WO2013071715A1 - 组蛋白去乙酰化酶抑制剂及其合成方法和制药用途 - Google Patents
组蛋白去乙酰化酶抑制剂及其合成方法和制药用途 Download PDFInfo
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- WO2013071715A1 WO2013071715A1 PCT/CN2012/071515 CN2012071515W WO2013071715A1 WO 2013071715 A1 WO2013071715 A1 WO 2013071715A1 CN 2012071515 W CN2012071515 W CN 2012071515W WO 2013071715 A1 WO2013071715 A1 WO 2013071715A1
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- C07F7/1804—Compounds having Si-O-C linkages
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/06—Tripeptides
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- Histone deacetylase inhibitor synthesis method thereof and pharmaceutical use
- the present invention is in the field of medicinal chemistry, and in particular relates to a class of histone deacetylase inhibitors, as well as synthetic methods and pharmaceutical uses of these compounds.
- Histone deacetylases are a group of organisms that regulate cell chromatin levels, by inducing histone deacetylation, including chromatin recombination, transcriptional activation or inhibition, cell cycle, cell differentiation, and apoptosis. The enzyme of the effect, especially the regulation of transcriptional expression of the gene after activation of the cell.
- Histone deacetylase inhibitors are a class of compounds that inhibit the activity of HDACs.
- Histone acetylation plays a very important role in the DNA transcription, replication and repair of chromosomes.
- Histone deacetylase inhibitors have been used as mood stabilizers and anti-epileptic drugs in the past.
- attention has been paid to the targeted therapeutic effects of histone deacetylase inhibitors in neurodegenerative diseases.
- Histone acetylation and deacetylation of chromatin is one of the key aspects regulating gene expression, and abnormal gene expression is the molecular biological basis for tumors and some genetic and metabolic diseases.
- the degree of histone acetylation is coordinated by histone acetylase (HAT) and histone deacetylase (HDAC).
- HDAC inhibitors increase the level of chromatin histone acetylation, thus leading to the activation of specific genes, which in turn leads to terminal differentiation of cells or apoptosis of cancer cells. Therefore, HDAC has become one of the most popular targets in the development of cancer chemotherapy drugs.
- Histone deacetylases are currently known to have 18 different subtypes, which are classified into 4 categories according to their germline: I (HDAC1, 2, 3, 8), II (HDAC4, 5, 6, 7, 9, 10 ), (SIRT1-SIRT7) and IV (HDAC11).
- I, II and IV are classical families and are Zn 2+ -dependent HDAC.
- the vast majority of HDAC inhibitors currently in clinical research are capable of inhibiting multiple subtypes of HDAC, which are often part of the Zn 2+ -dependent HDAC family.
- Histone deacetylase inhibitors can inhibit the activity of HDAC in cells, increase the degree of acetylation of intracellular histones, increase the expression of genes such as P 2J and p53, inhibit the proliferation of tumor cells, induce differentiation and apoptosis.
- Histone deacetylase inhibitors generally include a zinc ion binding region, a linking region and a surface recognition region. The direct action of the inhibitor with zinc ions is necessary to produce inhibitory activity.
- HDAC inhibitors mainly include the following four categories: (1) short-chain fatty acids such as butyric acid, phenylbutyric acid and its salts; (2) hydroxamic acids, which are the most widely studied HDAC inhibitors to date.
- HAHA suberoylanilide hydroxamic acid
- TSA trichostatin A
- cyclotetrapeptides cyclic peptides are the most complex class of inhibitors
- the amino acid macrocycle in the molecule of the cyclic peptide inhibitor acts as a hydrophobic surface recognition region, the alkyl chain serves as a linking region, and the alkyl chain end is linked to a zinc ion binding group such as trapoxin, HC-toxon, Apicidin, FK228 and Largazole et al;
- benzamides Such compounds are less active than typical hydroxamic acids and cyclic peptides, but have higher selectivity for class I HDACs.
- MS-275, CI-994 selectivity for class I HDACs.
- SAHA suberoylanilide hydroxamic acid SAHA
- vorinostat Zaolinza
- CTCL metastatic skin T-cell lymphoma
- FK228 (romidepsin) ⁇ bicyclic tetrapeptide isolated from Chrombacterium violaceum ⁇ broth medium.
- FK228 has a unique bicyclic structure consisting of 4 amino acid residues (L-Val, L-2-amino-2-butylenoic acid, D-Cys, D-Val) and (3S, 4R-3-hydroxy-7- Mercapto -4- heptenoic acid) forms a bicyclic lactone structure through a disulfide bond. Its selectivity for HDAC1 and HDAC2 is similar. Computer simulations show that the thiol group of FK228 can bind to Zn 2+ through a water molecule.
- the present invention provides a histone deacetylase inhibitor of a cyclic peptide, which solves the problems of inaccurate curative effects and large toxic side effects of existing drugs.
- the present invention also provides a method for preparing a histone deacetylase inhibitor of the cyclic peptide, and a pharmaceutical use.
- the present invention provides a cyclic peptide compound having a chemical structure represented by the general formula I, and a pharmaceutically acceptable salt, isomer, racemate, prodrug or solvate thereof:
- the Ri group is hydrogen, - 12 alkyl, -CH 2 -0- ( -12 alkyl), -CH2-NH- ( -12 alkyl), -CH 2 -S- ( -12 alkyl), C 6 - 12 aryl, heteroaryl, -CH 2 -(C 6 - 12 aryl) or -CH 2 -heteroaryl; the above C 6 - 12 aryl, heteroaryl, -CH 2 -C 6 - 12 aryl, -CH 2 -heteroaryl, may contain one or more substituents, and the substituent may be halogen, amino, hydroxy, nitro, cyano, -12 alkyl , 12 alkoxy, amino- 12 alkyl, acyl, acyloxy, thio- 12 alkyl, carboxy or phenyl;
- R 2 and R 3 groups are independently selected from hydrogen, _ 12 alkyl, -0- (d_ 12 alkyl), -NH- (_ 12 alkyl), -S- (Ci_i2-alkyl), C 6 - 12 aryl or heteroaryl;
- R4 groups are hydrogen, _ 12 alkyl, -0- (d_ 12 alkyl), -NH- (_ 12 alkyl), -S- (d_ 12 alkyl), C 6 -i2 aryl or heteroaryl base;
- the R 5 group is hydrogen, -12 alkyl, C 3 -12 cycloalkyl, -0-( -12 alkyl), -NH- ( -12 alkyl) or -S- (Ci_i2);
- R 6 , R 7 , R 8 groups are independently selected from the group consisting of hydrogen, 12 alkyl or t-butoxycarbonyl;
- X is a benzene ring which may have one or more substituents, and the substituent may be halogen, amino, hydroxy, nitro, cyano, - 12 alkyl, - 12 alkoxy, amino - 12 alkyl , acyl, acyloxy, thio- 12 alkyl, carboxy, phenyl or heterocyclic substituent.
- R 2 is H
- R4 is hydrogen or -12 alkyl.
- R 3 is hydrogen or -12 alkyl
- R 5 is hydrogen, - 12 alkyl or C 3 - 12 cycloalkyl
- R 6 , R 7 , R 8 groups are independently selected from hydrogen.
- R 3 is a methyl group
- R 6 , R 7 , and R 8 groups are all hydrogen; ⁇
- the invention also provides a process for the preparation of a cyclic peptide compound of formula I, which process comprises the steps of:
- Ri R 2 , R 3 , R 4 , R 5 R 6 R 7 , R 8 are as defined in claim 1;
- P is an amino protecting group.
- the condensing agent may be DCC, EDC, HATU, HOAt, HOBt, DEAD, HBTU or PyBOP;
- the organic base is selected from the group consisting of imidazole, triethylamine, diisopropylethylamine, piperidine, and Methylpyridine, LiHMDS, NaHMDS, KHMDS, N-methylmorpholine, DABCO or pyridine;
- the amino protecting group P is selected from Boc, Cbz, Bn, Fmoc, Alloc, Tos, Tfa, Trt or Bn.
- the invention also provides a process for the preparation of a compound of formula II, the process comprising the steps of:
- the necessary organic solvent may be selected from the group consisting of dichloromethane, tetrahydrofuran ( ), dimethylformamide engraving, ethylene glycol dimethyl ether, dichloroethane, dimethyl phthalate engraving, Methanol, ethanol, oil Ether, n-hexane or diethyl ether;
- the essential inorganic base may be selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, calcium carbonate;
- the necessary acid may be selected from trifluoroacetic acid, hydrochloric acid, sulfuric acid or nitric acid.
- the oxidizing agent can be
- the present invention also provides the use of the above compound for the preparation of a medicament for preventing or treating a mammalian disease associated with dysregulation of histone acetylase. key
- mammalian diseases associated with dysregulation of a histone acetylase include cancer, neurodegenerative diseases, malaria and diabetes. key
- mammalian diseases associated with dysregulation of a histone acetylase include lymphoma, lung cancer, gastric cancer, pancreatic cancer, breast cancer, prostate cancer, leukemia, cervical cancer, and colon cancer. key
- alkyl refers to a straight or branched chain
- alkyl refers to a saturated aliphatic hydrocarbon group of one carbon atom, including straight chain and branched chain.
- 33 ⁇ 4 yard group means that the group is an alkyl group.
- the number of carbon atoms in the carbon chain of the alkyl group is between 3 ⁇ 4t. It should be noted that, when the number of carbon atoms is not particularly limited, it means only the number of carbon atoms of the alkyl moiety specified therein, and does not include the number of carbon atoms on the substituent of the alkyl group. key
- pharmaceutically acceptable salt refers to a salt which, within the scope of sound medical judgment, is suitable for use in contact with mammalian, particularly human, tissues without undue toxicity, irritation, allergic response, etc., and which is commensurate with the reasonable benefit.
- Pharmaceutically acceptable salts such as amines, carboxylic acids and other types of compounds are well known in the art. key
- racemate refers to an equimolar mixture of an optically active chiral molecule and its enantiomer. It is composed of the same amount of molecules with opposite optical rotation and the same optical rotation. The optical rotation is due to these. The interaction between molecules cancels each other out and thus does not rotate. key
- solvate means a mixture of a compound and a solvent, for example, a crystal is a solvate.
- prodrug refers to a compound which is rapidly converted in vivo by hydrolysis in blood to produce a parent compound having the above formula. key
- the conventional post-treatment method is: after the reaction is completed, an appropriate amount of water is added to the reaction liquid, the organic phase and the aqueous phase are separated, and the organic phase is combined; if necessary, 5% HC1 is used in sequence.
- the solution and/or saturated NaSO 4 are dried, filtered and dried under reduced pressure to give a crude product which is purified by column chromatography to give the final product.
- the starting material (5.43 g, 15.0 mmol) was dissolved in 75 mL of tetrahydrofuran. Slowly add KOH (0.84 g, under ice bath)
- the starting material (9.2 g, 20.5 mmol) was dissolved in 50 mL of 50% methanol/dichloromethane solution, cooled to -10 ° C, and 0.96 g of camphorsulfonic acid was dissolved in 0.5 mL of methanol and added to the reaction flask. Hold at -10 °C and stir for 8 hours. The reaction was quenched with EtOAc (EtOAc) (EtOAc). 10 : 1 ), 5.5 g of a colorless oil was obtained, yield 82%.
- EtOAc EtOAc
- the starting material (3.5 g, 10.5 mmol) and tetrazolium compound (4.02 g, 10.5 mmol) were dissolved in 50 mL of tetrahydrofuran, cooled to -78 °C, and slowly added 2M NaHMDS in THF (5.4 mL). , 10.8 mmol), 1 hour, quenched with saturated aqueous ammonium chloride, EtOAc (EtOAc) EtOAc (EtOAc) The oil was 3.68 g, and the yield was 72%.
- the starting material (0.839 g, 1.94 mmol) was dissolved in 50% methanol/dichloromethane (10 mL), cooled to 0 ° C, and 0.455 g of camphorsulfonic acid was dissolved in 1 mL of methanol and added to the reaction flask, stirred. overnight. The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. Ether) gave 0.481 g of colorless oil, yield 78%.
- the starting material (0.61 g, 1.2 mmol) was dissolved in 50% methanol/dichloromethane (7 mL), cooled to 0 ° C, and 0.3 g of camphorsulfonic acid was dissolved in 1 mL of methanol and added to the reaction flask. Stir overnight. The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. ), 0.412 g of a colorless oil was obtained, yield 87%.
- the compound obtained in the previous step (0.212 g, 0.35 mmol) was dissolved in anhydrous dichloromethane, and the compound (0.145 g, 0.42 mmol), HATU (0.2 g, 0.53) was sequentially added at 0 °C. Methyl), HOAt (0.073 g, 0.53 mmol), DIPEA (0.18 ml, 1.05 mmol).
- the compound obtained in the previous step (0.412 g, 0.57 mmol) was dissolved in anhydrous dichloromethane.
- the compound (0.352 g, 0.69 mmol), HATU (0.326 g, 0.86) was sequentially added at 0 °C. Methyl), HOAt (0.117 g, 0.86 mmol), DIPEA (0.31 ml, 1.71 mmol).
- Successively washed with dilute hydrochloric acid, saturated NaCl, dried over anhydrous Na 2 S0 4, filtered, and dried under reduced pressure after spin column chromatography (petroleum ether: ethyl acetate 4: 1).
- a solid of 0.335 g was obtained in a yield of 70%.
- the compound obtained in the previous step (0.412 g, 0.585 mmol) was dissolved in anhydrous dichloromethane.
- the compound (0485 g, 0.72 mmol), HATU (0.34 g, 0.9 mmol) was sequentially added at 0 °C. ), HOAt (0.122 g, 0.9 mmol), DIPEA (0.33 ml, 1.78 mmol).
- Successively washed with dilute hydrochloric acid, saturated NaCl, dried over anhydrous Na 2 S0 4, filtered, and dried under reduced pressure after spin column chromatography (petroleum ether: ethyl acetate 4: 1).
- a solid of 0.392 g was obtained in a yield of 82%.
- NHBoc starting material (1.45 g, 2 mmol) was dissolved in dichloromethane.
- a colorless liquid of 0.776 g was obtained in a yield of 78%.
- the compound obtained in the previous step (0.283 g, 0.57 mmol) was dissolved in anhydrous dichloromethane.
- the compound (0.214 g, 0.69 mmol), HATU (0.325 g, 0.86) was sequentially added at 0 °C. Eth), HOAt (0.117 g, 0.86 mmol), DIPEA (0.3 ml, 1.71 mmol).
- Successively washed with dilute hydrochloric acid, saturated NaCl, dried over anhydrous Na 2 S0 4, filtered, and dried under reduced pressure after spin column chromatography (petroleum ether: ethyl acetate 4: 1). Obtained 0.377 g of solid, 80% yield
- the compound obtained in the previous step (0.24 g, 0.485 mmol) was dissolved in anhydrous dichloromethane.
- the compound (0.212 g, 0.59 mmol), HATU (0.276 g, 0.731) was sequentially added at 0 °C. Mmmol), HOAt (0.1g, 0.731mmol), DIPEA (0.255 ml, 1.45 mmol) was stirred at room temperature overnight.
- the compound obtained in the previous step (0.283 g, 0.57 mmol) was dissolved in anhydrous dichloromethane.
- the compound (0.453 g, 0.69 mmol), HATU (0.325 g, 0.86) was sequentially added at 0 °C. Eth), HOAt (0.117 g, 0.86 mmol), DIPEA (0.3 ml, 1.71 mmol).
- Successively washed with dilute hydrochloric acid, saturated NaCl, dried over anhydrous Na 2 S0 4, filtered, and dried under reduced pressure after spin column chromatography (petroleum ether: ethyl acetate 4: 1) to give a solid 0.298 g, 53% yield .
- the compound obtained in the previous step (0.626 g, 1.5 mmol) was dissolved in anhydrous dichloromethane.
- the compound (1.62 g, 1.56 mmol), HATU (0.855 g, 2.26) was sequentially added at 0 °C. Methyl), HOAt (0.117 g, 2.26 mmol), DIPEA (0.79 ml, 4.5 mmol).
- Successively washed with dilute hydrochloric acid, saturated NaCl, dried over anhydrous Na 2 S0 4, filtered, and dried under reduced pressure after spin column chromatography (petroleum ether: ethyl acetate 4: 1) to give 1.05 g of a solid, in 91% yield .
- the crude product of the previous step was dissolved in 50 ml of anhydrous DMF, and slowly dropped into HATU (0.78 g, 2.05 mmol), HOAt (0.28 g, 2.05 mmol), DIPEA (0.7 ml, 4.1 mmol) of anhydrous DMF The solution was stirred at 30 ° C for 3 days. The reaction solution The system concentration was 0.001 mol/L.
- the crude product of the previous step was dissolved in 40 ml of anhydrous DMF, and slowly dropped into HATU (0.665 g, 1.75 mmol), HOAt (0.238 g, 1.75 mmol), DIPEA (0.58 ml, 3.5 mmol) of anhydrous DMF. The solution was stirred at 30 ° C for 3 days. The concentration of the reaction liquid system was 0.001 mol/L.
- the crude product from the previous step was dissolved in 40 ml of anhydrous DMF, and slowly dropped into HATU (0.437 g, 1.15 mmol), HOAt (0.157 g, 1.15 mmol), DIPEA (0.38 ml, 2.3 mmol) of anhydrous DMF The solution was stirred at 30 ° C for 3 days. The concentration of the reaction liquid system was 0.001 mol/L.
- the crude product of the previous step was dissolved in 40 ml of anhydrous DMF, and slowly dropped into HATU (0.57 g, 1.5 mmol), HOAt (0.204 g, 1.5 mmol), DIPEA (0.5 ml, 3 mmol) in anhydrous DMF. The mixture was stirred at 30 ° C for 3 days. The concentration of the reaction liquid system was 0.001 mol/L.
- the crude product from the previous step was dissolved in 30 ml of anhydrous DMF, and slowly dropped into HATU (0.329 g, 0.865 mmol), HOAt (0.118 g, 0.865 mmol), DIPEA (0.29 ml, 1.73 mmol) in anhydrous DMF. In solution. Stir at 30 ° C for 3 days. The concentration of the reaction liquid system was 0.001 mol/L.
- the crude product from the previous step was dissolved in 40 ml of anhydrous DMF, and slowly dropped into HATU (0.494 g, 1.3 mmol), HOAt (0.177 g, 1.3 mmol), DIPEA (0.43 ml, 2.6 mmol) of anhydrous DMF In solution. Stir at 30 ° C for 3 days. The concentration of the reaction liquid system was 0.001 mol/L.
- the crude product from the previous step was dissolved in 40 ml of anhydrous DMF, and slowly dropped into HATU (0.333 g, 0.875 mmol), HOAt (0.119 g, 0.875 mmol), DIPEA (0.3 ml, 1.75 mmol) in anhydrous DMF. In the solution, stir at 30 ° C for 3 days. The concentration of the reaction liquid system was 0.001 mol/L.
- Example 41 155 mg (0.198 mmol, leq) i# of the starting material obtained in Example 41 was added to 5 ml of anhydrous dichloromethane, and 1 ml of trifluoroacetic acid was added thereto, and the mixture was stirred at room temperature for 24 hours, and then the solvent and TFA were removed under reduced pressure, and then 100 ml.
- Anhydrous DMF was slowly added dropwise to a solution of 150 mg (0.396 mmol, 2 eq) of HATU and 54 mg (0.396 mmol, 2 eq) of HOAT and 0.2 ml (1.188 mmol, 6 eq) of DIPEA in DMF (100 ml).
- the starting material obtained in Example 42 was obtained by dissolving 110 mg (0.136 mmol, leq) i# in 5 ml of anhydrous dichloromethane, 1 ml of trifluoroacetic acid, stirring at room temperature for 24 hours, and then removing the solvent and TFA under reduced pressure, using 70 ml.
- Anhydrous DMF was slowly added dropwise to a solution of 207 mg (0.544 mmol, 2 eq) of HATU and 74 mg (0.544 mmol, 4 eq) of HOAT and 0.18 ml (1.088 mmol, 8 eq) of DIPEA in DMF (70 ml).
- EtOAc EtOAc
- Example 45 190 mg (0.226 mmol, leq) i# of the starting material obtained in Example 45 was added to 5 ml of anhydrous dichloromethane, and 1 ml of trifluoroacetic acid was added thereto, and the mixture was stirred at room temperature for 24 hours, and then the solvent and TFA were removed under reduced pressure, and then 115 ml.
- Anhydrous DMF was slowly added dropwise to a solution of 344 mg (0.904 mmol, 4 eq) of HATU and 123 mg (0.904 mmol, 4 eq) of HOAT and 0.32 ml (1.808 mmol, 8 eq) of DIPEA in DMF (115 ml).
- the starting material (56 mg, 0.068 mmol, leq) was dissolved in 5 ml of anhydrous dichloromethane, and 1 ml of trifluoroacetic acid was added thereto, and the mixture was stirred at room temperature for 24 hours, and then the solvent and the TFA were evaporated under reduced pressure.
- Water DMF slowly added dropwise to a solution of 103 mg (0.072 mmol, 4 eq) of HATU and 37 mg (0.072 mmol, 4 eq) of HOAT and 0.1 ml (0.544 mmol, 8 eq) of DIPEA in DMF (115 ml). After that, the mixture was diluted with EtOAc (EtOAc)EtOAc. -2, yield 10%.
- the crude product of the previous step was dissolved in 50 ml of anhydrous DMF, and slowly dropped into HATU (0.78 g, 2.05 mmol), HOAt (0.28 g, 2.05 mmol), DIPEA (0.7 ml, 4.1 mmol) of anhydrous DMF In solution. Stir at 30 ° C for 3 days. The concentration of the reaction liquid system was 0.001 mol/L.
- the crude product of the previous step was dissolved in 50 ml of anhydrous DMF, and slowly dropped into HATU (0.588 g, 2.5 mmol). HOAt (0.34 g, 2.5 mmol), DIPEA (0.87 mL, 5 mmol) in anhydrous DMF. Stir at 30 ° C for 3 days. The concentration of the reaction liquid system was 0.001 mol/L.
- the crude product of the previous step was dissolved in 50 ml of dry DMF under argon, and slowly, dropwise, was applied to HATU (0.706 g, 3 mmol), HOAt (0.408 g, 3 mmol), DIPEA (1.05 ml, 6 mmol) in anhydrous DMF. Stir at 30 ° C for 3 days. The concentration of the reaction liquid system was 0.001 mol/L.
- the crude product of the previous step was dissolved in 50 ml of anhydrous DMF, and slowly dropped into HATU (0.588 g, 2.5 mmol), HOAt (0.34 g, 2.5 mmol), DIPEA (0.87 ml, 5 mmol) in anhydrous DMF. in. Stir at 30 ° C for 3 days.
- the concentration of the reaction liquid system was 0.001 mol/L.
- the crude product of the previous step was dissolved in 50 ml of anhydrous DMF, and slowly dropped into HATU (0.588 g, 2.5 mmol), HOAt (0.34 g, 2.5 mmol), DIPEA (0.87 ml, 5 mmol) in anhydrous DMF. in. Stir at 30 ° C for 3 days.
- the concentration of the reaction liquid system was 0.001 mol/L.
- the crude product of the previous step was dissolved in 50 ml of anhydrous DMF, and slowly dropped into HATU (0.588 g, 2.5 mmol), HOAt (0.34 g, 2.5 mmol), DIPEA (0.87 ml, 5 mmol) in anhydrous DMF. in. Stir at 30 ° C for 3 days.
- the concentration of the reaction liquid system was 0.001 mol/L.
- the crude product of the previous step was dissolved in 50 ml of anhydrous DMF, and slowly dropped into HATU (0.588 g, 2.5 mmol). HOAt (0.34 g, 2.5 mmol), DIPEA (0.87 mL, 5 mmol) in anhydrous DMF. Stir at 30 ° C for 3 days. The concentration of the reaction liquid system was 0.001 mol/L.
- the crude product of the previous step was dissolved in 50 ml of anhydrous DMF, and slowly dropped into HATU (0.588 g, 2.5 mmol), HOAt (0.34 g, 2.5 mmol), DIPEA (0.87 ml, 5 mmol) in anhydrous DMF. in. Stir at 30 ° C for 3 days.
- the concentration of the reaction liquid system was 0.001 mol/L.
- the crude product of the previous step was dissolved in 50 ml of anhydrous DMF, and slowly dropped into HATU (0.588 g, 2.5 mmol), HOAt (0.34 g, 2.5 mmol), DIPEA (0.87 ml, 5 mmol) in anhydrous DMF. in. Stir at 30 ° C for 3 days.
- the concentration of the reaction liquid system was 0.001 mol/L.
- the crude product of the previous step was dissolved in 50 ml of anhydrous DMF, and slowly dropped into HATU (0.588 g, 2.5 mmol), HOAt (0.34 g, 2.5 mmol), DIPEA (0.87 ml, 5 mmol) in anhydrous DMF. in. Stir at 30 ° C for 3 days.
- the reaction solution The system concentration was 0.001 mol/L.
- the crude product of the previous step was dissolved in 50 ml of anhydrous DMF, and slowly dropped into HATU (0.588 g, 2.5 mmol), HOAt (0.34 g, 2.5 mmol), DIPEA (0.87 ml, 5 mmol) in anhydrous DMF. in. Stir at 30 ° C for 3 days.
- the concentration of the reaction liquid system was 0.001 mol/L.
- Example 90 Synthesis of a compound of formula 4-3 A solution of the starting material (0.457 g, 0.5 mmol) in m. It was sparged under reduced pressure, and 5 ml of toluene was added and then dried to remove a large amount of trifluoroacetic acid. The crude product is directly fed to the next step.
- the crude product of the previous step was dissolved in 50 ml of anhydrous DMF, and slowly dropped into HATU (0.588 g, 2.5 mmol), HOAt (0.34 g, 2.5 mmol), DIPEA (0.87 ml, 5 mmol) in anhydrous DMF. in. Stir at 30 ° C for 3 days.
- the concentration of the reaction liquid system was 0.001 mol/L.
- the crude product of the previous step was dissolved in 50 ml of anhydrous DMF, and slowly dropped into HATU (0.588 g, 2.5 mmol), HOAt (0.34 g, 2.5 mmol), DIPEA (0.87 ml, 5 mmol) in anhydrous DMF. in. Stir at 30 ° C for 3 days.
- the concentration of the reaction liquid system was 0.001 mol/L.
- the crude product of the previous step was dissolved in 50 ml of anhydrous DMF, and slowly dropped into HATU (0.588 g, 2.5 mmol), HOAt (0.34 g, 2.5 mmol), DIPEA (0.87 ml, 5 mmol) in anhydrous DMF. in. Stir at 30 ° C for 3 days.
- the concentration of the reaction liquid system was 0.001 mol/L.
- the crude product of the previous step was dissolved in 50 ml of anhydrous DMF, and slowly dropped into HATU (0.588 g, 2.5 mmol), HOAt (0.34 g, 2.5 mmol), DIPEA (0.87 ml, 5 mmol) in anhydrous DMF. in. Stir at 30 ° C for 3 days.
- the concentration of the reaction liquid system was 0.001 mol/L.
- the crude product of the previous step was dissolved in 50 ml of anhydrous DMF, and slowly dropped into HATU (0.588 g, 2.5 mmol), HOAt (0.34 g, 2.5 mmol), DIPEA (0.87 ml, 5 mmol) in anhydrous DMF. in. Stir at 30 ° C for 3 days.
- the concentration of the reaction liquid system was 0.001 mol/L.
- the crude product of the previous step was dissolved in 50 ml of anhydrous DMF, and slowly dropped into HATU (0.78 g, 2.05 mmol), HOAt (0.28 g, 2.05 mmol), DIPEA (0.7 ml, 4.1 mmol) of anhydrous DMF In solution. Stir at 30 ° C for 3 days. The concentration of the reaction liquid system was 0.001 mol/L.
- Example 65 A solution of the compound of the formula 1-3 (0.26 g, 0.43 mmol) in acetonitrile (50 ml) obtained in Example 65 was added aqueous ammonia (28.9%, 5 ml). The reaction was carried out for 12 hours at room temperature. After completion of the reaction, the mixture was evaporated. mjjjjjjjj
- the biochemical activity of a compound is determined based on its degree of inhibition of the deacetylation of the HDAC enzyme. After incubation with a fluorescently labeled substrate containing an acetylated lysine side chain and HDAC enzyme, the fluorescent substrate is deacetylated. After the deacetylated fluorescently labeled substrate is cleaved by the enzyme, a fluorescent substance is released, which emits light at 460 nm under excitation of 360 nm light.
- the substrate of HDAC is diluted to 200M with reaction buffer (reaction concentration is 20M), the HDAC enzyme is diluted to the appropriate concentration, the compounds to be tested are added at different concentrations, reacted at 37 ° C for 30 minutes, and then added to the same volume. 2 times the concentration of substrate development developer (developer), incubate for 15 minutes at room temperature, and finally read the reading with a microplate reader, the excitation light is 360 nm, the emission light is 460 nm, and the data is processed by Prime 4 software.
- Commercially available Zolinza (SAHA) was used as a control.
- IC 5Q refers to the inhibitor concentration (50% inhibitory concentration) when it is inhibited by half.
- the principle of the MTT method is that yellow thiazolyl can enter the cell through the cell membrane, and the amber dehydrogenase in the living cell mitochondria can reduce the exogenous MTT to the blue-purple needle-like Formazan crystal which is hardly soluble in water and deposited on the cell.
- the crystal can be dissolved by dimethyl sulfoxide (DMSO), and its light absorption value is detected by an enzyme-linked immunosorbent detector at a wavelength of 490 nm / 570 nm, which can indirectly reflect the number of cells.
- DMSO dimethyl sulfoxide
- the cancer cell lines used were Hela (human cervical cancer cells), MCF-7 (human breast cancer cells), and shifted to BGC-823.
- Human gastric cancer cells A549 (human lung cancer cells), HT1080 (human fibrosarcoma cells), A431 (human epidermal squamous cell carcinoma cells), HUVEC (human umbilical vein endothelial cells), DU145 (human prostate cancer cells), K562 (human leukemia cells), U937 (human leukemia cells), Pac-1 (human pancreatic cancer cells), MOLT-4 (human acute lymphoblastic leukemia cells); cultured in DMEM + 10% FBS medium or 1640+, respectively 10% FBS culture.
- Negative control group 190 ⁇ 1 cell suspension +10 ⁇ 1 2% DMSO (final concentration of DMSO 0.1%)
- Positive control group 190 ⁇ 1 cell suspension +10 ⁇ 1 different concentrations of compound
- the positive control (SAHA) has an activity that significantly inhibits the growth of the listed tumor cells.
- Example 100 Compound 1-3 inhibits growth of human colon cancer HCT-116 nude mice subcutaneously transplanted tumor
- Compounds 1-3 were powders, and three dose groups were set: 20 mg/kg, 10 mg/kg, and 5 mg/kg; commercially available Zolinza (SAHA) was used as a positive control; the solvent was isopropanol and absolute ethanol (in a 1:1 volume) The mixture was mixed with a solvent and physiological saline in a ratio of 1:1 to prepare a solution, and the solution was dissolved in a ratio of 1:1 with physiological saline to prepare a solution as a negative control.
- SAHA commercially available Zolinza
- the subjects were BALB/cA nude mice, female, 4-5 weeks old, weighing 16 ⁇ 2 g, purchased from Shanghai Institute of Materia Medica, Chinese Academy of Sciences (production certificate number: SCXK (Shanghai) 2008-0017); each group Number of animals: 12 in the negative control group and 6 in the drug-administered group.
- the human colon cancer HCT-116 cell line was purchased from the cell bank of the Chinese Academy of Sciences. The cell line was used to inoculate the right axilla of the nude mice. The inoculation amount was 5 ⁇ 10 6 /piece, and the transplanted tumor was formed and then transmitted in nude mice. Used after 2 generations.
- the tumor tissue in the vigorous growth stage was cut into 1.5 mm 3 and inoculated subcutaneously in the right axilla of nude mice under aseptic conditions.
- the diameter of the transplanted tumor was measured with a vernier caliper in a nude mouse subcutaneous xenograft, and the animals were randomly divided into groups after the tumor was grown to 100-200 mm 3 .
- 1-3 Compounds 20mg/kg, 10mg/kg and 5mg/kg, administered intravenously three times a week for three weeks; positive control drug SAHA 50mg/kg, once a day intravenously for 3 weeks.
- the diameter of the transplanted tumor was measured twice a week during the entire experiment, and the body weight of the mice was weighed.
- Example 100 Compounds 1-4, 1-6, 1-7, and 1-8 were each provided at a dose of 20 mg/kg.
- the tumor inhibition rate was calculated according to the method described in Example 100; the experimental results are shown in Table 2. ⁇ .
- the experimental method was the same as that described in Example 100, and the cells inoculated were respectively shown in the following table, and each of the tumor-bearing mice was administered with a solvent, SAHA (50 mg/kg), Compound 1-3 (20 mg/kg), and a compound. 1-6 (20 mg/kg), Compound 1-8 (20 mg/kg), the tumor inhibition rate was calculated according to the method described in Example 100; the results are shown in Table 3.1.
- Compound 1-8 (20 mg/kg) 68.07
- compounds 1-3, 1-6, 1-8 against human lymphoma cell Ramos, human blood acute monocytic leukemia U937, human lung cancer cell NCI- H1975, human gastric adenocarcinoma cell line BGC-823, human melanoma cell A875 nude mouse subcutaneous xenograft tumor growth has a good inhibitory effect, except compound 1-3, compound 1-8 applied to human lung cancer cells NCI-H1975
- the tumor rate was slightly smaller than SAHA, and the tumor inhibition rate of other groups was greater than that of SAHA group.
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Abstract
本发明包括式I所示的组蛋白去乙酰化酶抑制剂,其中R1~R8如说明书中所定义;本发明还包括这些化合物的合成方法,以及这些化合物在制备预防或者治疗与组蛋白去乙酰化酶调节异常有关的哺乳动物疾病药物中的用途。
Description
组蛋白去乙酰化酶抑制剂及其合成方法和制药用途 技术领域
本发明属于药物化学领域, 具体地涉及一类组蛋白去乙酰化酶抑制剂, 以及这些化合物 的合成方法和制药用途。
背景技术
组蛋白去乙酰化酶 (HDACs)是一组在细胞染色质水平、 通过诱导组蛋白去乙酰化来 调控包括染色质重组、 转录活化或抑制、 细胞周期、 细胞分化及细胞凋亡等一系列生物 学效应的酶, 特别是与细胞活化后的基因转录表达调控有关。 组蛋白去乙酰化酶抑制剂 (HDAC inhibitor, HDACIs)则是一类抑制 HDACs活性的化合物。
组蛋白乙酰化作用在染色体的 DNA转录, 复制和修复过程中起着非常重要的作用。 组 蛋白去乙酰化酶抑制剂过去一直作为情绪稳定剂和抗癫痫药物使用, 近年来, 人们开始关注 组蛋白去乙酰化酶抑制剂在神经变性疾病的靶向治疗作用。 染色质的组蛋白乙酰化和去乙酰 化是调节基因表达的关键环节之一, 而异常的基因表达是肿瘤及一些遗传和代谢疾病发生的 分子生物学基础。 组蛋白的乙酰化程度, 有组蛋白乙酰化酶 (HAT) 和组蛋白去乙酰化酶 (HDAC) 协调控制的。 实验证明, HDAC抑制剂会使染色质组蛋白乙酰化水平提高, 因此 导致特定基因激活表达, 相应的导致细胞的末端分化或癌细胞的凋亡。 因此, HDAC已成为 目前肿瘤化疗药物研发领域最热门的靶标之一。
目前已知组蛋白去乙酰化酶有 18个不同的亚型, 按种系分为 4大类: I ( HDAC1、 2、 3、 8 )、 II (HDAC4、 5、 6、 7、 9、 10)、 ( SIRT1-SIRT7 )和 IV( HDAC11)。 其中 I、 II、 IV为经典家族, 是 Zn2+依赖性的 HDAC。 目前临床研究的绝大多数 HDAC抑制剂能够抑制 HDAC 的多个亚型, 这些亚型往往属于 Zn2+依赖性的 HDAC家族。
组蛋白去乙酰化酶抑制剂可以抑制细胞内 HDAC 的活性,使细胞内组蛋白的乙酰化程度 增加, 提高 P2J、 p53 等基因的表达, 进而抑制肿瘤细胞的增殖, 诱导其分化、 凋亡。 组蛋 白去乙酰化酶抑制剂一般包括锌离子结合区, 连接区和表面识别区三个部分。 抑制剂与锌离 子的直接作用是产生抑制活性所必须的。 HDAC抑制剂主要包括以下四类: (1 )短链脂肪酸, 如丁酸, 苯丁酸及其盐类化合物; (2)羟肟酸类, 这是迄今研究最广泛的一类 HDAC抑制剂, 如辛二酰苯胺异羟肟酸(suberoylanilide hydroxamic acid SAHA)和曲古抑菌素 A (trichostatin A, TSA); ( 3 ) 环四肽类, 环肽类化合物是结构最为复杂的一类抑制剂, 环肽类抑制剂的分 子中氨基酸大环作为疏水的表面识别区, 烷基链作为连接区, 烷基链末端连接着一个锌离子 结合基团, 如 trapoxin, HC-toxon, Apicidin, FK228和 Largazole等; (4)苯甲酰胺类化合物,
这类化合物的活性比一般的羟肟酸类和环肽类化合物低, 但是对 I类 HDAC具有较高的选择 性。 如 MS-275, CI-994等。 2006年, 美国 FDA批准默克公司的辛二酰苯胺异羟肟酸
( suberoylanilide hydroxamic acid SAHA) 以 vorinostat (Zolinza) 上市, 用于治疗转移性皮 肤 T细胞淋巴瘤 (CTCL), 这是第一个面世的组蛋白去乙酰化酶抑制剂类抗肿瘤药物。
FK228(romidepsin)^从紫色杆菌 (Chrombacterium violaceum)^肉汤培养基中分离得到的 双环四肽。 FK228具有一个独特的双环结构, 由 4个氨基酸残基 (L-Val, L-2-amino-2-butylenoic acid, D-Cys, D-Val)和 (3S,4R-3-hydroxy-7-mercapto -4- heptenoic acid)通过二硫键形成双环内 酯结构。 其对 HDAC1和 HDAC2的选择性相似。 计算机模拟的结果表明, FK228的硫醇基团可 以通过一个水分子与 Zn2+结合。 美国 FDA于 2009年 11月 6日批准环肽 FK228以注射用药物 Istodax (romidepsin) 上市, 也于治疗皮肤 T淋巴细胞瘤 (CTCL), 成为继 Zolinza 后, 第二 个上市的组蛋白去乙酰化酶抑制剂, 其针对慢性淋巴细胞白血病、 急性髓样白血病和其他实 体瘤的研究正处于临床阶段。
由于与组蛋白去乙酰化酶调节异常相关的疾病特别是相关的癌症的发病率高、 预后差, 并且现有的药物的疗效不确切、 毒副作用较大, 因此需要一种新的低毒高效的组蛋白去乙酰 化酶抑制药物, 本发明因此而来。
发明内容
本发明提供一种环肽类的组蛋白去乙酰化酶抑制剂, 用以解决现有药物疗效不确切、 毒 副作用较大的缺陷等问题。本发明还提供该种环肽类的组蛋白去乙酰化酶抑制剂的制备方法, 以及药物用途。
首先,本发明提供了具有通式 I 所示的化学结构的环肽化合物,及其药物上可接受的盐、 异构体、 外消旋体、 前体药物或溶剂合物:
I
其中,
Ri基团为氢, — 12烷基, -CH2-0- ( — 12烷基), -CH2-NH- ( — 12烷基), -CH2-S- ( — 12 烷基), C6— 12芳基, 杂芳基, -CH2- (C6— 12芳基)或 -CH2-杂芳基; 上述的 C6— 12芳基, 杂芳基,
-CH2-C6— 12芳基, -CH2-杂芳基, 可以含有 1个或多个取代基, 其取代基可以是卤素、 氨基、 羟基、 硝基、 氰基、 — 12烷基、 — 12烷氧基、 氨基 — 12烷基、 酰基、 酰氧基、 硫代 — 12烷 基、 羧基或苯基;
R2和 R3基团独立地选自氢, _12烷基, -0- (d_12烷基), -NH- ( _12烷基), -S- (Ci_i2 烷基), C6— 12芳基或杂芳基;
R4基团为氢, _12烷基, -0- (d_12烷基), -NH- ( _12烷基), -S- (d_12烷基), C6-i2 芳基或杂芳基;
R5基团为氢, _12烷基, C3_12环烷基, -0- ( _12烷基), -NH- ( _12烷基) 或 -S- (Ci_i2 院基);
R6, R7, R8基团独立地选自氢, — 12烷基或叔丁氧羰基;
d_12烷基, -O- ( _12烷基), -NH- ( _12烷基), -S- ( _12烷基), C6_12芳基, 杂芳基, 卤素, 氨基, 羟基, 硝基, 氰基或羧基;
或者 X为苯环, 其上可以含有 1个或多个取代基, 取代基可以是卤素、 氨基、 羟基、 硝 基、 氰基、 — 12烷基、 — 12烷氧基、 氨基 — 12烷基、 酰基、 酰氧基、 硫代 — 12烷基、 羧基、 苯基或杂环取代基。
进一步地, 上述的环肽化合物中
R2为 H,
=部分是双键,
R4为氢或 — 12烷基。
再进一步, 上述的环肽化合物中
R3为氢或 — 12烷基;
R5为氢, — 12烷基或 C3— 12环烷基;
R6, R7, R8基团独立地选自氢。
再进一步, 上述的环肽化合物中
R3为甲基;
(1)将式 II化合物、 式 III化合物和有机碱在縮合剂的作用下进行縮合反应, 得到式 IV 化合物; 反应过程如下所示:
(2) 将式 IV化合物、 式 V化合物和有机碱在縮合剂的作用下进行縮合反应, 得到式 VI化合物; 反应过程如下所示:
(3)脱去 VI化合物上的氨基保护基 P,然后在縮合剂和有机碱的作用下分子内关环得到 式 I化合物; 反应过程如下所示:
P为氨基保护基团。
进一步地, 所述的縮合剂可以为 DCC、 EDC、 HATU、 HOAt、 HOBt、 DEAD、 HBTU 或 PyBOP; 所述的有机碱选自咪唑、 三乙胺、 二异丙基乙胺、 哌啶、 二甲基吡啶、 LiHMDS、 NaHMDS、 KHMDS、 N-甲基吗啉、 DABCO或吡啶; 所述的氨基保护基团 P选自 Boc、 Cbz、 Bn、 Fmoc、 Alloc、 Tos、 Tfa、 Trt或 Bn。
本发明还提供制备通式 II化合物的方法, 该方法包括如下步骤:
(2) 化合物 b和樟脑磺酸反应得化合物 c, 再经氧化后得到的醛和化合物 d, 有机碱反 应得到化合物 e; 反应过程如下所示:
OTBSO z OTBS O
TBSO O^/Si、 ^ - HO、人 八
O
b c
(3) 化合物 e和樟脑磺酸反应得到化合物 f, 然后化合物 f、 取代的硫代酸、 三苯基膦和 縮合剂反应得到化合物 g, 化合物 g和樟脑磺酸反应得通式 II化合物;
上述的合成反应过程中, 必要的有机溶剂可以选自二氯甲烷、 四氢呋喃 ( )、 二甲基 甲酰胺雕 、 乙二醇二甲醚、 二氯乙烷、 邻苯二甲酸二甲酯雕 、 甲醇、 乙醇、 石油
醚、 正己烷或乙醚; 必要的无机碱可以选自氢氧化钠、 氢氧化锂、 碳酸钾、 碳酸钠、 碳酸氢 钠、碳酸钙;必要的酸可以选自三氟乙酸、盐酸、硫酸或硝酸。所述的氧化剂可以是
氧化剂、 氧化剂、 间氯过氧苯甲酸、 氯重铬酸吡啶 ( ) 或氯铬酸吡啶 ( )。 键 本发明还提供上述的化合物在制备预防或者治疗与去组蛋白乙酰化酶调节异常有关的哺 乳动物疾病药物中的应用。 键
进一步地, 所述的与去组蛋白乙酰化酶调节异常有关的哺乳动物疾病包括癌症、 神经变 性疾病、 疟疾和糖尿病。 键
更进一步地, 所述的与去组蛋白乙酰化酶调节异常有关的哺乳动物疾病包括淋巴瘤、 肺 癌、 胃癌、 胰腺癌、 乳腺癌、 前列腺癌、 白血病、 宫颈癌和结肠癌。 键
应当说明的是, 本文所使用相关术语诸如 "烷基" "芳基" "杂芳基" "卤素" "酰基"等 等与所属领域中所述术语的一般含义无明显不同。 键 例如, 术语 "烷基"指直链或支链, 烷基则表示 个碳原子的饱和的脂烃基, 包 括直链和支链,例如" 3¾院基"指的是该基团为烷基,且烷基的碳链上碳原子的数量在 ¾t间。 应当说明的是, 当没有特别限制其碳原子数时, 仅指其中指明的烷基部分的碳原子 数, 而并不包括烷基的取代基上碳原子数。 键
本领域的普通技术人员应当知道下列术语或縮写的含义。 键
术语 "药物上可接受的盐"是指在合理医学判断范围内适用于与哺乳动物特别是人的组 织接触而无过度毒性、 刺激、 过敏反应等并与合理的效益)风险比相称的盐, 比如胺、 羧酸和 其它类型化合物的医学上可接受的盐在所属领域中是被熟知的。 键
术语 "异构体"是指分子组成相同、 »结构和性质不同的两种或多种化合物。 键 术语 "外消旋体"是指一种具有旋光性的手性分子与其对映体的等摩尔混合物, 它由旋 光方向相反、旋光能力相同的分子等量混合而成, 其旋光性因这些分子间的作用而相互抵消, 因而是不旋光的。 键
术语 "溶剂合物"是指化合物与溶剂组成的混合物, 例如结晶体即是一种溶剂合物。 键 术语 "前体药物"指通过在血液中水解而活体内快速转化产生具有上述化学式的母体化 合物的化合物。 键
权利要求书或说明书中所用的英文縮写所对应的物质分别是: 键
(础 二环己基碳二亚胺 «tMW¾、 )、 键 乙基 E 二甲基氨基丙 i«fiffi )、 (实羟基 苯并 三氮唑 )、 (偶氮二甲酸二乙
酯, )、 ( ) 是 (六氟磷酸苯并三唑色 基 氧基三吡咯烷基磷是, m^m ) m , 二异丙基乙胺 些 ; ,作 二 ^甲基硅基瘦基锂修这 六甲基二硅基胺基钠些这 六甲基二硅基胺基 钾些 二氮杂二环 烷); 所述的氨基保护基团 选自 (叔丁氧羰基)、
(苄氧羰基)、 (苄基)、 (笏甲氧羰基)、 (丙氧羰基)、 (对甲苯磺酰基)、 (三氟乙酰基) 或 (三苯甲基)。 ,
具体实fc^:
为了更好的说明本发明的技术内容, 下面结合具体实例对本发明作进一步阐述。
应当说明的是, 下述实施例中, 常规后处理方法是: 反应完成后, 在反应液中加入适量 的水, 分离有机相和水相, 合并有机相; 如有需要, 依次使用 5% HC1溶液和 /或饱和 NaS04 干燥, 过滤之后减压选干, 得到粗产物, 再经过柱层析分离纯化之后得到最终产物。
实施例 1
0°C条件下, 向 L-苹果酸 (10 g,74.6 mmol) 的甲醇 (50 mL) 溶液中, 缓慢滴加二氯亚 砜 (21.8 mL), 滴定完全后, 室温下搅拌过夜, 或者回流 4小时。 反应液直接旋干甲醇, 再 用饱和 NaHC03, 饱和 NaCl依次洗涤, 无水 NaS04干燥, 过滤, 减压旋干直接投下一步, 得到粗产品 11.49 g, 产率 95 %。
实施例 2
无水无氧, 氩气保护, 0°C条件下, 将醋酸 (2.01 mL, 35.1 mmol) 溶解在 5 mL的 THF 中, 缓慢滴入 NaB 的 THF溶液中 (20 mL) , 平均两秒一滴。 滴完后, 反应一小时, 再将 苹果酸二甲酯(5 g, 30.5 mmol)溶解在 10 mL的 THF中, 慢慢滴入反应瓶, 然后置于室温下 搅拌过夜。 甲醇淬灭, 硅藻土抽滤, 旋干滤液, 直接柱层析 (石油醚 : 乙酸乙酯 = 1 : 1 - 纯 乙酸乙酯), 得到二醇 3.03 g, 产率 74 %。
实施例 3
OH 0 TBSCI, imidazole,
ΗΟ、人人 O—CH」 DMAP
"13,
原料(5 g, 37.3 mmol) , DMAP ( 0.5 g , 0.41 mmol)和咪唑 (8.6 g, 126.3 mmol)溶于 100 mL二氯甲烷中配成溶液。 在冰浴下, 缓慢滴加 TBDMSCl ( 11.2 g, 74.6 mmol) 的二氯 甲烷(10 mL)溶液。 滴完后, 室温搅拌过夜。 反应液依次用水, 饱和食盐水洗涤。 有机层用 无水硫酸钠干燥, 蒸干溶剂, 硅胶柱层析得到无色油状物 9.2 g, 产率 89 %。
原料 (5.43 g, 15.0 mmol)溶于 75 mL四氢呋喃中。 在冰浴下, 缓慢滴加 KOH ( 0.84 g ,
15.0 mmol) 的水 (5 mL) 溶液。 滴完后, 室温搅拌 1小时。 反应液用稀盐酸调 PH值为 3, 然后加入乙酸乙酯 100 mL。 有机相依次用水, 饱和食盐水洗涤。 有机层用无水硫酸钠干燥, 蒸干溶剂, 硅胶柱层析得到无色油状物 4.96 g, 产率 95 %。
室温搅拌,氩气保护下,上一步得到的化合物(3.48 g, 10.0 mmol) , DCC ( 0.5 g,10 mmol) 和 TMSEOH ( 8.6 g, 10 mmol) 溶于 100 mL二氯甲烷中配成溶液。 在冰浴下, 缓慢滴加 TBDMSCl ( 11.2 g , 74.6 mmol) 的二氯甲烷 (10 mL) 溶液。 滴完后, 室温搅拌过夜。 反应 液依次用水, 饱和食盐水洗涤。 有机层用无水硫酸钠干燥, 蒸干溶剂, 硅胶柱层析得到无色 油状物 9.2 g, 产率 89 %。
[a]23D: -31.7 (c= l, CHC13). 1H NMR (400MHz, CDC13): δ 4.17-4.12(m, 3H), 3.58 (dd, J = 9.6, 5.2 Hz, 1H), 3.41 (dd, J = 9.6, 7.2 Hz, 1H), 2.61 (dd, J =14.8, 4.4 Hz, 1H), 2.33 (dd, J = 14.8, 8.0 Hz, 1H), 0.98 (dd, J = 9.6, 7.2 Hz, 2H), 0.89 (s, 9H), 0.86 (s, 9H), 0.05 (s, 12H), 0.04 (s, 9H) ppm. 13C NMR (100 MHz, CDC13): 5172.1, 70.4, 67.0, 62.4, 40.4, 25.9, 25.8, 18.3, 18.0, 17.3, -4.4, -5.0, -5.4 ppm. MS (EI, m/z): 449 (M++l).
实施例 5
OTBS o I OTBS o I
CH2CI2, CH3OH
原料(9.2 g, 20.5 mmol)溶解在 50 mL 50 %的甲醇 /二氯甲烷溶液中, 冷却至 -10°C下, 将 0.96 g樟脑磺酸溶解在 0.5 mL甲醇中并加入到反应瓶中,保持 -10 °C,搅拌 8小时。用 5 mL饱 和碳酸氢钠淬灭反应, 蒸干有机溶剂, 二氯甲烷提取 3次, 水洗, 饱和食盐水洗, 无水硫酸 钠干燥,浓縮,柱层析纯化(石油醚 : 乙酸乙酯 = 10 : 1 ),得到无色油状物 5.5 g,产率 82 %。
[a]23D: -23.8 (c = 0.6, CHC13). 1H NMR (400 MHz, CDC13): δ 4.22-4.17 (m, 3H), 3.61 (m, 1H), 3.55 (m, 1H), 2.53 (dd, J = 6.2, 2.2 Hz, 2H), 1.92 (dd, J = 12, 5.6, OH), 0.99 (t, / = 4.0 Hz, 2H), 0.89 (s, 9H), 0.10 (s, 3H), 0.08 (s, 3H), 0.04 (s, 9H) ppm. 13C NMR (100 MHz,CDCl3): δ 171.3,
68.6, 66.2, 62.9, 38.1, 25.9, 18.3 ,17.3, -1.52, -5.42 ppm. MS (EI, m/z): 335 (M++l).
氩气保护, -78 °C下, 将 3mL干燥 DMSO缓慢加入到 1.8 mL重蒸草酰氯的二氯甲烷溶液中, 搅拌 30分钟后, 将溶解有原料 (3.5 g, 10.5 mmol) 的二氯甲烷溶液缓慢加入反应瓶。 搅拌 1 小时后, 缓慢滴加 12 mL干燥三乙胺, 升至室温, 反应 1小时。 饱和氯化铵淬灭, 饱和食盐 水洗涤, 收集有机层, 无水硫酸钠干燥, 浓縮, 得到淡黄色油状物 3.32 g, 产率 95 %。
实施例 7
氩气保护下, 原料 (3.5 g,10.5 mmol)和四氮唑化合物 (4.02 g,10.5 mmol)溶于四氢呋喃 50 mL中, 冷却至 -78 °C, 缓慢滴加 2M NaHMDS的 THF溶液 (5.4 mL, 10.8 mmol) , 反应 1小 时, 饱和氯化铵淬灭, 乙酸乙酯提取三次, 污水硫酸钠干燥有机层, 浓縮, 柱层析纯化 (5% 乙酸乙酯 /石油醚), 得到无色油状物 3.68 g, 产率 72%。
[a]23D: -22.8 (c = 0.5, CHC13). 1H NMR (400 MHz, CDC13): δ 5.63 (ddd, /= 15.6, 6.8, 6.8 Hz, 1H), 5.49 (dd, J = 15.6, 6.8 Hz, 1H), 4.54 (dd, J = 12.4, 7.2 Ηζ,ΙΗ), 4.14 (m, 2H), 3.63 (t, / = 6.8 Hz, 2H), 2.49 (dd, J = 14.4, 8.4 Hz, 1H), 2.38 (dd, J = 14.4, 4.8 Hz, 1H), 2.22 (dt, J = 13.4, 6.8 Hz, 2H), 0.98 (m, 2H), 0.89 (s, 9H),0.85(s, 9H), 0.07-0.03 (m, 21H) ppm. 13C NMR (100 MHz, CDC13): δ 171.3, 134.0, 127.7, 126.4(minor), 70.7, 66.1, 62.8, 62.6, 62.5, 44.2, 31.5, 26.0, 25.8, 25.7, 18.3, 18.0, 17.3, -1.5, -4.2, -4.3, -5.0, -5.3 ppm. MS (EI, m/z): 489 (M++l). HRMS (ESI): calcd for C24H53O4S13 [MH+] 489.3253, found 489.3258.
3.68 g原料溶解在 45 mL二氯甲烷溶液中,冷却至 -10 V,将 0.36 g樟脑磺酸溶解在 5 mL 甲醇中并加入到反应瓶中, 搅拌 8小时。 用 5mL饱和碳酸氢钠淬灭反应, 蒸干有机溶剂, 水 洗, 二氯甲烷提取 3次, 收集有机层, 无水硫酸钠干燥, 浓縮, 柱层析纯化 (15%乙酸乙酯 /
石油醚), 得到无色油状物 1.95 g, 产率 70%。
1H NMR (400MHz,CDCl3): 55.58 (m, 2H), 4.54 (dd, / = 12.4, 6.6 Hz, 1H), 4.13 (m, 2H), 3.65 (m, 2H), 2.51 (dd, J = 14.4, 7.2 Hz, 1H), 2.41 (dd, J = 14.4, 5.8 Hz, 1H), 2.27 (dt, J = 12.4, 6.0Hz, 2H), 0.97 (m, 2H), 0.88 (s, 9H), 0.05 (s, 15H) ppm. 13C NMR (100 MHz, CDC13): δ 171.3, 135.6, 126.9, 70.4, 62.6, 61.7, 44.1, 35.5, 25.8, 25.7, 18.1, 17.3, -1.5, -4.3,-5.0 ppm. MS (EI, mJz): 375 (M++l). HRMS (ESI): calcd for C18H38Na04Si2 [MNa+] 397.2206, found 397.2206.
实施例 9
nTR i , O OTBS O ι , ^ J 硫代辛酸, Ph3P L 八八人人 八 Si-
DEAD'DCM 冰浴,氩气保护下,将 DEAD ( 3.74 mL, 8.23 mmol)滴加到三苯基膦(2.16 g, 8.23 mmol) 的二氯甲烷溶液中,搅拌 15分钟,将原料 (1.95 g, 5.20 mmol),硫代正辛酸(1.32 g, 8.23 mmol) 依次加入反应瓶, 室温搅拌过夜。 依次用饱和碳酸氢钠溶液, 饱和食盐水洗涤, 收集有机层, 无水硫酸钠干燥, 浓縮, 柱层析纯化 (10%乙酸乙酯 /石油醚), 得到无色油状物 2 g, 产率 74 %。
[a]23D: -11.2 (c = 0.30, CHC13). 1H NMR (400 MHz, CDC13): δ 5.62 (m, 1H), 5.51 (dd, J =15.6, 6.4 Hz, 1H), 4.54 (dd, J = 13.6, 6.0 Ηζ,ΙΗ), 4.14 (m, 2H), 2.90 (t, / =7.2 Hz, 2H), 2.54-2.46 (m, 3H), 2.38 (dd, J =14.4, 5.2 Hz, 1H), 2.27 (dd, J =14.0, 7.2 Hz, 2H), 1.65 (t, J = 1.2 Hz, 2H), 1.30-1.27 (m, 8H),0.99 (m, 2H), 0.96-0.89 (12H), 0.07-0.03 (m, 15H) ppm. 13C NMR (100 MHz, CDC13): δ 199.5, 199.3 (minor), 171.3, 171.0 (minor), 134.3, 128.4, 127.3 (minor), 70.4, 65.9 (minor), 62.6, 44.2, 43.9 (minor), 32.0, 31.6, 28.9, 28.3, 27.9 (minor), 25.8, 25.7, 22.6, 18.0, 17.3, 14.0, -1.5, -4.2, -4.4, -5.0 ppm. MS (EI, m/z) 517 (M++1).HRMS (ESI): calcd for C26H52Na04SSi2 [MNa+] 539.3023, found 539.3027.
冰浴,氩气保护下,将 DEAD ( 3.74 mL, 8.23 mmol)滴加到三苯基膦(2.16 g, 8.23 mmol) 的二氯甲烷溶液中,搅拌 15分钟,将原料(1.95 g, 5.20 mmol) ,保护的 3-羟基硫代丙酸( 1.33 g, 8.23 mmol)依次加入反应瓶, 室温搅拌过夜。依次用饱和碳酸氢钠溶液, 饱和食盐水洗涤, 收集有机层, 无水硫酸钠干燥, 浓縮, 柱层析纯化 (10% 乙酸乙酯 /石油醚), 得到无色油状
物 3.46 g, 产率 81 %。
[a]23D: - 17.4 (c = 0.30, CHC13). 1H NMR (400 MHz, CDC13): δ 5.62 (m, 1H), 5.51 (dd, 1H), 4.54 (dd, 1H), 4.14 (t, 2H), 3.67 (t, 2H), 2.90 (t, 2H), 2.54-2.46 (m, 4H), 2.38 (d, 2H), 1.19(s, 9H), 0.99 (m, 2H), 0.96-0.89 (s, 9H), 0.21(s, 6H), 0.07-0.03 (m, 9H) ppm. 13C NMR (100 MHz, CDC13): δ 199.5, 173.1, 130.1 , 128.2, 81.8, 72.6, 67.2, 62.8, 45.3, 43.9, 37.9, 31.0, 28.2, 25.9, 22.9, 1.8ppm. MS (EI, m/z): 519 (M++l).
原料 (2 g, 3.87 mmol) 溶解在 50%的甲醇 /二氯甲烷 (20 mL) 溶液中, 冷却至 0 °C, 将 0.91 g 樟脑磺酸溶解在 l mL 甲醇中并加入到反应瓶中, 搅拌过夜。 用 5 mL饱和碳酸氢钠 淬灭反应, 蒸干有机溶剂, 水洗, 二氯甲烷提取 3次, 收集有机层, 无水硫酸钠干燥, 浓縮, 柱层析纯化 ( 20% 乙酸乙酯 /石油醚), 得到无色油状物 1.12 g, 产率 71 %。
[a]23D: - 10.1 (c= 0.95, CHC13). 1H NMR (400 MHz, CDC13): δ 5.70 (m, 1H), 5.55 (dd, J = 15.5, 6.1Hz, 1H), 4.49 (m, 1H), 4.20 (t, J = 8.6 Hz, 2H), 2.94 (d, J= 4 Hz,1H), 2.91 (t, J = 12 Hz, 2H), 2.56-2.45 (m, 4H), 2.30 (m, 2H), 1.65 (m, 2H), 1.29- 1.26 (m, 8H), 1.00 (t, J = 8.6 Hz, 2H) , 0.88 (t, / = 6.8 Hz, 3H), 0.03 (s, 9H) ppm. MS (EI, m/z): 403 (M++l). HRMS (ESI): calcd for
C20H38NaO4SSi [M Na+] 425.2158, found 425.2159.
冰浴,氩气保护下,将 DEAD ( 1.12 mL, 2.74 mmol)滴加到三苯基膦(0.65 g, 2.74 mmol) 的二氯甲烷溶液中,搅拌 15分钟,将原料(0.585 g , 1.56 mmol) ,硫代乙酸(0.4 g , 2.74 mmol ) 依次加入反应瓶, 室温搅拌过夜。 依次用饱和碳酸氢钠溶液, 饱和食盐水洗涤, 收集有机层, 无水硫酸钠干燥, 浓縮, 柱层析纯化 (10% 乙酸乙酯 /石油醚), 得到无色油状物 0.948 g, 产 率 80 %。
[a]23D: -31.2 (c = 0.60, CHC13). 1H NMR (400 MHz, CDC13): δ 5.72 (m, 1H), 5.63 (dd, 1H), 4.39 (m, 1H), 4.10 (t, 2H), 2.91 (d, 1H), 2.82 (t, 2H), 2.56-2.45 (m, 4H), 2.29 (m, 2H), 1.61 (m, 2H), 1.00 (t, 2H) , 0.81 (t, 3H), 0.03 (s, 9H) ppm. MS (EI, m/z): 433 (M++l).
原料 (0.839 g, 1.94 mmol) 溶解在 50%的甲醇 /二氯甲烷 (10mL) 溶液中, 冷却至 0°C, 将 0.455 g 樟脑磺酸溶解在 I mL 甲醇中并加入到反应瓶中, 搅拌过夜。用 5 mL饱和碳酸氢 钠淬灭反应, 蒸干有机溶剂, 水洗, 二氯甲烷提取 3次, 收集有机层, 无水硫酸钠干燥, 浓 縮, 柱层析纯化 ( 20% 乙酸乙酯 /石油醚), 得到无色油状物 0.481 g, 产率 78 %。
[a]23D: -21.9 (c = 0.50, CHC13). 1H NMR (400 MHz, CDC13): δ 5.72 (m, 1H), 5.52 (dd, 1H), 4.45 (m, 1H), 4.160 (t, 2H), 2.89 (d, 1H), 2.90 (t, 2H), 2.51-2.43 (m, 4H), 2.35 (m, 2H), 1.61 (m, 2H), 1.00 (t, 2H) , 0.81 (t, 3H), 0.02 (s, 9H) ppm. MS (EI, m/z): 319 (M++l).
冰浴,氩气保护下,将 DEAD ( 1.35 mL, 3.29 mmol)滴加到三苯基膦(0.78 g, 3.29 mmol) 的二氯甲烷溶液中,搅拌 15分钟,将原料(1.102 g , 1.88 mmol),硫代乙酸(0.758 g , 3.29 mmol ) 依次加入反应瓶, 室温搅拌过夜。 依次用饱和碳酸氢钠溶液, 饱和食盐水洗涤, 收集有机层, 无水硫酸钠干燥, 浓縮, 柱层析纯化 (10% 乙酸乙酯 /石油醚), 得到无色油状物 1.312 g, 产 率 68 %。
[a]23D: - 12.9 (c = 0.50, CHC13). 1H NMR (400 MHz, CDC13): δ 5.67 (m, 1H), 5.54 (dd, 1H), 4.54 (dd, 6.0 Hz, 1H), 4.12 (t, 2H), 2.91 (t, 2H), 2.54-2.46 (m, 4H), 2.38 (dd, 1H), 2.27 (dd, 2H), 1.65 (t, 2H), 1.30- 1.27 (m, 20H), 0.99 (m, 3H), 0.96-0.89 (12H), 0.07-0.03 (m, 15H) ppm. MS (EI, m/z): 587 (M++l).
实施例 15
O OTBS O 1 / CSA > 〇 OH O \
C12H25人 S^^ ^^〇^^Si_ CH2CI2,CH3〇H C12H25人 S^^ ^\ 〇^^ 原料(1.172 g, 2 mmol)溶解在 50%的甲醇 /二氯甲烷(10mL)溶液中, 冷却至 0°C, 将 0.52 g 樟脑磺酸溶解在 I mL 甲醇中并加入到反应瓶中, 搅拌过夜。用 5 mL饱和碳酸氢钠淬 灭反应, 蒸干有机溶剂, 水洗, 二氯甲烷提取 3次, 收集有机层, 无水硫酸钠干燥, 浓縮, 柱层析纯化 ( 20% 乙酸乙酯 /石油醚), 得到无色油状物 0.766 g, 产率 81 %。
[a]23D: - 11.0 (c = 0.50, CHC13). 1H NMR (400 MHz, CDC13): δ 5.70 (m, 1H), 5.65 (dd, 1H), 4.42 (m, 1H), 4.09 (t, 2H), 2.90 (d, 1H), 2.83 (t, 2H), 2.51-2.40 (m, 4H), 2.26 (m, 2H), 1.61 (m, 2H),
1.29- 1.21 (m, 20H), 1.00 (t, 2H) , 0.82 (t, 3H), 0.03 (s, 9H) ppm. MS (EI, m/z): 473 (M++l) 实施例 16
DEAD, Ph3P, DCM
冰浴,氩气保护下,将 DEAD ( 0.81 mL, 1.97 mmol)滴加到三苯基膦(0.47 g , 1.97 mmol) 的二氯甲烷溶液中,搅拌 15分钟,将原料(0.66 g , 1.13 mmol) ,硫代苯乙酸(0.3 g , 1.97 mmol) 依次加入反应瓶, 室温搅拌过夜。 依次用饱和碳酸氢钠溶液, 饱和食盐水洗涤, 收集有机层, 无水硫酸钠干燥, 浓縮, 柱层析纯化 (10% 乙酸乙酯 /石油醚), 得到无色油状物 0.611 g, 产 率 61 %。
[a]23D: -21.1 (c = 0.50, CHC13). 1H NMR (400 MHz, CDC13): δ 7.33 (m, 2H), 7.26 (m, 1H), 7.22(d, 2H), 5.62 (m, 1H), 5.51 (dd, 1H), 4.52 (dd, 6.0 Hz, 1H), 4.12 (t, 2H), 3.66 (s, 2H), 2.51-2.46 (m, 4H), 2.32 (dd, 1H), 2.27 (dd, 2H), 1.62 (t, 2H), 0.91 (m, 3H), 0.96-0.81 (12H), 0.07-0.03 (m, 15H) ppm. MS (EI, m/z): 509 (M++l).
原料(0.61 g, 1.2 mmol)溶解在 50%的甲醇 /二氯甲烷(7 mL)溶液中, 冷却至 0 °C, 将 0.3 g 樟脑磺酸溶解在 l mL甲醇中并加入到反应瓶中, 搅拌过夜。 用 5mL饱和碳酸氢钠淬 灭反应, 蒸干有机溶剂, 水洗, 二氯甲烷提取 3次, 收集有机层, 无水硫酸钠干燥, 浓縮, 柱层析纯化 ( 20% 乙酸乙酯 /石油醚), 得到无色油状物 0.412 g, 产率 87 %。
[a]23D: -35.0 (c = 0.50, CHC13). 1H NMR (400 MHz, CDC13): δ 7.33 (m, 2H), 7.26 (m, 1H), 7.22(d, 2H), 5.62 (m, 1H), 5.51 (dd, 1H), 4.52 (dd, 6.0 Hz, 1H), 4.12 (t, 2H), 3.66 (s, 2H), 2.51-2.46 (m, 4H), 2.32 (dd, 1H), 2.26 (m, 2H), 1.61 (m, 2H), 1.00 (t, 2H) , 0.82 (t, 3H), 0.03 (s, 9H) ppm. MS (EI, m/z): 395 (M++l).
实施例 18
氩气保护, 0 °C条件下, 向原料 (0.942 g, 2.34 mmol) ) 的二氯甲烷溶液中, 依次加入 Fmoc-L-Val-OH ( 2.376 g, 7 mmol) , EDCI ( 1.342 g, 7 mmol) , DMAP ( 0.057 g, 0.468 mmol) ,
DIPEA ( 1.2 mL, 7 mmol) , 室温下搅拌过夜。 饱和 NaHC03溶液, 用乙酸乙酯萃取三次, 合 并有机相, 饱和 NaCl洗涤, 无水 Na2S04干燥, 过滤, 减压旋干后柱层析 (石油醚 : 乙酸乙 酯 = 20: 1-10: D o 得到透明液体 1.45 g, 产率 86 %。
[a]23D: -13.5 (c = 0.52, CHC13). 1H NMR (400 MHz, CDC13): δ 7.76 (d, J =1.6 Hz, 2H), 7.60 (m, 2H), 7.40 (dd, J = 7.4 Hz, 2H), 7.31 (dd, J = 7.4 Hz, 2H), 5.84 and 5.76 (m, IH), 5.67 (dd, / = 13.6, 7.2 Hz, IH), 5.53 (dd, J = 15.2, 7.2 Hz, IH), 5.32 (d, / = 8.8 Hz, IH), 4.39 (t, / =6.8 Hz, 2H), 4.29 (dd, J = 9.2, 4.4 Hz, IH), 4.23 (t, J = 1.2, IH), 4.17 (t, J = 8.4Hz, 2H), 2.88 (t, J = 12 Hz, 2H), 2.71 (dd, / = 15.6, 7.6 Hz, 1H), 2.59 (dd, / = 15.6,5.6 Hz, 1H), 2.52 (t, J = 12 Hz, 2H), 2.29 (dt, J =13.6, 6.8 Hz, 2H), 2.18 (m, 1H),1.65 (m, 2H), 1.30-1.27 (m, 8H), 0.97-0.83 (m, 11H), 0.03(s, 9H) ppm. 13C NMR (100 MHz, CDC13): δ 199.2, 170.9, 169.5, 156.2, 144.0, 141.3, 133.3, 128.4, 127.7,127.6, 127.1, 125.1, 120.0, 71.8, 67.1, 63.1, 58.9, 47.1, 44.1, 39.7, 32.2, 31.6, 31.4,29.7, 28.9, 28.1, 25.6, 23.0, 22.6, 20.1, 19.0, 17.4, 14.0, -1.30 ppm. MS (EI, mJz): 723 (M++l). HRMS (ESI): calcd for C40H57NNaO7SSi [MNa+] 746.3523, found746.3521.
实施例 19
氩气保护, 0°C条件下, 向原料 (0.235 g, 0.58 mmol) 的二氯甲烷溶液中, 依次加入 Fmoc-L-Ala-OH( 0.363 g, 1.17 mmol) , DCC ( 0.241 g, 1.17 mmol) , DMAP( 0.014 g, 0.12 mmol) , 室温下搅拌过夜。 过滤, 减压旋干后柱层析(石油醚 : 乙酸乙酯 = 20 : 1 - 10 : 1 )。得到透明 液体 0.328 g, 产率 81 %。
[a]23D: -18.4 (c = 0.95, CHC13). 1H NMR (400 MHz, MeOD): δ 7.75 (d, J = 7.5 Hz, 2H), 7.59 (m, 2H), 7.39 (t, J = 7.4 Hz, 2H), 7.31 (t, J = 7.4 Hz, 2H), 5.76 (m, IH), 5.67 (m, IH), 5.6-5.4 (m, 2H), 4.37 (m, 3H), 4.20 (m, 4H), 2.89 (m, 2H), 2.70 (dd, J = 7.9 Hz, 15.7 Hz, 1H), 2.60 (m, 1H), 2.51 (m, 2H), 2.28 (m, 2H), 1.64 (m, 3H), 1.41 (d, J = 7.1 Hz, 2H), 1.27 (m, 8H), 0.98(t, J = 8.5 Hz, 2H), 0.87 (m, 3H)ppm. 13C NMR (100MHz, CDC13): δ 199.34, 172.36, 171.74, 169.56, 155.52, 143.95, 141.31, 132.75, 129.45,128.32, 127.68, 127.06, 125.08, 119.96, 71.71, 68.55, 67.02, 63.12, 49.68, 47.20, 44.12, 41.62, 39.70, 32.18, 31.59, 28.89, 28.18, 27.89, 25.62, 22.55, 18.71, 17.35, 14.01, 0.99, -1.54ppm. MS (EI, m/z): 718 (M++Na).HRMS (ESI): calcd for C38H53N07Ssi [MNa+]
718.3204, found 718.3203.
氩气保护, 0 °C条件下, 向原料 (0.255 g, 0.63 mmol) 的二氯甲烷溶液中, 依次加入 Fmoc-D-Ala-OH ( 0.392 g, 1.26 mmol) , DCC ( 0.260 g, 1.26 mmol) , DMAP ( 0.016 g, 0.13 mmol) , 室温下搅拌过夜。 过滤, 减压旋干后柱层析 (石油醚 : 乙酸乙酯 = 20 : 1 - 10 : 1 )。 得到透明液体 0.378 g, 产率 86 %。
[a]23D: -0.29 (c = 3.13, CHC13). 1H NMR (400 MHz, CDC13): 57.75 (d, J = 7.5 Hz, 2H), 7.59 (m, 2H), 7.39 (t, J = 7.4 Hz, 2H), 7.30 (d, J = 7.4 Hz, 2H), 5.77 (m, IH), 5.66 (m, IH), 5.6-5.4 (m, 2H), 4.36 (m, 3H), 4.25-4.1 (m, 4H), 2.90 (m, 2H), 2.68 (dd, J = 8.6 Hz, 15.7 Hz, 1H), 2.58 (m, 1H), 2.51 (m, 3H), 2.30 (m, 2H), 1.63 (m, 2H), 1.40 (d, J = 7.1 Hz, 3H), 1.27 (m, 8H), 0.98 (t, J = 8.6 Hz, 2H), 0.87 (m, 3H), 0.04 (s, 9H).ppm. 13C NMR (125 MHz, CDC13): δ 199.23, 171.91, 169.64, 155.54, 143.95, 143.83, 141.31, 132.71 , 128.23, 127.69, 127.06, 125.10, 119.96, 71.75, 68.56, 67.03, 63.09, 53.39, 49.73, 47.19, 44.12, 41.60, 39.68, 32.22, 31.59, 28.89, 27.84, 25.63, 22.56, 18.75, 17.39, 14.01 , 1.00, - 1.54ppm. MS (EI, m/z): 718 (M++Na). HRMS (ESI): calcd for
C38H53N07Ssi [MNa+] 718.3204, found 718.3206.
氩气保护, 0 °C条件下, 向原料 (0198 g, 0.5 mmol) 的二氯甲烷溶液中, 依次加入 Fmoc-L-ter-Leu-OH ( 0.265 g, 0.75 mmol) , DCC ( 0.155 g, 0.75 mmol) , DMAP ( 0.013 g, O. lmmol) ,室温下搅拌过夜。过滤,减压旋干后柱层析(石油醚 : 乙酸乙酯 = 20: 1 - 10: 1 ), 得到透明液体 0.209 g, 产率 57 %。
[a]23D: - 11.8 (c= 0.92, CHC13). 1H NMR (400 MHz, CDC13): δ 7.74 (d, J = 7.4 Hz, 2H), 7.58 (d, J = 7.4 Hz, 2H), 7.39 (t, J = 7.4 Hz, 2H), 7.31 (t, J = 7.4 Hz, 2H), 5.82 (m, IH), 5.66 (dd, J = 7.1 Hz 14 Hz, IH), 5.51 (m, IH), 5.42 (d, J = 9.7 Hz, IH), 4.45-4,3 (m, 3H), 4.22 (t, J=7 Hz, 2H), 4.15 (m, 3H), 2.87 (m, 2H), 2.72 (dd, J = 7.4 Hz 15.6 Hz, IH), 2.58 (dd, J = 6 Hz 15.6 Hz, IH), 2.51 (t, J = 7.5 Hz, 2H), 1.63 (m, 3H), 1.27 (m, 8H), 1.02 (t, 2H), 0.98 (s, 9H), 0.87 (t, J = 6.7 Hz, 3H).ppm. 13C NMR (100 MHz, CDC13): δ 199.10, 170.34, 169.47, 155.93, 143.82, 143.73, 141.21, 133.60, 128.25, 127.60, 126.97, 125.01, 71.80, 67.35, 66.92, 63.00, 61.95, 53.34, 47.13, 44.02, 39.59, 34.96,
32.07, 31.50, 28.80, 27.79, 26.69, 25.52, 22.47, 17.20, 13.95ppm. MS (EI, m/z): 760 (M++Na).
HRMS (ESI): calcd for C41H59NO7SSi[MNa+]760.3674, found 760.3675.
氩气保护, 0°C条件下, 向原料 (0.25 g, 0.63 mmol) 的二氯甲烷溶液中, 依次加入 Fmoc-L-Phe-OH( 0.728, 1.88 mmol), EDCI (0.36 g, 1.88 mmol), DMAP (0.015 g, 0.126 mmol), DIPEA (0.3 mL, 1.88 mmol) , 室温下搅拌过夜。 饱和 NaHC03溶液, 用乙酸乙酯萃取三次, 合并有机相, 饱和 NaCl洗涤, 无水 Na2S04干燥, 过滤, 减压旋干后柱层析 (石油醚 : 乙酸 乙酯 =20 : 1 -10 : 1), 得到透明液体 0.35 g, 产率 72%。
[a]23D: -21.2(c= 0.88, CHC13).1H NMR (400 MHz, CDC13): δ 7.77 (d, J =1.6 Hz, 2H), 7.56 (m, 2H),7.40 (dd, J =1.6 Hz, 2H), 7.31 (dd, /= 7.6 Hz, 2H), 7.28-7.25 (m, 3H), 7.11 (d, J=6.8 Hz, 2H), 5.85 and 5.75 (m, 1H), 5.65 (dd, J= 14.0, 6.8 Hz, 1H), 5.50 and 5.37 (dd, J= 15.6, 7.2 Hz, 1H), 5.27 (m, 1H), 4.63 (m, 1H), 4.43 (dd, /= 10.0, 7.4 Hz, 1H), 4.31 (m, 1H), 4.22-4.14 (m, 3H), 3.10 (m, 2H), 2.89 (t, J =12 Hz, 1H), 2.68 (dd, J= 15.6, 7.2 Hz, 1H), 2.57 (m, 1H), 2.52 (t, J =1.6 Hz, 2H), 2.30 (dt, J= 13.6, 6.8 Hz, 2H), 1.64 (m, 2H), 1.33-1.26 (m, 8H), 0.97 (t, /= 8.6 Hz, 2H), 0.83-0.89 (m, 3H), 0.03 (s, 9H) ppm. 13C NMR (125 MHz, CDC13): δ 199.10, 170.42, 169.51, 155.49, 143.87, 141.29, 135.73, 133.26, 129.54, 128.46, 128.18, 127.69, 127.05, 125.15, 119.97, 72.03, 67.80, 66.95, 63.09, 60.33, 54.71, 47.15, 44.11, 39.61, 38.10, 32.22, 31.60, 28.89, 28.10, 25.62, 22.58, 20.97, 17.32, 14.20, -1.30 ppm. MS (EI, m/z): 772 (M++l). HRMS (ESI): calcd for C44H57NNa07SSi [MNa+] 794.3523, found 794.3524.
实施例 23
氩气保护, 0°C条件下, 向原料 (0.26 g, 0.646 mmol) 的二氯甲烷溶液中, 依次加入 Fmoc-3-(l-萘基) -L-丙氨酸(0.596 g,1.3mmol), DCC (0.268 g, 1.3 mmol), DMAP(0.016 g, 0.13 mmol), 室温下搅拌过夜。 过滤, 减压旋干后柱层析 (石油醚 : 乙酸乙酯 =20 : 1 -10 : 1), 得到透明液体 0.397 g, 产率 75 %。
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将 100mg(0.25mmol, leq)原料与 148.6mg Fmoc-Gly-OH(0.5mmol, 2eq袼于 2ml无水二氯甲烷中, 加入 5.6mg DMAP(0.05mmol, 0.2eq),于 0 °C下加入 103mgDCC(0.5mmol, 2eq),0°C下反应 lh后过 滤除去固体,减压旋干溶剂,柱层析 (乙酸乙酯:石油醚 =1 : 10)得到无色液体 170mg,产率 100% .
[oJ^- 18.14 1H-NMR (400 MHz, CDC13) δ 7.75(d, 2-H), 7.60 (d, 2-H), 7.39(t, 2-H), 7.32(t, 2-H),
5.78(m, 1H), 5.69(q, 1H), 5.52(dd, 1H), 5.37(t, H), 4.39(d, 2H), 4.22(t, 1H), 4.20(t, 2H), 3.98(d, 2H), 2.89(t, 2H), 2.70(dd, 1H), 2.58(dd, 1H), 2.55(t, 2H), 2.29(m, 2H), 1.64(t, 2H), 1.28(m, 8H), 0.99(t, 2H), 0.87(t, 3H), 0.02(s, 9H); 13C NMR (500 MHz, CDC13) δ 199.3, 169.6, 168.9, 156.1, 143.8, 141.2, 132.8, 128.2, 127.6, 127.0, 125.0, 119.9, 71.7, 67.1 , 63.1, 47.0, 44.1, 39.5, 32.2, 31.5, 28.8, 27.7, 25.6, 22.5, 17.3, 14.0, - 1.69; MS(ESI) m/z 460.2 (100%) (M-Fmoc)+.
实施例 26
将 100mg(0.25mmol, leq)原料与 162mg Fmoc-N-Me-Gly-OH(0.5mmol, 2eq)i#于 2ml无水二 氯甲烷中,加入 5.6mg DMAP(0.05mmol, 0.2eq),于 0 °C下加入 103mgDCC(0.5mmol, 2eq),0°C下 反应 lh后过滤除去固体,减压旋干溶剂,柱层析 (乙酸乙酯:石油醚 =1 : 10), 得到无色液体 170mg, 产率 100% .
s =-24.34 1H-NMR (400 MHz, CDC13) δ 7.75(d, 2-H), 7.60 (d, 2-H), 7.39(t, 2-H), 7.32(t, 2-H),
5.78(m, 1-H), 5.69(q, 1-H), 5.37(t, 1-H), 4.91 and 4.89(q, l-H) 4.39(d, 1-H), 4.22(t, 1-H), 4.20(t,
1- H), 3.98(d, 2-H), 2.89(m, 5-H), 2.70(dd, 1-H), 2.58(dd, 1-H), 2.55(t, 2-H), 2.29(m, 2-H), 1.64(t,
2- H), 1.28(m, 8-H), 0.99(t, 2-H), 0.87 (t, 3-H), 0.02(s, 9-H); 13C-NMR (500 MHz, CDCl 3) δ 199.2, 170.7, 170.5, 156.1, 143.8, 141.2, 132.8, 128.2, 127.6, 127.0, 125.0, 119.9, 71.7, 67.8, 63.1 , 54.2, 47.0, 44.1 , 42.8, 39.5, 32.2, 31.5, 28.8, 27.7, 25.6, 22.5, 17.3, 14.0, -1.69; MS(ESI) m/z 488.2 (100%) (M-Fmoc)+.
实施例 27
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实施例 29
将 150mg(0.375mmol, leq)原料与 266mg Fmoc-Leu-OH(0.75mmol, 269赂于41111无水二氯 甲烷中,加入 8.4mg DMAP(0.075mmol, 0.2eq),于 0°C下加入 155mgDCC(0.75mmol, 2eq),0°C下 反应 lh后过滤除去固体,减压旋干溶剂,柱层析 (乙酸乙酯:石油醚 =1 : 10)得到无色液体 292mg,产 率 100% .
1H-NMR (400 MHz, CDC13) δ 7.75(d, 2-Η), 7.60 (d, 2-Η), 7.39(t, 2-Η), 7.32(t, 2-Η),
5.78(m, 1-Η), 5.65(q, 1-Η), 5.52(dd, 1-Η), 5.21(d, 1-Η), 4.48(t, 1-Η), 4.38(d, 2-Η), 4.16(t, 1-Η), 4.12(t, 2-Η), 2.87(t, 2-Η), 2.70(dd, 1-Η), 2.58(dd, 1-Η), 2.50(t, 3-Η), 2.28(q, 2-Η), 1.66(m, 6-Η), 1.28(m, 8-Η), 0.99(m, 9-Η), 0.87(t, 3-Η), 0.02(s, 9-H); 13C-NMR (500 MHz, CDC13) δ 199.2, 171.8, 169.6, 155.8, 143.9(2C), 141.2(2C), 132.9, 128.2, 127.6(2C), 127.0(2C), 125.0(2C), 119.9(2C), 71.7, 66.9, 63.1, 52.4, 47.0, 44.1, 41.7, 39.7, 32.1, 31.6, 31.5, 28.8(2C), 27.8, 25.6, 24.7, 22.9, 22.5, 21.8, 17.2, 14.0, - 1.58(3C); MS(ESI) m z 760.3 (100%) (M+Na)+.
实施例 30
将 210mg(0.52mmol, leq)原料与 554mg Fmoc-N-Me-Val-OH(1.57mmol, 3eq將于 10ml无 水二氯甲烷中,加入 12.6mg DMAP(0.1mmol, 0.2eq),于 0°C下加入 300mgEDCI(1.57mmol, 3eq) 和 0.26ml DIPEA(1.57mmol, 3eq),0°C下反应 3h后 15ml二氯甲烷稀释,依次用稀 HCl(20mlX2),饱 和 NaC120mlX2)萃取.无水硫酸钠干燥,减压旋干溶剂,柱层析 (乙酸乙酯:石油醚 =1 : 10)得到无色 液体 320mg,产率 83.3% .
[】iG=-48.2 1H-NMR (400 MHz, CDC13) δ 7.75(d, 2-Η), 7.60 (d, 2-Η), 7.39(t, 2-Η), 7.32(t, 2-Η),
5.75(m, 1-H), 5.60(q, 1-H), 5.51(dd, 1-H), 4.48(t, 1-H), 4.38(d, 1-H), 4.26(m, 1-H), 4.1 l (m, 3-H), 2.87(m, 5-H), 2.70(dd, 1-H), 2.58(dd, 1-H), 2.50(t, 3-H), 2.28(q, 2-H), 2.15(m, 1-H), 1.63(m, 2-H)
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无水 Na2S04干燥, 过滤, 减压旋干后柱层析 (石油醚:乙酸乙酯 =4: 1 ), 得到固体 0.378g, 产 率 81 %。
[a]23D: -7.57 (c 7.5, CHC13). 1H NMR (400MHz, CDC13): 58.60(s,lH), 8.10(s, lH), 6.60(m, 2H), 5.77(m, 1H), 5.62(dd, J=13.7Hz 7.2Hz,lH), 5.49(dd, J=13.7Hz 7.5Hz,lH), 5.42(m, 1H), 4.58(m, 3H), 4.14(t, J=8.6Hz, 2H), 2.85(t, J=7.2Hz, 2H), 2.68(dd, J=15.7Hz 7.7Hz, 2H), 2.50(t, J=7.5Hz, 2H), 2.26(q, J=7.1Hz, 2H), 2.18(m, 1H), 1.80(d, J=7Hz, 3H), 1.60(m, 2H), 1.46(m, 8H), 1.26(m, 9H), 0.96(m, 3H), 0.86(t, J=6.1Hz, 6H), 0.02(s, 9H)ppm. 13C NMR (125 MHz, CDC13): 5199.25, 170.70, 169.55, 164.33, 159.26, 148.88, 133.30, 129.39, 129.21, 128.30, 124.75, 71.77, 63.11, 57.16, 44.08, 39.63, 38.55, 32.13, 31.59, 31.55, 28.84, 28.28, 27.82, 25.58, 22.52, 18.91, 17.58, 17.26, 13.99, 13.94, 0.96, - 1.57ppm. MS (EI, m/z): 847 (M++Na).HRMS (ESI): calcd for
C39H64N409S2Si [MNa+] 847.3779, found 847.3777.
原料 (0.328g, 0.47mmol)溶解于二氯甲烷中, 加入哌啶 (0.23ml, 2.35mmol), 室温下搅拌 2 小时。 直接旋干, 快速柱层析 (石油醚:乙酸乙酯 =10: 1, 二氯甲烷:甲醇 =10: 1 )。 得到无色液 体 0.178g, 产率 80%。
氩气保护下, 上一步得到的化合物 (0.218g, 0.46mmol)溶于无水二氯甲烷中, 在 0 °C条件 下,依次加入化合物 (0.188g, 0.552mmol), HATU(0.262g, 0.69mmol), HOAt(0.094g, 0.69mmol), DIPEA(0.23ml, 1.38mmol), 1小时后室温下搅拌过夜。 依次用稀盐酸洗涤, 饱和 NaCl洗涤, 无水 Na2S04干燥, 过滤, 减压旋干后柱层析 (石油醚:乙酸乙酯 =2: 1 ), 得到固体 0.280g, 产 率 76%。
[a]23D: -7.4 (c 2.33, CHC13). 1H NMR (400MHz, CDC13): 58.58(s, 1H), 8.09(s, 1H), 6.77(d, J=6.8Hz, 1H), 6.63(q, J=7.0Hz, 1H), 5.73(m, 1H), 5.61 (dd, J=7Hz, 13.5Hz, 1H), 5.48(m, 2H), 4.59(m, 3H), 4.14(m, 2H), 2.86(t, J=7.1Hz, 2H), 2.68(dd, J=7.8Hz, 15.8Hz, 1H), 2.57(m, 1H), 2.50(m, 2H), 2.27(dd, J=7Hz, 14Hz, 2H), 1.79(d, J=7.0Hz, 3H), 1.62(m, 2H), 1.47(m, 8H), 1.40(d, J=7.1Hz, 3H), 1.21(m, 9H), 0.96(t, J=8.8Hz, 2H), 0.86(m, 3H), 0.02(s, 9H)ppm. 13C NMR
(100MHz, CDC13): 5199.24, 171.72, 169.61, 165.74, 163.94, 159.25, 148.95, 132.73, 129.68,
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91
原料 (0.29g, 0.4mmol)溶解于二氯甲烷中, 加入哌啶 (0.2ml, 2mmol), 室温下搅拌 2小时。 直接旋干,快速柱层析(石油醚:乙酸乙酯 =10: 1,二氯甲烷:甲醇 =10: 1 )。得到无色液体 0.146g, 产率 71 %。
氩气保护下, 上一步得到的化合物 (0.119g, 0.23mmol)溶于无水二氯甲烷中, 在 0 °C条件 下, 依次加入化合物 (0.095g, 0.28mmol), HATU(0.131g, 0.35mmol), HOAt(0.048g, 0.35mmol), DIPEA(0.12ml, 0.69mmol), 1小时后室温下搅拌过夜。 依次用稀盐酸洗涤, 饱和 NaCl洗涤, 无水 Na2S04干燥, 过滤, 减压旋干后柱层析 (石油醚:乙酸乙酯 =2: 1 )。 得到固体 0.151g, 产 率 78%。
[a]23D: 11.8(c 2.5, CHC13). 1H NMR (400MHz, CDC13): 58.92(s, 1H), 8.08(s, 1H), 6.69(d, J=9.3Hz, 1H), 6.56(m, 1H), 5.76(m, 1H), 5.58(m, 2H), 5.46(dd, J=7.8Hz 15.4Hz, 1H), 4.57(d, J=5.8Hz, 2H), 4.44(d, J=9.3Hz, 1H), 4.11(t, J=8.6Hz, 2H), 2.83(t, J=7.2Hz, 2H), 2.66(dd, J=7.2Hz 15.6Hz), 2.56-2.44(m, 3H), 2.23(m, 2H), 1.77(d, J=7Hz, 3H), 1.59(m, 2H), 1.23(m, 8H), 0.93(m, 11H), 0.83(t, 3H), -0.03(s, 9H).ppm. 13C NMR (100MHz, CDC13): 5199.20, 170.20, 169.54, 164.16, 159.38, 148.88, 133.59, 129.57, 128.35, 124.75, 123.81 , 71.87, 63.05, 60.24, 44.09, 39.65, 38.56, 35.38, 32.13, 31.55, 28.85, 28.30, 27.86, 25.85, 22.51 , 17.29, 13.98, -1.56ppm. MS (EI, m/z): 839 (M++l),861 (M++Na).HRMS (ESI): calcd for C40H66N4O9S2Si [MNa+] 861.3933, found 861.3936.
原料 (0.221g, 0.29mmol)溶解于二氯甲烷中, 加入哌啶 (0.14ml, 1.43mmol), 室温下搅拌 2 小时。 直接旋干, 快速柱层析 (石油醚:乙酸乙酯 =10: 1, 二氯甲烷:甲醇 =10: 1 )。 得到无色液 体 0.142g, 产率 89%。
氩气保护下, 上一步得到的化合物 (0.142g, 0.26mmol)溶于无水二氯甲烷中, 在 0 °C条件 下, 依次加入化合物 (0.106g, 0.31mmol), HATU(0.148g, 0.39mmol), HOAt(0.053g, 0.39mmol), DIPEA(0.13ml, 0.78mmol), 1小时后室温下搅拌过夜。 依次用稀盐酸洗涤, 饱和 NaCl洗涤, 无水 Na2S04干燥, 过滤, 减压旋干后柱层析 (石油醚:乙酸乙酯 =2: 1 ), 得到固体 0.152g, 产 率 67%。
[a]23D: 8.5(c 1.27, CHC13). 1H NMR (400MHz, CDC13): 58.50(s, 1H), 8.11 (s, 1H), 7.20-7.06(m, 5H), 6.56(m, 2H), 5.73(m, 1H), 5.59(dd, J=14.1Hz 7Hz, 1H), 5.45(m, lH), 5.30(s, 1H), 4.89(m, 1H), 4.61 (d, J=5.8Hz, 2H), 4.15(t, J=8.6Hz, 2H), 3.13(d, J=5.6Hz, 2H), 2.88(t, J=7.2Hz, 2H), 2.66(m, IH), 2.52(m, 1H), 2.30(m, 2H), 1.79(d, J=7Hz, 3H), 1.62(m, 8H), 1.27(s, 9H), 0.97(t, J=8.6Hz, 2H), 0.87(t, J=6.7Hz, 3H), 0.03(s, 9H). 13C NMR (100MHz, CDC13): 5199.13, 170.28, 169.48, 164.01, 159.16, 148.97, 135.68, 133.26, 129.58, 129.16, 128.37, 126.96, 124.69, 72.06, 63.07, 53.36, 44.12, 39.61 , 37.75, 32.19, 31.56, 28.87, 28.31, 27.83, 25.60, 22.51, 17.34, 13.96, - 1.55ppm. MS (EI, m z): 873 (M++l),895 (M++Na).HRMS (ESI): calcd for C43H64N409S2Si [MNa+] 895.3776, found 895.3778.
原料 (0.396g, 0.68mmol)溶解于二氯甲烷中, 加入哌啶 (0.24ml, 2.4mmol), 室温下搅拌 2 小时。 直接旋干, 快速柱层析 (石油醚:乙酸乙酯 =10: 1, 二氯甲烷:甲醇 =10: 1 )。 得到无色液 体 0.23g, 产率 80%。
氩气保护下, 上一步得到的化合物 (0.212g, 0.35mmol)溶于无水二氯甲烷中, 在 0 °C条件 下, 依次加入化合物 (0.145g, 0.42mmol), HATU(0.2g, 0.53mmol), HOAt(0.073g, 0.53mmol), DIPEA(0.18ml, 1.05mmol), 1小时后室温下搅拌过夜。 依次用稀盐酸洗涤, 饱和 NaCl洗涤, 无水 Na2S04干燥, 过滤, 减压旋干后柱层析 (石油醚:乙酸乙酯 =2: 1 ), 得到固体 0.241g, 产 率 75%。
[a]23D: 5.4 (c 0.9, CHC13). 1H NMR (400MHz, CDC13): 58.47(s, 1H), 8.13(d, J=8.4Hz, 1H), 8.07(s, IH), 7.80(d, J=8.0Hz, 1H), 7.7 l (d, J=8.0Hz, 1H), 7.45(m, 2H), 7.26(m, 2H), 6.73(d, J=7.5Hz, 1H), 6.51 (m, IH), 5.6-5.42(m, 3H), 5.17(dd, J=7.4Hz, 15.5Hz, IH), 4.99(m,lH), 4.58(d, J=5.8Hz, 2H),
4.09(m, 2H), 3.61 (dd, J=5.9Hz, 14Hz, 1H), 3.48(m, 2H), 2.52(m, 3H), 2.38(dd, J=6.5Hz, 15.6Hz, 1H), 2.21 (m, 2H), 1.75(d, J=7Hz, 3H), 1.62(m, 2H), 1.47(s, 9H), 1.24(m, 8H), 0.92(t, J=6.7Hz, 2H), 0.85(m, 3H), 0.02(s, 9H).ppm. 13C NMR (100MHz, CDC13): 5199.10, 170.66, 170.24, 169.47, 165.65, 164.37, 159.20, 155.82, 148.83, 133.76, 132.61 , 132.26, 132.12, 130.06, 128.98, 128.02, 126.30, 125.60, 125.17, 124.62, 123.65, 71.89, 70.98, 62.92, 61.65, 60.27, 53.55, 44.05, 42.29, 39.44, 38.51, 35.15, 32.11, 31.52, 28.81, 28.30, 27.78, 25.56, 22.61 , 17.22, 13.97, -1.58ppm. MS (EI, m/z): 923 (M++1).HRMS (ESI): calcd for C47H66N409S2Si [MNa+] 945.3933, found 945.3934.
原料 (0.464g, 0.55mmol)溶解于二氯甲烷中, 加入哌啶 (0.27ml, 2.75mmol), 室温下搅拌 2 小时。 直接旋干, 快速柱层析 (石油醚:乙酸乙酯 =10: 1, 二氯甲烷:甲醇 =10: 1 )。 得到无色液 体 0.2962g, 产率 87%。
氩气保护下, 上一步得到的化合物 (0.296g, 0.48mmol)溶于无水二氯甲烷中, 在 0 °C条件 下,依次加入化合物 (0.197g, 0.576mmol), HATU(0.274g, 0.72mmol), HOAt(0.098g, 0.72mmol), DIPEA(0.24ml, 1.44mmol), 1小时后室温下搅拌过夜。 依次用稀盐酸洗涤, 饱和 NaCl洗涤, 无水 Na2S04干燥, 过滤, 减压旋干后柱层析 (石油醚:乙酸乙酯 =2: 1 ), 得到固体 0.192g, 产 率 42%。
[a]23D: 4.7 (c 0.86, CHC13). 1H NMR (400MHz, CDC13): 58.44(s, 1H), 8.08(s, 1H), 6.95(d, J=8.3Hz, 2H), 6.76(d, J=8.3Hz, 2H), 6.58(m, 1H), 6.50(d, J=7.0Hz, 1H), 5.75(m, 1H), 5.59(m, 2H), 5.47(dd, J=7.5Hz, 15.3Hz, 1H), 4.83(m, 1H), 4.55(m, 2H), 4.14(t, J=8.5Hz, 2H), 3.07(m, 2H), 2.88(t, J=7.2Hz, 2H), 2.65(dd, J=7.2Hz, 15.6Hz, 1H), 2.51 (m, 3H), 2.29(m, 2H), 1.77(d, J=7.1Hz, 3H), 1.62(m, 2H), 1.47(m, 8H), 1.28(s, 18H), 0.96(t, J=8.6Hz, 2H), 0.85(m, 3H), 0.02(s, 9H).ppm. 13C NMR (125MHz, CDC13): 5199.15, 170.24, 169.48, 163.80, 159.05, 154.21, 148.74, 133.35, 130.39, 130.01 , 128.15, 124.071, 78.49, 72.02, 63.09, 53.02, 44.08, 39.58, 38.55, 36.82, 32.19, 31.54, 28.83, 28.29, 27.79, 25.57, 22.51, 17.27, 14.02, - 1.60ppm. MS (EI, m/z): 945 (M++l). HRMS (ESI): calcd for C47H72N4O10S2S1 [MNa+] 967.4351 , found 967.4354.
将 170mg(0.25mmol, leq)原料溶于 2ml无水乙腈中峰回路转入 0.1ml哌啶,常温下搅拌 2h后减 压旋干溶剂,加入 5ml无水二氯甲烷,于 0 °C加入 85mg (S)-2-(2-(((tert-butoxycarbonyl)amino)- -methyl)thiazole-4-carboxamido) butanoic acid (0.25mmol, leq), 然后依次力口入 51mg HOAT(0.375mmol, 1.5eq), 143mg HATU(0.375mmol, 1.5eq>^ 0.12ml DIPEA(0.75mmol, 3eq). 投毕,将反应升到常温反应 2h 后,加入 15ml 二氯甲烷稀释,依次用稀 HCl(20mlX2),饱和 NaC120mlX2)萃取.无水硫酸钠干燥,减压旋干溶剂.柱层析 (乙酸乙酯:石油醚 =1 :2)得到 155mg 无色液体,产率 81.7% . =-24.2 1H-NMR (400 MHz, CDC13) δ 8.68(s, 1-H), 7.96(s, 1-H), 7.11 (s, 1-H), 6.66(q, 1-H),
5.97(m, 1-H), 5.66(q, 1-H), 5.55(q, 1-H), 5.42(dd, 1-H), 4.50(d, 2-H), 4.07(t, 2-H), 3.99(t, 2-H), 2.82(t, 2-H), 2.70(dd, 1-H), 2.58(dd, 1-H), 2.55(t, 2-H), 2.22(m, 2-H), 1.73(d, 3-H), 1.57(t, 2-H), 1.55(s, 9-H), 1.28(m, 8-H), 0.99(t, 2-H), 0.87(t, 3-H), 0.02(s, 9-H); 13C-NMR (500 MHz, CDC1 3) δ 199.2, 170.2, 169.6, 169.0, 164.7, 159.6, 155.8, 148.6, 132.7, 131.1, 128.9, 128.1, 124.8, 80.2, 71.7, 63.1 , 60.3, 47.0, 44.0, 42.2, 39.5, 38.5, 32.1, 31.5, 28.8(2C), 28.3, 27.7, 25.6, 22.5, 20.9, 17.3, 14.9, 14.0, 13.8, - 1.69(3C); MS(ESI) m/z 805.2 (100%) (M+H)+.
将 180mg(0.35mmol, leq)原料溶于 2ml无水乙腈中峰回路转入 0.1ml哌啶,常温下搅拌 2h后减 压旋干溶剂,加入 5ml无水二氯甲烷,于 0 °C加入 179mg (S)-2-(2-(((tert-butoxycarbonyl)amino) -methyl)thiazole-4-carboxamido) butanoic acid (0.525mmol, 1.5eq),然后依次力口入 95mg HOAT(0.7mmol, 2eq), 266mg HATU(0.7mmol, 2eq)^ 0.12ml DIPEA(q.4mmol, 4eq).投毕,将反 应升到常温反应 2h后,加入 15ml二氯甲烷稀释,依次用稀 HCl(20mlX2),饱和 NaC120mlX2)萃取.
无水硫酸钠干燥,减压旋干溶剂.柱层析(乙酸乙酯:石油醚 =1 :2)得到 l lOmg 无色液体,产率 81.7% .
[«]s =-20.2 1H-NMR (400 MHz, CDC13) δ 8.68(s, 1-Η), 8.85(d, 1-Η), 8.01 (s, 1-Η), 5.78(m, 1-Η),
5.60(m, 4-Η), 5.13(q, 1-Η), 4.56(s, 2-Η), 4.13(t, 2-Η), 3.01 (s, 2-Η), 2.88(t, 3-Η), 2.66(m, 1-Η), 2.56(m, 3-Η), 2.50(q, 2-Η), 2.28(m, 1-Η), 1.93(d, 3-Η), 1.55(s, 11-Η), 1.28(m, 8-Η), 0.99(t, 2-Η), 0.87(t, 3-Η), 0.02(s, 9-H); 13C-NMR (500 MHz, CDC13) δ 199.3, 170.2, 169.6, 169.0, 164.7, 159.6, 155.8, 148.6, 132.7, 131.1, 128.9, 128.1, 124.8, 80.3, 71.4, 63.0, 47.0, 44.1 , 42.2, 39.7, 38.5, 32.2, 31.5, 28.8(2C), 28.3, 27.8, 25.6, 22.5, 17.3, 14.0, 13.8, 12.4, - 1.69(3C); MS(ESI) m/z 833.2 (100%) (M+H)+.
将 160mg(0.225mmol, leq)原料溶于 2ml无水乙腈中峰回路转入 0.1ml哌啶,常温下搅拌 2h后 减压旋干溶剂,加入 5ml无水二氯甲烷,于 0 °C加入 85mg (S)-2-(2-(((tert-butoxycarbonyl)amino)- -methyl)thiazole-4-carboxamido) butanoic acid (0.25mmol, l . leq),然后依次力口入 51mg HOAT(0.375mmol, 1.5eq), 143mg HATU(0.375mmol, 1.5eq>^ 0.12ml DIPEA(0.75mmol, 3eq). 投毕,将反应升到常温反应 2h 后,加入 15ml 二氯甲烷稀释,依次用稀 HCl(20mlX2),饱和 NaC120mlX2)萃取.无水硫酸钠干燥,减压旋干溶剂.柱层析 (乙酸乙酯:石油醚 =1 :2)得到 120mg 无色液体,产率 81.7% . :Β =- 17.3 1H-NMR (400 MHz, CDC13) δ 8.60(s, 1-H), 8.10(s, 1-H), 6.72(d, 1-H), 6.62(q, 1-H), 5.77(m, 1-H), 5.64(q, 1-H), 5.48(q, 1-H), 5.42(m, 1-H), 4.60(d, 3-H), 4.14(t, 2-H), 2.86(t, 2-H), 2.68(dd, 1-H), 2.56(dd, 1-H), 2.50(t, 2-H), 2.27(q, 2-H), 1.92(m, 1-H), 1.83(d, 3-H), 1.77(m, 1-H), 1.60(t, 1-H), 1.55(s, 9-H), 1.28(m, 8-H), 0.99(t, 2-H), 0.87(q, 6-H), 0.02(s, 9-H); 13C-NMR (500 MHz, CDC13) δ 199.3, 171.1, 169.6, 164.1 , 159.3, 148.9, 133.0, 129.5, 129.2, 128.3, 124.8, 80.2, 71.7, 63.1, 53.5, 44.0, 42.2, 39.6, 38.5, 32.1, 31.5, 28.8(2C), 28.3, 27.8, 25.6, 25.5, 22.5, 17.2, 14.0, 9.3, - 1.56(3C); MS(ESI) m/z 833.2 (100%) (M+H) +.
将 270mg(0.357mmol, leq)原料溶于 2ml无水乙腈中峰回路转入 0.1ml哌啶,常温下搅拌 2h后 减压旋干溶剂,加入 5ml无水二氯甲烷,于 0 °C加入 134mg (S)-2-(2-(((tert-butoxycarbonyl)amino) -methyl)thiazole-4-carboxamido) butanoic acid (0.393mmol, 1. leq),然后依次力口入 73mg HOAT(0.536mmol, 1.5eq), 203mg HATU(0. 365mmol, 1.5eq ¾ 0.18ml DIPEA(0.75mmol, 3eq). 投毕,将反应升到常温反应 2h 后,加入 15ml 二氯甲烷稀释,依次用稀 HCl(20mlX2),饱和 NaC120mlX2)萃取.无水硫酸钠干燥,减压旋干溶剂.柱层析 (乙酸乙酯:石油醚 =1 :2)得到 180mg 无色液体,产率 58.8% .
[a] =- 13.4 1H-NMR (400 MHz, CDC13) δ 8.58(s, 1-Η), 8.10(s, 1-Η), 6.93(d, 1-Η), 6.63(q, 1-Η),
5.77(m, 1-Η), 5.64(q, 1-Η), 5.48(q, 1-Η), 5.42(m, 1-Η), 4.72(q, 1-Η), 4.60(d, 2-Η), 4.14(t, 2-Η), 2.86(t, 2-Η), 2.78(s, 3-Η), 2.68(dd, 1-Η), 2.56(dd, 1-Η), 2.50(t, 4-Η), 2.27(q, 2-Η), 2.05(m, 1-Η), 2.01 (s, 3-Η), 1.89(m, 1-Η), 1.80(m, 5-Η), 1.60(m, 2-Η), 1.47(s, 9-Η), 1.26(m, 8-Η), 0.99(t, 2-Η), 0.86(t, 3-Η), 0.02(s, 9-H); 13C-NMR (500 MHz, CDC13) δ 199.3, 171.1, 169.6, 164.2, 159.3, 148.9, 133.0, 130.0, 129.0, 128.1, 124.8, 80.2, 72.0, 63.1, 52.0, 44.1, 39.6, 38.5, 32.1 , 31.5, 29.8, 28.8(2C), 28.3, 27.8, 25.6, 25.5, 17.3, 15.4, 14.0, 13.9, - 1.55(3C); MS(ESI) m/z 857.3 (100%) (M+H)+.
实施例 45
将 292mg(0.375mmol, leq)原料溶于 2ml无水乙腈中峰回路转入 0.1ml哌啶,常温下搅拌 2h后 减压旋干溶剂,加入 5ml无水二氯甲烷,于 0 °C加入 141mg (S)-2-(2-(((tert-butoxycarbonyl)amino) -methyl)thiazole-4-carboxamido) butanoic acid (0.412mmol, 1. leq),然后依次力口入 76.5mg HOAT(0.562mmol, 1.5eq), 214mg HATU(0. 362mmol, 1.5eq ¾ 0.18ml DIPEA(1.125mmol, 3eq). 投毕,将反应升到常温反应 2h 后,加入 15ml 二氯甲烷稀释,依次用稀 HCl(20mlX2),饱和 NaC120mlX2)萃取.无水硫酸钠干燥,减压旋干溶剂.柱层析 (乙酸乙酯:石油醚 =1 :2)得到 190mg
无色液体,产率 60.4% .
[α]:^=- 11.4 1H-NMR (400 MHz, CDC13) δ 8.63(s, 1-H), 8.06(s, 1-H), 6.67(d, 1-H), 6.60(q, 1-H),
5.74(m, 1-H), 5.58(q, 1-H), 5.48(q, 1-H), 5.42(m, 1-H), 4.72(q, 1-H), 4.60(d, 2-H), 4.14(t, 2-H), 2.85(t, 2-H), 2.68(dd, 1-H), 2.56(dd, 1-H), 2.50(t, 2-H), 2.27(q, 2-H), 2.07(s, 1-H), 1.78(s, 3-H), 1.65(m, 6-H), 1.45(s, 9-H), 1.26(m, 8-H), 0.99(t, 2-H), 0.91 (t, 6-H), 0.86(t, 3-H), 0.02(s, 9-H); 13C-NMR (500 MHz, CDC13) δ 199.3, 171.7, 169.8, 164.2, 159.3, 155.7, 132.9, 129.8, 129.0, 128.3 124.8, 80.4, 71.7, 63.1, 51.1 , 44.1 , 42.3, 41.5, 39.6, 32.1, 31.5, 29.8, 28.8(2C), 27.8, 25.6, 25.5, 24.7, 22.8, 22.5, 22.0, 17.3, 14.04, 13.98, - 1.57(3C); MS(ESI) m/z 839.3 (100%) (M+H)+.
实施例 46
将 320mg(0.433mmol, leq)原料溶于 10ml无水乙腈中峰回路转入 0.4ml哌啶,常温下搅拌 2h后 减压旋干溶剂,加入 5ml无水二氯甲烷,于 0 °C加入 295mg (S)-2-(2-(((tert-butoxycarbonyl) amino)methyl)thiazole-4-carboxamido) butanoic acid (0.866mmol, 2eq),然后依次力口入 118mg HOAT(0.866mmol, 2eq), 330mg HATU(0. 0.866mmol, 2eq>^ 0.29ml DIPEA(1.732mmol, 4eq). 投毕,将反应升到常温反应 2h 后,加入 15ml 二氯甲烷稀释,依次用稀 HCl(20mlX2),饱和 NaC120mlX2)萃取.无水硫酸钠干燥,减压旋干溶剂.柱层析 (乙酸乙酯:石油醚 =1 :2)得到 57mg无 色液体,产率 15.8% .
1H-NMR (400 MHz, CDC13) δ 8.77(s, 1-H), 8.03(s, 1-H), 6.67(d, 1-H), 6.60(q, 1-H),
5.74(m, 1-H), 5.58(q, 1-H), 5.48(q, 1-H), 5.42(m, 1-H), 4.72(q, 1-H), 4.60(d, 2-H), 4.14(t, 2-H), 2.85(t, 2-H), 2.68(dd, 1-H), 2.56(dd, 1-H), 2.50(t, 2-H), 2.27(q, 2-H), 2.07(s, 1-H), 1.78(s, 3-H), 1.65(m, 6-H), 1.45(s, 9-H), 1.26(m, 8-H), 0.99(t, 2-H), 0.91 (t, 6-H), 0.86(t, 3-H), 0.02(s, 9-H); 13C-NMR (500 MHz, CDC13) δ 199.3, 171.7, 169.8, 164.2, 159.3, 155.7, 132.9, 129.8, 129.0, 128.3, 124.8, 80.4, 71.7, 63.1, 51.1 , 44.1 , 42.3, 41.5, 39.6, 32.1, 31.5, 29.8, 28.8(2C), 27.8, 25.6, 25.5, 24.7, 22.8, 22.5, 22.0, 17.3, 14.04, 13.98, - 1.57(3C); MS(ESI) m/z 839.3 (100%) (M+H)+.
原料 (1.45g, 2mmol)溶解于二氯甲烷中, 加入哌啶 (lml, lOmmol), 室温下搅拌 2小时。 直 接旋干, 快速柱层析 (石油醚:乙酸乙酯 =10: 1, 二氯甲烷:甲醇 =10: 1 )。 得到无色液体 0.776g, 产率 78%。
氩气保护下, 上一步得到的化合物 (0.535g, 0.74mmol)溶于无水二氯甲烷中, 在 0 °C条件 下,依次加入化合物 (0.356g, 0.9mmol), HATU(0.0.423g, 1.12mmol), HOAt(0.152g, 1.12mmol), DIPEA(0.4ml, 2.22mmol), 1小时后室温下搅拌过夜。 依次用稀盐酸洗涤, 饱和 NaCl洗涤, 无水 Na2S04干燥, 过滤, 减压旋干后柱层析 (石油醚:乙酸乙酯 =4: 1 )。 得到固体 0.455g, 产 率 78%。
[a]23D: -23.6 (c= 5, CHC13). 1H NMR (400MHz, CDC13): 58.60(s,lH), 8.10(s, lH), 6.60(m, 2H), 5.77(m, 1H), 5.62(dd, J=13.7Hz 7.2Hz,lH), 5.49(dd, J=13.7Hz 7.5Hz,lH), 5.42(m, 1H), 4.58(m, 3H), 4.14(t, J=8.6Hz, 2H), 2.85(t, J=7.2Hz, 2H), 2.68(dd, J=15.7Hz 7.7Hz, 2H), 2.50(t, J=7.5Hz, 2H), 2.26(q, J=7.1Hz, 2H), 2.18(m, 1H), 1.80(d, J=7Hz, 3H), 1.60(m, 2H), 1.46(m, 8H), 1.26(m, 9H), 0.96(m, 3H), 0.86(t, J=6.1Hz, 6H), 0.02(s, 9H)ppm. 13C NMR (125 MHz, CDC13): 5199.25, 170.70, 169.55, 164.33, 159.26, 148.88, 133.30, 129.39, 129.21, 128.30, 124.75, 71.77, 63.11, 57.16, 44.08, 39.63, 38.55, 32.13, 31.59, 31.55, 28.84, 28.28, 27.82, 25.58, 22.52, 18.91, 17.58, 17.26, 13.99, 13.94, 0.96, - 1.57ppm. MS (EI, m/z): 831 (M++Na).
原料 (1.45g, 2mmol)溶解于二氯甲烷中, 加入哌啶 (lml, lOmmol), 室温下搅拌 2小时。 直 接旋干, 快速柱层析 (石油醚:乙酸乙酯 =10: 1, 二氯甲烷:甲醇 =10: 1 )。 得到无色液体 0.776g, 产率 78%。
氩气保护下, 上一步得到的化合物 (0.593g, 0.82mmol)溶于无水二氯甲烷中, 在 0 °C条件 下,依次加入化合物 (0.452g, 0.99mmol), HATU(0.465g, 1.23mmol), HOAt(0.167g, 1.23mmol), DIPEA(0.44ml, 2.44mmol), 1小时后室温下搅拌过夜。 依次用稀盐酸洗涤, 饱和 NaCl洗涤, 无水 Na2S04干燥, 过滤, 减压旋干后柱层析 (石油醚:乙酸乙酯 =4: 1 )。 得到固体 0.412g, 产 率 61 %。
[a]23D: -9.1 (c= 5, CHC13). 1H NMR (400MHz, CDC13): δ 8.60(s, lH), 6.60(m, 2H), 5.77(m, 1H), 5.66(dd,lH), 5.41(m, 1H), 4.34(m, 3H), 4.24(t, 2H), 3.7(m, 1H), 2.75(t, 2H), 2.68(dd, 2H), 2.50(t, J=7.5Hz, 2H), 2.26(q, 2H), 2.18(m, 1H), 1.80(d, J=7Hz, 3H), 1.60(m, 2H), 1.46(m, 8H), 1.26(m, 9H), 1.12(d, 3H), 0.96(m, 3H), 0.86(t, 6H), 0.02(s, 9H)ppm. 13C NMR (125 MHz, CDC13): 5199.5, 170.7, 169.4, 162.3, 159.2, 148.8, 133.3, 129.3, 129.2, 128.3, 124.7, 71.7, 63.1 , 57.6, 44.0, 39.6, 38.5, 32.1, 31.5, 31.5, 28.8, 28.2, 27.8, 25.5, 22.5, 22.3, 18.9, 17.5, 17.2, 13.9, 13.9, 0.9ppm. MS (EI, m/z) 847 (M++Na).
原料 (1.45g, 2mmol)溶解于二氯甲烷中, 加入哌啶 (lml, lOmmol), 室温下搅拌 2小时。 直 接旋干, 快速柱层析 (石油醚:乙酸乙酯 =10: 1, 二氯甲烷:甲醇 =10: 1 )。 得到无色液体 0.776g, 产率 78%。
氩气保护下, 上一步得到的化合物 (0.412g, 0.57mmol)溶于无水二氯甲烷中, 在 0 °C条件 下,依次加入化合物 (0.352g, 0.69mmol), HATU(0.326g, 0.86mmol), HOAt(0.117g, 0.86mmol), DIPEA(0.31ml, 1.71mmol), 1小时后室温下搅拌过夜。 依次用稀盐酸洗涤, 饱和 NaCl洗涤, 无水 Na2S04干燥, 过滤, 减压旋干后柱层析 (石油醚:乙酸乙酯 =4: 1 )。 得到固体 0.335g, 产 率 70%。
[a]23D: - 14.3 (c= 5, CHC13). 1H NMR (400MHz, CDC13): δ 8.60(s, lH), 6.60(m, 2H), 5.77(m, 1H), 5.66(dd,lH), 5.41(m, 1H), 4.34(m, 3H), 4.24(t, 2H), 3.7(m, 1H), 2.75(t, 2H), 2.68(dd, 2H), 2.50(t, 2H), 2.26(q, 2H), 2.18(m, 1H), 1.80(d, 3H), 1.60(m, 2H), 1.46(m, 8H), 1.26(m, 9H), 1.12(d, 3H), 0.96(m, 3H), 0.86(t, 6H), 0.02(s, 9H)ppm. 13C NMR (125 MHz, CDC13): 5199.6, 170.7, 169.4,
162.3, 159.2, 148.8, 133.3, 129.3, 129.2, 128.3, 124.7, 71.7, 63.1 , 57.6, 44.0, 39.5, 38.5, 32.1, 31.5 31.5, 28.8, 28.2, 27.8, 25.5, 22.5, 22.3, 18.9, 17.5, 16.2, 13.9, 13.9, 0.9ppm. MS (EI, mJz):
863(M++Na).
原料 (1.45g, 2mmol)溶解于二氯甲烷中, 加入哌啶 (lml, lOmmol), 室温下搅拌 2小时。 直 接旋干, 快速柱层析 (石油醚:乙酸乙酯 =10: 1, 二氯甲烷:甲醇 =10: 1 )。 得到无色液体 0.776g, 产率 78%。
氩气保护下, 上一步得到的化合物 (0.412g, 0.45mmol)溶于无水二氯甲烷中, 在 0 °C条件 下,依次加入化合物 (0.332g, 0.55mmol), HATU(0.261g, 0.69mmol), HOAt(0.094g, 0.69mmol), DIPEA(0.25ml, 1.37mmol), 1小时后室温下搅拌过夜。 依次用稀盐酸洗涤, 饱和 NaCl洗涤, 无水 Na2S04干燥, 过滤, 减压旋干后柱层析 (石油醚:乙酸乙酯 =4: 1 )。 得到固体 0.265g, 产 率 73%。
[a]23D: -21.3 (c= 5, CHC13). 1H NMR (400MHz, CDC13): δ 8.60(s, lH), 7.55(m, 2H), 5.77(m, 1H), 5.66(dd, 1H), 5.41 (m, 1H), 4.34(m, 3H), 4.24(t, 2H), 3.7(m, 1H), 3.0(t, 2H), 2.68(dd, 2H), 2.50(t, 2H), 2.26(q, 2H), 2.18(m, 1H), 1.80(d, 3H), 1.60(m, 2H), 1.46(m, 8H), 1.26(m, 9H), 1.12(d, 3H), 0.96(m, 3H), 0.86(t, 6H), 0.02(s, 9H)ppm. 13C NMR (125 MHz, CDC13): 5199.2, 180.3, 170.3, 169.4, 162.3, 159.2, 148.8, 133.3, 129.3, 129.2, 128.3, 124.7, 71.7, 63.1 , 57.6, 44.0, 39.5, 38.5, 32.1 , 31.5, 31.5, 28.8, 28.2, 27.8, 25.5, 22.5, 22.3, 18.9, 17.5, 16.2, 13.9, 13.9, 0.9ppm. MS (EI, mJz): 822 (M++Na).
实施例 51
原料 (1.45g, 2mmol)溶解于二氯甲烷中, 加入哌啶 (lml, lOmmol), 室温下搅拌 2小时。 直 接旋干, 快速柱层析 (石油醚:乙酸乙酯 =10: 1, 二氯甲烷:甲醇 =10: 1 )。 得到无色液体 0.776g, 产率 78%。
氩气保护下, 上一步得到的化合物 (0.412g, 0.45mmol)溶于无水二氯甲烷中, 在 0 °C条件 下,依次加入化合物 (0.313g, 0.55mmol), HATU(0.261g, 0.69mmol), HOAt(0.094g, 0.69mmol), DIPEA(0.25ml, 1.37mmol), 1小时后室温下搅拌过夜。 依次用稀盐酸洗涤, 饱和 NaCl洗涤, 无水 Na2S04干燥, 过滤, 减压旋干后柱层析 (石油醚:乙酸乙酯 =4: 1 )。 得到固体 0.265g, 产 率 73%。
[a]23D: -22.1 (c= 5, CHC13). 1H NMR (400MHz, CDC13): δ 8.60(s, lH), 7.55(m, 2H), 5.77(m, 1H), 5.66(dd, 1H), 5.41 (m, 1H), 4.34(m, 3H), 4.24(t, 2H), 3.7(m, 1H), 3.0(t, 2H), 2.68(dd, 2H), 2.50(t, 2H), 2.26(q, 2H), 2.18(m, 1H), 1.80(d, 3H), 1.60(m, 2H), 1.46(m, 8H), 1.26(m, 9H), 1.12(d, 3H), 0.96(m, 3H), 0.86(t, 6H), 0.02(s, 9H)ppm. 13C NMR (125 MHz, CDC13): 5199.2, 180.3, 170.3, 169.4, 162.3, 159.2, 148.8, 133.3, 129.3, 129.2, 128.3, 124.7, 71.7, 63.1 , 57.6, 44.0, 39.5, 38.5, 32.1 , 31.5, 31.5, 28.8, 28.2, 27.8, 25.5, 22.5, 22.3, 18.9, 17.5, 16.2, 13.9, 13.9, 0.9ppm. MS (EI, mJz): 822 (M++Na).
原料 (1.45g, 2mmol)溶解于二氯甲烷中, 加入哌啶 (lml, lOmmol), 室温下搅拌 2小时。 直 接旋干, 快速柱层析 (石油醚:乙酸乙酯 =10: 1, 二氯甲烷:甲醇 =10: 1 )。 得到无色液体 0.776g, 产率 78%。
氩气保护下, 上一步得到的化合物 (0.412g, 0.585mmol)溶于无水二氯甲烷中, 在 0 °C条件 下, 依次加入化合物 (0485g, 0.72mmol), HATU(0.34g, 0.9mmol), HOAt(0.122g, 0.9mmol), DIPEA(0.33ml, 1.78mmol), 1小时后室温下搅拌过夜。 依次用稀盐酸洗涤, 饱和 NaCl洗涤, 无水 Na2S04干燥, 过滤, 减压旋干后柱层析 (石油醚:乙酸乙酯 =4: 1 )。 得到固体 0.392g, 产 率 82%。
[a]23D: -39.1 (c= 5, CHC13). 1H NMR (400MHz, CDC13): δ 8.40(s, lH), 7.84(d, 1H), 7.75(s, 1H), 7.41 (m, 2H), 5.79(m, 2H), 5.66(dd, 1H), 5.32(m, 1H), 4.3 l (m, 3H), 4.24(t, 2H), 3.1(t, 2H), 2.68(dd,
2H), 2.50(t, 2H), 2.26(q, 2H), 2.18(m, 1H), 1.80(d, 3H), 1.60(m, 2H), 1.46(m, 8H), 1.26(m, 9H), 1.12(d, 3H), 0.96(m, 3H), 0.86(t, 6H), 0.02(s, 9H)ppm. 13C NMR (125 MHz, CDC13): 5199.3, 173.3 171.6, 166.8, 162.5, 156.9, 141.9, 134.1, 131.5, 130.6, 130.4, 128.9, 125.7, 125.4, 120.3, 19.6, 73.8, 67.8, 61.7, 44.9, 44.6, 38.4, 37.9, 31.8, 30.6, 30.4, 29.5, 28.5, 26.3, 22.9, 22.7, 19.8, 14.1 , 13.2, 1.5ppm. MS (EI, m/z): 818 (M++l).
原料 (1.45g, 2mmol)溶解于二氯甲烷中, 加入哌啶 (lml, lOmmol), 室温下搅拌 2小时。 直 接旋干, 快速柱层析 (石油醚:乙酸乙酯 =10: 1, 二氯甲烷:甲醇 =10: 1 )。 得到无色液体 0.776g, 产率 78%。
氩气保护下, 上一步得到的化合物 (0.412g, 0.76mmol)溶于无水二氯甲烷中, 在 0 °C条件 下, 依次加入化合物 (0.512g, 0.936mmol), HATU(0..442g, 1.17mmol), HOAt(0.159g, 1.17mmol), DIPEA(0.43ml, 2.31mmol), 1小时后室温下搅拌过夜。 依次用稀盐酸洗涤, 饱和 NaCl洗涤, 无水 Na2S04干燥, 过滤, 减压旋干后柱层析(石油醚:乙酸乙酯 =4: 1 )。 得到固体 0.46g, 产率 74%。
[a]23D: - 12.9 (c= 5, CHC13). 1H NMR (400MHz, CDC13): δ 8.90(d, 1H), 8.15(s,lH), 7.75(s, 1H), 5.75(m, 2H), 5.63(dd, 1H), 5.32(m, 1H), 4.31(m, 3H), 4.24(t, 2H), 3.1 (t, 2H), 2.68(dd, 2H), 2.50(t, 2H), 2.26(q, 2H), 2.18(m, 1H), 1.80(d, 3H), 1.60(m, 2H), 1.46(m, 8H), 1.26(m, 9H), 1.12(d, 3H), 0.96(m, 3H), 0.86(t, 6H), 0.02(s, 9H)ppm. 13C NMR (125 MHz, CDC13): 5199.1 , 173.3, 171.6, 166.8, 162.5, 156.9, 156.2, 149.2, 144.6, 131.5, 130.6, 130.4, 128.9, 125.7, 125.4, 120.3, 19.6, 73.8, 67.8, 61.7, 44.9, 44.6, 38.4, 37.9, 31.8, 30.6, 30.4, 29.5, 28.5, 26.3, 22.9, 22.7, 19.8, 14.1 , 13.2, 1.5ppm. MS (EI, m/z): 819 (M++l).
实施例 54
1.10% piperidine,DCM
2.HATU, HOAt, DIPEA:
Si—
NHBoc 原料 (1.45g, 2mmol)溶解于二氯甲烷中, 加入哌啶 (lml, lOmmol), 室温下搅拌 2小时。 直接旋干,快速柱层析(石油醚:乙酸乙酯 =10:1,二氯甲烷:甲醇 =10:1 )。得到无色液体 0.776g, 产率 78%。
氩气保护下, 上一步得到的化合物 (0.283g, 0.57mmol)溶于无水二氯甲烷中, 在 0°C条件 下, 依次加入化合物 (0.214g, 0.69mmol), HATU(0.325g, 0.86mmol), HOAt(0.117g, 0.86mmol), DIPEA(0.3ml, 1.71mmol), 1小时后室温下搅拌过夜。 依次用稀盐酸洗涤, 饱和 NaCl洗涤, 无水 Na2S04干燥, 过滤, 减压旋干后柱层析 (石油醚:乙酸乙酯 =4:1 )。 得到固体 0.377g, 产 率 80%
[a]23D: -22.0 (c= 5, CHC13). 1H NMR (400MHz, CDC13): δ 8.78(s, 1H), 5.74(m, 1H), 5.63(dd, 1H), 5.32(m, 1H), 4.3 l(m, 3H), 4.24(t, 2H), 3.1(t, 2H), 2.68(dd, 2H), 2.50(t, 2H), 2.26(q, 2H), 2.18(m, 1H), 1.80(d, 3H), 1.60(m, 2H), 1.46(m, 8H), 1.26(m, 9H), 1.12(d, 3H), 0.96(m, 3H), 0.86(t, 6H), 0.02(s, 9H)ppm. 13C NMR (125 MHz, CDC13): 5199.5, 173.5, 171.8, 165.9, 161.2, 156.3, 148.9, 130.1, 128.6, 124.2, 79.5, 73.9, 67.5, 61.2, 60.2, 44.1, 41.5, 37.8, 31.4, 30.7, 30.5, 29.5, 29.1, 28.5, 26.3, 25.3, 22.6, 22.1, 19.5, 14.2, 9.1, 1.5ppm. MS (EI, mJz): 827 (M++l).
实施例 55
原料 (1.45g, 2mmol)溶解于二氯甲烷中, 加入哌啶 (lml, lOmmol), 室温下搅拌 2小时。 直接旋干,快速柱层析(石油醚:乙酸乙酯 =10:1,二氯甲烷:甲醇 =10:1 )。得到无色液体 0.776g, 产率 78%。
氩气保护下, 上一步得到的化合物 (0.212g, 0.43mmol)溶于无水二氯甲烷中, 在 0°C条件 下, 依次加入化合物 (0.16g, 0.52mmol), HATU(0.244g, 0.65mmol), HOAt(0.088g, 0.65mmol), DIPEA(0.23ml, 1.28mmol), 1小时后室温下搅拌过夜。 依次用稀盐酸洗涤, 饱和 NaCl洗涤,
无水 Na2S04干燥, 过滤, 减压旋干后柱层析 (石油醚:乙酸乙酯 =4: 1 )。 得到固体 0.306g, 产 率 89%。
[a]23D: -22.0 (c= 5, CHC13). 1H NMR (400MHz, CDC13): δ 8.74(s, 1H), 5.74(m, 1H), 5.63(dd, 1H), 5.32(m, 1H), 4.3 l (m, 3H), 4.24(t, 2H), 3.1(t, 2H), 2.68(dd, 2H), 2.50(t, 2H), 2.26(q, 2H), 2.18(m, 1H), 1.46(m, 8H), 1.26(m, 9H), 1.12(d, 3H), 0.96(m, 3H), 0.86(t, 6H), 0.02(s, 9H)ppm. 13C NMR (125 MHz, CDC13): 5199.5, 173.5, 171.8, 165.9, 161.2, 156.3, 148.9, 130.1 , 128.6, 124.2, 79.5, 73.9, 67.5, 61.2, 60.2, 44.1, 41.5, 37.8, 31.4, 30.7, 30.5, 29.5, 28.5, 26.3, 25.3, 22.6, 19.5, 14.2, 9.1, 1.5ppm. MS (EI, m/z): 799 (M++l).
实施例 56
原料 (1.45g, 2mmol)溶解于二氯甲烷中, 加入哌啶 (lml, lOmmol), 室温下搅拌 2小时。 直接旋干,快速柱层析(石油醚:乙酸乙酯 =10: 1,二氯甲烷:甲醇 =10: 1 )。得到无色液体 0.776g, 产率 78%。
氩气保护下, 上一步得到的化合物 (0.425g, 0.86mmol)溶于无水二氯甲烷中, 在 0 °C条件 下, 依次加入化合物 (0.341g, 1.04mmol), HATU(0.488g, 1.3mmol), HOAt(0.175g, 1.3mmol), DIPEA(045ml, 2.67mmol), 1小时后室温下搅拌过夜。 依次用稀盐酸洗涤, 饱和 NaCl洗涤, 无水 Na2S04干燥, 过滤, 减压旋干后柱层析 (石油醚:乙酸乙酯 =4: 1 )。 得到固体 0.446g, 产 率 64%。
[a]23D: - 12.6 (c= 5, CHC13). 1H NMR (400MHz, CDC13): δ 8.74(s, 1H), 5.74(m, 1H), 5.63(dd, 1H), 5.45-5.10(m, 3H), 4.3 l (m, 3H), 4.24(t, 2H), 3.1 (t, 2H), 2.68(dd, 2H), 2.50(t, 2H), 2.26(q, 2H), 2.18(m, 1H), 1.46(m, 8H), 1.26(m, 9H), 1.12(d, 3H), 0.96(m, 3H), 0.86(t, 6H), 0.02(s, 9H)ppm. 13C NMR (125 MHz, CDC13): 5199.5, 173.5, 171.8, 165.9, 161.2, 156.3, 148.9, 133.9, 130.1, 128.6, 124.2, 104.6, 79.5, 73.9, 67.5, 61.2, 60.2, 44.1, 41.5, 37.8, 31.4, 30.7, 30.5, 29.5, 28.5, 26.3, 25.3, 22.6, 19.5, 14.2, 9.1, 1.5ppm. MS (EI, m/z): 811 (M++1).
实施例 57
1 .10% piperidine, DCM
2.HATU, HOAt, DIPEA.
Si—
C7H C7H NHBoc 原料 (1.45g, 2mmol)溶解于二氯甲烷中, 加入哌啶 (lml, lOmmol), 室温下搅拌 2小时。 直 接旋干, 快速柱层析 (石油醚:乙酸乙酯 =10: 1, 二氯甲烷:甲醇 =10: 1 )。 得到无色液体 0.776g, 产率 78%。
氩气保护下, 上一步得到的化合物 (0.396g, 0.798mmol)溶于无水二氯甲烷中, 在 0 °C条件 下, 依次加入化合物 (0.352g, 0.966mmol), HATU(0.455g, 1.2mmol), HOAt(0.164g, 1.2mmol), DIPEA(0.3ml, 0.42mmol), 1小时后室温下搅拌过夜。 依次用稀盐酸洗涤, 饱和 NaCl洗涤, 无水 Na2S04干燥, 过滤, 减压旋干后柱层析 (石油醚:乙酸乙酯 =4: 1 ), 得到固体 0.581g, 产 率 84%。
[a]23D: -41.6 (c= 5, CHC13). 1H NMR (400MHz, CDC13): δ 8.74(s, 1H), 5.74(m, 2H), 5.63(dd, 1H), 4.3 l (m, 3H), 4.24(t, 4H), 3.1 (t, 2H), 2.68(dd, 2H), 2.50(t, 2H), 2.26(q, 2H), 2.18(m, 2H), 2.05(d, 3H), 1.46(m, 8H), 1.26(m, 9H), 1.12(d, 6H), 0.96(m, 6H), 0.86(t, 6H), 0.02(s, 9H)ppm. 13C NMR (125 MHz, CDC13): 5199.6, 173.5, 171.6, 169.8, 167.4, 162.9, 155.5, 147.6, 131.4, 130.4, 128.1 , 124.6, 120.5, 79.6, 73.8, 60.8, 61.5, 60.5, 44.0, 38.4, 37.9, 34.5, 31.8, 30.5, 30.1 , 29.8, 28.5, 22.5, 18.9, 18.4, 14.2, 12.9, 1.5ppm. MS (EI, mJz): 867(M++1).
原料 (1.45g, 2mmol)溶解于二氯甲烷中, 加入哌啶 (lml, lOmmol), 室温下搅拌 2小时。 直 接旋干, 快速柱层析 (石油醚:乙酸乙酯 =10: 1, 二氯甲烷:甲醇 =10: 1 )。 得到无色液体 0.776g, 产率 78%。
氩气保护下, 上一步得到的化合物 (0.24g, 0.485mmol)溶于无水二氯甲烷中, 在 0 °C条件 下, 依次加入化合物 (0.212g, 0.59mmol), HATU(0.276g, 0.731mmol), HOAt(0.1g, 0.731mmol),
DIPEA(0.255ml, 1.45mmol), 1小时后室温下搅拌过夜。 依次用稀盐酸洗涤, 饱和 NaCl洗涤, 无水 Na2S04干燥, 过滤, 减压旋干后柱层析 (石油醚:乙酸乙酯 =4: 1 ), 得到固体 0.358g, 产 率 88%。
[a]23D: -8.5 (c= 5, CHC13). 1H NMR (400MHz, CDC13): δ 8.74(s, 1H), 5.74(m, 2H), 5.63(dd, 1H), 4.3 l (m, 3H), 4.24(t, 4H), 3.1 (t, 2H), 2.68(dd, 2H), 2.50(t, 2H), 2.26(q, 2H), 2.18(m, 2H), 2.05(d, 3H), 1.54(d, 3H), 1.46(m, 8H), 1.26(m, 9H), 1.12(d, 3H), 0.96(m, 3H), 0.86(t, 6H), 0.02(s, 9H)ppm. 13C NMR (125 MHz, CDC13): 5199.6, 173.5, 171.6, 169.8, 167.4, 162.9, 155.5, 147.6, 131.4, 130.4, 128.1 , 124.6, 120.5, 79.6, 73.8, 60.8, 61.5, 60.5, 52.6, 38.4, 37.9, 34.5, 31.8, 30.5, 30.1 , 29.8, 28.5, 22.5, 18.9, 18.4, 14.2, 12.9, 1.5ppm. MS (EI, mJz): 839(M++1).
原料 (1.45g, 2mmol)溶解于二氯甲烷中, 加入哌啶 (lml, lOmmol), 室温下搅拌 2小时。 直 接旋干, 快速柱层析 (石油醚:乙酸乙酯 =10: 1, 二氯甲浣:甲醇 =10: 1 ), 得到无色液体 0.776g, 产率 78%。
氩气保护下, 上一步得到的化合物 (0.318g, 0.64mmol)溶于无水二氯甲烷中, 在 0 °C条件 下, 依次加入化合物 (0.295g, 0.78mmol), HATU(0.366g, 0.97mmol), HOAt(0.132g, 0.97mmol), DIPEA(0.34ml, 1.92mmol), 1小时后室温下搅拌过夜。 依次用稀盐酸洗涤, 饱和 NaCl洗涤, 无水 Na2S04干燥, 过滤, 减压旋干后柱层析 (石油醚:乙酸乙酯 =4: 1 ), 得到固体 0.474g, 产 率 81 %。
[a]23D: - 12.5 (c= 5, CHC13). 1H NMR (400MHz, CDC13): δ 8.94(s, 1H), 7.40(m, 2H), 7.29 (d, 2H), 7.25(m, 1H), 5.74(m, 2H), 5.63(dd, 1H), 4.30(m, 2H), 4.24(t, 4H), 3.23(m, 2H), 2.68(dd, 2H), 2.50(t, 2H), 2.26(q, 2H), 2.18(m, 2H), 2.05(d, 3H), 1.54(d, 3H), 1.46(m, 8H), 1.26(m, 9H), 1.12(d, 3H), 0.96(m, 3H), 0.86(t, 6H), 0.02(s, 9H)ppm. 13C NMR (125 MHz, CDC13): 5199.6, 173.5, 171.6, 169.8, 167.4, 162.9, 155.5, 147.6, 139.4, 130.4, 129.4, 128.1, 125.9, 124.6, 120.5, 79.6, 73.8, 60.8, 61.5, 60.5, 52.6, 38.4, 37.9, 34.5, 31.8, 30.5, 30.1 , 29.8, 28.5, 22.5, 18.9, 18.4, 14.2, 12.9, 1.5ppm. MS (EI, m/z): 915(M++1).
实
原料 (1.45g, 2mmol)溶解于二氯甲烷中, 加入哌啶 (lml, lOmmol), 室温下搅拌 2小时。 直 接旋干, 快速柱层析 (石油醚:乙酸乙酯 =10: 1, 二氯甲烷:甲醇 =10: 1 ), 得到无色液体 0.776g, 产率 78%。
氩气保护下, 上一步得到的化合物 (0.283g, 0.57mmol)溶于无水二氯甲烷中, 在 0 °C条件 下, 依次加入化合物 (0.453g, 0.69mmol), HATU(0.325g, 0.86mmol), HOAt(0.117g, 0.86mmol), DIPEA(0.3ml, 1.71mmol), 1小时后室温下搅拌过夜。 依次用稀盐酸洗涤, 饱和 NaCl洗涤, 无水 Na2S04干燥, 过滤, 减压旋干后柱层析 (石油醚:乙酸乙酯 =4: 1 ), 得到固体 0.298g, 产 率 53%。
[a]23D: -42.5 (c= 5, CHC13). 1H NMR (400MHz, CDC13): δ 8.94(s, 1H), 7.18(m, 2H), 6.95 (d, 2H), 5.74(m, 2H), 5.63(dd, 1H), 4.30(m, 2H), 4.24(t, 4H), 3.23(m, 2H), 2.68(dd, 2H), 2.50(t, 2H), 2.26(q, 2H), 2.18(m, 2H), 2.05(d, 3H), 1.54(d, 3H), 1.46(m, 8H), 1.26(m, 9H), 1.12(d, 6H), 0.96(m, 3H), 0.86(t, 6H), 0.02(s, 9H)ppm. 13C NMR (125 MHz, CDC13): 5199.6, 173.5, 171.6, 169.8, 167.4, 162.9, 155.5, 147.6, 139.4, 130.4, 129.4, 124.6, 120.5, 79.6, 73.8, 60.8, 61.5, 60.5, 52.6, 38.4, 37.9, 34.5, 31.8, 30.5, 30.1, 29.8, 28.5, 27.6, 22.5, 18.9, 18.4, 14.2, 12.9, 1.5ppm. MS (EI, mJz):
987(M++1).
实施例 61
原料 (1.28g, 2mmol)溶解于二氯甲烷中, 加入哌啶 (lml, lOmmol), 室温下搅拌 2小时。 直 接旋干, 快速柱层析 (石油醚:乙酸乙酯 =10: 1, 二氯甲烷:甲醇 =10: 1 ), 得到无色液体 0.626g,
产率 75%。
氩气保护下,上一步得到的化合物 (0.626g, 1.5mmol)溶于无水二氯甲烷中,在 0 °C条件下, 依次加入化合物 (1.62g, 1.56mmol), HATU(0.855g, 2.26mmol), HOAt(0.117g, 2.26mmol), DIPEA(0.79ml, 4.5mmol), 1小时后室温下搅拌过夜。 依次用稀盐酸洗涤, 饱和 NaCl洗涤, 无水 Na2S04干燥, 过滤, 减压旋干后柱层析(石油醚:乙酸乙酯 =4: 1 ), 得到固体 1.05g, 产率 91 %。
[a]23D: - 15.3 (c= 0.5, CHC13). 1H NMR (400MHz, CDC13): 58.60(s,lH), 8.10(s, lH), 6.60(m, 2H), 5.77(m, 1H), 5.62(dd, 1H), 5.49(dd, 1H), 5.42(m, 1H), 4.58(m, 3H), 4.14(t, 2H), 2.85(t, 2H), 2.68(dd, 2H), 2.50(t, 2H), 2.31(s, 3H), 2.18(m, 1H), 1.60(m, 2H), 1.46(m, 8H), 1.26(m, 9H), 0.96(m, 3H), 0.86(t, J=6.1Hz, 6H), 0.02(s, 9H)ppm. 13C NMR (125 MHz, CDC13): 5199.25, 170.70, 169.55, 164.33, 159.26, 148.88, 133.30, 129.39, 129.21, 128.30, 124.75, 71.77, 63.11, 57.16, 44.08, 39.63, 38.55, 30.5, 28.84, 28.28, 27.82, 25.58, 22.52, 18.91 , 17.58, 17.26, 13.99, 13.94, 0.96, -1.57ppm. MS (EI, m/z) 741 (M++l).
实施例 62
原料 (1.587g, 2mmol)溶解于二氯甲烷中, 加入哌啶 (lml, lOmmol), 室温下搅拌 2小时。直 接旋干, 快速柱层析 (石油醚:乙酸乙酯 =10: 1, 二氯甲烷:甲醇 =10: 1 ), 得到无色液体 0.724g, 产率 65%。
氩气保护下, 上一步得到的化合物 (0.326g, 0.57mmol)溶于无水二氯甲烷中, 在 0 °C条件 下, 依次加入化合物 (0.234g, 0.69mmol), HATU(0.325g, 0.86mmol), HOAt(0.117g, 0.86mmol), DIPEA(0.3ml, 1.71mmol), 1小时后室温下搅拌过夜。 依次用稀盐酸洗涤, 饱和 NaCl洗涤, 无水 Na2S04干燥, 过滤, 减压旋干后柱层析 (石油醚:乙酸乙酯 =4: 1 ), 得到固体 0.428g, 产 率 84%。
[a]23D: - 15.3 (c= 0.5, CHC13).. 1H NMR (400MHz, CDC13): 58.60(s,lH), 8.10(s, lH), 6.60(m, 2H), 5.77(m, 1H), 5.62(dd, J=13.7Hz 7.2Hz,lH), 5.49(dd, J=13.7Hz 7.5Hz,lH), 5.42(m, 1H), 4.58(m, 3H), 4.14(t, J=8.6Hz, 2H), 2.85(t, J=7.2Hz, 2H), 2.68(dd, J=15.7Hz 7.7Hz, 2H), 2.50(t, J=7.5Hz,
2H), 2.26(q, J=7.1Hz, 2H), 2.18(m, 1H), 1.80(d, J=7Hz, 3H), 1.60(m, 2H), 1.46(m, 20H), 1.26(m, 9H), 0.91 (m, 3H), 0.86(t, J=6.1Hz, 6H), 0.02(s, 9H)ppm. 13C NMR (125 MHz, CDC13): 5199.25 170.70, 169.55, 164.33, 159.26, 148.88, 133.30, 129.39, 129.21 , 128.30, 124.75, 71.77, 63.11, 57.16, 44.08, 39.63, 38.55, 32.13, 31.59, 31.55, 29.6, 28.84, 28.28, 27.82, 25.58, 22.52, 18.91, 17.58, 17.26, 13.99, 13.94, 0.96, - 1.57ppm. MS (EI, m/z): 895 (M++l).
原料 (1.43g, 2mmol)溶解于二氯甲烷中, 加入哌啶 (lml, lOmmol), 室温下搅拌 2小时。 直 接旋干, 快速柱层析 (石油醚:乙酸乙酯 =10: 1, 二氯甲浣:甲醇 =10: 1 ), 得到无色液体 0.711g, 产率 72%。
氩气保护下, 上一步得到的化合物 (0.281g, 0.57mmol)溶于无水二氯甲烷中, 在 0 °C条件 下, 依次加入化合物 (0.234g, 0.69mmol), HATU(0.325g, 0.86mmol), HOAt(0.117g, 0.86mmol), DIPEA(0.3ml, 1.71mmol), 1小时后室温下搅拌过夜。 依次用稀盐酸洗涤, 饱和 NaCl洗涤, 无水 Na2S04干燥, 过滤, 减压旋干后柱层析 (石油醚:乙酸乙酯 =4: 1 ), 得到固体 0.363g, 产 率 78%。
[a]23D: -35.1 (c= 0.5, CHC13).. 1H NMR (400MHz, CDC13): 58.60(s,lH), 8.10(s, lH), 7.29(d,2H), 7.21 (m, 1H), 7.11 (m,lH), 6.60(m, 2H), 5.77(m, 1H), 5.62(dd, J=13.7Hz 7.2Hz, lH), 5.49(dd, J= 13.7Hz 7.5Hz,lH), 5.42(m, 1H), 4.58(m, 3H), 4.14(t, J=8.6Hz, 2H), 3.66(s,2H), 2.85(t, J=7.2Hz, 2H), 2.68(dd, J=15.7Hz 7.7Hz, 2H), 2.50(t, J=7.5Hz, 2H), 2.26(q, J=7.1Hz, 2H), 2.18(m, 1H), 1.26(m, 9H), 0.96(m, 3H), 0.86(t, J=6.1Hz, 6H), 0.02(s, 9H)ppm. 13C NMR (125 MHz, CDC13): 5202.3, 173.7, 171.5, 167.6, 165.5, 162.6, 156.2, 147.4, 138.6, 131.4, 129.2, 127.8, 124.3, 120.5, 79.5, 73.7, 67.2, 61.5, 41.8, 38.3, 33.6, 30.7, 28.4, 22.9, 18.9, 13.1, 1.5ppm. MS (EI, m/z): 817 (M++l).
实施例 64
NHFmoc 1 .10% piperidine, DCM
2. HATU, HOAt, DIPEA;
Si— t-BuO' NHBoc t-Bu〇' 原料 1.45g, 2mmol)溶解于二氯甲烷中, 加入哌啶 (lml, lOmmol), 室温下搅拌 2小时。 直 接旋干, 快速柱层析 (石油醚:乙酸乙酯 =10:1, 二氯甲烷:甲醇 =10:1 ), 得到无色液体 1.39g, 产率 84%。
氩气保护下, 上一步得到的化合物 (0.612g, 0.74mmol)溶于无水二氯甲烷中, 在 0°C条件 下,依次加入化合物 (0.356g, 0.9mmol), HATU(0.0.423g, 1.12mmol), HOAt(0.152g, 1.12mmol), DIPEA(0.4ml, 2.22mmol), 1小时后室温下搅拌过夜。 依次用稀盐酸洗涤, 饱和 NaCl洗涤, 无水 Na2S04干燥, 过滤, 减压旋干后柱层析 (石油醚:乙酸乙酯 =4:1 ), 得到固体 0.391g, 产 率 64%。
[a]23D: -20.1 (c= 5, CHC13). 1H NMR (400MHz, CDC13): 58.76(s,lH), 8.10(s,lH), 6.60(m, 2H), 5.77(m, 1H), 5.62(dd, 1H), 5.42(m, 1H), 4.28(m, 3H), 4.14(t, 2H), 3.64(t, 2H), 2.91(t , 2H), 2.68(m, 4H), 2.50(t, 2H), 2.26(q, 2H), 2.05(d, 3H), 1.60(m, 2H), 1.26(m, 9H), 0.96(m, 3H), 0.86(t, 15H), 0.02(s, 9H)ppm. 13C NMR (125 MHz, CDC13): 5199..5, 173.2, 171.6, 147.4, 165.4, 162.6, 156.1, 147.4, 131.4, 130.2, 128.4, 124.1, 120.3, 81.8, 79.5, 73.7, 67.2, 62.6, 61.6, 45.3, 41.8, 38.3, 37.9, 30.7, 30.5, 28.4, 28.2., 22.5, 18.9, 13.0, 1.5ppm. MS (EI, mJz): 827 (M++l).
-3化合物的合成
向实施例 34制得的原料 (0.34g, 0.41mmol)的无水二氯甲垸 (5ml)溶液中, 加入 lml三氟乙 酸, 室温下搅拌 24小时。 减压旋干, 加入 5ml甲苯再旋干, 除去大量三氟乙酸。 粗产物直接 投入下一步。
氩气保护下,上一步的粗产物用 50ml无水 DMF溶解,缓慢滴入 HATU(0.78g, 2.05mmol), HOAt(0.28g, 2.05mmol), DIPEA(0.7ml, 4.1mmol)的无水 DMF溶液中, 30°C搅拌 3天。反应液
体系浓度为 0.001mol/L。 减压旋干 DMF, 乙酸乙酯溶解, 依次用稀盐酸洗涤, 饱和 NaCl洗 涤,无水 Na2S04干燥,过滤,减压旋干后柱层析(石油醚:乙酸乙酯:甲醇 =20:20: 1 ),得到 0.121g 固体 1-3, 产率 49%。
[a]23D: 19.2 (c 0.9, CHC13). 1H NMR (400MHz, CDCl3):58.54(s,lH), 8.08(s, lH), 6.97(q, J=7Hz, 1H), 6.82(m, 1H), 6.5 l (d, J=10.1Hz, lH), 5.74-5.6(m,2H), 5.47(dd, J=15.5Hz 6.8Hz, 1H), 5.14(dd, J=16Hz 8.2Hz ,1H), 4.70(dd, J=10.1Hz 3.2Hz , 1H) 4.32(dd, J=17.4Hz, 3.5Hz, 1H), 2.82(t, J=7.2Hz, 2H), 2.75-2.59(m, 2H), 2.47 (t, J=7.5Hz, 2H), 2.24(m, 2H), 1.82(d, J=7Hz, 3H), 1.58(m, 2H), 1.24(m, 8H), 0.83(m, 3H), 0.74(d, J=6.7Hz,3H), 0.55(d, J=6.7Hz,3H)ppm. 13C NMR (125MHz, CDC13): 5199.39, 169.69, 169.04, 167.46, 163.37, 158.79, 147.85, 134.59, 132.54, 128.20, 127.12, 124.35, 71.77, 56.96, 43.98, 40.69, 40.01, 32.10, 31.52, 28.74, 27.67, 25.49, 22.42, 18.90, 16.31 , 14.53, 13.91, 0.03ppm. MS (EI, m/z) 607 (M++l), 629 (M++Na). HRMS (ESI): calcd for
C29H42N406S2 [MNa+] 629.2438, found 629.2440.
向实施例 35制得的原料 (0.279g, 0.35mmol)的无水二氯甲垸 (5ml)溶液中, 加入 1ml三氟 乙酸, 室温下搅拌 24小时。 减压旋干, 加入 5ml甲苯再旋干, 除去大量三氟乙酸。 粗产物直 接投入下一步。
氩气保护下,上一步的粗产物用 40ml无水 DMF溶解,缓慢滴入 HATU(0.665g, 1.75mmol), HOAt(0.238g, 1.75mmol), DIPEA(0.58ml, 3.5mmol)的无水 DMF溶液中, 30 °C搅拌 3天。反应 液体系浓度为 0.001mol/L。 减压旋干 DMF, 乙酸乙酯溶解, 依次用稀盐酸洗涤, 饱和 NaCl 洗涤, 无水 Na2S04干燥, 过滤, 减压旋干后柱层析 (石油醚:乙酸乙酯:甲醇 =20:20: 1 ), 得到 0.116g固体 1-4, 产率 58%。
[a]23D: 60.2 (c 0.5, CHC13). 1H NMR (400MHz, CDC13): 58.67(s, 1H), 8.07(s, 1H), 6.95-6.8(m, 3H), 5.72(m, 2H), 5.42(dd, J=7.1Hz, 15.5Hz, 1H), 5.14(dd, J=7.8Hz, 17.4Hz, 1H), 4.76(m, 1H), 4.31 (dd, J=4.3Hz, 17.4Hz, 1H), 2.85(m, 3H), 2.77(m, 1H), 2.63(d, J=16..5Hz, 1H), 2.50(t, J=7.5Hz, 2H), 2.25(dd, J=7Hz, 14Hz, 2H), 1.79(d, J=7.1Hz, 3H), 1.61 (m, 2H), 1.34- 1.2(m, 11H), 0.85(m, 3H) ppm. 13C NMR (125MHz, CDC13): 5199.40, 170.63, 169.58, 166.86, 163.39, 157.72, 147.88,
132.84, 128.20, 126.84, 124.20, 71.54, 53.39, 48.37, 44.05, 41.04, 39.74, 32.14, 31.51, 28.81, 27.72, 25.56, 22.49, 17.64, 14.92, 13.98, 0.92ppm. MS (EI, m z):579 (M++l). HRMS (ESI): calcd for C27H38N406S2 [MNa+] 601.2125, found 601.2129.
-5化合物的合成
向实施例 36制得的原料 (0.184g, 0.32mmol)的无水二氯甲垸 (5ml)溶液中, 加入 1ml三氟 乙酸, 室温下搅拌 24小时。 减压旋干, 加入 5ml甲苯再旋干, 除去大量三氟乙酸。 粗产物直 接投入下一步。
氩气保护下,上一步的粗产物用 40ml无水 DMF溶解,缓慢滴入 HATU(0.437g, 1.15mmol), HOAt(0.157g, 1.15mmol), DIPEA(0.38ml, 2.3mmol)的无水 DMF溶液中, 30°C搅拌 3天。反应 液体系浓度为 0.001mol/L。 减压旋干 DMF, 乙酸乙酯溶解, 依次用稀盐酸洗涤, 饱和 NaCl 洗涤, 无水 Na2S04干燥, 过滤, 减压旋干后柱层析 (石油醚:乙酸乙酯:甲醇 =20:20:1 ), 得到 0.081g固体 1-5, 产率 61%。
[a]23D:30.8 (c 0.86, CHC13). 1H NMR (400MHz, CDC13): 58.64(s, 1H), 8.10(s, 1H), 6.99(m, 1H), 6.47(d, J=8.7Hz, 1H), 6.33(s, 1H), 5.85(dd, J=7.3Hz, 15.8Hz, 1H), 5.75(m, 1H), 5.64(m, 1H), 4.95-4.6(m, 3H), 2.88(m, 2H), 2.64(m, 2H), 2.5 l(t, J=7.6Hz, 2H), 2.28(m, 2H), 1.85(d, J=7.4Hz, 3H), 1.61(m, 2H), 1.34(d, J=6.8Hz, 3H), 1.26(m, 8H), 0.86(m, 3H) ppm. 13C NMR (125MHz, CDC13): 5199.42, 177.15, 169.72, 168.99, 166.95, 163.07, 157.86, 148.85, 133.68, 133.25, 128.15, 126.39, 123.67, 72.49, 60.37, 49.61, 44.11, 40.52, 39.92, 32.13, 31.56, 29.66, 28.86, 27.88, 25.60, 22.54, 21.02, 19.30, 15.08, 12.16, 0.978ppm. MS (EI, m z):579 (M++l). HRMS (ESI): calcd for C27H38N406S2 [MNa+] 601.2125, found 601.2127.
向实施例 37制得的原料 (0.252g, 0.3mmol)的无水二氯甲垸 (5ml)溶液中, 加入 1ml三氟乙 酸, 室温下搅拌 24小时。 减压旋干, 加入 5ml甲苯再旋干, 除去大量三氟乙酸。 粗产物直接 投入下一步。
氩气保护下,上一步的粗产物用 40ml无水 DMF溶解,缓慢滴入 HATU(0.57g, 1.5mmol), HOAt(0.204g, 1.5mmol), DIPEA(0.5ml, 3mmol)的无水 DMF溶液中, 30°C搅拌 3天。 反应液 体系浓度为 0.001mol/L。 减压旋干 DMF, 乙酸乙酯溶解, 依次用稀盐酸洗涤, 饱和 NaCl洗 涤,无水 Na2S04干燥,过滤,减压旋干后柱层析(石油醚:乙酸乙酯:甲醇 =20:20:1 ),得到 0.102g 固体 1-6, 产率 55%。
[a]23D: 6.9(c 0.95, CHC13). 1H NMR (400MHz, CDC13): 58.49(s, 1H), 8.12(s, 1H), 7.03(m, 1H), 6.75-6.65(m, 2H), 5.8-5.55(m, 3H), 5.11(dd, J=7.6Hz 17.5Hz, 1H), 4.57(d, J=10.5Hz, 1H), 4.45(dd, J=3.9Hz 17.4Hz, 1H), 2.85(t, J=7.1Hz, 2H), 2.67(m, 2H), 2.27(dd, J=6.8Hz, 13.6Hz, 2H), 1.87(d, J=7Hz, 3H), 1.59(m, 2H), 1.23(m, 8H), 0.9-0.77(m, 12H).ppm. 13C NMR (125, CDC13): 5199.45, 168.88, 168.09, 167.38, 163.09, 158.99, 148.322, 135.28, 132.29, 128.42, 127.09, 124.45, 71.49, 60.46, 44.05, 41.02, 40.68, 35.58, 32.13, 31.52, 29.61, 28.81, 27.80, 26.39, 25.56, 22.49, 14.61, 13.98, 0.94ppm. MS (EI, m z):621 (M++l), 643 (M++Na). HRMS (ESI): calcd for C30H44N4O6S2 [MNa+] 643.2595, found 643.2596.
实施例 69 式 1-7化合物的合成
向实施例 38制得的原料 (0.151g, 0.173mmol)的无水二氯甲垸 (5ml)溶液中, 加入 1ml三氟 乙酸, 室温下搅拌 24小时。 减压旋干, 加入 5ml甲苯再旋干, 除去大量三氟乙酸。 粗产物直
接投入下一步。
氩气保护下, 上一步的粗产物用 30ml无水 DMF溶解, 缓慢滴入 HATU(0.329g, 0.865mmol), HOAt(0.118g, 0.865mmol), DIPEA(0.29ml, 1.73mmol)的无水 DMF溶液中。 30°C 搅拌 3天。 反应液体系浓度为 0.001mol/L。 减压旋干 DMF, 乙酸乙酯溶解, 依次用稀盐酸洗 涤, 饱和 NaCl洗涤, 无水 Na2S04干燥, 过滤, 减压旋干后柱层析 (石油醚:乙酸乙酯:甲醇 =20:20:1 ), 得到 0.05g固体 1-7, 产率 44%。
[a]23D: 15.6(c 0.45, CHC13). 1H NMR (400MHz, CDC13): 58.24(s, 1H), 8.10(s, 1H), 7.09(m, 1H), 7.05-6.90(m, 5H), 6.44(d, J=10.4Hz, 1H), 5.75-5.65(m, 2H), 5.78(m, 1H), 5.50(m, 1H), 5.26(m, 1H), 4.65(dd, J=17.3Hz, 6Hz,lH), 4.53(dd, J=17.3Hz 5.3Hz, 1H), 3.37(dd, J=13.6Hz 3.4Hz, 1H), 2.91-2.81(m,3H), 2.55-2.45(m,4H), 2.26(q, J=6.8Hz, 2H), 1.93(d, J=7.2Hz, 3H), 1.58(m, 2H), 1.25(m, 8H), 0.87(m, 3H).ppm. 13C NMR (100MHz, CDC13): 5199.29, 169.53, 168.30, 166.72, 162.78, 158.33, 148.35, 135.47, 134.59, 132.63, 129.50, 128.29, 127.52, 126.78, 126.35, 123.83, 52.34, 44.00, 40.60, 40.36, 38.07, 32.07, 31.50, 28.79, 27.70, 25.53, 22.47, 14.76, 13.95, 0.91ppm. MS (EI, m z):655 (M++l), 677 (M++Na). HRMS (ESI): calcd for C33H42N406S2 [MNa+] 677.2438, found 677.2437.
向实施例 39制得的原料 (0.24g, 0.26mmol)的无水二氯甲垸 (5ml)溶液中, 加入 1ml三氟乙 酸, 室温下搅拌 24小时。 减压旋干, 加入 5ml甲苯再旋干, 除去大量三氟乙酸。 粗产物直接 投入下一步。
氩气保护下,上一步的粗产物用 40ml无水 DMF溶解,缓慢滴入 HATU(0.494g, 1.3mmol), HOAt(0.177g, 1.3mmol), DIPEA(0.43ml, 2.6mmol)的无水 DMF溶液中。 30°C搅拌 3天。 反应 液体系浓度为 0.001mol/L。 减压旋干 DMF, 乙酸乙酯溶解, 依次用稀盐酸洗涤, 饱和 NaCl 洗涤, 无水 Na2S04干燥, 过滤, 减压旋干后柱层析 (石油醚:乙酸乙酯:甲醇 =20:20:1 ), 得到 0.077g固体 1-9, 产率 42%。
[a]23D: -26.5 (c 0.78, CHC13). 1H NMR (400MHz, CDC13): 58.03(s, 1H), 7.95(s, 1H), 7.93(s, 1H),
7.64(d, J=8.1Hz, 1H), 7.53(d, J=7.8Hz, 1H), 7.41 (t, J=7.5Hz, 1H), 7.32(t, J=7.5Hz, 1H), 7.14(m, 2H), 7.02(m, 1H), 6.56(d, J=10.1Hz, 1H), 5.6-5.4(m, 3H), 4.92(m, 1H), 4.61(dd, J=6.6Hz, 17.2Hz, 1H), 4.10(m, 1H), 3.75(dd, J=3.5Hz, 14.2Hz, 1H), 3.50(dd, J=5.6Hz, 14.2Hz, 1H), 2.74(t, J=7.1Hz, 2H), 2.41 (t, J=7.5Hz, 2H), 2.30(dd, J=5.2Hz, 15.3Hz,lH), 2.14(m, 2H), 1.89(d, J=7.2Hz, 3H), 1.54(m, 2H), 1.22(m, 8H), 0.84(m, 3H),ppm. 13C NMR (100MHz, CDC13): 5199.13, 169.48, 168.09, 166.22, 162.85, 158.12, 148.76, 134.27, 133.44, 132.34, 128.52, 127.19, 126.86, 126.26, 125.33, 123.82, 123.46, 71.81, 52.68, 44.02, 40.49, 38.57, 34.61, 32.03, 31.55, 28.84, 27.74, 25.56, 22.52, 20.98, 14.99, 13.99, 0.97ppm. MS (EI, m z):705 (M++l), 727 (M++Na). HRMS (ESI): calcd for C37H44N4O6S2 [MNa+] 727.2595, found 727.2596.
-8化合物的合成
向实施例 40制得的原料 (0.165g, 0.175mmol)的无水二氯甲烷 (5ml)溶液中,加入 lml三 氟乙酸, 室温下搅拌 24小时。 减压旋干, 加入 5ml甲苯再旋干, 除去大量三氟乙酸。 粗产物 直接投入下一步。
氩气保护下, 上一步的粗产物用 40ml无水 DMF溶解, 缓慢滴入 HATU(0.333g, 0.875mmol), HOAt(0.119g, 0.875mmol), DIPEA(0.3ml, 1.75mmol)的无水 DMF溶液中, 30°C 搅拌 3天。 反应液体系浓度为 0.001mol/L。 减压旋干 DMF, 乙酸乙酯溶解, 依次用稀盐酸洗 涤, 饱和 NaCl洗涤, 无水 Na2S04干燥, 过滤, 减压旋干后柱层析 (石油醚:乙酸乙酯:甲醇 =20:20:1 ), 得到 0.075g固体 1-8, 产率 64%。
[a]23D: 7.9 (c 0.65, CHC13). 1H NMR (400MHz, MeOD): 58.20(s, 1H), 7.67(d, J=9.4Hz, 1H), 6.83(d, J=8.3Hz, 2H), 6.72(m, 1H), 6.50(d, J=8.3Hz, 2H), 5.75-5.65(m, 2H), 5.55(dd, J=6.7Hz, 15.6Hz, 1H), 4.97(d, J=17.4Hz, 1H), 4.39(d, J=17.4Hz, 1H), 3.34(s, 1H), 2.99(m, 1H), 2.95-2.83(m, 4H), 2.63(d, J=16.8Hz, 1H), 2.53(t, J=7.4Hz, 2H), 2.26(dd, J=6.9Hz, 13.8Hz, 2H), 1.79(d, J=7.1Hz, 3H), 1.62(m, 2H), 1.29(m, 8H), 0.89(t, J=6.2Hz, 3H)ppm. 13C NMR (125MHz, MeOD): 5200.92, 172.72, 171.43, 168.56, 165.56, 160.83, 156.88, 149.07, 133.91, 133.26, 131.49, 130.06, 128.97, 128.53, 125.67, 116.08, 73.22, 54.88, 44.83, 41.76, 40.29, 37.83, 33.37, 32.80, 30.05, 29.94, 28.77, 26.78, 23.64, 14.88, 14.42ppm. MS (EI, m z):671 (M++1), 693 (M++Na). HRMS (ESI): calcd for
C33H42N4O7S2 [MNa+] 693.2387, found 693.2386.
实施例 72 式 1-1化合物的合成
取实施例 41制得的原料 155mg(0.198mmol, leq)i#于 5ml无水二氯甲烷,加入 1ml三氟乙 酸,反应常温下搅拌 24小时后,减压旋去溶剂与 TFA后,用 100ml无水 DMF,慢慢滴加入溶有 150mg(0.396mmol, 2eq) HATU与 54mg(0.396mmol, 2eq) HOAT与 0.2ml(1.188 mmol, 6eq) DIPEA的 DMF溶液 (100ml)中.反应于常温下反应 72h后,减压旋去 DMF,乙酸乙酉旨 (20ml)稀释, 用饱和 NaCl (20mlX2)洗涤.无水硫酸钠干燥,,减压旋干溶剂.柱层析 (乙酸乙酯)得到 22mg白色 固体 1-1, 产率 20%.
1H-NMR (400 MHz, CDC13) δ 8.70(s, 1-H), 8.10(s, 1-H), 7.11(s, 1-H), 6.92(q, 1-H),
6.84(d, 1-H), 6.61(t, 1-H), 5.73(t,l-H), 5.68(dd, 1-H), 5.50(dd, 1-H), 5.15(dd, 1-H), 4.68(q, 1-H), 4.35(dd, 1-H), 3.65(d,l-H), 2.82(t, 2-H), 2.70(dd, 1-H), 2.58(dd, 1-H), 2.55(t, 2-H), 2.22(q, 2-H), 1.95(s,3-H), 1.83(d, 3-H), 1.57(t, 2-H), 1.28(m, 8-H), 0.87(t, 3-H); 13C-NMR (500 MHz, CDC1 3) δ 199.5, 169.6, 168.0, 166.8, 163.7, 157.8, 148.1, 133.3, 132.9, 128.1, 126.9, 124.3, 71.7, 44.0, 42.2, 41.0, 39.9, 32.2, 31.6, 28.9(2C), 27.7, 25.6, 22.5, 14.9,14.0,; MS(ESI) m/z 564.72 (100%) (M+H)+. 实施 73 式 5-1化合物的合成
取实施例 42制得的原料 110mg(0.136mmol, leq)i#于 5ml无水二氯甲烷,加入 1ml三氟乙 酸,反应常温下搅拌 24小时后,减压旋去溶剂与 TFA后,用 70ml无水 DMF,慢慢滴加入溶有 207mg(0.544mmol, 2eq) HATU与 74mg(0.544mmol, 4eq) HOAT与 0.18ml(1.088 mmol, 8eq) DIPEA的 DMF溶液 (70ml)中.反应于常温下反应 72h后,减压旋去 DMF,乙酸乙酉旨 (20ml)稀释, 用饱和 NaCl (20mlX2)洗涤.无水硫酸钠干燥,,减压旋干溶剂, 柱层析 (乙酸乙酯)得到 10mg白
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取实施例 44制得的原料 180mg(0.21mmol, leq)i#于 5ml无水二氯甲烷,加入 1ml三氟乙酸, 反应常温下搅拌 24 小时后,减压旋去溶剂与 TFA后,用 105ml无水 DMF,慢慢滴加入溶有 320mg(0.84mmol, 4eq) HATU与 115mg(0.84mmol, 4eq) HOAT与 0.28ml(1.68 mmol, 8eq) DIPEA的 DMF溶液 (105ml)中.反应于常温下反应 72h后,减压旋去 DMF,乙酸乙酉旨 (20ml)稀释, 用饱和 NaCl (20mlX2)洗涤.无水硫酸钠干燥,,减压旋干溶剂.柱层析 (乙酸乙酯)得到 28mg白色 固体 1-10, 产率 20.9%。
[κ] ^=106.8 1H-NMR (400 MHz, CDC13) δ 8.65(s, 1-Η), 8.10(s, 1-Η), 7.17(d, 1-Η), 6.97 (q, 1-Η),
6.42(brs, 1-Η), 5.76(m, 2-Η), 5.49(dd,l-H), 5.13(dd, 1-H), 4.72(q, 1-H), 4.37(dd, 1-H), 3.72(s, 1-H), 2.88(t, 2-H), 2.70(dd, 1-H), 2.60(dd, 1-H), 2.50(m, 5-H), 2.28(q, 2-H), 2.17(m, 1-H), 2.12(m, 2-H), 1.95(s,3-H), 1.83(m, 3-H), 1.67(m, 3-H), 1.28(m, 8-H), 0.87(t, 6-H); 13C-NMR (500 MHz, CDC13) δ 199.4, 170.0, 169.2, 166.9, 163.4, 157.9, 148.1, 133.3, 132.7, 128.2, 126.9, 124.3, 71.4, 51.6, 44.1, 41.0, 40.0, 32.2, 31.6, 30.0, 29.6, 28.9(2C), 27.8, 25.6, 22.5, 14.97, 14.90, 14.0; MS(ESI) mJz 593.2 (100%) (M+H)+。
实施例 76 式 1-11化合物的合成
取实施例 45制得的原料 190mg(0.226mmol, leq)i#于 5ml无水二氯甲烷,加入 1ml三氟乙 酸,反应常温下搅拌 24小时后,减压旋去溶剂与 TFA后,用 115ml无水 DMF,慢慢滴加入溶有 344mg(0.904mmol, 4eq) HATU与 123mg(0.904mmol, 4eq) HOAT与 0.32ml(1.808 mmol, 8eq) DIPEA的 DMF溶液 (115ml)中.反应于常温下反应 72h后,减压旋去 DMF,乙酸乙酉旨 (20ml)稀释, 用饱和 NaCl (20mlX2)洗涤.无水硫酸钠干燥,,减压旋干溶剂.柱层析 (乙酸乙酯)得到 43mg白色 固体 1-11, 产率 35.6%.
1H-NMR (400 MHz, CDC13) δ 8.65(s, 1-H), 8.12(s, 1-H), 6.93(q, 1-H), 6.50(d, 2-H),
6.42(brs, 1-H), 5.76(m, 2-H), 5.49(dd,l-H), 5.13(dd, 1-H), 4.72(q, 1-H), 4.37(dd, 1-H), 2.88(t, 2-H), 2.75(m, 2-H), 2.50(m, 2-H), 2.28(q, 2-H), 1.95(d,3-H), 1.83(m, 3-H), 1.67(m, 3-H), 1.50(m, 3-H), 1.28(m, 8-H), 0.90(m, 6-H); 13C-NMR (500 MHz, CDC13) δ 199.4, 170.0, 169.4, 166.8, 163.5 157.7, 148.1, 133.0, 132.7, 128.3, 127.0, 124.3, 71.4, 50.8, 44.1, 41.6, 40.1, 32.2, 28.9(2C), 27.8, 25.6, 24.5, 22.5, 21.6, 15.0, 14.0; MS(ESI) mJz 621.2 (100%) (M+H)+.
实施例 77 式 5-2化合物的合成
向实施例 46制得原料 (56mg, 0.068mmol, leq)溶于 5ml无水二氯甲烷,加入 1ml三氟乙酸, 反应常温下搅拌 24 小时后,减压旋去溶剂与 TFA后,用 115ml无水 DMF,慢慢滴加入溶有 103mg(0.072mmol, 4eq) HATU与 37mg(0.072mmol, 4eq) HOAT与 0.1ml(0.544 mmol, 8eq) DIPEA的 DMF溶液 (115ml)中.反应于常温下反应 72h后,减压旋去 DMF,乙酸乙酉旨 (20ml)稀释, 用饱和 NaCl (20mlX2)洗涤.无水硫酸钠干燥,,减压旋干溶剂.柱层析 (乙酸乙酯)得到 4mg白色 固体 5-2, 产率 10%.
【¾ =201·7 1H-NMR (400 MHz, CDC13) δ 8.74(s, 1-H), 8.01(s, 1-H), 6.26(m, 2-H), 6.00(t, 1-H)
5.80(dd, 1-H), 5.74(dd, 1-H), 5.06(dd, 1-H), 4.76(d, 1-H), 4.30(dd, 1-H), 2.88(t, 2-H), 2.75(m, 2-H), 2.50(m, 2-H), 2.28(q, 2-H), 1.95(d,3-H), 1.83(m, 3-H), 1.67(m, 3-H), 1.50(m, 3-H), 1.28(m, 8-H). 0.90(m, 6-H); 13C-NMR (500 MHz, CDC13) δ 199.4, 170.0, 169.4, 166.8, 163.5, 157.7, 148.1 133.0, 132.7, 128.3, 127.0, 124.3, 71.4, 50.8, 44.1, 41.6, 40.1, 32.2, 28.9(2C), 27.8, 25.6, 24.5, 22.5, 21.6, 15.0, 14.0; MS(ESI) m/z 621.2 (100%) (M+H)+.
向实施例 47制得原料 (0.331g, 0.41mmol)的无水二氯甲垸 (5ml)溶液中, 加入 1ml三氟乙 酸, 室温下搅拌 24小时。 减压旋干, 加入 5ml甲苯再旋干, 除去大量三氟乙酸。 粗产物直接 投入下一步。
氩气保护下,上一步的粗产物用 50ml无水 DMF溶解,缓慢滴入 HATU(0.78g, 2.05mmol), HOAt(0.28g, 2.05mmol), DIPEA(0.7ml, 4.1mmol)的无水 DMF溶液中。 30°C搅拌 3天。反应液 体系浓度为 0.001mol/L。 减压旋干 DMF, 乙酸乙酯溶解, 依次用稀盐酸洗涤, 饱和 NaCl洗 涤,无水 Na2S04干燥,过滤,减压旋干后柱层析(石油醚:乙酸乙酯:甲醇 =20:20:1 ),得到 0.102g 固体 2-1, 产率 42%。
[a]23D: 35.6 (c 0.9, CHC13). 1H NMR (400MHz, CDC13):5 8.54(s,lH), 8.08(s,lH), 6.94(q, 1H), 6.82(m, 1H), 6.5 l(d, 1H), 5.74-5.6(m, 2H), 5.47 (dd, 1H), 5.14(dd, 1H), 4.70(dd, 1H) 4.32(dd, 1H), 2.82(t, 2H), 2.75-2.59(m, 2H), 2.47(t, 2H), 2.24(m, 2H), 1.82(d, 3H), 1.58(m, 2H), 1.24(m, 8H), 0.83(m, 3H), 0.74(d, 3H), 0.55(d, 3H)ppm. 13C NMR (125MHz, CDC13) :5199.5, 171.5, 168.8, 168.1, 164.5, 150.6, 141.5, 136.2, 131.5, 130.1, 128.2, 120.3, 74.5, 66.1, 44.1, 42.4, 38.6, 37.6, 31.9, 30.8, 30.4, 29.1, 26.2, 22.8, 18.5, 14.1ppm. MS(ESI) m/z 591 (100%) (M+H)+
79 式 2-2化合物的合成
向实施例 48制得原料 (0.412g, 0.5mmol)的无水二氯甲烷 (5ml)溶液中,加入 1ml三氟乙酸, 室温下搅拌 24小时。 减压旋干, 加入 5ml甲苯再旋干, 除去大量三氟乙酸。 粗产物直接投入 下一步。
氩气保护下,上一步的粗产物用 50ml无水 DMF溶解,缓慢滴入 HATU(0.588g, 2.5mmol),
HOAt(0.34g, 2.5mmol), DIPEA(0.87ml, 5mmol)的无水 DMF溶液中。 30°C搅拌 3天。 反应液 体系浓度为 0.001mol/L。 减压旋干 DMF, 乙酸乙酯溶解, 依次用稀盐酸洗涤, 饱和 NaCl洗 涤,无水 Na2S04干燥,过滤,减压旋干后柱层析(石油醚:乙酸乙酯:甲醇 =20:20:1 ),得到 0.121g 固体 2-2, 产率 40%。
[a]23D: 14.3 (c 0.5, CHC13). 1H NMR (400MHz, CDC13):5 6.82(m, 1H), 6.51(d, 1H), 5.74-5.6(m, 2H), 5.45(dd, 1H), 4.84(dd, 1H) 4.40(d, 1H), 3.8(m, 1H), 3.1(t, 2H), 2.75-2.59(m, 5H), 2.47(t, 2H), 2.24(m, 2H), 1.82(d, 3H), 1.58(m, 2H), 1.24(m, 8H), 0.83(m, 3H), 0.74(d, 3H), 0.55(d, 3H)ppm. 13C NMR (125MHz, CDC13) :5199.5, 171.5, 168.8, 167.2, 164.5,, 131.5, 130.1, 128.2, 120.3, 83.5, 74.8, 74.5, 66.1, 46.8, 44.1, 42.4, 38.6, 37.6, 31.9, 30.8, 30.4, 29.1, 26.2, 22.8, 22.0, 18.5, 14.1ppm. MS(ESI) m/z 606 (M+H)+
实施例 80 式 2-3化合物的合成
向实施例 49制得原料 (0.504g, 0.6 mmol)的无水二氯甲烷 (5ml)溶液中,加入 1ml三氟乙酸, 室温下搅拌 24小时。 减压旋干, 加入 5ml甲苯再旋干, 除去大量三氟乙酸。 粗产物直接投入 下一步。
氩气保护下, 上一步的粗产物用 50ml无水 DMF溶解, 缓慢滴入 HATU(0.706g, 3mmol), HOAt(0.408g, 3mmol), DIPEA(1.05ml, 6mmol)的无水 DMF溶液中。 30°C搅拌 3天。反应液体 系浓度为 0.001mol/L。 减压旋干 DMF, 乙酸乙酯溶解, 依次用稀盐酸洗涤, 饱和 NaCl洗涤, 无水 Na2S04干燥, 过滤, 减压旋干后柱层析 (石油醚:乙酸乙酯:甲醇 =20:20:1 ), 得到 0.131g 固体 2-3, 产率 35%。
[a]23D: 29.1 (c 0.9, CHC13). 1H NMR (400MHz, CDC13):5 6.82(m, 1H), 5.74-5.6(m,2H), 5.47 (dd, 1H), 4.79(dd, 1H) 4.31(dd, 1H), 2.99(t, 2H), 2.75-2.59(m, 3H), 2.47(t, , 2H), 2.24(m, 5H), 1.82(d, 3H), 1.58(m, 2H), 1.24(m, 11H), 0.83(m, 3H), 0.74(d, 3H), 0.55(d, 3H)ppm. 13C NMR (125MHz, CDC13):5 199.4, 179.2, 171.4, 168.4, 168.2, 131.2, 130.2, 129.5, 128.1, 76.3, 74.2, 66.4, 47.5, 44.5, 38.4, 31.8, 30.8, 30.5, 29.4, 29.1, 26.7, 24.5, 22.3, 21.0, 19.3, 14.1, 13.0ppm MS(ESI) m/z 623
(M+H)+
实施例 81 式 2-4化合物的合成
向实施例 50制得原料 (0.404g, 0.5mmol)的无水二氯甲烷 (5ml)溶液中,加入 1ml三氟乙酸, 室温下搅拌 24小时。 减压旋干, 加入 5ml甲苯再旋干, 除去大量三氟乙酸。 粗产物直接投入 下一步。
氩气保护下,上一步的粗产物用 50ml无水 DMF溶解,缓慢滴入 HATU(0.588g, 2.5mmol), HOAt(0.34g, 2.5mmol), DIPEA(0.87ml, 5mmol)的无水 DMF溶液中。 30°C搅拌 3天。 反应液 体系浓度为 0.001mol/L。 减压旋干 DMF, 乙酸乙酯溶解, 依次用稀盐酸洗涤, 饱和 NaCl洗 涤,无水 Na2S04干燥,过滤,减压旋干后柱层析(石油醚:乙酸乙酯:甲醇 =20:20:1 ),得到 0.091g 固体 2-4, 产率 31%。
[a]23D: 34.7(c 0.9, CHC13). 1H NMR (400MHz, CDC13):5 7.6(d, 1H), 5.78-5.6(m,2H), 5.54(dd, 1H), 5.11(dd, 1H), 4.35(d, 1H), 3.4(dd, 2H), 2.9 l(t, 2H), 2.47 (m, 2H), 2.24(m, 2H), 1.82(d, J=7Hz, 3H), 1.58(m, 2H), 1.24(m, 8H), 0.83(m, 3H), 0.74(d, 3H), 0.55(d, 3H)ppm. 13C NMR (125MHz, CDC13): 199.3, 180.3, 171.7, 167.3, 166.5, 163.7, 131.6, 129.4, 128.4, 74.6, 66.2, 62.2, 46.4, 44.0, 38.4, 30.8, 30.5, 26.3, 22.7, 18.9, 14.2, 12.9ppm. MS(ESI) m/z 590(M+H)+
实施例 82 式 2-5化合物的合成
向实施例 51制得原料 (0.404g, 0.5mmol)的无水二氯甲烷 (5ml)溶液中,加入 1ml三氟乙酸, 室温下搅拌 24小时。 减压旋干, 加入 5ml甲苯再旋干, 除去大量三氟乙酸。 粗产物直接投入 下一步。
氩气保护下,上一步的粗产物用 50ml无水 DMF溶解,缓慢滴入 HATU(0.588g, 2.5mmol), HOAt(0.34g, 2.5mmol), DIPEA(0.87ml, 5mmol)的无水 DMF溶液中。 30°C搅拌 3天。 反应液 体系浓度为 0.001mol/L。 减压旋干 DMF, 乙酸乙酯溶解, 依次用稀盐酸洗涤, 饱和 NaCl洗 涤,无水 Na2S04干燥,过滤,减压旋干后柱层析(石油醚:乙酸乙酯:甲醇 =20:20:1 ),得到 0.103g 固体 2-5, 产率 35%。
[a]23D: 34.7(c 0.9, CHC13). 1H NMR (400MHz, CDC13): 5.76-5.6(m,2H), 5.51(dd, 1H), 4.87(dd, 1H), 4.41(d, 1H), 3.4(d, 2H), 2.9 l(t, 2H), 2.47(m, 2H), 2.24(m, 2H), 1.82(d, J=7Hz, 3H), 1.58(m, 2H), 1.4(s, 1H), 1.24(m, 8H), 0.83(m, 3H), 0.74(d, 3H), 0.55(d, 3H)ppm. 13C NMR (125MHz, CDC13): 199.3, 180.3, 171.7, 167.3, 160.3, 158.3, , 131.6, 129.4, 128.4, 120.3, 74.6, 66.2, 62.2, 46.4, 44.0, 38.4, 30.8, 30.5, 26.3, 22.7, 18.9, 14.2, 12.9ppm. MS(ESI) m/z 590 (M+H)+
施例 83 式 2-6化合物的合成
向实施例 52制得原料 (0.409g, 0.5mmol)的无水二氯甲烷 (5ml)溶液中,加入 1ml三氟乙酸, 室温下搅拌 24小时。 减压旋干, 加入 5ml甲苯再旋干, 除去大量三氟乙酸。 粗产物直接投入 下一步。
氩气保护下,上一步的粗产物用 50ml无水 DMF溶解,缓慢滴入 HATU(0.588g, 2.5mmol), HOAt(0.34g, 2.5mmol), DIPEA(0.87ml, 5mmol)的无水 DMF溶液中。 30°C搅拌 3天。 反应液 体系浓度为 0.001mol/L。 减压旋干 DMF, 乙酸乙酯溶解, 依次用稀盐酸洗涤, 饱和 NaCl洗 涤,无水 Na2S04干燥,过滤,减压旋干后柱层析(石油醚:乙酸乙酯:甲醇 =20:20:1 ),得到 0.165g 固体 2-6, 产率 55%。
[a]23D: 34.1(c 0.9, CHC13). 1H NMR (400MHz, CDC13): 7.84(d, 1H), 7.74(s, 1H), 7.40(m, 2H), 5.76-5.6(m,2H), 5.51(dd, 1H), 4.87(dd, 1H), 4.41 (d, 1H), 4.3(d, 2H), 3.4(d, 2H), 2.91(t, 2H), 2.47(m, 2H), 2.24(m, 2H), 1.82(d, 3H), 1.58(m, 2H), 1.4(s, 1H), 1.24(m, 8H), 0.83(m, 3H), 0.74(d, 3H), 0.55(d, 3H)ppm. 13C NMR (125MHz, CDC13): 199.7, 171.5, 168.4, 164.7, 141.8, 134.5, 130.5, 130.2, 128.5, 125.6, 125.3, 120.4, 74.5, 66.5, 48.5, 44.5, 38.5, 37.8, 31.5, 30.8, 30.5, 29.1, 26.1, 22.6, 18.9, 14.5, 13.1ppm. MS(ESI) m/z 600 (M+H)+
实施例 84 式 2-7化合物的合成
向实施例 53制得原料 (0.410g, 0.5mmol)的无水二氯甲烷 (5ml)溶液中,加入 1ml三氟乙酸, 室温下搅拌 24小时。 减压旋干, 加入 5ml甲苯再旋干, 除去大量三氟乙酸。 粗产物直接投入 下一步。
氩气保护下,上一步的粗产物用 50ml无水 DMF溶解,缓慢滴入 HATU(0.588g, 2.5mmol), HOAt(0.34g, 2.5mmol), DIPEA(0.87ml, 5mmol)的无水 DMF溶液中。 30°C搅拌 3天。 反应液 体系浓度为 0.001mol/L。 减压旋干 DMF, 乙酸乙酯溶解, 依次用稀盐酸洗涤, 饱和 NaCl洗 涤,无水 Na2S04干燥,过滤,减压旋干后柱层析(石油醚:乙酸乙酯:甲醇 =20:20:1 ),得到 0.183g 固体 2-7, 产率 61%。
[a]23D: 21.9(c 0.9, CHC13). 1H NMR (400MHz, CDC13): 8.93(d, 1H), 8.16(s, 1H), 7.56(d, 1H), 5.8-5.7(m,2H), 5.52(dd, IH), 4.87(dd, IH), 4.79(s, IH), 4.41 (d, IH), 3.4(d, 2H), 2.92(t, 2H), 2.47(m, 4H), 2.08(d, 3H), 1.58(m, 2H), 1.25(m, 8H), 0.83(m, 3H), 0.74(d, 3H), 0.55(d, 3H)ppm. 13C NMR (125MHz, CDC13): 199.3, 180.3, 171.7, 167.3, 160.3, 158.3, , 131.6, 129.4, 128.4, 120.3, 74.6, 66.2, 62.2, 46.4, 44.0, 38.4, 30.8, 30.5, 26.3, 22.7, 18.9, 14.2, 12.9ppm. MS(ESI) m z601 (M+H)+
85 式 3-2化合物的合成
向实施例 54制得原料 (0.413g, 0.5mmol)的无水二氯甲烷 (5ml)溶液中,加入 1ml三氟乙酸, 室温下搅拌 24小时。 减压旋干, 加入 5ml甲苯再旋干, 除去大量三氟乙酸。 粗产物直接投入 下一步。
氩气保护下,上一步的粗产物用 50ml无水 DMF溶解,缓慢滴入 HATU(0.588g, 2.5mmol),
HOAt(0.34g, 2.5mmol), DIPEA(0.87ml, 5mmol)的无水 DMF溶液中。 30°C搅拌 3天。 反应液 体系浓度为 0.001mol/L。 减压旋干 DMF, 乙酸乙酯溶解, 依次用稀盐酸洗涤, 饱和 NaCl洗 涤,无水 Na2S04干燥,过滤,减压旋干后柱层析(石油醚:乙酸乙酯:甲醇 =20:20:1 ),得到 0.128g 固体 3-2, 产率 42%。
[a]23D: 28.1 (c 0.9, CHC13). 1H NMR (400MHz, CDCl3):58.94(s,lH), 8.08(s,lH), 6.51(d, 1H), 5.74-5.6(m,2H), 5.47(dd, 1H), 4.89(dd, 1H), 4.5-4.35(m, 4H), 2.82(t, 2H), 2.75-2.59(m, 2H), 2.47(t, 2H), 2.24(m, 2H), 1.82(m, 2H), 1.24(m, 8H), 0.92(t, 3H), 0.83(m, 3H), 0.74(d, 3H), 0.55(d,
3H)ppm. 13C NMR (125MHz, CDC13): 5199.5, 171.6, 170.8, 168.6, 167.4, 165.8, 148.9, 130.1, 128.1, 124.5, 74.3, 66.4, 61.8, 44.1, 38.6, 37.8, 31.7, 30.6, 29.4, 29.2, 26.3, 25.4, 22.8, 18.9, 14.2, 9.4ppm. MS (EI, m/z) 609 (M++l), 631 (M++Na).
向实施例 55制得原料 (0.399g, 0.5mmol)的无水二氯甲烷 (5ml)溶液中,加入 1ml三氟乙酸, 室温下搅拌 24小时。 减压旋干, 加入 5ml甲苯再旋干, 除去大量三氟乙酸。 粗产物直接投入 下一步。
氩气保护下,上一步的粗产物用 50ml无水 DMF溶解,缓慢滴入 HATU(0.588g, 2.5mmol), HOAt(0.34g, 2.5mmol), DIPEA(0.87ml, 5mmol)的无水 DMF溶液中。 30°C搅拌 3天。 反应液 体系浓度为 0.001mol/L。 减压旋干 DMF, 乙酸乙酯溶解, 依次用稀盐酸洗涤, 饱和 NaCl洗 涤,无水 Na2S04干燥,过滤,减压旋干后柱层析(石油醚:乙酸乙酯:甲醇 =20:20:1 ),得到 0.154g 固体 3-3, 产率 53%。
[a]23D: 19.1 (c 0.9, CHC13). 1H NMR (400MHz, CDCl3):58.94(s,lH), 8.08(s,lH), 5.74-5.6(m,2H), 5.47(dd, 1H), 4.89(dd, 1H), 4.5-4.35(m, 4H), 3.85(t, 2H), 2.82(t, 2H), 2.75-2.59(m, 2H), 2.47(t, 2H), 2.24(m, 2H), 1.82(m, 2H), 1.24(m, 8H), 0.92(t, 3H), 0.74(d, 3H), 0.55(d, 3H)ppm. 13C NMR (125MHz, CDC13): 5199.5, 171.6, 168.6, 168.2, 165.8, 148.9, 130.1, 128.1, 124.5, 74.3, 66.4, 44.1, 42.2, 38.6, 37.8, 31.7, 30.6, 29.4, 29.2, 26.3, 25.4, 22.8, 18.9, 14.2 ppm. MS (EI, mJz): 581 (M++l), 实施例 87 式 3-1化合物的合成
1 .TFA,CH2CI:
2. HATU, HOAt, DIPEA
C7H NHBoc 向实施例 56制得原料 (0.405g, 0.5mmol)的无水二氯甲烷 (5ml)溶液中,加入 1ml三氟乙酸, 室温下搅拌 24小时。 减压旋干, 加入 5ml甲苯再旋干, 除去大量三氟乙酸。 粗产物直接投入 下一步。
氩气保护下,上一步的粗产物用 50ml无水 DMF溶解,缓慢滴入 HATU(0.588g, 2.5mmol), HOAt(0.34g, 2.5mmol), DIPEA(0.87ml, 5mmol)的无水 DMF溶液中。 30°C搅拌 3天。 反应液 体系浓度为 0.001mol/L。 减压旋干 DMF, 乙酸乙酯溶解, 依次用稀盐酸洗涤, 饱和 NaCl洗 涤,无水 Na2S04干燥,过滤,减压旋干后柱层析(石油醚:乙酸乙酯:甲醇 =20:20:1 ),得到 0.136g 固体 3-1, 产率 46%。
[a]23D: 14.1 (c 0.9, CHC13). 1H NMR (400MHz, CDCl3):58.94(s,lH), 8.08(s,lH), 5.74-5.6(m,2H), 5.45(d, 1H), 5.13(d, 1H), 4.89(dd, 1H), 4.5-4.35(m, 3H), 2.82(t, 2H), 2.75-2.59(m, 2H), 2.47(t, 2H), 2.24(m, 2H), 1.82(m, 2H), 1.24(m, 8H), 0.92(t, 3H), 0.74(d, 3H), 0.55(d, 3H)ppm. 13C NMR (125MHz, CDC13): 5199.5, 171.6, 168.6, 168.2, 165.8, 148.9, 138.1, 130.2, 128.1, 124.5, 104.6, 74.3, 66.4, 44.1, 42.2, 38.6, 37.8, 31.7, 30.6, 29.4, 29.2, 26.3, 25.4, 22.8, 14.2 ppm. MS (EI, mJz): 593 (M++l),
向实施例 57制得原料 (0.433g, 0.5mmol)的无水二氯甲烷 (5ml)溶液中,加入 1ml三氟乙酸, 室温下搅拌 24小时。 减压旋干, 加入 5ml甲苯再旋干, 除去大量三氟乙酸。 粗产物直接投入 下一步。
氩气保护下,上一步的粗产物用 50ml无水 DMF溶解,缓慢滴入 HATU(0.588g, 2.5mmol), HOAt(0.34g, 2.5mmol), DIPEA(0.87ml, 5mmol)的无水 DMF溶液中。 30°C搅拌 3天。 反应液
体系浓度为 0.001mol/L。 减压旋干 DMF, 乙酸乙酯溶解, 依次用稀盐酸洗涤, 饱和 NaCl洗 涤,无水 Na2S04干燥,过滤,减压旋干后柱层析(石油醚:乙酸乙酯:甲醇 =20:20:1 ),得到 0.085g 固体 4-1, 产率 26%。
[a]23D: 6.9 (c 0.9, CHC13). 1H NMR (400MHz, CDCl3):58.95(s,lH), 5.91(q,lH), 5.74-5.6(m,2H), 4.87-4.81(m,lH)„4.40(d, 1H), 2.82(m, 2H), 2.75-2.59(m, 2H), 2.47(t, 2H), 2.24(m, 2H), 1.82(d, J=7Hz, 3H), 1.58(m, 2H), 1.24(m, 8H), 0.83(m, 3H), 0.74(d, 6H), 0.55(d, 6H)ppm. 13C NMR (125MHz, CDC13): 5199.5, 171.5, 169.4, 168.2, 168.0, 164.3, 147.4, 131.5, 130.2, 128.5, 124.2, 120.3, 74.3,. 66.2, 63.8, 44.2, 38.9, 34.6, 31.8, 30.7, 30.4, 29.8, 29.4, 26.1, 22.7, 18.9, 18.6, 14.2, 13.1ppm. MS (EI, m/z) 649 (M++l)
实施例 89 式 4-2化合物的合成
向实施例 58制得原料 (0.419g, 0.5mmol)的无水二氯甲烷 (5ml)溶液中,加入 1ml三氟乙酸, 室温下搅拌 24小时。 减压旋干, 加入 5ml甲苯再旋干, 除去大量三氟乙酸。 粗产物直接投入 下一步。
氩气保护下,上一步的粗产物用 50ml无水 DMF溶解,缓慢滴入 HATU(0.588g, 2.5mmol), HOAt(0.34g, 2.5mmol), DIPEA(0.87ml, 5mmol)的无水 DMF溶液中。 30°C搅拌 3天。 反应液 体系浓度为 0.001mol/L。 减压旋干 DMF, 乙酸乙酯溶解, 依次用稀盐酸洗涤, 饱和 NaCl洗 涤,无水 Na2S04干燥,过滤,减压旋干后柱层析(石油醚:乙酸乙酯:甲醇 =20:20:1 ),得到 0.059g 固体 4-2, 产率 19%。
[a]23D: 17.3 (c 0.9, CHC13). 1H NMR (400MHz, CDCl3):58.95(s,lH), 5.91(q,lH), 5.74-5.6(m,2H), 4.87-4.81(m,lH)„4.40(d, 1H), 2.82(m, 2H), 2.75-2.59(m, 2H), 2.47(t, 2H), 2.24(m, 2H), 1.82(d, J=7Hz, 3H), 1.58(m, 2H), 1.48(d, 3H), 1.24(m, 8H), 0.83(m, 3H), 0.74(d, 3H), 0.55(d, 3H)ppm. 13C NMR (125MHz, CDC13): 5199.5, 171.5, 169.4, 168.2, 168.0, 164.3, 147.4, 131.5, 130.2, 128.5, 124.2, 120.3, 74.3,. 66.2, 63.8, 53.6, 44.0, 38.9, 34.6, 31.8, 30.7, 30.4, 29.8, 29.4, 26.1, 22.7, 18.9, 14.2, 13.1ppm. MS (EI, mJz): 621 (M++l)
实施例 90 式 4-3化合物的合成
向实施例 59制得原料 (0.457g, 0.5mmol)的无水二氯甲烷 (5ml)溶液中,加入 1ml三氟乙酸, 室温下搅拌 24小时。 减压旋干, 加入 5ml甲苯再旋干, 除去大量三氟乙酸。 粗产物直接投入 下一步。
氩气保护下,上一步的粗产物用 50ml无水 DMF溶解,缓慢滴入 HATU(0.588g, 2.5mmol), HOAt(0.34g, 2.5mmol), DIPEA(0.87ml, 5mmol)的无水 DMF溶液中。 30°C搅拌 3天。 反应液 体系浓度为 0.001mol/L。 减压旋干 DMF, 乙酸乙酯溶解, 依次用稀盐酸洗涤, 饱和 NaCl洗 涤,无水 Na2S04干燥,过滤,减压旋干后柱层析(石油醚:乙酸乙酯:甲醇 =20:20:1 ),得到 0.059g 固体 4-3, 产率 17%。
[a]23D: 48.3 (c 0.9, CHC13). 1H NMR (400MHz, CDCl3):58.95(s,lH), 7.41(m, 2H), 7..28(m, 3H), 5.91(q,lH), 5.74-5.6(m,2H), 4.87-4.81(m,lH)„4.40(d, 1H), 2.82(m, 2H), 2.75-2.59(m, 2H), 2.47(t, 2H), 2.24(m, 2H), 1.82(d, J=7Hz, 3H), 1.58(m, 2H), 1.48(d, 3H), 1.24(m, 8H), 0.83(m, 3H), 0.74(d, 3H), 0.55(d, 3H)ppm. 13C NMR (125MHz, CDC13): 5199.5, 171.5, 169.4, 168.2, 168.0, 164.3, 147.4, 131.5, 130.2, 128.5, 128.4, 127.7, 124.2, 120.3, 74.3,. 66.2, 63.8, 53.6, 44.0, 38.9, 34.6, 31.8, 30.7, 30.4, 29.8, 29.4, 26.1, 22.7, 18.9, 14.2, 13.1ppm. MS (EI, mJz): 697 (M++l)
实施例 91 式 4-4化合物的合成
向实施例 60制得原料 (0.493g, 0.5mmol)的无水二氯甲烷 (5ml)溶液中,加入 1ml三氟乙酸, 室温下搅拌 24小时。 减压旋干, 加入 5ml甲苯再旋干, 除去大量三氟乙酸。 粗产物直接投入
下一步。
氩气保护下,上一步的粗产物用 50ml无水 DMF溶解,缓慢滴入 HATU(0.588g, 2.5mmol), HOAt(0.34g, 2.5mmol), DIPEA(0.87ml, 5mmol)的无水 DMF溶液中。 30°C搅拌 3天。 反应液 体系浓度为 0.001mol/L。 减压旋干 DMF, 乙酸乙酯溶解, 依次用稀盐酸洗涤, 饱和 NaCl洗 涤,无水 Na2S04干燥,过滤,减压旋干后柱层析(石油醚:乙酸乙酯:甲醇 =20:20:1 ),得到 0.039g 固体 4-4, 产率 11%。
[a]23D:5.1 (c 0.9, CHC13). 1H NMR (400MHz, CDCl3):58.95(s,lH), 7.12(d, 2H), 6.7(d, 2H), 5.91(q,lH), 5.74-5.6(m,2H), 5.3(s, 1H), 4.87-4.81(m,lH)„4.40(d, 1H), 2.82(m, 2H), 2.75-2.59(m, 2H), 2.47 (t, 2H), 2.24(m, 2H), 1.82(d, J=7Hz, 3H), 1.58(m, 2H), 1.48(d, 3H), 1.24(m, 8H), 0.83(m, 3H), 0.74(d, 3H), 0.55(d, 3H)ppm. 13C NMR (125MHz, CDC13): 5199.5, 171.5, 169.4, 168.2, 168.0, 164.3, 147.4, 132.1, 130.2, 128.5, 128.4, 115.8, 120.3, 74.3,. 66.2, 63.8, 53.6, 44.0, 38.9, 34.6, 31.8, 30.7, 30.4, 29.8, 29.4, 26.1, 22.7, 18.9, 14.2, 13.1ppm. MS (EI, mJz): 713 (M++l)
实施例 92 式 6-2化合物的合成
向实施例 61制得原料 (0.370g, 0.5mmol)的无水二氯甲烷 (5ml)溶液中,加入 1ml三氟乙酸, 室温下搅拌 24小时。 减压旋干, 加入 5ml甲苯再旋干, 除去大量三氟乙酸。 粗产物直接投入 下一步。
氩气保护下,上一步的粗产物用 50ml无水 DMF溶解,缓慢滴入 HATU(0.588g, 2.5mmol), HOAt(0.34g, 2.5mmol), DIPEA(0.87ml, 5mmol)的无水 DMF溶液中。 30°C搅拌 3天。 反应液 体系浓度为 0.001mol/L。 减压旋干 DMF, 乙酸乙酯溶解, 依次用稀盐酸洗涤, 饱和 NaCl洗 涤,无水 Na2S04干燥,过滤,减压旋干后柱层析(石油醚:乙酸乙酯:甲醇 =20:20:1 ),得到 0.125g 固体 6-2, 产率 48%。
[a]23D:28.1 (c 0.9, CHC13). 1H NMR (400MHz, CDC13):5 8.95(s, 1H), 5.91(q, 1H), 5.74-5.6(m, 2H), 4.87-4.81(m,3H)„4.40(d, 1H), 2.82(m, 2H), 2.75-2.59(m, 2H), 2.47(t, 2H), 2.24(m, 5H), 1.82(d, 3H), 1.58(m, 2H), 1.48(d, 3H), 0.83(m, 3H), 0.74(d, 3H), 0.55(d, 3H)ppm. 13C NMR (125MHz, CDC13): 5194.5, 171.5, 168.4, 165.5, 164.2, 147.4, 131.4, 130.0, 128.1, 124.2, 120.3,
74.2, 66.1, 44.5, 36.6, 37.6, 30.7, 30.5, 30.1, 18.9, 13.1ppm MS (EI, m/z): 523 (M++l) 实施例 93 式 6-3化合物的合成
向实施例 62制得原料 (0.447g, 0.5mmol)的无水二氯甲烷 (5ml)溶液中,加入 1ml三氟乙酸, 室温下搅拌 24小时。 减压旋干, 加入 5ml甲苯再旋干, 除去大量三氟乙酸。 粗产物直接投入 下一步。
氩气保护下,上一步的粗产物用 50ml无水 DMF溶解,缓慢滴入 HATU(0.588g, 2.5mmol), HOAt(0.34g, 2.5mmol), DIPEA(0.87ml, 5mmol)的无水 DMF溶液中。 30°C搅拌 3天。 反应液 体系浓度为 0.001mol/L。 减压旋干 DMF, 乙酸乙酯溶解, 依次用稀盐酸洗涤, 饱和 NaCl洗 涤,无水 Na2S04干燥,过滤,减压旋干后柱层析(石油醚:乙酸乙酯:甲醇 =20:20:1 ),得到 0.142g 固体 6-3, 产率 42%。
[a]23D:28.1 (c 0.9, CHC13). 1H NMR (400MHz, CDC13):5 8.95(s, 1H), 5.91(q, 1H), 5.74-5.6(m, 2H), 4.87-4.81(m,3H)„4.40(d, 1H), 2.82(m, 2H), 2.75-2.59(m, 2H), 2.47(t, 2H), 2.24(m, 2H), 1.82(d, 3H), 1.58(m, 2H), 1.48(d, 3H), 0.83(m, 20H), 0.74(d, 3H), 0.55(d, 3H)ppm. 13C NMR (125MHz, CDC13): 5194.5, 171.5, 168.4, 165.5, 164.2, 147.4, 131.4, 130.0, 128.1, 124.2, 120.3, 74.2, 66.1, 44.5, 36.6, 37.6, 30.7, 30.5, 30.1, 29.6, 29.3, 22.7, 18.9, 14.1, 13.1ppm MS (EI, m/z): 677 (M++l)
94 式 6-4化合物的合成
向实施例 63制得原料 (0.408g, 0.5mmol)的无水二氯甲烷 (5ml)溶液中,加入 1ml三氟乙酸, 室温下搅拌 24小时。 减压旋干, 加入 5ml甲苯再旋干, 除去大量三氟乙酸。 粗产物直接投入
下一步。
氩气保护下,上一步的粗产物用 50ml无水 DMF溶解,缓慢滴入 HATU(0.588g, 2.5mmol), HOAt(0.34g, 2.5mmol), DIPEA(0.87ml, 5mmol)的无水 DMF溶液中。 30°C搅拌 3天。 反应液 体系浓度为 0.001mol/L。 减压旋干 DMF, 乙酸乙酯溶解, 依次用稀盐酸洗涤, 饱和 NaCl洗 涤,无水 Na2S04干燥,过滤,减压旋干后柱层析(石油醚:乙酸乙酯:甲醇 =20:20:1 ),得到 0.132g 固体 6-4, 产率 44%。
[a]23D:32.8 (c 0.9, CHC13). 1H NMR (400MHz, CDC13):5 8.95(s, 1H), 7.33(m, 2H), 7.23(m, 3H), 5.91(q, 1H), 5.74-5.6(m, 2H), 4.87-4.81(m,3H)„4.40(d, 1H), 3.66(s, 2H), 2.82(m, 2H), 2.75-2.59(m, 2H), 2.47(t, 2H), 2.24(m, 2H), 1.82(d, 3H), 1.58(m, 2H), 1.48(d, 3H), 0.74(d, 6H),ppm. 13C NMR (125MHz, CDC13): 5194.5, 171.5, 168.4, 165.5, 164.2, 147.4, 138.2, 131.4, 130.1, 129.2, 127.6,
124.5, 120.3, 74.3, 66.3, 44.5, 38.5, 37.4, 33.9, 30.4, 30.1, 19.8, 13.0ppm MS (EI, m/z): 599 (M++l)
向实施例 64制得原料 (0.339g, 0.41mmol)的无水二氯甲垸 (5ml)溶液中, 加入 1ml三氟乙 室温下搅拌 24小时。 减压旋干, 加入 5ml甲苯再旋干, 除去大量三氟乙酸。 粗产物直接
.下一步。
氩气保护下,上一步的粗产物用 50ml无水 DMF溶解,缓慢滴入 HATU(0.78g, 2.05mmol), HOAt(0.28g, 2.05mmol), DIPEA(0.7ml, 4.1mmol)的无水 DMF溶液中。 30°C搅拌 3天。反应液 体系浓度为 0.001mol/L。 减压旋干 DMF, 乙酸乙酯溶解, 依次用稀盐酸洗涤, 饱和 NaCl洗 涤,无水 Na2S04干燥,过滤,减压旋干后柱层析(石油醚:乙酸乙酯:甲醇 =20:20:1 ),得到 0.144g 固体 6-5, 产率 52%。
[a]23D: 11.3 (c 0.9, CHC13). 1H NMR (400MHz, CDCl3):58.64(s,lH), 8.08(s,lH), 6.97(q, J=7Hz, 1H), 6.82(m, 1H), 6.5 l(d, J=10.1Hz,lH), 5.74-5.6(m,2H), 5.47(dd, J=15.5Hz 6.8Hz, 1H), 5.14(dd, J=16Hz 8.2Hz ,1H), 4.70(dd, J=10.1Hz 3.2Hz ,1H) 4.32(dd, J=17.4Hz, 3.5Hz, 1H), 3.86(m,lH), 3.65(s,lH), 2.82(t, J=7.2Hz, 2H), 2.75-2.59(m, 2H), 2.47(t, J=7.5Hz, 2H), 2.24(m, 2H), 1.82(d, J=7Hz, 3H), 1.58(m, 2H), 0.74(d, J=6.7Hz,3H), 0.55(d, J=6.7Hz,3H)ppm.
13C NMR (125MHz, CDC13): 5199.5, 171.5, 168.5, 165.5, 164.3, 147.4, 131.4, 130.0, 128.0, 124.2,
120.3, 74.3, 66.2, 58.9, 46.9, 44.5, 37.9, 30.7, 30.5, 18.9, 13.0ppm. MS (EI, m/z): 553 (M++l) 实施例
向实施例 65制得的式 1-3化合物 ( 0.26 g, 0.43 mmol)的乙腈(50 ml)溶液中加入氨水(28.9%, 5 ml)。室温下反应 12小时,反应完毕后减压浓縮,残留物直接柱层析, 乙酸乙酯: 甲醇 = 10 : 1, 得到 0.17g产 6-1, 收率 79 %。
[a]23D: 25.4 (c 0.6, CHC13) 1H NMR (400 MHz, CDC13) δ 7.79 (s, 1 H), 7.18 (d, J = 9.2 Hz, 1 H), 6.64 (dd, J = 8.8, 3.2 Hz, 1 H), 5.89 (ddd, J = 15.6, 6.8, 6.8 Hz, 1 H), 5.69 (dd, J = 6.8, 6.8 Hz, 1 H), 5.54 (dd, J = 15.6, 6.8 Hz, 1 H), 5.25 (dd, J = 17.6, 9.2 Hz, 1 H), 4.61 (dd, J = 9.6, 3.6 Hz, 1 H) 4.21 (dd, / = 17.6, 3.2 Hz, 1 H), 4.03 (d, / = 11.2 Hz, 1 H), 3.28 (d, / = 11.2 Hz, 1 H), 2.87 (dd, J = 16.4, 10.0 Hz, 1 H), 2.71 (dd, J = 6.8, 6.8 Hz, 1 H), 2.68 -2.75 (m, 1 H), 2.44 (ddd, J = 7.2, 7.2, 7.2 Hz, 2 H), 2.07-2.13 (m, 1 H), 1.86 (s, 3 H), 0.70 (d, J = 6.8 Hz, 1 H), 0.53 (d, J = 6.8 Hz, 1 H), IR (neat) 3374.5, 3305.1, 2961.8, 2929.1, 2851.4, 1731.6, 1666.2, 1596.7, 1502.7, 1237.0, 1179.8, 1114.4, 1020.4 cm— 1 ; MS (EI, m/z): 481(M++1).
实施 97 式 6-6化合物的合成
0°C条件下, 向实施例 96制得的式 6-1 (0.96 g, 2 mmol) 化合物的 200ml无水二氯甲烷中, 加入三乙胺(1 ml, 4 mmol)和酰氯(10mmol), 室温下反应 2小时。加入哌啶(10 mmol), 反应 1小时,反应完全后, 降温至 0°C, 甲醇淬灭,柱层析,得到 0.88g式 6-6化合物,产率 80%。
[a]23D: 18.6 (c 0.9, CHC13). 1H NMR (400MHz, CDC13): δ 8.69(s,lH), 8.08(s,lH), 6.97(q, J=7Hz, 1H), 6.82(m, 1H), 6.5 l(d, J=10.1Hz,lH), 5.74-5.6(m,2H), 5.47(dd, J=15.5Hz 6.8Hz, 1H), 5.40(dd, J=16Hz 8.2Hz ,1H), 4.68(dd, J=10.1Hz 3.2Hz ,1H) 4.32(dd, J=17.4Hz, 3.5Hz, 1H), 3.86(m,lH), 3.65(s,lH), 2.82(t, J=7.2Hz, 2H), 2.75-2.59(m, 2H), 2.47(t, J=7.5Hz, 2H), 2.24(m, 2H), 1.82(d,
J=7Hz, 3H), 1.58(m, 2H), 0.74(d, J=6.7Hz,3H), 0.55(d, J=6.7Hz,3H)ppm. 13C NMR (125MHz, CDCI3): 5198.5, 171.5, 168.4, 165.5, 164.3, 147.4, 131.4, 130.0, 128.0, 124.2, 120.3, 74.3, 66.2, 58.9, 46.9, 44.5, 37.9, 30.7, 30.5, 18.9, 13.0 ppm. MS (EI, m/z): 552 (M++l),
实施例 98 HDAC生化活性的测定
1. 测定原理: 化合物生化活的性测定是根据其抑制 HDAC酶的去乙酰化作用程度来确定的。 用荧光标记的含有乙酰化的赖氨酸侧链的底物和 HDAC酶作用之后,该荧光底物被去乙酰化。 去乙酰化后的荧光标记底物被酶裂解后, 释放出荧光物质, 该荧光物质在 360nm光的激发下 产生 460nm的发射光。
2. 具体步骤: HDAC的底物用反应缓冲液稀释至 200M (反应浓度为 20M), 将 HDAC酶 稀释至适当浓度, 加入不同浓度待测化合物, 37°C反应 30分钟, 然后加入相同体积的 2倍浓 度底物发展液 (developer),室温孵育 15分钟,最后用微孔板读板仪测定读数,激发光为 360nm, 发射光为 460nm, 数据用 Prime 4软件处理。 市售 Zolinza ( SAHA) 作为对照。
3. 检测结果与分析:
Κ50 (μΜ)
sample HDAC1 HDAC7
SAHA 0.15 no activity
1-1 <0.1 no activity
1-2 <0.19 no activity
1-3 <10 no activity
1-4 <1.0 no activity
1-5 <10 no activity
1-6 <10 no activity
1-7 <10 no activity
1-8 <0.102 no activity
1-9 <10 no activity
1-10 <0.10 no activity
1-11 <0.10 no activity
1-12 <0.1 no activity
2-1 <0.1 no activity
2-2 <10 no activity
2-3 <10 no activity
2-4 <10 no activity
2-5 <10 no activity
2-6 <10 no activity
2-7 <10 no activity
3-1 <10 no activity
3-2 <10 no activity
3-3 <10 no activity
4-1 <10 no activity
4-2 <0.1 no activity
4-3 <10 no activity
4-4 <10 no activity
5-1 <10 no activity
5-2 <10 no activity
6-1 <0.1 no activity
6-2 <10 no activity
6-3 <10 no activity
6-4 <10 no activity
6-5 <10 no activity
6-6 <1.0 no activity
上表中 IC5Q是指被抑制一半时抑制剂的浓度 (50%inhibitory concentration)。
从上表中结果可以看出: 上述的化合物与阳性对照 (SAHA) 相比, 具有显著的抑制
HDAC酶的去乙酰化作用的活性。
实施例 99 检测化合物对癌细胞活性实验
1. 实验原理: 化合物抑制癌细胞生长用 MTT方法来检测。 MTT法的原理是, 黄色的噻唑 兰可透过细胞膜进入细胞内, 活细胞线粒体中的琥珀脱氢酶能使外源性 MTT还原为难溶 于水的蓝紫色的针状 Formazan结晶并沉积在细胞中, 结晶能被二甲基亚砜 (DMSO) 溶 解, 用酶联免疫检测仪在 490nm/570nm波长处检测其光吸收值, 可间接反映细胞数量。
2. 实验材料:所使用的癌细胞系为 Hela (人宫颈癌细胞), MCF-7(人乳腺癌细胞),移 BGC-823
(人胃癌细胞), A549 (人肺癌细胞), HT1080 (人纤维肉瘤细胞), A431 (人表皮鳞状 细胞癌细胞), HUVEC (人脐静脉内皮细胞), DU145 (人前列腺癌细胞), K562 (人白 血病细胞), U937(人白血病细胞), Pac-1 (人胰腺癌细胞), MOLT-4 (人急性淋巴母细胞白 血病细胞) ; 分别用 DMEM+10%FBS培养基培养或者使用 1640+10%FBS培养。
3. 实验方法与结果分析:
实验组: 190μ1细胞悬液 + ΙΟμΙ不同浓度的药物 (终浓度为 10— 5〜10— 1()Μ)
空白对照组: 200μ1 ΡΒ3
阴性对照组: 190μ1细胞悬液 +10μ1 2% DMSO (DMSO终浓度为 0.1% )
阳性对照组: 190μ1细胞悬液 +10μ1不同浓度的化合物
a) .细胞接种于 96孔板, 接种量为 1500个 /孔, 190μ1/孔, 37°C 5%的 C02培养箱培养过夜; b) .次日每孔加入 ΙΟμΙ不同药物, 药物终浓度为 10— 5〜10— 1()Μ, 设三个平行孔; 37°C、 5%的 C02培养箱孵育 72小时;
c) .每孔加入 20μ1 5mg/ml的 ΜΤΤ, 37 °C 5%的 C02培养箱孵育 4小时;
d) .弃上清, 每孔加入 ΙΟΟμΙ的 DMSO, 振荡;
e) .570nm读数, 计算细胞存活率, 根据结果计算 GI5。, 得下表。
sample ΟΙ50 (μΜ)切
Hela MCF7 A549 BGC823 HT1080 lncap Dul45 U937 PANC-1 Molt-4
SAHA 37.8 1.8 7.70 4.50 3.80 4.56 NA 2.31 7.46 NA
1-1 0.4 0.09 0.09 0.1 0.05 0.05 0.008 0.007 0.3 0.009
1-2 0.1 0.05 0. 3 0.02 0.1 0.07 0.004 0.004 0.2 0.03
1-3 1.0 1.2 10.0 0.06 4.0 2.0 0.3 0.5 6.0 1.0
1-4 1.3 0.2 2.9 2.5 0.8 0.2 0.36 0.03 1.6 0.1
1-5 2.0 0.8 0.6 0.1 1.0 0.6 0.1 0.1 3.0 1.0
1-6 1.0 0.6 0.5 0.4 1.3 1.2 0.05 0.2 3.0 1.0
1-7 5.0 0.7 0.4 0.3 0.3 0.5 0.02 0.02 1.5 0.1
1-8 0.1 0.1 0.1 0.3 0.07 0.2 0.03 0.02 0.1 0.02
1-9 0.05 0.05 0.03 0.05 0.04 0.03 0.003 0.005 0.6 0.01
1-10 0.1 0.001 0.1 0.2 0.1 0.08 0.01 0.02 1.3 0.02
1-11 0.1 0.09 5.09 0.16 0.08 0.03 0.006 0.009 0.8 0.01
1-12 0.9 0.8 1.2 0.06 1.0 0.3 0.1 0.1 6.0 0.1
2-1 0.2 0.5 0.9 5 4.1 2.01 0.05 1.3 2.06 0.1
2-2 0.6 2.3 2.0 1.6 4.5 23.6 56.5 10.2 0.6 26.2
2-3 26.5 21.4 2.6 1.56 40.5 0.5 0.56 1.23 2.65 23.1
2-4 23 52.6 4.5 2.6 1.6 85.2 6.4 18.6 4.2 0.9
2-5 12 26 2.13 20.6 1.02 0.56 5.46 21.03 26.4 1.03
2-6 0.5 0.65 4.2 56.2 12.0 11.65 0.56 12.6 45.01 64.5
2-7 0.1 0.09 0.09 0.1 0.08 0.65 0.006 0.009 0.8 2.1
3-1 0.01 2.1 0.35 1.2 1.06 5.4 2.03 21.5 10.6 0.15
3-2 0.6 0.1 0.36 1.02 1.35 1.42 1.06 5.26 1.23 1.06
3-3 0.45 1.20 1.09 5.94 0.06 0.45 0.05 0.14 4.13 2.12
4-1 0.26 0.13 0.54 0.23 0.85 1.03 1.65 1.56 1.34 4.02
4-2 1.23 0.15 25.1 2.12 0.03 1.23 4.02 5.01 1.03 2.00
4-3 1.06 2.55 4.66 7.12 3.03 1.02 0.14 0.65 0.01 0.03
4-4 1.003 0.006 0.01 1.02 0.65 4.26 2.1 10.2 3.012 0.05
5-1 3.05 3.65 21.3 2.10 19.6 73.5 0.65 0.34 0.65 0.01
5-2 0.35 0.69 0.24 1.3 1.05 5.03 6.41 0.02 21.36 10.26
6-1 0.6 0.059 0.1 0.36 0.05 0.042 0.034 0.005 0.23 0.65
6-2 73.5 59.6 15.6 4.6 41.02 0.9 1.6 2.65 0.68 0.4
6-3 45 56.6 41.0 5.0 25 12 13.6 10.1 0.89 3.64
6-4 0.5 0.69 4.6 2.55 1.33 0.63 0.42. 6.35 1.25 2.65
6-5 0.54 4.12 0.365 26.5 1.65 0.45 0.695 2.658 1.645 0.268
6-6 0.86 0.952 0.001 0.065 4.16 0.65 0.3 1.29 1.653 56.4 上表中 GI5Q表示的是细胞 50%生长抑制所需的药物浓度 ( 50% growth inhibition) 从上表中结果可以看出: 上述的药物与阳性对照 (SAHA) 相比, 具有显著地抑制所列 肿瘤细胞生长的活性。
实施例 100 化合物 1-3对人结肠癌 HCT-116裸小鼠皮下移植瘤的生长抑制作用
1. 实验材料
化合物 1-3为粉末,设置三个剂量组: 20mg/kg、 10mg/kg和 5mg/kg;市售 Zolinza ( SAHA) 作为阳性对照; 溶剂为异丙醇和无水乙醇 (按 1:1的体积比混合); 受试物用溶剂与生理盐水 按 1 : 1溶解配成溶液使用, 并且用上述溶剂与生理盐水按 1 : 1溶解配成溶液作为阴性对照。 受试对象为 BALB/cA裸小鼠, 雌性, 4-5周龄, 体重 16±2 g, 购自中国科学院上海药物 研究所 (生产合格证编号: SCXK (沪) 2008-0017 ); 每组动物数: 阴性对照组 12只, 给药 组 6只。 人结肠癌 HCT-116 细胞株购自中国科学院细胞库, 用该细胞株接种裸小鼠右侧腋窝皮 下, 细胞接种量为 5 X 106/只, 形成移植瘤后再在裸小鼠体内传 2代后使用。
2. 实验方法与结果分析 取生长旺盛期的瘤组织剪切成 1.5mm3左右, 在无菌条件下, 接种于裸小鼠右侧腋窝皮 下。 裸小鼠皮下移植瘤用游标卡尺测量移植瘤直径, 待肿瘤生长至 100-200 mm3后将动物随 机分组。 1-3 化合物 20mg/kg、 10mg/kg和 5mg/kg, 每周尾静脉给药三次, 连续三周; 阳性 对照药 SAHA 50mg/kg, 每天尾静脉给药一次, 连续 3周,。 整个实验过程中, 每周 2次测量 移植瘤直径, 同时称量小鼠体重。 肿瘤体积 (tumor volume, TV)的计算公式为: TV= l/2 X aX b2, 其中 a、 b分别表示长、 宽。 根据测量的结果计算出相对肿瘤体积(relative tumor volume, RTV), 计算公式为: RTV = Vt/VQ。 其中 VQ为分笼给药时 (即 dQ)测量所得肿瘤体积, ¼为每 一次测量时的肿瘤体积。 抗肿瘤活性的评价指标为 1 ) 相对肿瘤增殖率 T/C(%), 计算公式如
下: T/C(%)= (TRTV/CRTV)X100 %, TRTV: 治疗组 RTV ; CRTV: 阴性对照组 RTV; 2) 肿瘤 体积增长抑制率 GI%, 计算公式如下: GI%=[l-(TVt-TV。)/(CVt-CTQ)]X100%, TVt 为治疗组 每次测量的瘤体积; TVQ为治疗组分笼给药时所得瘤体积; CVt 为对照组每次测量的瘤体积; CVo为对照组分笼给药时所得瘤体积; 3) 瘤重抑制率, 计算公式如下: 瘤重抑制率 =(Wc-WT)AVcX 100%, Wc: 对照组瘤重, WT: 治疗组瘤重。 实验过程中, 各给药组无小鼠死亡, 结果如表 1.1〜1.3所示。
表 1.1 1-3对人结肠癌 HCT-116裸小鼠移植瘤的錄治疗作用
动物数 体重 (g) TV (mm: 3) (mean士 SD)
组别 剂量、 给药方式 RTV
do d21 do d21 do d21 (mean士 SD) 溶剂对照 0.3ml/只 q3dx3w iv 12 12 16.1 13.4 120±17 1246±262 10.38±2.95
SAHA 50mg/kg qd><3w iv 6 6 16.6 13.3 116±27 566±221 4.87±1.68* 52.99
20mg/kg q3dx3w iv 6 6 16.7 13.1 116±26 358±201 3.09±3.14* 70.26
1-3 10mg/kg q3dx3w iv 6 6 17.5 13.5 120±19 751 ±244 6.26±3.33* 39.71
5mg/kg q3d><3w iv 6 6 16.7 13.3 122±25 1166±201 9.56±2.44 7.92 t student's test vs J对照组, * p<0.05 表 1.2 1-3对人结肠癌 HCT-116裸小鼠移植瘤肿瘤側的影响
肿瘤側 TV (mean±SD)
2011-09-03 2011-09-05 2011-09-09 2011-09-12 2011-09-16 2011-09-19 2011-09-:
d0 d3 d7 d10 d14 d17 d21 翻对照 120±17 178±29 328±90 522±150 735±213 914±203 1246±2f
SAHA 50mg/kg 116±27 146±38 191 ±25 283±41 326±45 417±140 566±22
1-3 20mg/kg 116±26 129±10 155±28 193±68 245±117 275±112 358±20
1-3 10mg/kg 120±19 163±38 217±67 302±105 408±70 571 ±175 751 ±24
1-3 5mg/kg 122±25 179±15 343±58 454±41 605±60 895±138 1166±2C 表 1.3 1-3对人结肠癌 HCT-116荷瘤鼠体重的影响
体重 (g) (mean±SD)
2011-09-03 2011-09-05 2011-09-09 2011-09-12 2011-09-16 2011-09-19 2011-09-2 d0 d3 d7 d10 d14 d17 d21 翻对照 16.1±0.8 15.3±1.1 14.8±1.5 14.4±1.3 13.9±1.3 13.6±1.2 13.4±1.i SAHA 50mg/kg 16.6±1.5 15.9±1.5 14.9±1.8 14.6±1.4 14.1±1.3 13.6±1.3 13.3±1.1 1-3 20mg/kg 16.7±0.5 16.1±0.4 14.6±0.4 14.7±0.4 13.7±0.3 13.0±0.3 13.1±0.f 1-3 10mg/kg 17.5±1.6 16.6±1.9 15.8±2.0 15.7±2.0 14.8±1.8 14.2±1.7 13.5±1.f 1-3 5mg/kg 16.7±0.6 15.9±0.7 15.0±0.9 14.5±1.2 14.1±1.0 13.5±0.9 13.3±1.( 如上表结果可知,给药三周后,对于人结肠癌 HCT-116裸小鼠皮下移植瘤,阳性对照药 SAHA 的抑瘤率 (1-T/C)为 52.99%, 20mg/kg剂量的化合物 1-3的抑瘤率 (1-T/C)为 70.26%, 改果明 显好于阳性对照药 SAHA。
实施例 101 化合物 1-4、 1-6、 1-7、 1-8对人结肠癌 HCT-116裸小鼠皮下移植瘤的生长抑制 作用
实验方法与过程同实施例 100所述, 化合物 1-4、 1-6、 1-7、 1-8各设 20mg/kg—个剂量。 根据实施例 100所述的方法计算抑瘤率; 实验结果如表 2. 〜 所示。
表 2.1 1-4、 1-6、 1-7、 1-8对人结肠癌 HCT-116裸小鼠移植瘤的錄治疗作用
动物数 体重 (g) TV (mm: 3) (mean士 SD)
组别 剂量、 给药方式 RTV
do d21 do d21 do d21 (mean士 SD) 翻对照 0.3ml/只 q3dx3w iv 12 12 16.5 13.2 119±17 1238±233 10.40±1.95
SAHA 50mg/kg qd><3w iv 6 6 16.9 13.4 118±25 536±203 4.54±1.72* 56.32
1-4 20mg/kg q3dx3w iv 6 6 16.6 13.0 116±23 308±198 2.65±1.70* 74.46
1-6 20mg/kg q3dx3w iv 6 6 16.9 13.1 121 ±28 326±221 2.69±1.82* 74.09
1-7 20mg/kg q3dx3w iv 6 6 16.6 13.2 115±20 332±186 2.89±1.62* 72.24
1-8 20mg/kg q3dx3w iv 6 6 16.1 12.9 116±22 368±241 3.17±2.08* 69.49 t student's test vs J对照组, * p<0.05 表 2.2 1-4、 1-6、 1-7、 1-8对人结肠癌 HCT-116裸小鼠移植瘤肿瘤側的影响
肿瘤側 TV (mean±SD)
2011-12-12 2011-12-15 2011-12-19 2011-12-22 2011-12-26 2011-12-29 2012-1-:
d0 d3 d7 d10 d14 d17 d21 翻对照 119±17 175±26 322±88 512±153 716±222 928±211 1238±2:
SAHA 50mg/kg 120±25 146±36 189±20 263±33 300±35 402±146 536±20
1-420mg/kg 118±23 126±12 157±26 189±52 234±103 262±132 308±19
1-620mg/kg 120±28 129±15 156±23 195±58 249±110 265±122 326±22
1-720mg/kg 116±21 131±11 158±26 199±68 245±107 275±132 332±18
1-820mg/kg 118±22 139±15 165±28 203±69 265±127 305±142 368±24 表 2.3 1-4、 1-6、 1-7、 1-8对人结肠癌 HCT-116荷瘤鼠体重的影响
体重 (g) (mean±SD)
2011-12-12 2011-12-15 2011-12-19 2011-12-22 2011-12-26 2011-12-29 2012-1-2 d0 d3 d7 d10 d14 d17 d21 翻对照 16.5±0.8 15.2±1.0 14.6±1.3 14.2±1.3 13.9±1.3 13.5±1.2 13.2±1.〔
SAHA 50mg/kg 16.8±1 ■0 15.7±1.2 14.9±1.6 14.6±1 ■5 14.2±1.4 13.8±1.3 13.4±1.1
1-4 20mg/kg 16.6±1 .2 16.2±1.4 14.8±1.2 14.5±1 .0 13.8±0.9 13.3±0.9 13.0±1.(
1-6 20mg/kg 16.9±1 ■0 16.6±1.8 15.9±1.6 15.5±1 .6 14.8±1.8 14.2±1.7 13.1±1.f
1-7 20mg/kg 16.6±1 ■ 1 15.9±0.7 15.1±0.9 14.5±1 .2 14.0±1.0 13.5±1.0 13.2±1.(
1-8 20mg/kg 16.3±1 ■0 15.8±1.1 15.1±0.9 14.5±1 .2 14.0±1.0 13.5±0.9 12.9±0.i 如上表结果可知, 给药三周后, 对于人结肠癌 HCT-116裸小鼠皮下移植瘤, 20mg/kg剂 量的化合物 1-4、 1 -6、 1-7、 1-8的抑瘤率 (1-T/C)分别为 74.46%、 74.09% 72.24% 69.49%, 效果好于阳性对照药 SAHA的 52.99%。
实施例 102化合物 1-3、 1-6、 1-8对肿瘤的抑瘤率比较
实验方法同实施例 100所述, 所接种的细胞分别为下表中所示, 针对每种荷瘤小鼠分别 给予溶剂、 SAHA ( 50mg/kg)、 化合物 1-3 (20mg/kg)、 化合物 1-6 (20mg/kg)、 化合物 1-8 (20mg/kg), 根据实施例 100所述的方法计算抑瘤率; 结果如表 3.1所示。
表 3.1 1-3、 1-6、 1-8对不同肿瘤抑瘤率比较
接种细胞 细蘇源 抑瘤率
(1-T/C)X 100% 人淋巴瘤细 美国标准生物品收 溶剂 ―
胞 Ramos 藏中心 (ATCC) SAHA (50mg/kg) 57.81
化合物 1-3 (20mg/kg) 70.08
化合物 1-6 (20mg/kg) 60.94
化合物 1-8 (20mg/kg) 58.33
人血急性单 中国科学院细胞库 溶剂 ―
核细胞性白 SAHA (50mg/kg) 63.22
血病 U937 化合物 1-3 (20mg/kg) 65.21
化合物 1-6 (20mg/kg) 66.37
化合物 1-8 (20mg/kg) 68.32
人肺癌细胞 中国科学院细胞库 溶剂 ―
NCI-H1975 SAHA (50mg/kg) 58.03
化合物 1-3 (20mg/kg) 56.40
化合物 1-6 (20mg/kg) 59.19
化合物 1-8 (20mg/kg) 53.23
人胃腺癌细 中国科学院细胞库 溶剂 ―
胞 BGC-823 SAHA (50mg/kg) 54.89
化合物 1-3 (20mg/kg) 59.38
化合物 1-6 (20mg/kg) 60.26
化合物 1-8 (20mg/kg) 56.83
人黑色素瘤 中国科学院细胞库 溶剂 ―
细胞 A875 SAHA (50mg/kg) 62.01
化合物 1-3 (20mg/kg) 63.89
化合物 1-6 (20mg/kg) 66.64
化合物 1-8 (20mg/kg) 68.07 由上表结果可知, 化合物 1-3、 1-6、 1-8对人淋巴瘤细胞 Ramos、 人血急性单核细胞性 白血病 U937、 人肺癌细胞 NCI-H1975、 人胃腺癌细胞 BGC-823、 人黑色素瘤细胞 A875裸小 鼠皮下移植瘤的生长有良好的抑制作用, 除化合物 1-3、 化合物 1-8 施药于人肺癌细胞 NCI-H1975时抑瘤率略小于 SAHA外, 其他组的抑瘤率均大于 SAHA组。
应当说明的是, 上述的实施例仅用于说明而不是限制本发明的技术方案。
Claims
1. 具有通式 I 所示的化学结构的环肽化合物, 及其药物上可接受的盐、 异构体、 外消旋体、 前体药物或溶剂合物:
Ri基团为氢, — 12烷基, -CH2-0- ( — 12烷基), -CH2-NH- ( — 12烷基), -CH2-S- ( — 12 烷基), C6— 12芳基, 杂芳基, -CH2- (C6— 12芳基)或 -CH2-杂芳基; 上述的 C6— 12芳基, 杂芳基, -CH2-C6— 12芳基, -CH2-杂芳基, 可以含有 1个或多个取代基, 其取代基可以是卤素、 氨基、 羟基、 硝基、 氰基、 — 12烷基、 — 12烷氧基、 氨基 — 12烷基、 酰基、 酰氧基、 硫代 — 12烷 基、 羧基或苯基;
R2和 R3基团独立地选自氢, _12烷基, -0- (d_12烷基), -NH- ( _12烷基), -S- (Ci_i, 烷基), C6— 12芳基或杂芳基;
R4基团为氢, _12烷基, -0- (d_12烷基), -NH- ( _12烷基), -S- (d_12烷基), C6-i2 芳基或杂芳基;
R5基团为氢, _12烷基, C3_12环烷基, -0- ( _12烷基), -NH- ( _12烷基) 或 -S- (Ci_i, 院基);
R6, R7, R8基团独立地选自氢, — 12烷基或叔丁氧羰基;
, 其中 R9基团是氢, d_12烷基, -0- ( _12烷基), -NH- ( _12烷基), -S- ( _12烷基), C6_12芳基, 杂芳基, 卤素, 氨基, 羟基, 硝基, 氰基或羧基;
或者 X为苯环, 其上可以含有 1个或多个取代基, 取代基可以是卤素、 氨基、 羟基、 硝 基、 氰基、 — 12烷基、 — 12烷氧基、 氨基 — 12烷基、 酰基、 酰氧基、 硫代 — 12烷基、 羧基、 苯基或杂环取代基。
2. 根据权利要求 1的所述的环肽化合物, 其特征在于, 其中
R2为 H,
=部分是双键,
R4为氢或 — 12烷基。
3. 根据权利要求 2的所述的环肽化合物, 其特征在于, 其中
R3为氢或 — 12烷基,
R5为氢, — 12烷基或 C3— 12环烷基,
R6, R7, R8基团独立地选自氢。
4. 根据权利要求 3的所述的环肽化合物, 其特征在于, 其中
R3为甲基,
R6,
5. 根据权利要求 4任一项所述的环肽化合物, 其特征在于, 所述化合物选自
6. 制备权利要求 1所述的环肽化合物的方法, 其特征在于, 该方法包括如下步骤:
( 1 )将式 II化合物、 式 III化合物和有机碱在縮合剂的作用下进行縮合反应, 得到式 IV 化合物; 反应过程如下所示:
(3)脱去 VI化合物上的氨基保护基 P, 然后在縮合剂和有机碱的作用下, 分子内关环得 到式 I化合物; 反应过程如下所示:
Ri R2、 R3、 R4、 R5 R6 R7、 R8同权利要求 1中所述;
P为氨基保护基团。
7. 根据权利要求 6所述的方法, 其特征在于, 所述的縮合剂可以为 DCC、 EDC、 HATU、 HOAt、 HOBt、 DEAD、 HBTU或 PyBOP, 所述的有机碱选自咪唑、 三乙胺、 二异丙基乙胺、 哌啶、 二甲基吡啶、 LiHMDS、 NaHMDS、 KHMDS、 N-甲基吗啉、 DABCO或吡啶, 所述的 氨基保护基团 P选自 Boc、 Cbz、 Bn、 Fmoc、 Alloc、 Tos、 Tfa、 Trt或 Bn。
8. 制备通式 II化合物的方法, 其特征在于, 该方法包括如下步骤:
(2) 化合物 b和樟脑磺酸反应得化合物 c, 再经氧化后得到的醛和化合物 d, 有机碱反 应得到化合物 e; 反应过程如下所示:
TBSO
(3) 化合物 e和樟脑磺酸反应得到化合物 f, 然后化合物 f、 取代的硫代酸、
縮合剂反应得到化合物 g, 化合物 g和樟脑磺酸反应得通式 II化合物;
权利要求 所述的与组蛋白去乙酰化酶调节异常有关的哺乳动物疾病包括癌症、神经变性 疾病、 疟疾和糖尿病。
权利要求 所述的与组蛋白去乙酰化酶调节异常有关的哺乳动物疾病包括淋巴瘤、肺癌、 胃癌、 胰腺癌、 乳腺癌、 前列腺癌、 白血病、 宫颈癌和结肠癌。
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WO2017045456A1 (zh) * | 2015-09-17 | 2017-03-23 | 广州康缔安生物科技有限公司 | 环肽类化合物及其应用 |
JP2019142868A (ja) * | 2014-05-27 | 2019-08-29 | オンキュアー,インコーポレイテッド | 環状デプシペプチドの調製方法 |
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WO2016144814A1 (en) * | 2015-03-06 | 2016-09-15 | Colorado State University Research Foundation | Synthesis and utility of new capgroup largazole analogs |
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2012
- 2012-02-23 WO PCT/CN2012/071515 patent/WO2013071715A1/zh active Application Filing
- 2012-02-23 US US13/980,308 patent/US8933195B2/en not_active Expired - Fee Related
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WO2011150283A1 (en) * | 2010-05-27 | 2011-12-01 | The Regents Of The University Of Colorado | Macrocyclic compounds useful as inhibitors of histone deacetylases |
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US10065990B2 (en) | 2013-09-02 | 2018-09-04 | Hangzhou Guanyu Bio-Medical Co., Ltd. | Cyclic peptide compound, and preparation method, pharmaceutical composition and use thereof |
EP3042913A4 (en) * | 2013-09-02 | 2016-08-24 | Hangzhou Guanyu Bio Medical Co Ltd | CYCLIC PEPTIDE COMPOUND, AND PREPARATION METHOD, PHARMACEUTICAL COMPOSITION AND USE THEREOF |
TWI711627B (zh) * | 2014-05-27 | 2020-12-01 | 美商昂克爾公司 | 製備環縮肽之方法 |
JP2019142868A (ja) * | 2014-05-27 | 2019-08-29 | オンキュアー,インコーポレイテッド | 環状デプシペプチドの調製方法 |
KR20200057797A (ko) * | 2014-05-27 | 2020-05-26 | 온쿠레 인코포레이티드 | 사이클릭뎁시펩타이드의 제조 방법 |
US10689419B2 (en) | 2014-05-27 | 2020-06-23 | Onkure, Inc. | Process for the preparation of cyclic depsipeptides |
JP2021073221A (ja) * | 2014-05-27 | 2021-05-13 | オンキュアー,インコーポレイテッド | 環状デプシペプチドの調製方法 |
US11053284B2 (en) | 2014-05-27 | 2021-07-06 | Onkure, Inc. | Process for the preparation of cyclic depsipeptides |
KR102368235B1 (ko) | 2014-05-27 | 2022-03-02 | 온쿠레 인코포레이티드 | 사이클릭뎁시펩타이드의 제조 방법 |
JP7033677B2 (ja) | 2014-05-27 | 2022-03-10 | オンキュアー,インコーポレイテッド | 環状デプシペプチドの調製方法 |
JP2022068364A (ja) * | 2014-05-27 | 2022-05-09 | オンキュアー,インコーポレイテッド | 環状デプシペプチドの調製方法 |
JP7269398B2 (ja) | 2014-05-27 | 2023-05-08 | オンキュアー,インコーポレイテッド | 環状デプシペプチドの調製方法 |
US11739123B2 (en) | 2014-05-27 | 2023-08-29 | Onkure, Inc. | Process for the preparation of cyclic depsipeptides |
WO2017045456A1 (zh) * | 2015-09-17 | 2017-03-23 | 广州康缔安生物科技有限公司 | 环肽类化合物及其应用 |
Also Published As
Publication number | Publication date |
---|---|
US20140243501A1 (en) | 2014-08-28 |
US8933195B2 (en) | 2015-01-13 |
CN102391359A (zh) | 2012-03-28 |
CN102391359B (zh) | 2014-07-16 |
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