.78(dd,J＝14.2,9.4Hz,1H),2.65 (d,J＝7.0Hz,2H),1.37(t,J＝7.0Hz,3H)；19F NMR(565MHz,CDCl3):-69.74(d, J＝9.4Hz)。
85. Preparation of target Compound T85
Referring to the preparation method of T28, T83 and dimethylamino chloroethane hydrochloride are used as raw materials to prepare T85. ESI-MS M/z 574.2[ M + H ]]+；1H NMR(600MHz,CDCl3):7.63(d,J＝8.7 Hz,2H),7.29-7.23(m,3H),7.20(t,J＝7.3Hz,1H),7.12(d,J＝8.6Hz,2H),7.09(d, J＝7.1Hz,2H),6.86(d,J＝8.9Hz,2H),6.83(d,J＝8.6Hz,2H),6.53(d,J＝8.7Hz, 1H),4.79-4.70(m,1H),4.00(t,J＝5.8Hz,2H),3.81(s,3H),3.51(td,J＝10.8,10.4, 3.2Hz,2H),3.31-3.27(m,1H),3.03(qd,J＝6.7,3.2Hz,1H),2.93(dd,J＝14.2,5.9 Hz,1H),2.78(dd,J＝14.2,9.5Hz,1H),2.69(t,J＝5.8Hz,2H),2.66(d,J＝6.9Hz, 2H),2.31(s,6H)；19F NMR(565MHz,CDCl3):-69.81。
86. Preparation of target Compound T86
Referring to the preparation method of T01, the T86 is prepared by taking M25 and 4-trifluoromethylbenzoic acid as raw materials. ESI-MS M/z 631.2[ M + H ]]+,653.2[M+Na]+；1H NMR(600MHz,CDCl3):7.70(d, J＝8.1Hz,2H),7.60(d,J＝8.1Hz,2H),7.38(d,J＝6.8Hz,2H),7.37-7.32(m,2H), 7.32-7.26(m,3H),7.22(t,J＝7.4Hz,1H),7.14-7.08(m,4H),6.88(d,J＝8.7Hz,2H), 6.80(d,J＝8.8Hz,1H),5.00(s,2H),4.79-4.73(m,1H),3.60-3.51(m,2H),3.32(dd, J＝11.2,5.4Hz,1H),3.12-3.05(m,1H),2.96(dd,J＝14.2,5.3Hz,1H),2.74(dd,J＝ 14.2,9.9Hz,1H),2.70(d,J＝7.0Hz,2H)；19F NMR(565MHz,CDCl3):-62.98, -70.02。
87. Preparation of target Compound T87
Referring to the preparation method of T27, T86 is used as a raw material to prepare T87. ESI-MS M/z 563.2[ M + Na ]]+；1H NMR(600MHz,CD3OD):7.78(d,J＝8.1Hz,2H),7.71(d,J＝8.3Hz, 2H),7.27(t,J＝7.4Hz,2H),7.23-7.14(m,3H),7.03(d,J＝8.1Hz,2H),6.66(d,J＝8.1Hz,2H),4.61-4.45(m,1H),3.71-3.59(m,1H),3.47(dd,J＝11.1,4.1Hz,1H), 3.39-3.35(m,1H),3.10-3.03(m,1H),2.98(dd,J＝14.0,4.4Hz,1H),2.81-2.72(m, 2H),2.68(dd,J＝13.5,6.8Hz,1H)；19F NMR(565MHz,CD3OD):-64.42,-71.86。
88. Preparation of target Compound T88
Referring to the preparation method of T28, T87 and methyl iodide are used as raw materials to prepare T88. ESI-MS M/z 577.2[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.75(d,J＝8.1Hz,2H),7.64(d, J＝8.1Hz,2H),7.31(dd,J＝8.1,6.7Hz,2H),7.28-7.23(m,1H),7.17-7.11(m,4H), 6.86-6.82(m,2H),6.80(d,J＝8.8Hz,1H),4.83-4.75(m,1H),3.78(s,3H),3.61-3.55 (m,2H),3.36(dd,J＝11.2,5.4Hz,1H),3.15-3.07(m,1H),2.99(dd,J＝14.2,5.4Hz, 1H),2.77(dd,J＝14.3,9.8Hz,1H),2.73(d,J＝7.1Hz,2H)；19F NMR(565MHz, CDCl3):-63.02,-69.99。
89. Preparation of target Compound T89
See the above-mentioned system of T28The preparation method takes T87 and iodoethane as raw materials to prepare T89. ESI-MS M/z 591.2[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.75(d,J＝8.1Hz,2H),7.64(d,J＝ 8.0Hz,2H),7.31(t,J＝7.4Hz,2H),7.25(t,J＝7.4Hz,1H),7.17-7.09(m,4H),6.83 (d,J＝8.6Hz,2H),6.76(dd,J＝9.0,3.7Hz,1H),4.83-4.72(m,1H),4.00(q,J＝7.0 Hz,2H),3.63-3.50(m,2H),3.36(dt,J＝11.3,5.7Hz,1H),3.16-3.07(m,1H),2.99 (dd,J＝14.2,5.4Hz,1H),2.77(dd,J＝14.3,9.8Hz,1H),2.73(d,J＝7.0Hz,2H), 1.40(t,J＝7.0Hz,3H)；19F NMR(565MHz,CDCl3):-63.02,-69.98。
90. Preparation of target Compound T90
Referring to the preparation method of T28, T87 and iodopropane are used as raw materials to prepare T90. ESI-MS M/z 605.3[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.71(d,J＝8.1Hz,2H),7.60(d,J＝8.0Hz,2H),7.28(t,J＝7.4Hz,2H),7.22(t,J＝7.4Hz,1H),7.14-7.05(m,4H),6.80 (d,J＝8.6Hz,2H),6.77(d,J＝8.6Hz,1H),4.81-4.68(m,1H),3.85(td,J＝6.6,1.1 Hz,2H),3.61-3.48(m,2H),3.33(dt,J＝11.0,5.2Hz,1H),3.14-3.03(m,1H),2.96 (dd,J＝14.3,5.5Hz,1H),2.74(dd,J＝14.2,9.8Hz,1H),2.70(d,J＝7.0Hz,2H), 1.77(h,J＝7.2Hz,2H),1.00(t,J＝7.4Hz,3H)；19F NMR(565MHz,CDCl3): -63.02,-69.97。
91. Preparation of target Compound T91
Referring to the preparation method of T28, T87 and 1-bromo-3-methyl-2-butene are used as raw materials to prepare T91. ESI-MS M/z 609.2[ M + H ]]+,631.2[M+Na]+；1H NMR(600MHz,CDCl3):7.73(d, J＝7.7Hz,2H),7.63(d,J＝8.2Hz,2H),7.29(t,J＝7.5Hz,2H),7.23(t,J＝7.3Hz, 1H),7.13-7.08(m,4H),6.83(d,J＝8.6Hz,2H),6.72(p,J＝6.8,6.0Hz,1H), 5.48-5.43(m,1H),4.80-4.72(m,1H),4.45(d,J＝6.8Hz,2H),3.55(dd,J＝11.3,3.4 Hz,2H),3.34(dd,J＝11.2,5.3Hz,1H),3.12-3.05(m,1H),2.96(dd,J＝14.3,5.4Hz, 1H),2.74(dd,J＝14.3,9.8Hz,1H),2.70(d,J＝6.4Hz,2H),1.77(s,3H),1.71(s, 3H)；19F NMR(565MHz,CDCl3):-63.00,-69.96。
92. Preparation of target Compound T92
Referring to the preparation method of T28, T87 and dimethylamino chloroethane hydrochloride are used as raw materials to prepare T92. ESI-MS M/z 612.3[ M + H ]]+,634.2[M+Na]+；1H NMR(600MHz,CDCl3): 7.74(d,J＝8.0Hz,2H),7.62(d,J＝8.0Hz,2H),7.31(t,J＝7.4Hz,2H),7.25(t,J＝ 7.3Hz,1H),7.17-7.09(m,4H),6.93-6.86(m,1H),6.84(d,J＝8.6Hz,2H),4.82-4.73 (m,1H),4.01(t,J＝5.6Hz,2H),3.63-3.54(m,2H),3.35(dd,J＝11.2,5.5Hz,1H), 3.14-3.07(m,1H),2.98(dd,J＝14.2,5.2Hz,1H),2.76(dd,J＝14.3,9.9Hz,1H), 2.74-2.68(m,4H),2.31(s,6H)；19F NMR(565MHz,CDCl3):-63.01,-70.11。
93. Preparation of target Compound T93
Referring to the preparation method of T28, T87 and diethylaminoethyl chloride hydrochloride are used as raw materials to prepare T93. ESI-MS M/z 640.3[ M + H ]]+,662.3[M+Na]+；1H NMR(600MHz,CDCl3): 7.75(d,J＝8.1Hz,2H),7.64(d,J＝8.0Hz,2H),7.31(t,J＝7.4Hz,2H),7.25(t,J＝ 7.3Hz,1H),7.16-7.10(m,4H),6.83(d,J＝8.6Hz,2H),6.79(d,J＝9.4Hz,1H), 4.82-4.74(m,1H),4.00(td,J＝6.4,1.5Hz,2H),3.62-3.53(m,2H),3.35(dd,J＝11.2, 5.4Hz,1H),3.15-3.06(m,1H),2.98(dd,J＝14.2,5.3Hz,1H),2.85(t,J＝6.3Hz,2H), 2.80-2.75(m,1H),2.73(d,J＝7.0Hz,2H),2.63(q,J＝7.1Hz,4H),1.06(t,J＝7.1Hz, 6H)；19F NMR(565MHz,CDCl3):-63.01,-70.05。
94. Preparation of target Compound T94
Referring to the preparation method of T01, the T94 is prepared by taking M25 and 4-methylbenzoic acid as raw materials. ESI-MS M/z 599.2[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.58(d,J＝8.2Hz, 2H),7.43(d,J＝7.1Hz,2H),7.39(t,J＝7.6Hz,2H),7.34(t,J＝7.2Hz,1H), 7.32-7.29(m,2H),7.24(t,J＝7.4Hz,1H),7.20(d,J＝8.0Hz,2H),7.17(d,J＝8.6Hz, 2H),7.12(d,J＝6.9Hz,2H),6.92(d,J＝8.7Hz,2H),6.54(d,J＝8.8Hz,1H),5.04(s, 2H),4.84-4.76(m,1H),3.54(ddd,J＝18.6,11.7,6.3Hz,2H),3.33(dd,J＝11.3,5.5 Hz,1H),3.11-3.03(m,1H),2.97(dd,J＝14.2,6.0Hz,1H),2.81(dd,J＝14.3,9.4Hz, 1H),2.70(d,J＝7.0Hz,2H),2.46(s,1H),2.39(s,3H)；19F NMR(565MHz,CDCl3) :-69.70。
95. Preparation of target Compound T95
Referring to the preparation method of T27, T94 is used as a raw material to prepare T95. ESI-MS M/z 509.1[ M + Na ]]+；1H NMR(600MHz,CD3OD):7.52(d,J＝8.1Hz,2H),7.22(t,J＝7.5Hz, 2H),7.19-7.11(m,5H),7.03(d,J＝8.5Hz,2H),6.65(d,J＝8.4Hz,2H),4.56-4.47(m, 1H),3.58(dq,J＝8.3,4.4Hz,1H),3.42(dd,J＝11.1,4.1Hz,1H),3.32(dd,J＝5.5Hz, 1H),3.04-2.98(m,1H),2.93(dd,J＝14.1,4.3Hz,1H),2.76(dd,J＝14.1,10.9Hz, 1H),2.71(dd,J＝13.6,7.3Hz,1H),2.64(dd,J＝13.6,6.7Hz,1H),2.31(s,3H)；19F NMR(565MHz,CD3OD):-71.83(d,J＝6.6Hz)。
96. Preparation of target Compound T96
Referring to the preparation method of T28, T95 and methyl iodide are used as raw materials to prepare T96. ESI-MS M/z 524.2[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.58-7.51(m,2H),7.26(t,J＝7.5Hz, 2H),7.23-7.19(m,1H),7.17(d,J＝7.9Hz,2H),7.15-7.10(m,2H),7.10-7.06(m,2H), 6.86-6.76(m,2H),6.53(d,J＝8.7Hz,1H),4.82-4.71(m,1H),3.75(s,3H),3.51(ddd, J＝12.0,9.8,3.1Hz,2H),3.30(dd,J＝11.2,5.5Hz,1H),3.06-2.99(m,1H),2.93(dd, J＝14.2,6.0Hz,1H),2.78(dd,J＝14.2,9.4Hz,1H),2.66(d,J＝7.0Hz,3H),2.36(s, 3H)；19F NMR(565MHz,CDCl3):-69.71。
97. Preparation of target Compound T97
Referring to the preparation method of T28, T95 and iodoethane are used as raw materials to prepare T97. ESI-MS M/z 537.2[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.54(d,J＝7.7Hz,2H),7.30-7.23(m, 2H),7.23-7.18(m,1H),7.16(t,J＝4.7Hz,2H),7.11(d,J＝8.1Hz,2H),7.08(d,J＝ 7.5Hz,2H),6.80(d,J＝8.0Hz,2H),6.52(q,J＝9.8,9.4Hz,1H),4.82-4.70(m,1H), 3.97(d,J＝7.1Hz,2H),3.57-3.43(m,2H),3.29(dd,J＝11.4,5.5Hz,1H),3.07-2.98 (m,1H),2.93(dd,J＝14.3,6.0Hz,1H),2.78(dd,J＝14.2,9.4Hz,1H),2.65(d,J＝7.0 Hz,3H),2.36(s,3H),1.38(t,J＝7.0Hz,3H)；19F NMR(565MHz,CDCl3):-69.71 (d,J＝11.6Hz)。
98. Preparation of target Compound T98
Referring to the preparation method of T28, T98 is prepared by using T95 and isopropyl iodide as raw materials. ESI-MS M/z 551.2[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.53(d,J＝8.3Hz,2H),7.26(dd, J＝8.0,6.7Hz,2H),7.20(t,J＝7.4Hz,1H),7.15(d,J＝7.3Hz,2H),7.10(d,J＝8.6 Hz,2H),7.08(d,J＝7.1Hz,2H),6.80(d,J＝8.6Hz,2H),6.58-6.48(m,1H), 4.79-4.71(m,1H),4.48(hept,J＝6.1Hz,1H),3.56-3.46(m,2H),3.29(dd,J＝11.4, 5.5Hz,1H),3.07-2.99(m,1H),2.92(dd,J＝14.2,6.1Hz,1H),2.78(dd,J＝14.3,9.4 Hz,1H),2.65(d,J＝7.0Hz,2H),2.35(s,3H),1.29(d,J＝6.1Hz,6H)；19F NMR(565 MHz,CDCl3):-69.72(d,J＝6.9Hz)。
99. Preparation of target Compound T99
Referring to the preparation method of T28, T95 and dimethylamino chloroethane hydrochloride are used as raw materials to prepare T99. ESI-MS M/z 580.3[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.54(d,J＝8.1 Hz,2H),7.28-7.23(m,2H),7.23-7.16(m,1H),7.14(dd,J＝8.3,2.8Hz,2H),7.10(d, J＝8.3Hz,3H),7.11-7.06(m,3H),6.84-6.78(m,2H),6.70(dd,J＝19.5,10.2Hz,1H), 4.80-4.71(m,1H),3.98(t,J＝5.6Hz,3H),3.50(dd,J＝11.2,3.6Hz,2H),3.28(dd, J＝11.2,5.6Hz,1H),3.03(dq,J＝6.9,3.3Hz,1H),2.92(dd,J＝14.3,5.6Hz,1H), 2.77(dd,J＝14.3,9.6Hz,1H),2.71-2.63(m,4H),2.34(s,3H),2.31-2.27(m,6H)；19F NMR(565MHz,CDCl3):-69.87。
100. Preparation of target Compound T100
Referring to the preparation method of T28, T100 was prepared from T95 and diethylaminoethyl chloride hydrochloride. ESI-MS M/z 608.3[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.55(d,J＝8.2 Hz,2H),7.29-7.23(m,2H),7.20(t,J＝7.3Hz,1H),7.15(d,J＝8.6Hz,2H),7.11(d, J＝8.5Hz,3H),7.09(d,J＝6.7Hz,3H),6.80(d,J＝8.4Hz,2H),6.64(dd,J＝9.0,3.6 Hz,1H),4.80-4.71(m,1H),4.01(t,J＝6.2Hz,2H),3.51(dd,J＝11.2,3.4Hz,2H), 3.29(dd,J＝11.2,5.6Hz,1H),3.07-3.00(m,1H),2.92(dd,J＝14.2,5.8Hz,1H),2.87 (t,J＝6.2Hz,2H),2.78(dd,J＝14.2,9.6Hz,1H),2.68-2.61(m,6H),2.35(s,3H), 1.06(t,J＝7.1Hz,6H)；19F NMR(565MHz,CDCl3):-69.84。
101. Preparation of target Compound T101
Referring to the preparation method of T01, the T101 is prepared by taking M25 and 3,4, 5-trimethoxybenzoic acid as raw materials. ESI-MS M/z 675.3[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.41-7.38(m, 2H),7.37-7.34(m,2H),7.32-7.26(m,4H),7.23-7.20(m,1H),7.18-7.15(m,1H), 7.13(d,J＝8.6Hz,2H),7.11(d,J＝6.8Hz,2H),6.89(d,J＝8.6Hz,2H),6.85(s,2H), 6.54(d,J＝8.8Hz,1H),5.00(s,2H),4.78-4.70(m,1H),3.85(s,3H),3.82(s,6H), 3.56-3.50(m,2H),3.32(dd,J＝11.3,5.4Hz,1H),3.06(qd,J＝6.8,3.7Hz,1H),2.96 (dd,J＝14.3,5.7Hz,1H),2.81-2.76(m,1H),2.69(d,J＝7.0Hz,2H)；19F NMR(565 MHz,CDCl3):-70.03。
102. Preparation of target Compound T102
Referring to the above T27 preparation method, T102 was prepared using T101 as the starting material. ESI-MS M/z 585.2[ M + Na ]]+；1H NMR(600MHz,CD3OD):7.32-7.27(m,2H),7.24-7.17(m,3H),7.10 (d,J＝8.4Hz,2H),6.94(s,2H),6.72(d,J＝8.4Hz,2H),4.60-4.55(m,1H),3.85(s, 6H),3.80(s,3H),3.70-3.65(m,1H),3.53(dd,J＝11.1,4.0Hz,1H),3.42(dd,J＝11.1, 5.5Hz,1H),3.14-3.09(m,1H),3.01(dd,J＝14.1,4.3Hz,1H),2.83(dd,J＝14.1,11.2 Hz,1H),2.79(dd,J＝13.6,7.2Hz,1H),2.73(dd,J＝13.6,6.7Hz,1H)；19F NMR (565MHz,CD3OD):-71.98。
103. Preparation of target Compound T103
Referring to the above T28 production method, T103 was produced using T102 and methyl iodide as raw materials. ESI-MS M/z 599.2[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.31-7.25(m,2H),7.21(t,J＝7.3 Hz,1H),7.15-7.07(m,4H),6.84(s,2H),6.81(dd,J＝8.5,1.6Hz,2H),6.65-6.53(m, 1H),4.79-4.68(m,1H),3.84(d,J＝1.1Hz,3H),3.82-3.78(m,6H),3.75(d,J＝1.2Hz, 3H),3.59-3.49(m,2H),3.33(dd,J＝11.3,5.4Hz,1H),3.10-3.03(m,1H),2.96(dd, J＝14.3,5.6Hz,1H),2.77(dd,J＝14.3,9.7Hz,1H),2.69(d,J＝7.0Hz,2H)；19F NMR(565MHz,CDCl3):-70.05(d,J＝6.1Hz)。
104. Preparation of target Compound T104
Referring to the preparation method of T28, T104 is prepared by taking T102 and 1-bromo-3-methyl-2-butene as raw materials. ESI-MS M/z 653.3[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.27(t,J＝7.6Hz, 2H),7.24-7.18(m,1H),7.14-7.08(m,4H),6.87-6.78(m,4H),6.65(q,J＝10.8,10.1 Hz,1H),5.48-5.42(m,1H),4.77-4.69(m,1H),4.44(d,J＝6.8Hz,2H),3.84(d,J＝ 1.6Hz,3H),3.81-3.77(m,6H),3.54(dt,J＝10.9,3.5Hz,2H),3.32(dd,J＝11.3,5.4 Hz,1H),3.10-3.03(m,1H),2.95(dd,J＝14.3,5.5Hz,1H),2.77(dd,J＝14.3,9.7Hz, 1H),2.69(d,J＝7.0Hz,2H),1.77(s,3H),1.71(s,3H)；19F NMR(565MHz,CDCl3) :-70.06(d,J＝8.1Hz))。
105. Preparation of target Compound T105
Referring to the above T28 preparation method, T105 was prepared from T102 and dimethylaminoethyl chloride hydrochloride. ESI-MS M/z 635.2[ M + H ]]+,658.3[M+Na]+；1H NMR(600MHz,CDCl3): 7.31-7.24(m,2H),7.21(t,J＝6.8Hz,1H),7.15-7.08(m,4H),6.87(s,2H),6.84-6.78 (m,2H),6.78-6.64(m,1H),4.77-4.69(m,1H),4.03-3.95(m,2H),3.85-3.82(m,3H), 3.82-3.77(m,6H),3.57-3.50(m,2H),3.31(dd,J＝11.1,5.4Hz,1H),3.10-3.03(m, 1H),2.94(dd,J＝14.3,4.7Hz,1H),2.77(dd,J＝14.3,9.8Hz,1H),2.69(d,J＝6.4Hz, 4H),2.34-2.27(m,6H)；19F NMR(565MHz,CDCl3):-70.10--70.26(m)。
106. Preparation of target Compound T106
Referring to the above T28 preparation method, T106 was prepared from T102 and diethylaminoethyl chloride hydrochloride. ESI-MS M/z 662.3[ M + H ]]+,684.2[M+Na]+；1H NMR(600MHz,CDCl3): 7.27(t,J＝7.4Hz,2H),7.21(t,J＝7.4Hz,1H),7.15-7.08(m,4H),6.87(s,2H),6.81 (d,J＝8.4Hz,2H),6.67-6.58(m,1H),4.77-4.69(m,1H),4.00(t,J＝6.3Hz,2H), 3.85(d,J＝1.0Hz,3H),3.84-3.79(m,6H),3.58-3.50(m,2H),3.32(dd,J＝11.3,5.5 Hz,1H),3.11-3.03(m,1H),2.95(dd,J＝14.3,5.5Hz,1H),2.86(t,J＝6.2Hz,2H), 2.78(dd,J＝14.3,9.7Hz,1H),2.69(d,J＝7.0Hz,2H),2.64(q,J＝7.1Hz,4H),1.06 (t,J＝7.2Hz,6H)；19F NMR(565MHz,CDCl3):-70.12(d,J＝11.2Hz)。
107. Preparation of target Compound T107
Referring to the preparation method of T01, T107 was prepared from M25 and 3-bromobenzoic acid. ESI-MS M/z 663.2[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.80(s,1H),7.60(d,J＝ 8.0Hz,1H),7.56(d,J＝8.2Hz,1H),7.43(d,J＝7.2Hz,2H),7.39(t,J＝7.6Hz,2H), 7.36-7.29(m,3H),7.27-7.21(m,2H),7.15(d,J＝8.6Hz,4H),6.92(d,J＝8.6Hz,2H), 6.74(q,J＝10.8,9.6Hz,1H),5.03(s,2H),4.81-4.74(m,1H),3.61-3.52(m,2H),3.36 (dd,J＝11.2,5.4Hz,1H),3.13-3.07(m,1H),2.98(dd,J＝14.2,5.5Hz,1H),2.78(dd, J＝14.3,9.8Hz,1H),2.73(d,J＝7.0Hz,2H)；19F NMR(565MHz,CDCl3):-69.91。
108. Preparation of target Compound T108
Referring to the preparation method of T01, T108 was prepared from M25 and 2-chlorobenzoic acid. ESI-MS M/z 619.2[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.44-7.40(m,2H),7.37 (t,J＝7.6Hz,2H),7.35-7.26(m,6H),7.22(q,J＝7.5Hz,2H),7.15(d,J＝8.6Hz,2H), 7.12(d,J＝5.6Hz,2H),6.92(d,J＝8.6Hz,2H),6.59-6.47(m,1H),5.04(s,2H), 4.83-4.75(m,1H),3.62-3.52(m,2H),3.33(dd,J＝11.4,5.2Hz,1H),3.14-3.07(m, 1H),2.94(dd,J＝14.2,5.7Hz,1H),2.77-2.64(m,3H)；19F NMR(565MHz,CDCl3) :-69.46。
109. Preparation of target Compound T109
Referring to the preparation method of T01, T109 was prepared from M25 and 3-trifluoromethylbenzoic acid. ESI-MS M/z 631.2[ M + H ]]+,651.2[M+Na]+；1H NMR(600MHz,CDCl3): 7.90(s,1H),7.80(d,J＝7.8Hz,1H),7.71(d,J＝7.7Hz,1H),7.49(t,J＝7.8Hz,1H), 7.39(d,J＝7.2Hz,2H),7.35(t,J＝7.5Hz,2H),7.32-7.26(m,3H),7.24-7.20(m,1H), 7.14-7.09(m,4H),6.88(d,J＝8.6Hz,2H),6.82(d,J＝8.7Hz,1H),5.00(s,2H), 4.81-4.74(m,1H),3.60-3.51(m,2H),3.37-3.30(m,1H),3.12-3.05(m,1H),2.97(dd, J＝14.2,5.3Hz,1H),2.75(dd,J＝14.2,9.8Hz,1H),2.70(d,J＝7.0Hz,2H),2.21(s, 1H)；19F NMR(565MHz,CDCl3):-62.71,-70.05。
110. Preparation of target Compound T110
Referring to the preparation method of T01, T110 was prepared from M25 and 3-methylbenzoic acid. ESI-MS M/z 599.2[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.46(s,1H),7.42-7.38 (m,3H),7.35(t,J＝7.5Hz,2H),7.32-7.26(m,4H),7.20(t,J＝7.3Hz,1H),7.13(d, J＝8.6Hz,2H),7.09(d,J＝6.9Hz,2H),6.90(d,J＝8.5Hz,2H),6.50(d,J＝8.6Hz, 1H),5.00(s,2H),4.81-4.73(m,1H),3.57-3.45(m,2H),3.30(dd,J＝11.3,5.5Hz, 1H),3.07-3.00(m,1H),2.94(dd,J＝14.2,6.1Hz,1H),2.79(dd,J＝14.2,9.4Hz,1H), 2.66(d,J＝7.0Hz,2H),2.57(s,1H),2.34(s,3H)；19F NMR(565MHz,CDCl3): -69.65。
111. Preparation of target Compound T111
Referring to the preparation method of T01, T111 is prepared by taking M25 and 4-methylthiobenzoic acid as raw materials. ESI-MS M/z 609.2[ M + H ]]+,631.2[M+Na]+；1H NMR(600MHz,CDCl3):7.59(d, J＝8.5Hz,2H),7.43(d,J＝6.9Hz,2H),7.39(t,J＝7.4Hz,2H),7.36-7.29(m,3H), 7.26-7.20(m,3H),7.16-7.12(m,3H),6.91(d,J＝8.6Hz,2H),6.61(d,J＝8.8Hz,1H), 5.03(s,2H),4.79(tdd,J＝9.0,5.6,2.7Hz,1H),3.54(qd,J＝9.8,8.4,3.1Hz,2H), 3.33(dd,J＝11.2,5.5Hz,1H),3.07(qd,J＝6.9,3.4Hz,1H),2.97(dd,J＝14.2,5.8Hz, 1H),2.80(dd,J＝13.9,9.8Hz,1H),2.70(d,J＝7.0Hz,2H),2.50(s,3H)；19F NMR (565MHz,CDCl3):-69.82。
112. Preparation of target Compound T112
Referring to the above T27 preparation method, T112 was prepared from T109. ESI-MS M/z 541.0 [ M + H ]]+,563.2[M+Na]+；1H NMR(600MHz,CD3OD):7.96(s,1H),7.91(d,J＝ 7.9Hz,1H),7.82(d,J＝7.8Hz,1H),7.63(t,J＝7.7Hz,1H),7.30(dd,J＝8.6,6.7Hz, 2H),7.24-7.18(m,3H),7.10(d,J＝8.5Hz,2H),6.72(d,J＝8.5Hz,2H),4.63-4.55(m, 1H),3.68(tt,J＝8.0,4.0Hz,1H),3.52(dd,J＝11.1,4.1Hz,1H),3.41(dd,J＝11.1, 5.5Hz,1H),3.13-3.08(m,1H),3.04(dd,J＝14.1,4.4Hz,1H),2.85-2.80(m,1H), 2.80-2.75(m,1H),2.72(dd,J＝13.6,6.8Hz,1H)；19F NMR(565MHz,CDCl3): -60.24,-67.95。
113. Preparation of target Compound T113
Referring to the above T27 preparation method, T113 was prepared from T110. ESI-MS M/z 509.0[ M + Na ]]+；1H NMR(600MHz,CD3OD):7.50-7.43(m,2H),7.36-7.26(m,4H), 7.24-7.18(m,3H),7.09(d,J＝8.5Hz,2H),6.72(d,J＝8.5Hz,2H),4.61-4.53(m,1H), 3.69-3.62(m,1H),3.49(dd,J＝11.1,4.2Hz,1H),3.43-3.38(m,1H),3.12-3.05(m, 1H),3.00(dd,J＝14.1,4.3Hz,1H),2.82(dd,J＝14.0,11.1Hz,1H),2.80-2.75(m, 1H),2.71(dd,J＝13.7,6.7Hz,1H),2.38(s,3H)；19F NMR(565MHz,CDCl3): -67.94。
114. Preparation of target Compound T114
Referring to the above T28 preparation method, T114 was prepared from T112 and methyl iodide as raw materials. ESI-MS M/z 577.0[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.91(s,1H),7.82(d,J＝7.8Hz, 1H),7.72(d,J＝07.8Hz,1H),7.54-7.47(m,1H),7.31(t,J＝7.5Hz,2H),7.27-7.23 (m,1H),7.17-7.11(m,4H),6.89(q,J＝8.4,7.4Hz,1H),6.83(d,J＝8.5Hz,2H), 4.83-4.75(m,1H),3.77(s,3H),3.62-3.55(m,2H),3.37(dd,J＝11.1,5.5Hz,1H), 3.15-3.08(m,1H),2.99(dd,J＝14.2,5.3Hz,1H),2.78(dd,J＝14.3,9.9Hz,1H),2.74 (d,J＝7.0Hz,2H)；19F NMR(565MHz,CDCl3):-62.74,-70.05。
115. Preparation of target Compound T115
Referring to the preparation method of T28, T115 was prepared from T112 and iodoethane. ESI-MS M/z 591.2[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.92(s,1H),7.82(d,J＝7.7Hz, 1H),7.73(d,J＝7.8Hz,1H),7.51(t,J＝7.8Hz,1H),7.31(t,J＝7.5Hz,2H), 7.27-7.22(m,1H),7.16-7.11(m,4H),6.88-6.78(m,3H),4.83-4.74(m,1H),3.99(q, J＝7.1Hz,2H),3.62-3.54(m,2H),3.37(dd,J＝11.2,5.5Hz,1H),3.11(qd,J＝6.9, 3.4Hz,1H),2.99(dd,J＝14.3,5.4Hz,1H),2.78(dd,J＝14.3,9.8Hz,1H),2.73(d, J＝7.0Hz,2H),1.40(t,J＝7.0Hz,3H)；19F NMR(565MHz,CD3Cl):-62.75, -70.04。
116. Preparation of target Compound T116
T116 was prepared from T112 and 1-bromo 3-methyl 2-butene, according to the procedure for preparation of T28 described above. ESI-MS M/z 609.2[ M + H ]]+,631.2[M+Na]+；1H NMR(600MHz,CDCl3):7.93(s, 1H),7.83(d,J＝7.8Hz,1H),7.73(d,J＝7.8Hz,1H),7.52(t,J＝7.8Hz,1H),7.31(t, J＝7.5Hz,2H),7.25(t,J＝7.4Hz,1H),7.16-7.11(m,4H),6.88-6.82(m,3H),5.48(tt, J＝6.7,1.5Hz,1H),4.83-4.75(m,1H),4.47(d,J＝6.8Hz,2H),3.64-3.53(m,2H), 3.37(dd,J＝11.2,5.5Hz,1H),3.16-3.07(m,1H),2.99(dd,J＝14.2,5.4Hz,1H),2.78 (dd,J＝14.3,9.8Hz,1H),2.73(d,J＝6.9Hz,2H),2.36(d,J＝13.8Hz,1H),1.79(s, 3H),1.74(s,3H)；19F NMR(565MHz,CDCl3):-62.74,-70.03。
117. Preparation of the object Compound T117
T117 was prepared from T112 and dimethylaminoethyl chloride hydrochloride by the method for preparing T28. ESI-MS M/z 612.2[ M + H ]]+,634.2[M+Na]+；1H NMR(600MHz,CDCl3):7.90(s, 1H),7.81(d,J＝7.8Hz,1H),7.69(d,J＝7.8Hz,1H),7.48(t,J＝7.8Hz,1H), 7.31-7.26(m,2H),7.22(t,J＝7.3Hz,1H),7.15-7.08(m,4H),6.92(s,1H),6.81(d, J＝8.6Hz,2H),4.80-4.70(m,1H),3.99(td,J＝5.8,2.0Hz,2H),3.55(dd,J＝11.0,3.4 Hz,2H),3.33(dd,J＝11.1,5.5Hz,1H),3.13-3.05(m,1H),2.96(dd,J＝14.2,5.2Hz, 1H),2.75(dd,J＝14.2,9.9Hz,1H),2.70(d,J＝6.9Hz,2H),2.68(t,J＝5.7Hz,2H), 2.29(s,6H)；19F NMR(565MHz,CDCl3):-62.72,-70.17。
118. Preparation of target Compound T118
T118 was prepared from T112 and diethylaminoethyl chloride hydrochloride by the method for preparing T28. ESI-MS M/z 640.2[ M + H ]]+,662.2[M+Na]+；1H NMR(600MHz,CDCl3):7.93(d, J＝2.2Hz,1H),7.84(d,J＝8.1Hz,1H),7.73(d,J＝8.4Hz,1H),7.53(t,J＝7.8Hz, 1H),7.31(dd,J＝8.2,6.8Hz,2H),7.27-7.23(m,1H),7.14(td,J＝5.7,3.2Hz,4H), 6.83(d,J＝8.7Hz,3H),4.83-4.74(m,1H),4.02(td,J＝6.3,2.5Hz,2H),3.58(dd,J＝ 11.1,3.3Hz,2H),3.36(dd,J＝11.1,5.5Hz,1H),3.14-3.08(m,1H),2.99(dd,J＝14.2, 5.3Hz,1H),2.87(t,J＝6.2Hz,2H),2.78(dd,J＝14.3,9.9Hz,1H),2.73(d,J＝7.0Hz, 2H),2.65(q,J＝7.2Hz,4H),1.08(t,J＝7.2Hz,6H)；19F NMR(565MHz,CDCl3): -62.73,-70.11。
119. Preparation of target Compound T119
Referring to the above T28 preparation method, T119 was prepared using T113 and methyl iodide as raw materials. ESI-MS M/z 523.2[ M + Na ]]+,662.2[M+Na]+；1H NMR(600MHz,CDCl3):7.49(s,1H), 7.44(d,J＝7.3Hz,1H),7.33-7.26(m,4H),7.24(t,J＝7.3Hz,1H),7.16(d,J＝8.1Hz, 2H),7.11(d,J＝7.4Hz,2H),6.85(d,J＝8.0Hz,2H),6.55(d,J＝8.8Hz,1H), 4.84-4.74(m,1H),3.79(s,3H),3.60-3.48(m,2H),3.34(dd,J＝11.5,5.6Hz,1H), 3.11-3.02(m,1H),2.97(dd,J＝14.3,6.1Hz,1H),2.82(dd,J＝14.2,9.4Hz,1H),2.69 (d,J＝7.0Hz,2H),2.37(s,3H)；19F NMR(565MHz,CDCl3):-69.65。
120. Preparation of target Compound T120
Referring to the above T28 preparation method, T120 was prepared from T113 and iodoethane. ESI-MS M/z 515.0[ M + H ]]+,537.2[M+Na]+；1H NMR(600MHz,CDCl3):7.48(s,1H),7.43 (d,J＝7.4Hz,1H),7.32-7.26(m,4H),7.23(t,J＝7.3Hz,1H),7.15(d,J＝8.4Hz,2H), 7.11(d,J＝7.3Hz,2H),6.84(d,J＝8.6Hz,2H),6.55(d,J＝8.8Hz,1H),4.83-4.74(m, 1H),4.00(q,J＝7.0Hz,2H),3.59-3.49(m,2H),3.33(dd,J＝11.4,5.5Hz,1H), 3.09-3.02(m,1H),2.97(dd,J＝14.3,6.1Hz,1H),2.82(dd,J＝14.3,9.4Hz,1H),2.72 (s,1H),2.69(d,J＝6.9Hz,2H),2.37(s,3H),1.41(t,J＝7.0Hz,3H)；19F NMR(565 MHz,CDCl3):-69.65。
121. Preparation of the target Compound T121
Referring to the preparation method of T28, T121 is prepared by taking T113 and 1-bromo-3-methyl-2-butene as raw materials. ESI-MS M/z 577.2[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.47(s,1H), 7.41(d,J＝6.9Hz,1H),7.32-7.25(m,6H),7.21(t,J＝7.3Hz,1H),7.13(d,J＝8.7Hz, 2H),7.09(d,J＝7.2Hz,2H),6.85(d,J＝8.5Hz,2H),6.41(d,J＝8.8Hz,1H),5.47(td, J＝6.0,5.4,3.3Hz,1H),4.81-4.72(m,1H),4.47(d,J＝6.8Hz,2H),3.54(dd,J＝11.3, 3.3Hz,1H),3.53-3.47(m,1H),3.31(dd,J＝11.7,5.4Hz,1H),3.08-3.00(m,1H), 2.95(dd,J＝14.4,6.1Hz,1H),2.79(dd,J＝14.2,9.3Hz,1H),2.66(d,J＝7.0Hz,2H), 2.47(s,1H),2.36(s,3H),1.78(s,3H),1.72(s,3H)；19F NMR(565MHz,CDCl3): -69.60。
122. Preparation of target Compound T122
Referring to the above T27 preparation method, T122 was prepared from T66. ESI-MS M/z 488.2 [ M + H ]]+,1H NMR(600MHz,CD3OD):7.48(d,J＝8.7Hz,2H),7.25(t,J＝7.5Hz, 2H),7.21-7.11(m,3H),7.05(d,J＝8.5Hz,2H),6.68(d,J＝8.5Hz,2H),6.62(d,J＝ 8.7Hz,2H),4.57-4.49(m,1H),3.58(qd,J＝8.2,3.5Hz,1H),3.43(dd,J＝11.1,4.2 Hz,1H),3.34(d,J＝7.8Hz,1H),3.07-2.98(m,1H),2.92(dd,J＝14.1,4.4Hz,1H), 2.78(dd,J＝14.1,10.7Hz,1H),2.72(dd,J＝13.6,7.3Hz,1H),2.66(dd,J＝13.6,6.7 Hz,1H)；19F NMR(565MHz,CD3OD):-71.84。
123. Preparation of target Compound T123
Referring to the preparation method of T28, T123 was prepared from T95 and 1-bromo 3-methyl 2-butene as raw materials. ESI-MS M/z 577.3[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.55(d,J＝8.2Hz,2H), 7.29-7.23(m,2H),7.20(t,J＝7.3Hz,1H),7.15(d,J＝8.6Hz,2H),7.11(d,J＝8.5Hz, 3H),7.09(d,J＝6.7Hz,3H),6.80(d,J＝8.4Hz,2H),6.64(dd,J＝9.0,3.6Hz,1H), 4.80-4.71(m,1H),4.01(t,J＝6.2Hz,2H),3.51(dd,J＝11.2,3.4Hz,2H),3.29(dd, J＝11.2,5.6Hz,1H),3.07-3.00(m,1H),2.92(dd,J＝14.2,5.8Hz,1H),2.87(t,J＝6.2 Hz,2H),2.78(dd,J＝14.2,9.6Hz,1H),2.68-2.61(m,6H),2.35(s,3H),1.06(t,J＝ 7.1Hz,6H)；19F NMR(565MHz,CDCl3):-69.84。
124. Preparation of target Compound T124
Referring to the preparation method of T28, T124 was prepared using T122 and isopropyl iodide as raw materials. ESI-MS M/z 552.3[ M + Na ]]+；1H NMR(600MHz,CD3Cl):7.90(d,J＝8.4Hz,1H), 7.56(d,J＝8.7Hz,2H),7.33(t,J＝7.5Hz,2H),7.26(s,3H),7.20(d,J＝8.6Hz,2H), 6.84(d,J＝8.6Hz,2H),6.59(d,J＝8.7Hz,2H),5.68(s,2H),4.70(t,J＝5.4Hz,1H), 4.57(h,J＝6.0Hz,1H),4.51-4.40(m,1H),3.65(tt,J＝8.3,4.1Hz,1H),3.42(s,3H), 3.32(dh,J＝21.9,5.2Hz,2H),3.03-2.90(m,3H),2.75(dd,J＝13.5,7.0Hz,1H),2.67 (dd,J＝13.6,6.4Hz,1H),2.60-2.56(m,1H),2.28(dd,J＝7.4,5.1Hz,1H),1.28(d, J＝6.0Hz,6H)；19F NMR(565MHz,CD3Cl):-65.26。
125. Preparation of target Compound T125
Referring to the above T28 preparation method, T125 was prepared from T113 and diethylaminoethyl chloride. ESI-MS M/z 586.2[ M + H ]]+；1H NMR(600MHz,CDCl3):7.51-7.46(m,1H), 7.46-7.41(m,1H),7.33-7.25(m,5H),7.23(t,J＝7.4Hz,1H),7.15(d,J＝8.6Hz,2H), 7.12(d,J＝7.2Hz,2H),6.85(d,J＝8.7Hz,2H),6.54(dt,J＝9.3,2.6Hz,1H), 4.83-4.73(m,1H),4.03(t,J＝6.4Hz,2H),3.59-3.49(m,2H),3.33(dd,J＝11.3,5.6 Hz,1H),3.10-3.03(m,1H),2.96(dd,J＝14.3,6.0Hz,1H),2.88(t,J＝6.3Hz,2H), 2.81(dd,J＝14.3,9.5Hz,1H),2.69(d,J＝7.0Hz,2H),2.66(q,J＝7.1Hz,4H),2.38 (s,3H),1.08(t,J＝7.2Hz,6H)；19F NMR(565MHz,CDCl3):-69.70。
126. Preparation of target Compound T126
Referring to the preparation method of T01, T126 was prepared from M25 and 3-iodobenzoic acid as raw materials. ESI-MS M/z 711.1[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.99(s,1H),7.80(d,J＝ 7.8Hz,1H),7.59(d,J＝7.7Hz,1H),7.43(d,J＝7.5Hz,2H),7.39(t,J＝7.5Hz,2H), 7.37-7.29(m,3H),7.25(t,J＝7.4Hz,1H),7.14(d,J＝7.9Hz,4H),7.11(t,J＝7.8Hz, 1H),6.92(d,J＝8.2Hz,2H),6.74(d,J＝8.9Hz,1H),5.04(s,2H),4.77(qd,J＝9.2, 7.1,2.9Hz,1H),3.61-3.52(m,2H),3.39-3.34(m,1H),3.10(qd,J＝6.8,3.4Hz,1H), 2.98(dd,J＝14.3,5.4Hz,1H),2.78(dd,J＝14.2,9.8Hz,1H),2.73(d,J＝7.0Hz,2H)；19F NMR(565MHz,CDCl3):-69.92。
127. Preparation of target Compound T127
Referring to the preparation method of T01, T127 was prepared from M27 and p-3-bromobenzoic acid. ESI-MS M/z 575.2[ M + Na ]]+；1H NMR(600MHz,DMSO-d6):9.18-9.12(m,1H), 8.45(d,J＝8.6Hz,1H),7.89(s,1H),7.75-7.68(m,2H),7.41(t,J＝7.9Hz,1H),7.27 (t,J＝7.6Hz,2H),7.23-7.14(m,3H),7.05(d,J＝8.3Hz,2H),6.64(d,J＝8.3Hz,2H), 4.65(t,J＝5.3Hz,1H),4.43-4.33(m,1H),3.69-3.58(m,1H),3.33(dt,J＝10.0,4.8 Hz,1H),3.26(dt,J＝11.0,5.6Hz,1H),3.04-2.92(m,2H),2.82(dd,J＝14.0,11.2Hz, 1H),2.68(dd,J＝13.6,7.2Hz,1H),2.63(dd,J＝13.6,6.4Hz,1H),2.27(dd,J＝7.9, 4.7Hz,1H)；19F NMR(565MHz,DMSO-d6):-70.01。
128. Preparation of target Compound T128
Referring to the preparation method of T01, T128 was prepared from M27 and 2-chlorobenzoic acid. ESI-MS M/z 529.3[ M + Na ]]+；1H NMR(600MHz,DMSO-d6):9.20(s,1H),8.48(d, J＝8.8Hz,1H),7.44(d,J＝7.8Hz,1H),7.43-7.39(m,1H),7.35(td,J＝7.4,1.3Hz, 1H),7.29(t,J＝7.5Hz,2H),7.25-7.17(m,3H),7.14(dd,J＝7.6,1.7Hz,1H),7.08(d, J＝8.0Hz,2H),6.71(d,J＝8.1Hz,2H),4.59(t,J＝5.4Hz,1H),4.44-4.33(m,1H), 3.71-3.57(m,1H),3.38-3.36(m,1H),3.32-3.25(m,1H),3.03-2.89(m,2H), 2.77-2.59(m,3H),2.21(dd,J＝8.2,4.5Hz,1H)；19F NMR(565MHz,DMSO-d6): -69.81。
129. Preparation of target Compound T129
Referring to the preparation method of T01, T129 was prepared from M27 and 4-chlorobenzoic acid. ESI-MS M/z 529.3[ M + Na ]]+；1H NMR(600MHz,DMSO-d6):9.14(s,1H),8.39(d, J＝8.6Hz,1H),7.75(d,J＝8.6Hz,2H),7.52(d,J＝8.6Hz,2H),7.27(t,J＝7.5Hz, 2H),7.23-7.15(m,3H),7.04(d,J＝8.5Hz,2H),6.63(d,J＝8.5Hz,2H),4.64(t,J＝ 5.3Hz,1H),4.42-4.33(m,1H),3.68-3.57(m,1H),3.31(dt,J＝10.9,4.7Hz,1H), 3.25(dt,J＝11.0,5.6Hz,1H),3.01-2.91(m,2H),2.82(dd,J＝14.0,11.3Hz,1H), 2.68(dd,J＝13.6,7.2Hz,1H),2.62(dd,J＝13.6,6.3Hz,1H),2.26(dd,J＝7.6,4.8Hz, 1H)；19F NMR(565MHz,DMSO-d6):-70.04。
130. Preparation of target Compound T130
Referring to the preparation method of T28, T130 was prepared from T127 and iodoisopropane as starting materials. ESI-MS M/z 595.3[ M + H ]]+,617.3[M+Na]+；1H NMR(600MHz,CDCl3):7.77(s, 1H),7.58(dd,J＝7.8,1.9Hz,1H),7.53(dd,J＝7.8,1.4Hz,1H),7.28(t,J＝7.5Hz, 2H),7.23(q,J＝7.8Hz,2H),7.10(t,J＝7.9Hz,4H),6.80(d,J＝8.6Hz,2H),6.60(q, J＝5.5,4.3Hz,1H),4.73(tdd,J＝9.0,5.5,2.9Hz,1H),4.49(hept,J＝6.1Hz,1H), 3.54(td,J＝10.3,9.3,3.2Hz,2H),3.33(dd,J＝11.2,5.4Hz,1H),3.07(qd,J＝7.0, 3.4Hz,1H),2.94(dd,J＝14.2,5.6Hz,1H),2.74(dd,J＝14.3,9.7Hz,1H),2.69(d, J＝7.0Hz,2H),1.29(d,J＝6.1Hz,6H)；19F NMR(565MHz,CDCl3):-69.87。
131. Preparation of target Compound T131
Referring to the preparation method of T28, T131 was prepared from T127 and dimethylaminoethyl chloride. ESI-MS M/z 624.3[ M + H ]]+,646.3[M+Na]+；1H NMR(600MHz,CDCl3):7.80(t, J＝1.8Hz,1H),7.61-7.55(m,2H),7.31(d,J＝7.5Hz,2H),7.28-7.21(m,2H), 7.16-7.10(m,4H),6.83(d,J＝8.6Hz,2H),4.75(tdd,J＝8.8,5.1,2.9Hz,1H),4.05 (td,J＝5.8,1.8Hz,2H),3.60-3.51(m,2H),3.38-3.32(m,1H),3.09(qd,J＝6.8,3.4 Hz,1H),2.99-2.93(m,1H),2.81-2.75(m,3H),2.72(d,J＝7.0Hz,2H),2.37(s,6H)；19F NMR(565MHz,CDCl3):-70.07。
132. Preparation of target Compound T132
Referring to the above T28 preparation method, T132 was prepared from T127 and methyl iodide as raw materials. ESI-MS M/z 567.3[ M + H ]]+,589.3[M+Na]+；1H NMR(600MHz,CDCl3):7.80(s,1H),7.61 (d,J＝7.9Hz,1H),7.57(d,J＝8.2Hz,1H),7.31(t,J＝7.5Hz,2H),7.26(dt,J＝9.4, 7.6Hz,2H),7.17-7.10(m,4H),6.84(d,J＝8.7Hz,2H),6.67(d,J＝8.8Hz,1H), 4.80-4.73(m,1H),3.79(s,3H),3.58(dd,J＝11.2,3.3Hz,1H),3.55(dd,J＝7.9,2.8 Hz,1H),3.36(dd,J＝11.2,5.4Hz,1H),3.15-3.04(m,1H),2.97(dd,J＝14.2,5.6Hz, 1H),2.77(dd,J＝14.2,9.7Hz,1H),2.72(d,J＝7.0Hz,2H)；19F NMR(565MHz, CDCl3):-69.89。
133. Preparation of target Compound T133
Referring to the preparation method of T28, T133 was prepared using T128 and isopropyl iodide as raw materials. ESI-MS M/z 549.3[ M + H ]]+,571.5[M+Na]+；1H NMR(600MHz,CD3Cl): 7.38-7.31(m,3H),7.31-7.27(m,2H),7.25-7.20(m,2H),7.17-7.09(m,4H),6.84(d, J＝8.5Hz,2H),6.45(d,J＝8.7Hz,1H),4.84-4.75(m,1H),4.52(hept,J＝6.0Hz,1H), 3.62-3.53(m,2H),3.34(dd,J＝11.6,5.2Hz,1H),3.11(qd,J＝7.0,3.5Hz,1H),2.94 (dd,J＝14.3,5.9Hz,1H),2.78-2.64(m,3H),2.35(s,1H),1.32(d,J＝6.0Hz,6H)；19F NMR(565MHz,CD3Cl):-69.45。
134. Preparation of target Compound T134
Referring to the preparation method of T28, T134 was prepared from T129 and dimethylaminoethyl chloride. ESI-MS M/z 578.3[ M + H ]]+,600.3[M+Na]+；1H NMR(600MHz,CDCl3):7.59(d, J＝8.1Hz,2H),7.34-7.29(m,2H),7.27(t,J＝7.5Hz,3H),7.21(t,J＝7.3Hz,1H), 7.18-7.09(m,4H),6.83-6.77(m,2H),4.78-4.69(m,1H),4.02(td,J＝5.4,4.6,2.8Hz, 2H),3.52(dt,J＝10.8,3.2Hz,2H),3.35-3.27(m,2H),3.10-3.03(m,1H),2.97-2.89 (m,1H),2.81-2.73(m,3H),2.69(d,J＝7.0Hz,2H),2.35(s,6H)；19F NMR(565MHz, CDCl3):-70.13。
135. Preparation of the target Compound T135
Referring to the preparation method of T28, T135 is prepared by taking T129 and iodoisobutane as raw materials. ESI-MS M/z 585.5[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.61(d,J＝8.6Hz,2H), 7.37(d,J＝8.5Hz,2H),7.32-7.29(m,2H),7.27-7.22(m,1H),7.16-7.09(m,4H), 6.83(d,J＝8.6Hz,2H),6.58(d,J＝8.7Hz,1H),4.82-4.72(m,1H),3.69(dd,J＝6.6, 1.5Hz,2H),3.59-3.51(m,2H),3.34(dd,J＝11.2,5.4Hz,1H),3.11-3.04(m,1H), 2.97(dd,J＝14.3,5.7Hz,1H),2.77(dd,J＝14.2,9.5Hz,1H),2.71(d,J＝7.0Hz,2H), 2.07(hept,J＝6.7Hz,1H),1.03(d,J＝6.7Hz,6H)；19F NMR(565MHz,CDCl3): -69.85。
136. Preparation of target Compound T136
T136 was prepared by the method for preparing T28 described above using T129 and isopropyl iodide as starting materials. ESI-MS M/z 571.3[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.56(d,J＝8.5Hz,2H), 7.33(d,J＝8.5Hz,2H),7.28(t,J＝7.4Hz,2H),7.22(t,J＝7.4Hz,1H),7.10(td,J＝ 5.9,3.2Hz,4H),6.80(d,J＝8.6Hz,2H),6.56(d,J＝8.7Hz,1H),4.74(tdd,J＝8.9, 5.6,2.9Hz,1H),4.48(hept,J＝6.0Hz,1H),3.56-3.48(m,2H),3.31(dd,J＝11.2,5.4 Hz,1H),3.06(qd,J＝6.8,3.3Hz,1H),2.94(dd,J＝14.3,5.7Hz,1H),2.75(dd,J＝ 14.3,9.6Hz,1H),2.68(d,J＝7.0Hz,2H),1.29(d,J＝6.0Hz,6H)；19F NMR(565 MHz,CDCl3):-69.88。
137. Preparation of target Compound T137
Referring to the above T28 production method, T137 was produced using T129 and methyl iodide as raw materials. ESI-MS M/z 543.3[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.57(d,J＝8.5Hz,2H),7.33(d, J＝8.5Hz,2H),7.30-7.26(m,2H),7.22(t,J＝7.4Hz,1H),7.15-7.04(m,4H),6.81(d, J＝8.6Hz,2H),6.62(d,J＝8.8Hz,1H),4.80-4.69(m,1H),3.75(s,3H),3.57-3.48(m, 2H),3.32(dd,J＝11.2,5.4Hz,1H),3.09-3.02(m,1H),2.94(dd,J＝14.2,5.6Hz,1H), 2.75(dd,J＝14.3,9.7Hz,1H),2.68(d,J＝7.0Hz,2H)；19F NMR(565MHz,CDCl3) :-69.90。
138. Preparation of the target Compound T138
Referring to the preparation method of T01, T138 was prepared from M25 and 2-methylbenzoic acid. ESI-MS M/z 599.5[ M + Na ]]+；1H NMR(600MHz,CDCl3):7.41(d,J＝7.2Hz,2H), 7.37(t,J＝7.5Hz,2H),7.33-7.25(m,4H),7.21(t,J＝7.3Hz,1H),7.16-7.11(m,5H), 7.11-7.06(m,2H),6.91(d,J＝8.8Hz,2H),6.10(d,J＝9.0Hz,1H),5.03(s,2H),4.77 (qd,J＝9.0,7.5,2.9Hz,1H),3.59(dd,J＝11.3,3.4Hz,1H),3.51(qd,J＝7.9,2.9Hz, 1H),3.34(dd,J＝11.3,5.5Hz,1H),3.14-3.06(m,1H),2.91(dd,J＝14.2,5.5Hz,1H), 2.73-2.62(m,3H),2.15(s,3H)；19F NMR(565MHz,CDCl3):-69.47。
139. Preparation of target Compound T139
Referring to the above T27 preparation method, T139 was prepared from T138. ESI-MS M/z 487.5 [ M + H ]]+,509.5[M+Na]+；1H NMR(600MHz,CD3OD):7.35-7.29(m,2H),7.28(td, J＝7.5,1.5Hz,1H),7.26-7.21(m,3H),7.18-7.14(m,2H),7.13-7.08(m,3H),6.77(d, J＝8.5Hz,2H),4.68-4.59(m,1H),3.69-3.61(m,1H),3.57(dd,J＝11.2,4.1Hz,1H), 3.44(dd,J＝11.2,5.1Hz,1H),3.18-3.12(m,1H),3.00(dd,J＝14.0,4.1Hz,1H),2.82 (dd,J＝13.6,7.1Hz,1H),2.76-2.67(m,2H),2.09(s,3H)；19F NMR(565MHz, CD3OD):-71.48。
140. Preparation of target Compound T140
Referring to the above T28 preparation method, T139 and dimethylaminoethyl chloride hydrochloride are used as raw materials to prepare T140. ESI-MS M/z 558.3[ M + H ]]+,580.3[M+Na]+；1H NMR(600MHz,CDCl3): 7.31-7.25(m,5H),7.22(t,J＝7.3Hz,1H),7.17-7.08(m,7H),6.90-6.83(m,2H),6.09 (d,J＝9.0Hz,1H),4.82-4.72(m,1H),4.08(t,J＝5.6Hz,2H),3.60(dd,J＝11.3,3.4 Hz,1H),3.56-3.48(m,1H),3.36(dd,J＝11.3,5.5Hz,1H),3.16-3.09(m,1H),2.92 (dd,J＝14.2,5.4Hz,1H),2.80(t,J＝5.7Hz,2H),2.75-2.65(m,4H),2.39(s,6H), 2.18(s,3H)；19F NMR(565MHz,CDCl3):-69.52。
Example 3 in vitro anti-HBV assay of representative Compounds of interest
The experimental method is as follows: HepG2.2.15 cells in the logarithmic growth phase are taken and inoculated into a 96-well plate, and the experiment is started after the cells adhere to the wall. Activity screening experiments: each compound is prepared into liquid medicine with the concentration of 20 mu mol, 4 mu mol and 0.8 mu mol and liquid medicine concentration of 2 mu mol, 10 mu mol and 50 mu mol respectively according to the toxicity of the compound, and an ETV10 mu mol/L (entecavir) positive control group, a virus control group and a 0.2% DMSO control group are respectively added into a 96-well culture plate, wherein each concentration is 3 wells. Changing the same concentration liquid medicine on the 3 rd day of administration; cells were harvested on day 6 of dosing. The cell lysate uses DNA fast extracting solution to extract total DNA, and uses Taqman probe as fluorescent quantitative PCR to detect HBV-DNA load in cells. The results are shown in Table 1.
Figure BDA0002622973250000651
TABLE 1 inhibitory Activity of the representative Compounds of the invention on HepG2.2.15 cell HBV-DNA replication
Figure BDA0002622973250000652
Figure BDA0002622973250000661
Figure BDA0002622973250000671
Figure BDA0002622973250000681
Example 4 Metabolic stability testing of representative target Compounds
Respectively mixing N- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-butyl-2-yl ] -phenylalaninol derivative T58 and MTS derivative MTS101 to be detected with a phase I metabolic stability kit (MVT-1.0(5MC1) and a male beagle dog liver microparticle kit) (produced by Beijing Virginian Taikang medicine technology Co., Ltd.) by adopting an in vitro liver microsome incubation method to prepare a T58 group incubation liquid with a concentration of about 50 mu mol/L, an MTS101 group incubation liquid and a blank control group incubation liquid without a sample, wherein 200 mu L of each of the T58 group incubation liquid, the MTS101 group incubation liquid and the blank control group incubation liquid are respectively placed in an EP tube with a specification of 1.5mL, then, incubating each group of incubation liquid samples at constant temperature of 37 ℃ for 0min, 30min, 60 min and 120min in a metal bath, taking out the EP tube corresponding to each group of samples, placing the EP tube on ice, and immediately adding 200 mu L of precooled ice methanol to terminate the reaction. Each of the above incubation liquid samples was centrifuged at 12000rpm (4 ℃) for 15min, and the supernatant was injected and examined for the content of T58 or MTS101 in each sample by high performance liquid chromatography. The results show that the content of the compound T58 is reduced by about 2 to 5 percent within 120 min. While the MTS101 content is reduced by about 60-70%. This indicates that: the N- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-butyl-2-yl ] -phenylalaninol derivative is not easy to be hydrolyzed by enzyme, has better metabolic stability and obviously prolonged elimination half-life.
The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof, and it should be understood that various changes and modifications can be effected therein by one skilled in the art without departing from the spirit and scope of the invention as defined in the appended claims.

Claims (12)

  1. An N- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-but-2-yl ] -phenylalaninol derivative, characterized in that: is a compound shown in the following general formula I and pharmaceutically acceptable salt or hydrate thereof,
    Figure FDA0002622973240000011
    the R is1And R3Independently selected from hydrogen, fluorine, chlorine, bromine, -NO2、-NH2、-NHR、-NRR′、-NHCOR、-NHCO(CH2)nCOOH、-OH、-OCOR、-OR、-O(CH2)nNRR′、-O(CH2)nCOOR and-O (CH)2)nA single or a combination of two or more of COOH;
    the R is2Is an aromatic ring containing a substituent;
    the R is4is-OH, -O (CO) R, -OR;
    the R and R' are selected from the same or different C1-C6Straight or branched alkyl, C3-C7Cycloalkyl radical, C2-C7An alkylene group;
    and n is an integer of 1 to 4.
  2. 2. The N- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-but-2-yl ] -phenylalaninol derivative according to claim 1, wherein: the aromatic ring is a benzene ring, a pyridine ring, a furan ring or a thiophene ring.
  3. 3. The N- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-but-2-yl ] -phenylalaninol derivative according to claim 2, wherein: the substituents on the aromatic ring are mono-or polysubstituted.
  4. 4. N- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-but-2-yl ] as claimed in claim 3]-phenylalaninol derivatives, characterized in that: the substituents on the aromatic ring are selected from hydrogen, fluorine, chlorine, bromine, iodine, -CN, -NO2、-NH2、-OH、-SH、-COOH、-OR、-SR、-NHR、-NRR′、C1-C6An alkyl group.
  5. 5. The N- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-but-2-yl ] -phenylalaninol derivative according to claim 1 or 4, wherein: the alkyl and cycloalkyl groups are optionally substituted with 1-2 substituents selected from hydroxy, nitro, haloalkyl, cyano, trifluoromethyl.
  6. 6. The N- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-but-2-yl ] -phenylalaninol derivative according to claim 1, wherein: the derivative is selected from any one of T01-T140,
    Figure FDA0002622973240000021
    Figure FDA0002622973240000031
    Figure FDA0002622973240000041
    Figure FDA0002622973240000051
    Figure FDA0002622973240000061
    Figure FDA0002622973240000071
  7. 7. n- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-but-2-yl ] according to any one of claims 1 to 6]-a process for the preparation of phenylalaninol derivatives, characterized in that: according to the following synthetic route, with R1Substituted L-phenylalaninol SM1 is used as starting material, which reacts with trityl chloromethane in the presence of tertiary amine to obtain intermediate M1, then M1 is subjected to Swern oxidation to obtain intermediate M2, M2 reacts with trifluoromethyl trimethylsilane in the presence of tetrabutylammonium fluoride to obtain intermediate M3, M3 is subjected to acid catalysis to remove trityl protecting group to obtain intermediate M4, M4 reacts with N-Boc to obtain intermediate M5, M5 is subjected to Dess-Martin oxidation to obtain intermediate M6, M6 and R6 are subjected to R-Martin oxidation to obtain intermediate M35523Coupling substituted L-phenylalaninol SM2 to obtain an intermediate M7, opening ring of M7 under the action of lithium aluminum hydride to obtain an intermediate M8, removing Boc protecting group from M8 to obtain an intermediate M9, and reacting M9 with aryl formic acid to obtain a target molecule TM with the structure of a general formula I:
    Figure FDA0002622973240000081
  8. 8. a process for the preparation of N- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-but-2-yl ] -phenylalaninol derivatives according to claim 7, characterized in that: in the synthetic route: a is trityl chloromethane and N, N-diisopropylethylamine (or triethylamine); b is oxalyl chloride, dimethyl sulfoxide, DIPEA (or triethylamine) and dichloromethane; c is trifluoromethyl trimethylsilane, tetrabutylammonium fluoride and N, N-dimethylformamide; d is concentrated hydrochloric acid (or p-toluenesulfonic acid, trifluoroacetic acid) and methanol; e is di-tert-butyl dicarbonate, water-soluble carbonate and tetrahydrofuran-water; f is Dess-Martin reagent and dichloromethane; g is toluene (or tetrahydrofuran), and refluxing is carried out; h is lithium aluminum hydride and tetrahydrofuran (or toluene); i is hydrochloric acid (or trifluoroacetic acid, p-toluenesulfonic acid) and dichloromethane; j is a condensing agent and dichloromethane.
  9. 9. Use of a derivative of Λ/- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-but-2-yl ] -phenylalaninol according to any one of claims 1 to 8, for the preparation of a medicament for the treatment of viral infections.
  10. 10. Use of a derivative of Λ/- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-but-2-yl ] -phenylalaninol according to claim 9, for the preparation of a medicament for the treatment of viral infections, characterized in that: the N- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-butyl-2-yl ] -phenylalaninol derivative is used as an active ingredient, and one or more pharmaceutically acceptable carriers or excipients are added to prepare the pharmaceutical preparation for treating viral infection.
  11. 11. Use of a derivative of Λ/- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-but-2-yl ] -phenylalaninol according to claim 10, for the preparation of a medicament for the treatment of viral infections, characterized in that: the pharmaceutical preparation is a clinically acceptable oral preparation, injection preparation or external preparation.
  12. 12. Use of a derivative of Λ/- [ 4-phenyl-3- (benzoylamino) -1,1, 1-trifluoro-but-2-yl ] -phenylalaninol according to claim 9, for the preparation of a medicament for the treatment of viral infections, characterized in that: the antiviral infection medicine is anti-hepatitis B virus medicine or anti-human immunodeficiency virus medicine.
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