CN108101821B - Naphthyl sulfonamide amino acid derivative, preparation method and medical application thereof - Google Patents
Naphthyl sulfonamide amino acid derivative, preparation method and medical application thereof Download PDFInfo
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Abstract
The invention discloses a naphthyl sulfamide amino acid derivative, a preparation method and medical application thereof, wherein the naphthyl sulfamide amino acid derivative R3The substituent represents a substituent having an amino acid structure in which the substituent contains at least one carboxyl group and a secondary or tertiary amine, and the substituent is bonded to the above parent nucleus through the secondary or tertiary amine. The naphthyl sulfonamide amino acid derivative provided by the invention can interfere with the binding of Keap1-Nrf2 and activate Nrf2, thereby relieving inflammatory injury, improving inflammatory microenvironment and having potential anti-inflammatory activity. One skilled in the art will recognize that Nrf2 activators may be useful in inhibiting the inflammatory response of a disease and, therefore, the compounds of the present invention may be useful in the preparation of anti-inflammatory drugs for the treatment of inflammation-related diseases, including chronic obstructive pulmonary disease, alzheimer's disease, parkinson's disease, atherosclerosis, chronic kidney disease, diabetes, intestinal inflammation, rheumatoid arthritis, and the like.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to compounds with anti-inflammatory activity and using naphthyl sulfonamide amino acids as basic skeletons, and also relates to a preparation method of the compounds and medical application of the compounds in the field of anti-inflammatory.
Background
Anti-inflammatory therapies currently in common use are mainly classified into steroidal anti-inflammatory drugs, mainly corticosteroids and non-steroidal anti-inflammatory drugs, mainly cyclooxygenase inhibitors. Although the chemical structures of nonsteroidal anti-inflammatory drugs are different, they have antipyretic, analgesic and anti-inflammatory effects by inhibiting prostaglandin synthesis in many cases. The anti-inflammatory drugs used clinically at present produce anti-inflammatory effects by inhibiting inflammatory reactions, and cannot or rarely improve the causes of inflammation. Fundamentally, treatment of inflammation requires improvement of the microenvironment that forms the inflammation and activation of the anti-inflammatory system in the body. Inflammatory responses and oxidative stress have important intrinsic correlations. Oxidative stress can cause damage to protein, nucleic acid and lipid molecules, thereby causing inflammatory injury, activating inflammatory factors, and inducing and exacerbating inflammatory reactions, wherein the inflammation is closely related to the occurrence and development of tumors, cardiovascular diseases, Parkinson, Alzheimer, chronic kidney diseases and other diseases; while proteins associated with antioxidant stress can scavenge reactive oxygen species, accelerate foreign body metabolism and elevate the antioxidant protein content in vivo to improve the inflammatory microenvironment for the treatment of inflammation [ references: trends Biochem Sci 2009; 34(4) 176-188; annu Rev Pharmacol Toxicol 2007; 89 to 116 parts by weight; j Biochem Mol Biol 2004; 37(2), 139 to 143; genes Cells 2011; 16(2):123-140].
Nrf2 was first identified in 1994 in heme-induced erythroid K562 cells as a key transcription factor involved in the regulation of oxidative stress. Nrf2 belongs to the family of leucine zipper nuclear transcription factors, and is highly homologous to the drosophila CNC family, human Nrf2 and nuclear factor erythroid 2 subunit p 45. Most antioxidant genes associated with oxidative stress include an Antioxidant Response Element (ARE), and Nrf2 exerts transcription initiation activity by binding to the ARE. Common sequence of ARE is 5 '-RTGAYnnnGCR-3' (where R ═ aor G and Y ═ C orT). Keap1 is a major negative regulatory protein of intracellular Nrf2, whose primary function is to maintain normally low levels of Nrf2 in the cell; the negative regulation effect on the Nrf2 is released under the stress state, and the level of the Nrf2 is increased. The level of Nrf2 can be effectively increased by inhibiting the negative regulation effect of the Keap1 on Nrf2, an in-vivo antioxidant system is activated, inflammatory injury is relieved, and an inflammatory microenvironment is improved, so that the effect of fundamentally relieving and treating inflammation is achieved.
Presently, Nrf2 activators have been used to treat inflammatory related diseases. Such as dimethyl fumarate, have been FDA approved for the treatment of multiple sclerosis, and CDDO-Me is developing a second phase clinic for the treatment of Pulmonary Arterial Hypertension (PAH). Other natural and natural-like products with anti-inflammatory activity have also been shown to activate Nrf2, such as curcumin, resveratrol, chalcones, and the like.
These Nrf2 activators mostly have a polyunsaturated structure capable of binding to a thiol group of Keap1, and are considered to be covalently modified Nrf2 activators. Recently, competitive interference with Keap1-Nrf2 interaction has been reported to effectively release the negative regulation of Keap1 on Nrf2 and activate Nrf 2. The mode for activating the Nrf2 has the characteristics of competitiveness, specificity, reversibility and high selectivity, avoids the potential toxicity of covalently modified activated Nrf2, and is a hotspot for the current research on Nrf2 activated inflammatory disease treatment drugs.
Disclosure of Invention
The invention aims to provide a compound containing amino acid and monosulfonamide structure, and a preparation method and application thereof. Preliminary activity tests prove that the compounds with the structure can interfere with Keap1-Nrf2 to be combined and activate Nrf2, so that inflammatory injury is reduced, the inflammatory microenvironment is improved, potential anti-inflammatory activity is achieved, and the compounds can be used for preparing anti-inflammatory drugs for inflammatory injury of various inflammation-related diseases, such as Chronic Obstructive Pulmonary Disease (COPD), Alzheimer disease, Parkinson, atherosclerosis, Chronic Kidney Disease (CKD), diabetes, intestinal inflammation, rheumatoid arthritis and the like.
The above object of the present invention is achieved by the following technical solutions:
a naphthyl sulfonamide amino acid derivative of formula (I):
wherein: r1Represents 4-trifluoromethyl, 4-trifluoromethoxy, 4-nitro, 4-hydroxy, 4-hydroxymethyl, 4-cyano or 4-amino; mono-, di-or tri-substituted H, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamino or C1-C3 acylamino;
R3Represents a substituent having an amino acid structure in which the substituent contains at least one carboxyl group and a secondary or tertiary amine, and the substituent is bonded to the above-mentioned mother nucleus through the secondary or tertiary amine.
Preferably, R3Represents the following substituents:
wherein: x represents H, O or S; r4Represents methyl, ethyl, tert-butyl, phenyl, 4-methoxyphenyl or benzyl.
More preferably, the chemical formula of the naphthyl sulfonamide amino acid derivative is as follows:
preferably, R3Represents the following substituents:
wherein:
R5represents H, methyl, isopropyl, sec-butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexylmethyl, hydroxymethyl, tert-butyloxymethyl, benzyloxymethyl, phenyl, benzyl, phenethyl, 4-fluorobenzyl, 4-chlorobenzyl, 4-hydroxybenzyl, 4-methoxybenzyl, 4-benzyloxybenzyl, 2-indolylmethyl, 4-aminobutyl, 1-naphthylmethyl, carboxymethyl, carboxyethyl, methylthioethyl, methylsulfoxoethyl, methylsulfoloethyl, methyl-sulfonylethyl, methyl-benzyloxybenzyl, 2-indolylmethyl, 4-aminobutyl, 1-naphthylmethyl, carboxymethyl, carboxyethyl, methylthioethyl, methyl-sulfoxethyl,
n takes the value 0 or 1.
More preferably, the chemical formula of the naphthyl sulfonamide amino acid derivative is as follows:
or the chemical structural formula is as follows:
or the chemical structural formula is as follows:
or the chemical structural formula is as follows:
the preparation method of the naphthyl sulfonamide amino acid derivative comprises the following steps, wherein R2Represents H, -CH2COOH or
In the synthesis steps of the compounds (1) to (2), tert-butyl hydroperoxide is used as a raw material, dimethyl sulfoxide and water are preferably used as solvents, the volume ratio is preferably 4:1, and the amount of the compound (1) and a reactant tert-butyl hydroperoxide (t-BuOOH) substance is preferably 1: 3.5-1: 4.0; in the synthesis steps of the compounds (2) to (3), the mass ratio of the compound (2) to the reactant Tf2O is preferably 1: 1.5-1: 2, and the adopted base is preferably triethylamine or DIPEA.
In the steps of synthesizing the compounds (3) to (4), the base used is preferably cesium carbonate and DIPEA, and the catalyst is preferably Pd2(dba)3、Pd(dea)2The ligand is preferably BINAP, RuPhos, the solvent is preferably one or more of toluene, 1, 4-dioxane and tert-butanol.
In the synthesis steps of the compounds (4) to (5), hydrogen, palladium and carbon are adopted for reduction, the adopted solvents are preferably methanol and tetrahydrofuran, and the feeding amount of the palladium and carbon is preferably 10% mol.
In the synthesis steps of the compounds (5) to (6), the base used is preferably potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, pyridine, triethylamine, DIPEA, and is preferably reacted in the following solvent: tetrahydrofuran, toluene and 1, 4-dioxane.
The weight ratio of the compound (6) to the methyl bromoacetate is preferably 1: 2-1: 3, the adopted base is preferably potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, pyridine and triethylamine, and the reaction is preferably carried out in the following solvents: dimethyl sulfoxide, N-dimethylformamide, 1, 4-dioxane and acetonitrile. The reaction temperature is room temperature.
The compound (7) to the compound (8), the feeding amount of lithium hydroxide is preferably selected, the concentration of lithium hydroxide in the solution is 1-3mol/L, the solvent system is a methanol/water system or an ethanol/water system, and the reaction is carried out at room temperature.
The lithium hydroxide of the compound (6) to the compound (9) is preferably fed in an amount such that the concentration of the lithium hydroxide in the solution is 1-3mol/L, the solvent system is a methanol/water system or an ethanol/water system, and the reaction is carried out at room temperature.
The compound (7) to the compound (10), the feeding amount of lithium hydroxide is preferably selected, the concentration of lithium hydroxide in the solution is 1-3mol/L, the solvent system is a methanol/water system or an ethanol/water system, and the reaction is carried out at room temperature.
The preparation method of the naphthyl sulfonamide amino acid derivative comprises the following steps, wherein R2Represents
Synthesis methods of compounds (1) to (6) and compounds of formula (I) wherein R is3is-CH2COOH and-H are the same.
Compounds (6) to (11), the base used is preferably potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, preferably in the following solvents: dimethyl sulfoxide, N-dimethylformamide, 1, 4-dioxane and acetonitrile, wherein the material ratio (the material amount ratio) of the raw material 6 to bromoacetonitrile is 1:1-1:4, and the reaction temperature is room temperature.
The compound (11) to the compound (12), ammonium chloride inventory (mass ratio) 1:4 to 1:8, are preferably reacted in the following solvents: heating one or more of N, N-dimethylformamide and 1, 4-dioxane to reflux reaction.
And (3) adding the compound (12) to the target compound (13), wherein the lithium hydroxide is preferably added in an amount that the concentration of the lithium hydroxide in the solution is 1-3mol/L, the solvent system is a methanol/water system or an ethanol/water system, and the reaction is carried out at room temperature.
Pharmaceutically acceptable salts of the above naphthyl sulfonamide amino acid derivatives.
Use of the naphthyl sulfonamide amino acid derivatives and pharmaceutically acceptable salts thereof for the preparation of Nrf2 activators.
The naphthyl sulfonamide amino acid derivative and the pharmaceutically acceptable salt thereof are used for preparing the medicine for treating or relieving the inflammation of the diseases, such as chronic obstructive pulmonary disease, Alzheimer disease, Parkinson, atherosclerosis, chronic kidney disease, diabetes, intestinal inflammation or rheumatoid arthritis.
The invention has the advantages that:
the compound containing amino acids and a monosulfonamide structure provided by the invention can interfere with the binding of Keap1-Nrf2 and activate Nrf2, thereby relieving inflammatory injury, improving inflammatory microenvironment, having potential anti-inflammatory activity, and being capable of being used for preparing anti-inflammatory drugs for inflammatory injury of various inflammation-related diseases, such as Chronic Obstructive Pulmonary Disease (COPD), Alzheimer disease, Parkinson, atherosclerosis, Chronic Kidney Disease (CKD), diabetes, intestinal inflammation, rheumatoid arthritis and the like.
Detailed Description
The following examples are given to illustrate the essence of the present invention, but not to limit the scope of the present invention.
Example 1:
(4- ((4-methoxyphenyl) sulfonamido) naphthalen-1-yl) -L-proline (I-a-1)
(1) 4-Nitro-1-naphthol (1-1)
1-nitronaphthalene (8.5g, 49.1mmol) was dissolved in 20.0mL of DMSO (dimethyl sulfoxide), followed by potassium hydroxide (11.0g, 196.3mmol) in 10.0mL of water, dropwise added to the reaction system in ice bath, and finally a solution of t-butyl peroxy alcohol (9.8mL, 98.2mmol) in 10.0mL of LDMSO was added dropwise to the reaction system. After the addition, the mixture was stirred for about 10.0min, the ice bath was removed, and the reaction was carried out at room temperature. Reacting for 4h, adding Na2S2O3(1.5g, 9.3mmol) was stirred for 1.0h, then 200.0mL water was added, the pH was adjusted to 4 with dilute hydrochloric acid, extracted three times with 30mL EA (ethyl acetate), the organic layers were combined, washed 3 times with saturated sodium chloride solution, the pH was adjusted to 10 with 4M sodium hydroxide, the aqueous layer was washed 3 times with EA, the aqueous layer was adjusted to pH 4 with dilute hydrochloric acid solution, yellow solid precipitated, filtered with suction, dried to give 5.2g bright yellow solid, yield 55.4%, m.p.156-159 ℃.1H-NMR(300MHz,DMSO-d6):11.98(br,1H),8.68(d,1H,J=8.79Hz),8.42(d,1H,J=8.70Hz),8.33(d,1H,J=8.34Hz),7.78-7.83(m,1H),7.61-7.66(m,1H),6.98(d,1H,J=8.70Hz);EI-MS m/z:190[M+H]+。
(2) 4-Nitro-naphthalen-1-yl trifluoromethanesulfonate (1-2)
4-Nitro-1-naphthol (1-1) (2.0g, 10.6mmol) was dissolved in 20ml DCM and Et was added successively under ice bath conditions3N (4.4ml, 31.9mmol,) and Tf2O ((2.7ml, 16.3mmol), after the addition was complete, the reaction was stirred at room temperature for 2.0h until TLC monitored the reaction completion, the reaction was quenched with saturated NaHCO3(20ml) neutralized, the organic phase was washed twice with water (20ml) and again withWashed twice with saturated NaCl (20 ml). Finally using anhydrous Na2SO4Drying, spin-drying organic solvent, and performing column chromatography to obtain 2.0g of light yellow solid with yield of 56% m.p.59-61 deg.C; EI-MS m/z: 322[ M + H]+。
(3) (4-Nitro-naphthalen-1-yl) -L-proline methyl ester (1-3)
In a dry reaction flask, compound (1-2) (1g, 3.11mmol) and L-proline methyl ester hydrochloride (0.62g, 3.7mmol) were added followed by rapid addition of Cs2CO3(2g, 6.22mmol), (+ -) -BINAP (0.29g, 0.47mmol) and Pd2(dba)3(0.14g,0.16mmol), DIPEA (1.1ml,6.22mmol) and dioxane (10ml) were added in time and reacted for 20h at 100 ℃ under nitrogen. Cooling to room temperature, filtering with diatomite, drying by rotary drying, and performing column chromatography to obtain 0.47g of yellow oily liquid with the yield of 51%.1H-NMR(300MHz,CDCl3)8.84(ddd,J=8.8,1.3,0.6Hz,1H),8.31(d,J=8.8Hz,1H),8.25-8.18(m,1H),7.69-7.61(m,1H),7.48(ddd,J=8.4,6.9,1.3Hz,1H),6.75(d,J=8.9Hz,1H),4.69(t,J=7.3Hz,1H),4.12(td,J=9.7,6.2Hz,1H),3.62(s,3H),3.61-3.53(m,1H),2.61-2.49(m,1H),2.25-2.11(m,2H),2.02-1.88(m,1H);EI-MS m/z:301[M+H]+。
(4) (4- ((4-methoxyphenyl) sulfonylamino) naphthalen-1-yl) -L-prolinate methyl ester (1-4)
Compound (1-3) (470mg, 1.57mmol) was dissolved in 50ml of THF, and 5% palladium on carbon (33mg, 0.31mmol) was added in time to carry H2Ball at H2The reaction was heated to 50 ℃ in the ambient. TLC monitoring reaction completion (5h), palladium on carbon removal by celite, 4-methoxybenzenesulfonyl chloride (390mg, 1.89mmol), pyridine (380. mu.L, 4.71mmol), N-addition to filtrate2Heating to 80 ℃ for reaction for 4h under protection, monitoring by TLC (thin layer chromatography) after the reaction is complete, evaporating THF under reduced pressure, adding EA to be completely dissolved, washing with 1M dilute hydrochloric acid (20ml) solution for three times, washing with saturated NaCl (20ml) solution for 2 times, drying with anhydrous sodium sulfate, evaporating EA, and carrying out column chromatography to obtain 500mg of white solid with the yield of 72 percent and the m.p.120-123 ℃.1H-NMR(300MHz,CDCl3)8.18(dd,J=6.9,2.7Hz,1H),7.94-7.80(m,1H),7.72-7.62(m,2H),7.50-7.35(m,2H),7.20-7.10(m,1H),6.93(dt,J=8.1,1.7Hz,1H),6.88-6.74(m,3H),4.47(s,1H),3.93(q,J=8.3,7.6Hz,1H),3.85-3.75(m,3H),3.57-3.46(m,3H),3.16(q,J=8.7,6.0Hz,1H),2.54-2.37(m,1H),2.15(q,J=7.4Hz,2H),2.04(d,J=13.5Hz,1H);EI-MS m/z:441[M+H]+。
(5) (4- ((4-methoxyphenyl) sulfonamido) naphthalen-1-yl) -L-proline (I-a-1)
Compound (1-4) (200.0mg, 454.0. mu. mol) was dissolved in 5.0mL of methanol, 5.0mL of water was added, and LiOH. H.was added2O (191mg, 4.54mmol) was stirred at room temperature overnight. The next day, insoluble matter in the reaction solution was filtered off, 50ml of water was added to the filtrate, the pH was adjusted to 4-5 with hydrochloric acid solution, and the solution gradually precipitated a precipitate as an off-white solid (120.0mg, 62% yield, m.p.130-133 ℃ C.).1H-NMR(300MHz,DMSO-d6)9.80(br,1H),8.17-8.07(m,1H),7.95(dd,J=7.4,2.2Hz,1H),7.65-7.53(m,2H),7.40(tt,J=7.3,5.3Hz,2H),7.06-6.97(m,2H),6.90(d,J=1.3Hz,2H),4.38(m,1H),3.82-3.86(m,1H),3.78(s,3H),3.01(s,1H),2.34(q,J=8.4Hz,1H),2.00-1.96(m,2H),1.92-1.88(m,1H);EI-MS m/z:427[M+H]+。
Example 2:
(4- ((N- (carboxymethyl) -4-methoxyphenyl) sulfonamido) naphthalen-1-yl) -L-proline (I-a-2)
1-4 Synthesis same as example 1
(1) (4- ((4-methoxy-N- (2-methoxy-2-oxoethyl) phenyl) sulfonamido) naphthalen-1-yl) -L-proline methyl ester (2-1)
Compound (1-4) (200.0mg, 454. mu. mol) was dissolved in 5.0mL of DMF, potassium carbonate (280.0mg, 2.0mmol) was added, and methyl bromoacetate (83.0mg, 545. mu. mol) was added and stirred at room temperature. Reacting for 4h, adding water to the solution until solid is separated out, extracting with EA (30ml) for three times, combining organic phases, washing with saturated NACl aqueous solution (30ml) for three times, and then using anhydrous Na for the organic phases2SO4Drying, making sand, and performing column chromatography to obtain light yellow oily substance 190mg with yield of 82%.1H-NMR(300MHz,CDCl3)8.22(d,J=8.8Hz,1H),8.08-7.94(m,1H),7.69(ddd,J=11.1,8.8,2.5Hz,2H),7.46(s,2H),7.21-7.07(m,1H),6.92(t,J=7.9Hz,3H),4.72(t,J=17.4Hz,1H),4.49(d,J=8.4Hz,1H),4.20(d,J=19.9Hz,1H),4.00(dd,J=18.6,8.9Hz,1H),3.88(dt,J=3.8,1.9Hz,3H),3.74-3.63(m,3H),3.62-3.53(m,3H),3.23(s,1H),2.46(d,J=9.0Hz,1H),2.16(s,2H),2.00(s,1H);EI-MS m/z:513[M+H]+。
(2) (4- ((N- (carboxymethyl) -4-methoxyphenyl) sulfonamido) naphthalen-1-yl) -L-proline (I-a-2)
The same procedure as described for the synthesis of Compound (I-a-1) was repeated except that Compound (2-1) (180.0mg, 351.2. mu. mol), LiOH. H2O (295.0g, 7.0mmol) as starting material, the reaction gave 110.0mg of a white solid in 65% yield, m.p.75-78 ℃.1H-NMR(300MHz,DMSO-d6)12.45(br,2H),8.16(d,J=6.9Hz,1H),8.08-7.94(m,1H),7.60(t,J=7.4Hz,2H),7.45(q,J=4.6Hz,2H),7.06(t,J=7.5Hz,3H),6.86(dd,J=11.5,8.2Hz,1H),4.49-4.37(m,2H),4.24(dd,J=17.7,11.6Hz,1H),3.92(t,J=7.8Hz,1H),3.84(s,3H),3.10(s,1H),2.44-2.35(m,1H),2.45-2.02(m,2H),1.99-1.89(m,1H);EI-MS m/z:485[M+H]+。
Example 3:
(4- ((4-Acylaminophenyl) sulfonamido) naphthalen-1-yl) -L-proline (I-a-3)
1-3 Synthesis the same as in example 1
(1) (4- ((4-Acylaminophenyl) sulfonamido) naphthalen-1-yl) -L-proline methyl ester (3-1)
In the same manner as the synthesis of the compound (1-4), the compound (1-3) (500mg, 1.67mmol) was hydrogenolyzed and then reacted with 4-acetamidobenzenesulfonyl chloride (468mg, 2mmol) and pyridine (404. mu.L, 5.01mmol) as starting materials to give 258mg of a white solid in a yield of 33% m.p.109-112 ℃.1H-NMR(300MHz,C)8.17(d,J=7.8Hz,1H),7.84(d,J=7.8Hz,1H),7.62(d,J=8.5Hz,2H),7.56(s,1H),7.48(d,J=8.6Hz,2H),7.39(s,2H),7.11(d,J=8.3Hz,2H),6.90(d,J=8.2Hz,1H),6.74(s,1H),4.47(s,1H),3.91(d,J=8.7Hz,1H),3.54(s,3H),3.15(s,1H),2.45(d,J=10.8Hz,1H),2.15(s,5H),2.01(s,3H);EI-MS m/z:468[M+H]+。
(2) (4- ((4-Acylaminophenyl) sulfonamido) naphthalen-1-yl) -L-proline (I-a-3)
With compound (3-1) (120.0mg, 257.0. mu. mol) and LiOH. H2O (108.0mg, 2.57mmol) as starting material gave 80.0mg of a white solid, yield 69%, m.p.122-124 ℃.1H-NMR(300MHz,DMSO-d6)10.24(s,1H),9.79(s,1H),8.11(d,J=8.0Hz,1H),7.98(d,J=8.0Hz,1H),7.66(d,J=8.6Hz,2H),7.58(d,J=8.6Hz,2H),7.42(p,J=6.7Hz,2H),6.92(t,J=6.3Hz,2H),4.48(s,1H),3.79(q,J=7.5Hz,1H),3.04(s,1H),2.39(q,J=8.2Hz,1H),2.02(d,J=22.9Hz,3H);EI-MS m/z:454[M+H]+。
Example 4:
(4- ((4-acetylamino-N- (carboxymethyl) phenyl) sulfonylamino) naphthalen-1-yl) -L-proline (I-a-4)
1-3 Synthesis in full accordance with example 1
(1) (4- ((4-acetamido-N- (2-methoxy-2-oxoethyl) phenyl) sulfonylamino) naphthalen-1-yl) -L-proline methyl ester (4-1)
In the same manner as in the synthesis of the compound (2-1), starting from the compound (3-1) (120.0mg, 257. mu. mol), potassium carbonate (107.0mg, 0.77mmol) and methyl bromoacetate (47.2mg, 308. mu. mol), 113mg of a pale yellow oil was obtained in 82% yield.1H-NMR(300MHz,C)8.15(d,J=7.8Hz,1H),7.80(d,J=7.8Hz,1H),7.64(d,J=8.6Hz,2H),7.53(s,1H),7.50(d,J=8.6Hz,2H),7.39(s,2H),7.11(d,J=8.3Hz,2H),6.90(d,J=8.2Hz,1H),6.72(s,1H),4.45(s,1H),4.23(m,2H),3.90(d,J=8.7Hz,1H),3.50(s,3H),3.20(s,1H),2.44(d,J=10.8Hz,1H),2.17(s,5H),2.00(s,3H);EI-MS m/z:540[M+H]+。
(2) (4- ((4-acetylamino-N- (carboxymethyl) phenyl) sulfonylamino) naphthalen-1-yl) -L-proline (I-a-4)
Synthesis of Compound (I-a-1)The same procedure was followed using compound (4-1) (113.0mg, 210. mu. mol), LiOH. H2O (176.4g, 4.2mmol) as starting material, reaction gave 90.0mg of a white solid, 73% yield, m.p.137-141 ℃.1H-NMR(300MHz,DMSO-d6)12.45(br,2H),8.15(d,J=7.7Hz,2H),7.45(d,J=7.2Hz,2H),7.28(d,J=7.4Hz,2H),7.02(d,J=6.2Hz,1H),6.88(t,J=9.2Hz,1H),6.57(d,J=8.5Hz,2H),6.03(s,1H),4.41(d,J=8.1Hz,1H),4.26(m,2H),3.91(s,1H),3.11(d,J=14.0Hz,1H),2.41(s,1H),2.00(m,3H);EI-MS m/z:512[M+H]+。
Example 5:
(2S, 4R) -4- (benzyloxy) -1- (4- ((4-methoxyphenyl) sulfonylamino) naphthalen-1-yl) pyrrolidine-2-carboxylic acid (I-a-6)
1-2 Synthesis the same as in example 1
(1) (2S, 4R) -4- (benzyloxy) -1- (4-nitronaphthalen-1-yl) pyrrolidine-2-carboxylic acid methyl ester (5-1)
The synthesis method of the compound (1-3) comprises the steps of using the compound (1-2) (1g, 3.11mmol), O-benzyl-trans-4-hydroxy-L-proline methyl ester hydrochloride (1.01g, 3.73mmol) and Cs2CO3(2g,6.22mmol)、(±)-BINAP(0.29g,0.47mmol)、Pd2(dba)3Starting from (0.14g,0.16mmol) DIPEA (1.1ml,6.22mmol) 0.80g of a yellow oily liquid was obtained in 63% yield.1H NMR(300MHz,CDCl3)8.84(ddd,J=8.8,1.3,0.6Hz,1H),8.31(d,J=8.8Hz,1H),8.25-8.18(m,1H),7.69-7.61(m,1H),7.48(ddd,J=8.4,6.9,1.3Hz,1H),6.75(d,J=8.9Hz,1H),4.69(t,J=7.3Hz,1H),4.12(td,J=9.7,6.2Hz,1H),3.62(s,3H),3.61-3.53(m,1H),2.61-2.49(m,1H),2.25-2.11(m,2H),2.02-1.88(m,1H);EI-MS m/z:407[M+H]+。
(2) (2S, 4R) -4- (benzyloxy) -1- (4- ((4-methoxyphenyl) sulfonylamino) naphthalen-1-yl) pyrrolidine-2-carboxylic acid methyl ester (5-2)
In the same manner as in the synthesis of compound (1-4), compound (5-1) (800mg, 1.97mmol) was hydrogenolyzed and then reacted with 4-methoxybenzenesulfonyl chloride (489mg,2.36mmol), pyridine (476. mu.L, 5.91mmol) as starting material gave 450mg of a white solid in 42% yield m.p.102-103 ℃.1H-NMR(300MHz,CDCl3)8.17-8.06(m,1H),7.80-7.71(m,1H),7.63-7.52(m,2H),7.27-7.18(m,5H),7.07(d,J=8.1Hz,1H),6.90(d,J=8.1Hz,1H),6.80-6.69(m,2H),6.44(s,1H),4.61(t,J=7.7Hz,1H),4.42(d,J=2.7Hz,2H),4.26(s,1H),4.06(dd,J=10.7,4.7Hz,1H),3.72(s,3H),3.46(s,3H),3.24-3.12(m,1H),2.49(dd,J=13.2,7.1Hz,1H),2.27(ddd,J=13.4,8.3,5.5Hz,1H);EI-MS m/z:547[M+H]+。
(3) (2S, 4R) -4- (benzyloxy) -1- (4- ((4-methoxyphenyl) sulfonylamino) naphthalen-1-yl) pyrrolidine-2-carboxylic acid (I-a-5)
The same procedure as for the synthesis of Compound (I-a-1) was repeated except that Compound (5-2) (200.0mg, 366.0. mu. mol) and LiOH. H2O (154.0mg, 3.66mmol) as starting material gave 150.0mg of a white solid in 77% yield m.p.100-102 ℃.1H-NMR(300MHz,DMSO-d6)12.41(br,1H),9.76(s,1H),8.10(d,J=8.0Hz,1H),7.96(d,J=7.9Hz,1H),7.60(d,J=8.5Hz,2H),7.40(d,J=6.8Hz,2H),7.27(d,J=2.1Hz,5H),7.00(d,J=8.8Hz,2H),6.91(q,J=8.2Hz,2H),4.58-4.39(m,3H),4.29(s,1H),4.14(dd,J=10.6,4.5Hz,1H),3.31(s,2H),3.11(d,J=10.6Hz,1H),2.26-2.17(m,2H);EI-MS m/z:533[M+H]+。
Example 6:
(2S, 4R) -4- (benzyloxy) -1- (4- ((N- (carboxymethyl) -4-methoxyphenyl) sulfonylamino) naphthalen-1-yl) pyrrolidine-2-carboxylic acid (I-a-6)
5-2 Synthesis is in full accordance with example 5
(1) (2S, 4R) -4- (benzyloxy) -1- (4- ((4-methoxy-N- (2-methoxy-2-oxoethyl) phenyl) sulfonylamino) naphthalen-1-yl) pyrrolidine-2-carboxylic acid methyl ester (6-1)
In the same manner as the synthesis of the compound (2-1), starting from the compound (5-2) (200.0mg, 366. mu. mol), potassium carbonate (152.0mg, 1.1mmol) and methyl bromoacetate (67.2mg, 439. mu. mol), a pale yellow oil was obtained183mg of the substance was obtained, representing a yield of 81%.1H-NMR(300MHz,CDCl3)8.20(dd,J=9.0,4.5Hz,1H),8.12-7.96(m,1H),7.75-7.65(m,2H),7.54-7.43(m,2H),7.32(ddd,J=10.5,8.1,2.9Hz,5H),7.15(dd,J=20.3,8.1Hz,1H),6.97-6.83(m,3H),4.78-4.65(m,2H),4.50(d,J=8.3Hz,2H),4.36-4.30(m,1H),4.27-4.15(m,2H),3.87(s,3H),3.67(d,J=4.4Hz,3H),3.60(d,J=5.1Hz,3H),3.35(dd,J=11.8,9.8Hz,1H),2.58(dd,J=13.0,7.4Hz,1H),2.34(ddd,J=13.0,9.0,5.3Hz,1H);EI-MS m/z:619[M+H]+。
(2S, 4R) -4- (benzyloxy) -1- (4- ((N- (carboxymethyl) -4-methoxyphenyl) sulfonylamino) naphthalen-1-yl) pyrrolidine-2-carboxylic acid (I-a-6)
The same procedure as described for Compound (I-a-1) was carried out using Compound (6-1) (180.0mg, 295.8. mu. mol), LiOH. H2O (248.5g, 5.9mmol) as a starting material, reacted to give 130.0mg of a white solid, 7% yield, m.p.107-111 ℃.1H-NMR(300MHz,DMSO-d6)12.62(br,2H),8.14(td,J=6.2,5.4,3.3Hz,1H),8.08-7.96(m,1H),7.68-7.56(m,2H),7.51-7.41(m,2H),7.27(dtd,J=18.3,6.2,5.5,3.1Hz,5H),7.11-7.02(m,3H),6.85(t,J=8.2Hz,1H),4.60(d,J=2.8Hz,1H),4.53-4.45(m,2H),4.45-4.40(m,1H),4.34-4.24(m,2H),4.24-4.14(m,1H),3.84(d,J=2.6Hz,3H),3.27-3.15(m,1H),2.29-2.15(m,1H);EI-MS m/z:591[M+H]+。
Example 7:
(4- ((N- (carboxymethyl) -4-methoxyphenyl) sulfonamido) naphthalen-1-yl) -L-phenylalanine (I-b-1)
1-2 Synthesis the same as in example 1
(1) (4-Nitro-naphthalen-1-yl) -L-phenylalanine methyl ester (7-1)
The same method as that of compound (1-3) was carried out using compound (1-2) (1g, 3.11mmol), L-phenylalanine methyl ester hydrochloride (0.81g, 3.73mmol), and Cs2CO3(2g,6.22mmol)、(±)-BINAP(0.29g,0.47mmol)、Pd2(dba)3Starting from (0.14g,0.16mmol) DIPEA (1.1ml,6.22mmol), 0.55g of a yellow oily liquid was obtained in 51% yield.1HNMR(300MHz,CDCl3)8.86(d,J=8.8Hz,1H),8.32(d,J=8.8Hz,1H),7.69(d,J=8.5Hz,1H),7.59-7.50(m,1H),7.38-7.27(m,4H),7.22-7.14(m,2H),6.34(d,J=8.9Hz,1H),6.03(d,J=7.5Hz,1H),4.62(q,J=6.3Hz,1H),3.82(s,3H),3.34(qd,J=13.7,5.9Hz,2H);EI-MS m/z:351[M+H]+。
(2) (4- ((4-methoxyphenyl) sulfonylamino) naphthalen-1-yl) -L-phenylalanine ester methyl ester (7-2)
Following hydrogenolysis of compound (7-1) (550.0mg, 1.57mmol) with 4-methoxybenzenesulfonyl chloride (390mg, 1.88mmol), pyridine (380. mu.L, 4.71mmol) as starting material, 312mg of a white solid was obtained in 41% yield m.p.105-108 ℃.1H-NMR(300MHz,CDCl3)7.91-7.82(m,1H),7.73(d,J=7.6Hz,1H),7.67-7.58(m,2H),7.47-7.38(m,2H),7.29(d,J=12.3Hz,3H),7.23-7.14(m,2H),7.05(d,J=8.1Hz,1H),6.89-6.79(m,2H),6.39(d,J=8.9Hz,2H),4.99(d,J=8.1Hz,1H),4.51(d,J=7.4Hz,1H),3.81(d,J=3.6Hz,3H),3.72(s,3H),3.27(dd,J=10.4,6.0Hz,2H);EI-MS m/z:491[M+H]+。
(3) (4- ((4-methoxy-N- (2-methoxy-2-oxoethyl) phenyl) sulfonamido) naphthalen-1-yl) -L-phenylalanine methyl ester (7-3)
Using compound (2-1), compound (7-2) (212.0mg, 432. mu. mol), potassium carbonate (180.0mg,1.3mmol) and methyl bromoacetate (80.0mg, 518. mu. mol) as starting materials, 110mg of a pale yellow oil was obtained in 45% yield.1H-NMR(300MHz,CDCl3)8.03(dd,J=20.4,8.1Hz,1H),7.75(d,J=8.1Hz,1H),7.71-7.64(m,2H),7.54-7.43(m,2H),7.37-7.22(m,5H),7.19-7.05(m,2H),6.91(t,J=7.3Hz,2H),6.41-6.28(m,1H),4.72(d,J=17.3Hz,1H),4.50(d,J=7.9Hz,1H),4.24(d,J=17.8Hz,1H),3.88(d,J=3.3Hz,3H),3.73(dt,J=13.7,1.7Hz,3H),3.67(t,J=3.2Hz,3H),3.33-3.18(m,2H);EI-MS m/z:563[M+H]+。
(4) (4- ((N- (carboxymethyl) -4-methoxyphenyl) sulfonamido) naphthalen-1-yl) -L-phenylalanine (I-b-1)
The same procedure as described for the synthesis of Compound (I-a-1) was repeated except that Compound (7-3) (110.0mg, 195.4. mu. mol), LiOH. H2O (380.0g, 9.0mmol) as a raw material, 96.0mg of white solid was obtained by the reaction, the yield was 96%,m.p.120-122℃.1H-NMR(300MHz,DMSO-d6)12.74(br,2H),8.26(s,1H),7.95(s,1H),7.59(dd,J=17.2,8.4Hz,2H),7.40(dd,J=17.9,7.4Hz,4H),7.22(ddt,J=21.4,13.7,7.2Hz,3H),7.04(t,J=8.1Hz,2H),6.93(dd,J=18.2,8.2Hz,1H),6.25(dd,J=11.8,8.4Hz,1H),4.39(d,J=17.8Hz,1H),4.28-4.08(m,2H),3.82(d,J=4.5Hz,3H),3.27-3.18(m,2H);EI-MS m/z:535[M+H]+。
example 8:
(4- ((N- (carboxymethyl) -4-acetylphenyl) sulfonamido) naphthalen-1-yl) -L-phenylalanine (I-b-2)
Synthesis of 7-1 was the same as in example 7
(1) (4- ((4-Acetylphenyl) sulfonamido) naphthalen-1-yl) -L-phenylalanine ester methyl ester (8-1)
In the same manner as the synthesis of the compound (7-2), the compound (7-1) (550.0mg, 1.57mmol) was hydrogenolyzed and then reacted with 4-acetamidobenzenesulfonyl chloride (390mg, 1.88mmol) and pyridine (380. mu.L, 4.71mmol) as starting materials to give 312mg of a white solid in 41% yield m.p.115-118 ℃.1H-NMR(300MHz,CDCl3)7.91-7.82(m,1H),7.73(d,J=7.8Hz,1H),7.67-7.58(m,2H),7.47-7.38(m,2H),7.29(d,J=12.5Hz,3H),7.23-7.14(m,2H),7.05(d,J=8.1Hz,1H),6.89-6.79(m,2H),6.39(d,J=8.9Hz,2H),4.99(d,J=8.1Hz,1H),4.51(d,J=7.4Hz,1H),3.72(s,3H),3.27(dd,J=10.4,6.0Hz,2H),2.02(s,3H);EI-MS m/z:506[M+H]+。
(2) (4- ((4-acetylamino-N- (2-methoxy-2-oxoethyl) phenyl) sulfonylamino) naphthalen-1-yl) -L-phenylalanine methyl ester (8-2)
Starting from compound (8-1) (212.0mg, 412. mu. mol), potassium carbonate (180.0mg,1.3mmol) and methyl bromoacetate (80.0mg, 518. mu. mol), compound (2-1) gave 160mg of a pale yellow oil in 65% yield.1H-NMR(300MHz,CDCl3)8.03(dd,J=20.4,8.1Hz,1H),7.75(d,J=8.1Hz,1H),7.71-7.64(m,2H),7.54-7.43(m,2H),7.37-7.22(m,5H),7.19-7.05(m,2H),6.91(t,J=7.3Hz,2H),6.41-6.28(m,1H),4.72(d,J=17.3Hz,1H),4.50(d,J=7.9Hz,1H),4.24(d,J=17.8Hz,1H),3.88(d,J=3.3Hz,3H),3.67(t,J=3.2Hz,3H),3.33-3.18(m,2H),2.00(s,3H);EI-MS m/z:578[M+H]+。
(3) (4- ((N- (carboxymethyl) -4-acetylaminophenyl) sulfonylamino) naphthalen-1-yl) -L-phenylalanine (I-b-2)
The same procedure as described for the synthesis of Compound (I-a-1) was repeated except that Compound (8-2) (110.0mg, 185.4. mu. mol), LiOH. H2O (370.0g, 8.7mmol) as starting material, 96.0mg of a white solid was obtained by reaction, yield 94%, m.p.125-128 ℃.1H-NMR(300MHz,DMSO-d6)12.74(br,2H),8.26(s,1H),7.95(s,1H),7.59(dd,J=17.2,8.4Hz,2H),7.40(dd,J=17.9,7.4Hz,4H),7.22(ddt,J=21.4,13.7,7.2Hz,3H),7.04(t,J=8.1Hz,2H),6.93(dd,J=18.2,8.2Hz,1H),6.25(dd,J=11.8,8.4Hz,1H),4.39(d,J=17.8Hz,1H),4.28-4.08(m,2H),3.27-3.18(m,2H),2.00(s,3H);EI-MS m/z:550[M+H]+。
Example 9:
(4- ((N- (carboxymethyl) -4-methylphenyl) sulfonylamino) naphthalen-1-yl) -L-phenylalanine (I-b-3)
Synthesis of 7-1 was the same as in example 7
(1) (4- ((4-Methylphenyl) sulfonamido) naphthalen-1-yl) -L-phenylalanine ester methyl ester (9-1)
In the same manner as the synthesis of compound (7-2), compound (7-1) (550.0mg, 1.57mmol) was hydrogenolyzed and then reacted with 4-methylbenzenesulfonyl chloride (385mg, 1.93mmol), pyridine (395. mu.L, 4.88mmol) as a starting material to give 332mg of a white solid in a yield of 45% m.p.111-114 ℃.1H-NMR(300MHz,CDCl3)7.91-7.82(m,1H),7.73(d,J=7.8Hz,1H),7.67-7.58(m,2H),7.47-7.38(m,2H),7.29(d,J=12.5Hz,3H),7.23-7.14(m,2H),7.05(d,J=8.1Hz,1H),6.89-6.79(m,2H),6.39(d,J=8.9Hz,2H),4.99(d,J=8.1Hz,1H),4.51(d,J=7.4Hz,1H),3.72(s,3H),3.27(dd,J=10.4,6.0Hz,2H),2.42(s,3H);EI-MS m/z:475[M+H]+。
(2) (4- ((4-methyl-N- (2-methoxy-2-oxoethyl) phenyl) sulfonamido) naphthalen-1-yl) -L-phenylalanine methyl ester (9-2)
Synthesis of Compound (2-1) from Compound (9-1) (212.0mg, 412. mu. mol), potassium carbonate (180.0mg,1.3mmol) and methyl bromoacetate (80.0mg, 518. mu. mol) as starting materials gave 165mg of a pale yellow oil in 65% yield.1H-NMR(300MHz,CDCl3)8.03(dd,J=20.4,8.1Hz,1H),7.75(d,J=8.1Hz,1H),7.71-7.64(m,2H),7.54-7.43(m,2H),7.37-7.22(m,5H),7.19-7.05(m,2H),6.91(t,J=7.3Hz,2H),6.41-6.28(m,1H),4.72(d,J=17.3Hz,1H),4.50(d,J=7.9Hz,1H),4.24(d,J=17.8Hz,1H),3.88(d,J=3.3Hz,3H),3.67(t,J=3.2Hz,3H),3.33-3.18(m,2H),2.40(s,3H);EI-MS m/z:547[M+H]+。
(3) (4- ((N- (carboxymethyl) -4-methylphenyl) sulfonylamino) naphthalen-1-yl) -L-phenylalanine (I-b-3)
The same procedure as described for the synthesis of Compound (I-a-1) was repeated except that Compound (9-2) (110.0mg, 185.4. mu. mol), LiOH. H2O (370.0g, 8.9mmol) as starting material, the reaction gave 90.0mg of a white solid, 94% yield, m.p.127-130 ℃.1H-NMR(300MHz,DMSO-d6)12.74(br,2H),8.26(s,1H),7.95(s,1H),7.59(dd,J=17.2,8.4Hz,2H),7.40(dd,J=17.9,7.4Hz,4H),7.22(ddt,J=21.4,13.7,7.2Hz,3H),7.04(t,J=8.1Hz,2H),6.93(dd,J=18.2,8.2Hz,1H),6.25(dd,J=11.8,8.4Hz,1H),4.39(d,J=17.8Hz,1H),4.28-4.08(m,2H),3.27-3.18(m,2H),2.40(s,3H);EI-MS m/z:519[M+H]+。
Example 10:
(4- ((N- (carboxymethyl) -2,4, 6-trimethylphenyl) sulfonylamino) naphthalen-1-yl) -L-phenylalanine (I-b-4)
Synthesis of 7-1 was the same as in example 7
(1) (4- ((2,4, 6-trimethylphenyl) sulfonamido) naphthalen-1-yl) -L-phenylalanine ester methyl ester (10-1)
The same synthesis method as that of compound (7-2) includes hydrogenolysis of compound (7-1) (550.0mg, 1.57mmol), and reaction with 2,4, 6-trimethyl benzenesulfonyl chloride (395mg, 1.90mmol) and pyridine (385 uL, 4.78mmol) as raw materials342mg of white solid are obtained, the yield is 44%, m.p.109-112 ℃.1H-NMR(300MHz,CDCl3)7.91-7.82(m,1H),7.73(d,J=7.8Hz,1H),7.67-7.58(m,2H),7.47-7.38(m,2H),7.29(d,J=12.0Hz,1H),7.23-7.14(m,2H),7.05(d,J=8.1Hz,1H),6.89-6.79(m,2H),6.39(d,J=8.9Hz,1H),4.99(d,J=8.1Hz,1H),4.51(d,J=7.4Hz,1H),3.72(s,3H),3.27(dd,J=10.4,6.0Hz,2H),2.62(s,6H),2.22(s,3H);EI-MS m/z:503[M+H]+。
(2) (4- ((2,4, 6-trimethyl-N- (2-methoxy-2-oxoethyl) phenyl) sulfonamido) naphthalen-1-yl) -L-phenylalanine methyl ester (10-2)
Synthesis of Compound (2-1) from Compound (9-1) (212.0mg, 412. mu. mol), potassium carbonate (180.0mg,1.3mmol) and methyl bromoacetate (80.0mg, 518. mu. mol) as starting materials gave 165mg of a pale yellow oil in 65% yield.1H-NMR(300MHz,CDCl3)8.03(dd,J=20.4,8.1Hz,1H),7.75(d,J=8.1Hz,1H),7.71-7.64(m,2H),7.54-7.43(m,2H),7.37-7.22(m,4H),7.19-7.05(m,2H),6.91(t,J=7.3Hz,1H),6.41-6.28(m,1H),4.72(d,J=17.3Hz,1H),4.50(d,J=7.9Hz,1H),4.24(d,J=17.8Hz,1H),3.88(d,J=3.3Hz,3H),3.67(t,J=3.2Hz,3H),3.33-3.18(m,2H),2.62(s,6H),2.22(s,3H);EI-MS m/z:575[M+H]+。
(3) (4- ((N- (carboxymethyl) -2,4, 6-trimethylphenyl) sulfonylamino) naphthalen-1-yl) -L-phenylalanine (I-b-4)
The same procedure as described for the synthesis of Compound (I-a-1) was repeated except that Compound (10-2) (110.0mg, 175.6. mu. mol), LiOH. H2O (370.0g, 8.8mmol) as starting material, 96.0mg of a white solid was obtained by reaction, yield 94%, m.p.117-120 ℃.1H-NMR(300MHz,DMSO-d6)12.74(br,2H),8.26(s,1H),7.95(s,1H),7.59(dd,J=17.2,8.4Hz,2H),7.40(dd,J=17.9,7.4Hz,3H),7.22(ddt,J=21.4,13.7,7.2Hz,3H),7.04(t,J=8.1Hz,1H),6.93(dd,J=18.2,8.2Hz,1H),6.25(dd,J=11.8,8.4Hz,1H),4.39(d,J=17.8Hz,1H),4.28-4.08(m,2H),3.27-3.18(m,2H),2.62(s,6H),2.22(s,3H);EI-MS m/z:547[M+H]+。
Example 11:
(4- ((N- (carboxymethyl) -4-methoxyphenyl) sulfonamido) naphthalen-1-yl) -L-valine (I-c-1)
1-2 Synthesis the same as in example 1
(1) (4-Nitro-naphthalen-1-yl) -L-valine methyl ester (11-1)
The same procedure as used for the synthesis of Compound (1-3) was repeated except that Compound (1-2) (1g, 3.11mmol), L-phenylalanine methyl ester hydrochloride (0.63g, 3.73mmol), and Cs2CO3(2g,6.22mmol)、(±)-BINAP(0.29g,0.47mmol)、Pd2(dba)3(0.14g,0.16mmol) and DIPEA (1.1ml,6.22mmol) as the starting materials, 0.42g of a yellow oil was obtained in 45% yield,1H NMR(300MHz,CDCl3)8.99(dd,J=8.8,1.2Hz,1H),8.43(d,J=8.9Hz,1H),7.94(d,J=8.5Hz,1H),7.73(ddd,J=8.7,6.9,1.3Hz,1H),7.58(ddd,J=8.3,6.9,1.3Hz,1H),6.47(d,J=8.9Hz,1H),5.84(d,J=8.1Hz,1H),4.22(dd,J=8.1,5.4Hz,1H),3.82(s,3H),2.35(pd,J=6.9,5.4Hz,1H),1.18(d,J=6.9Hz,3H),1.08(d,J=6.8Hz,3H);EI-MS m/z:303[M+H]+。
(2) (4- ((4-methoxyphenyl) sulfonamido) naphthalen-1-yl) -L-valine ester methyl ester (11-2)
The same synthesis method as compound (1-4) was carried out, after hydrogenolysis of compound (11-1) (420.0mg, 1.39mmol), with 4-methoxybenzenesulfonyl chloride (345mg, 1.67mmol) and pyridine (336. mu.L, 4.17mmol) as raw materials, 320mg of white solid was obtained, yield 52%, m.p.95-98 ℃,1H-NMR(300MHz,CDCl3)7.87(dt,J=8.2,1.9Hz,2H),7.69-7.58(m,2H),7.49-7.36(m,2H),7.04(dd,J=8.1,1.8Hz,1H),6.84(dt,J=8.9,2.6Hz,2H),6.48-6.33(m,2H),4.98(d,J=8.8Hz,1H),4.01(ddd,J=8.4,5.8,1.9Hz,1H),3.82(d,J=1.9Hz,3H),3.75(d,J=1.9Hz,3H),2.33-2.19(m,1H),1.15(dd,J=6.8,1.9Hz,3H),1.07(dd,J=6.8,1.9Hz,3H);EI-MS m/z:442[M+H]+。
(3) (4- ((4-methoxy-N- (2-methoxy-2-oxoethyl) phenyl) sulfonamido) naphthalen-1-yl) -L-valine methyl ester (11-3)
As the same method as the synthesis of Compound (2-1), Compound (11-2) (160.0mg, 362. mu. mol), potassium carbonate (150.0mg, 1.1mmol) and methyl bromoacetate (66.0mg, 518. mu. mol) were used as starting materialsObtaining 120mg of light yellow oily matter with the yield of 59 percent,1H-NMR(300MHz,CDCl3)8.09-7.97(m,1H),7.89(dt,J=6.4,2.3Hz,1H),7.74-7.64(m,2H),7.55-7.44(m,2H),7.10(dd,J=13.9,8.2Hz,1H),6.92(ddd,J=8.9,4.8,2.6Hz,2H),6.34(t,J=7.9Hz,1H),5.07(dd,J=26.6,8.6Hz,1H),4.71(dd,J=17.8,2.7Hz,1H),4.23(d,J=17.8Hz,1H),4.02(ddd,J=11.0,8.6,5.7Hz,1H),3.87(d,J=1.8Hz,3H),3.76(d,J=16.4Hz,3H),3.66(s,3H),1.11(ddd,J=26.3,11.7,6.8Hz,6H);EI-MS m/z:563[M+H]+。
(4) (4- ((N- (carboxymethyl) -4-methoxyphenyl) sulfonamido) naphthalen-1-yl) -L-valine (I-c-1)
The same procedure as described for the synthesis of Compound (I-a-1) was repeated except that Compound (12-3) (120.0mg, 247.0. mu. mol), LiOH. H2O (207.0mg, 4.9mmol) as starting material, the reaction gave 98.0mg of a white solid in 82% yield, m.p.199-201 ℃.1H-NMR(300MHz,DMSO-d6)12.63(br,2H),8.32(dt,J=7.3,3.6Hz,1H),7.97(ddd,J=17.8,6.6,3.6Hz,1H),7.66-7.56(m,2H),7.45(dq,J=6.6,3.6,2.6Hz,2H),7.06(d,J=8.5Hz,2H),6.95(dd,J=13.8,8.5Hz,1H),6.31(t,J=9.0Hz,1H),6.23(t,J=9.0Hz,1H),4.40(dd,J=17.7,5.1Hz,1H),4.21(dd,J=17.7,9.1Hz,1H),3.83(s,3H),3.75-3.67(m,1H),2.28(q,J=7.2,6.7Hz,1H),1.14-0.97(m,6H);EI-MS m/z:459[M+H]+。
Example 12:
(4- ((N- (carboxymethyl) -4-methoxyphenyl) sulfonamido) naphthalen-1-yl) -L-isoleucine (I-c-1)
1-2 Synthesis the same as in example 1
(1) (4-Nitro-naphthalen-1-yl) -L-isoleucine methyl ester (12-1)
The same method as that of compound (1-3) was carried out using compound (1-2) (1g, 3.11mmol), L-leucine methyl ester hydrochloride (0.68g, 3.73mmol), and Cs2CO3(2g,6.22mmol)、(±)-BINAP(0.29g,0.47mmol)、Pd2(dba)3(0.14g,0.16mmol) and DIPEA (1.1ml,6.22mmol) as raw materials to obtain 0.66g yellow oily liquid, yield 67%,1H NMR(300MHz,CDCl3)9.00(d,J=8.8Hz,1H),8.44(d,J=8.9Hz,1H),7.94(d,J=8.5Hz,1H),7.74(ddd,J=8.6,7.0,1.3Hz,1H),7.59(ddd,J=8.3,6.9,1.4Hz,1H),6.47(d,J=8.9Hz,1H),5.88(d,J=8.0Hz,1H),4.31(dd,J=7.9,5.3Hz,1H),3.82(s,3H),2.10(s,1H),1.73(ddd,J=13.0,7.5,5.3Hz,1H),1.45(dt,J=14.7,7.6Hz,1H),1.16-0.96(m,6H);EI-MS m/z:317[M+H]+。
(2) (4- ((4-methoxyphenyl) sulfonamido) naphthalen-1-yl) -L-isoleucine ester methyl ester (12-2)
In the same manner as the synthesis of compound (1-4), compound (12-1) (660.0mg, 2.09mmol) was hydrogenolyzed and then reacted with 4-methoxybenzenesulfonyl chloride (519mg, 2.51mmol), pyridine (505. mu.L, 6.27mmol) as a starting material to give 465mg of a white solid with a yield of 49%, m.p.105-107 ℃,1H NMR(300MHz,CDCl3)7.89-7.82(m,2H),7.67-7.61(m,2H),7.43(ddd,J=7.3,4.9,1.7Hz,2H),7.07-7.02(m,1H),6.88-6.80(m,2H),6.44-6.35(m,2H),5.01(s,1H),4.11(d,J=5.9Hz,1H),3.83(s,3H),3.75(s,3H),2.03(q,J=6.9Hz,2H),1.73(ddd,J=12.4,7.4,4.7Hz,1H),1.47-1.38(m,1H),1.06-0.97(m,6H);EI-MS m/z:457[M+H]+。
(3) (4- ((4-methoxy-N- (2-methoxy-2-oxoethyl) phenyl) sulfonamido) naphthalen-1-yl) -L-isoleucine methyl ester (12-3)
Using compound (12-2) (300.0mg, 568. mu. mol), potassium carbonate (218.0mg, 1.7mmol) and methyl bromoacetate (104.3mg, 682. mu. mol) as starting materials, 300mg of a pale yellow solid was obtained in 84% yield, m.p.124-127 ℃,1H NMR(300MHz,CDCl3)8.07-7.97(m,1H),7.89-7.80(m,1H),7.74-7.64(m,2H),7.49(dt,J=6.9,3.1Hz,2H),7.10(dd,J=11.4,8.2Hz,1H),6.98-6.86(m,2H),6.34(dd,J=8.3,5.4Hz,1H),5.10(d,J=27.8Hz,1H),4.71(dd,J=17.8,3.5Hz,1H),4.23(d,J=17.8Hz,1H),4.11(s,1H),3.87(d,J=1.9Hz,3H),3.76(d,J=16.3Hz,3H),3.67(s,3H),2.01(s,1H),1.81-1.67(m,1H),1.41(dd,J=14.6,7.3Hz,1H),1.02(ddt,J=12.4,7.5,3.9Hz,6H);EI-MS m/z:528[M+H]+。
(4) (4- ((N- (carboxymethyl) -4-methoxyphenyl) sulfonamido) naphthalen-1-yl) -L-isoleucine (I-c-1)
The same method as the compound (I-a-1) comprises the steps of synthesizing the compound (12-3) (300.0mg, 600.0 mu mol), LiOH & H2O (504.0mg, 12.0mmol) as the starting material, reacted to give 230.0mg of a white solid, 73% yield, m.p.>250℃.1HNMR(300MHz,DMSO-d6)12.65(br,2H),8.43-8.26(m,1H),8.04-7.89(m,1H),7.60(dt,J=8.8,6.6Hz,2H),7.49-7.34(m,2H),7.12-7.02(m,2H),6.97(t,J=8.6Hz,1H),6.45(dd,J=10.5,7.5Hz,1H),6.24(dd,J=8.5,4.6Hz,1H),4.41(dd,J=17.6,4.0Hz,1H),4.28-4.14(m,1H),4.02(s,1H),3.83(s,3H),2.06-1.75(m,2H),1.73-1.52(m,1H),1.09-0.71(m,6H).EI-MS m/z:501[M+H]+。
Example 13:
(S) -2- ((4- ((N- (naphthalen-1-ylcarboxymethyl) -4-methoxyphenyl) sulfonylamino)) amino) -3- (4-chlorophenyl) propanoic acid (I-c-3)
1-2 Synthesis the same as in example 1
(1) (S) -3- (4-chlorophenyl) -2- ((4-nitronaphthalen-1-yl) amino) propionic acid methyl ester (13-1)
The same procedure as used for the synthesis of compound (1-3) was repeated except that compound (1-2) (1g, 3.11mmol), (S) -2-amino-3- (4-chlorophenyl) propionic acid methyl ester hydrochloride (0.93g, 3.73mmol), and Cs2CO3(2g,6.22mmol)、(±)-BINAP(0.29g,0.47mmol)、Pd2(dba)3Starting from (0.14g,0.16mmol) DIPEA (1.1ml,6.22mmol), 1.0g of a yellow oily liquid was obtained in 84% yield.1H-NMR(300MHz,CDCl3)8.95(d,J=8.7Hz,1H),8.40(d,J=8.8Hz,1H),7.77(d,J=8.5Hz,1H),7.70(t,J=7.8Hz,1H),7.52(t,J=7.7Hz,1H),7.24(s,2H),7.04(d,J=7.9Hz,2H),6.45(d,J=8.8Hz,1H),5.86(d,J=7.3Hz,1H),4.67(q,J=5.9Hz,1H),3.82(s,3H),3.30(qd,J=13.9,5.4Hz,2H);EI-MS m/z:385[M+H]+。
(2) (S) -methyl 3- (4-chlorophenyl) -2- ((4- ((4-methoxyphenyl) sulfonamido) naphthalen-1-yl) amino) propanoate (13-2)
The same as the method for synthesizing the compound (1-4), Compound (13-1) (1)1.0g, 2.60mmol) was hydrogenolysed and reacted with 4-methoxybenzenesulfonyl chloride (646mg, 3.12mmol) and pyridine (628. mu.L, 7.8mmol) as starting materials to give 550mg of a white solid with a yield of 40%, m.p.104-108 ℃.1H-NMR(300MHz,CDCl3)7.87(dt,J=7.7,2.6Hz,1H),7.73(dt,J=7.9,2.7Hz,1H),7.67-7.58(m,2H),7.46-7.38(m,2H),7.26(dd,J=7.2,1.4Hz,2H),7.13-7.01(m,3H),6.88-6.77(m,2H),6.50(s,1H),6.39(d,J=8.2Hz,1H),5.01(d,J=7.8Hz,1H),4.51(q,J=6.3Hz,1H),3.82(s,3H),3.73(s,3H),3.23(qd,J=13.7,5.7Hz,2H);EI-MS m/z:525[M+H]+。
(3) (S) -methyl 3- (4-chlorophenyl) -2- ((4- ((4-methoxy-N- (2-methoxy-2-oxoethyl) phenyl) sulfonylamino) naphthalen-1-yl) amino) propanoate (13-3)
In the same manner as in the synthesis of the compound (2-1), starting from the compound (13-2) (330.0mg, 629. mu. mol), potassium carbonate (260.8mg, 1.89mmol) and methyl bromoacetate (115.5mg, 755. mu. mol), 300mg of a pale yellow oil was obtained in 80% yield.1H-NMR(300MHz,CDCl3)8.10-7.97(m,1H),7.79-7.74(m,1H),7.73-7.63(m,2H),7.55-7.44(m,2H),7.30(d,J=8.3Hz,1H),7.24(d,J=8.4Hz,1H),7.18-7.04(m,3H),6.95-6.87(m,2H),6.41-6.29(m,1H),5.09(s,1H),4.72(dd,J=17.8,6.4Hz,1H),4.50(dt,J=12.1,5.7Hz,1H),4.24(dd,J=17.8,3.8Hz,1H),3.87(d,J=4.0Hz,3H),3.77-3.70(m,3H),3.67(d,J=6.5Hz,3H),3.31-3.16(m,2H);EI-MS m/z:597[M+H]+。
(4) (S) -2- ((4- ((N- (naphthalen-1-ylcarboxymethyl) -4-methoxyphenyl) sulfonylamino)) amino) -3- (4-chlorophenyl) propanoic acid (I-c-3)
The same procedure as described for the synthesis of Compound (I-a-1) was repeated except that Compound (13-3) (300.0mg, 503.2. mu. mol), LiOH. H2O (422.7mg, 10.1mmol) as starting material, the reaction gave 270.0mg of a white solid, 94% yield, m.p.131-133 ℃.1H-NMR(300MHz,DMSO-d6)12.77(s,2H),8.26(q,J=5.5Hz,1H),7.94(ddd,J=14.3,6.7,2.7Hz,1H),7.65-7.53(m,2H),7.43(ddd,J=12.1,9.3,7.5Hz,4H),7.36-7.25(m,2H),7.08-7.00(m,2H),6.93(dd,J=17.4,8.3Hz,1H),6.59(t,J=9.8Hz,1H),6.26(dd,J=11.7,8.5Hz,1H),4.39(dd,J=17.7,2.1Hz,1H),4.20(dt,J=20.8,13.0Hz,2H),3.83(d,J=4.1Hz,3H),3.23(dq,J=14.6,9.2,7.5Hz,2H);EI-MS m/z:569[M+H]+。
Example 14:
(S) -2- ((4- ((N- (naphthalen-1-ylcarboxymethyl) -4-methoxyphenyl) sulfonamido)) amino) -3- (4-methoxyphenyl) propionic acid (I-c-4)
1-2 Synthesis the same as in example 1
(1) (S) -methyl 3- (4-methoxyphenyl) -2- ((4-nitronaphthalen-1-yl) amino) propanoate (14-1)
The same procedure as for the synthesis of compound (1-3) was repeated except for using compound (1-2) (1g, 3.11mmol), (S) -2-amino-3- (4-methoxyphenyl) propionic acid methyl ester hydrochloride (0.92g, 3.73mmol), and Cs2CO3(2g,6.22mmol)、(±)-BINAP(0.29g,0.47mmol)、Pd2(dba)3Starting from (0.14g,0.16mmol) DIPEA (1.1ml,6.22mmol), 1.0g of a yellow oily liquid was obtained in 85% yield.1H-NMR(300MHz,CDCl3)8.99(dd,J=8.9,1.2Hz,1H),8.43(d,J=8.8Hz,1H),7.80(d,J=8.5Hz,1H),7.73(ddd,J=8.5,6.8,1.3Hz,1H),7.56(ddd,J=8.5,5.3,1.5Hz,1H),7.07-7.02(m,2H),6.86-6.82(m,2H),6.46(d,J=8.8Hz,1H),5.81(d,J=7.1Hz,1H),4.65(dt,J=7.5,5.5Hz,1H),3.81(s,3H),3.79(s,3H),3.36-3.29(m,1H),3.27-3.20(m,1H);EI-MS m/z:381[M+H]+。
(2) (S) -methyl 3- (4-methoxyphenyl) -2- ((4- ((4-methoxyphenyl) sulfonamido) naphthalen-1-yl) amino) propanoate (14-2)
The same synthesis as that of compound (1-4) was carried out using compound (14-1) (1.0g, 2.63mmol) hydrogenolyzed and 4-methoxybenzenesulfonyl chloride (653mg, 3.16mmol) and pyridine (636. mu.L, 7.89mmol) as starting materials to give 800mg of a white solid in 58% yield m.p.82-85 ℃.1H-NMR(300MHz,CDCl3)7.89-7.83(m,1H),7.73(dt,J=5.1,3.3Hz,1H),7.65-7.60(m,2H),7.44-7.39(m,2H),7.12-7.08(m,2H),7.04(d,J=8.1Hz,1H),6.85(d,J=2.5Hz,2H),6.82(d,J=2.8Hz,2H),6.44-6.36(m,2H),4.98(d,J=7.7Hz,1H),4.47(t,J=6.5Hz,1H),3.82(s,3H),3.79(s,3H),3.72(s,3H),3.21(dd,J=10.6,5.8Hz,2H);EI-MS m/z:521[M+H]+。
(3) (S) -methyl 2- ((4- ((4-methoxy-N- (2-methoxy-2-oxoethyl) phenyl) sulfonylamino) naphthalen-1-yl) amino) -3- (4-methoxyphenyl) propanoate (14-3)
In the same manner as in the synthesis of the compound (2-1), starting from the compound (14-2) (600.0mg, 1154. mu. mol), potassium carbonate (180.0mg, 3.46mmol) and methyl bromoacetate 211.8mg, 1385. mu. mol), 600mg of a pale yellow oil was obtained in a yield of 92%.1H-NMR(300MHz,CDCl3)8.09-7.96(m,1H),7.77-7.72(m,1H),7.67(dd,J=8.8,5.5Hz,2H),7.54-7.42(m,2H),7.16-7.04(m,3H),6.95-6.80(m,4H),6.34(dd,J=17.6,8.2Hz,1H),4.71(dd,J=17.8,5.3Hz,1H),4.46(dt,J=11.2,5.8Hz,1H),4.24(dd,J=17.8,2.8Hz,1H),3.87(d,J=4.1Hz,3H),3.80(d,J=8.1Hz,3H),3.73(d,J=13.0Hz,3H),3.67(d,J=5.2Hz,3H),3.27-3.15(m,2H);EI-MS m/z:563[M+H]+。
(4) (S) -2- ((4- ((N- (naphthalen-1-ylcarboxymethyl) -4-methoxyphenyl) sulfonamido)) amino) -3- (4-methoxyphenyl) propionic acid (I-c-4)
The same procedure as for the synthesis of Compound (I-a-1) was repeated except that Compound (14-3) (120.0mg, 213.1. mu. mol), LiOH. H2O (179.0g, 4.3mmol) was used as starting material and the reaction gave 100.0mg of a white solid in 83% yield, m.p.>250℃.1H-NMR(300MHz,DMSO-d6)12.74(br,2H),8.26(s,1H),7.96(s,1H),7.66-7.52(m,2H),7.43(dd,J=6.9,2.9Hz,2H),7.39-7.24(m,2H),7.04(t,J=8.4Hz,2H),6.98-6.76(m,3H),6.54(s,1H),6.23(dd,J=13.2,8.5Hz,1H),4.38(dd,J=17.8,2.2Hz,1H),4.17(dd,J=21.2,17.7Hz,2H),3.82(d,J=4.4Hz,3H),3.73-3.63(m,3H),3.16(s,2H);EI-MS m/z:565[M+H]+。
Example 15:
(4- ((N- (carboxymethyl) -4-methoxyphenyl) sulfonamido) naphthalen-1-yl) -L-methionine (I-c-5)
1-2 Synthesis the same as in example 1
(1) (4-Nitro-naphthalen-1-yl) -L-methionine methyl ester (15-1)
The same procedure as used for the synthesis of compound (1-3) was repeated except that compound (1-2) (1g, 3.11mmol), L-methionine methyl ester hydrochloride (0.75g, 3.73mmol), and Cs2CO3(2g,6.22mmol)、(±)-BINAP(0.29g,0.47mmol)、Pd2(dba)3(0.14g,0.16mmol) and DIPEA (1.1ml,6.22mmol) as starting materials, 0.48g of a yellow oily liquid was obtained in a yield of 46%,1H-NMR(300MHz,CDCl3)8.94(dd,J=8.7,1.2Hz,1H),8.40(d,J=8.8Hz,1H),7.93(d,J=8.4Hz,1H),7.69(ddd,J=8.6,6.9,1.2Hz,1H),7.53(ddd,J=8.3,6.8,1.2Hz,1H),6.51(d,J=8.9Hz,1H),6.13(d,J=7.6Hz,1H),4.59(q,J=6.5Hz,1H),3.85(s,3H),2.68(td,J=6.8,2.5Hz,2H),2.31(ddq,J=21.2,14.3,7.2Hz,2H),2.14(s,3H);EI-MS m/z:335[M+H]+。
(2) (4- ((4-methoxyphenyl) sulfonamido) naphthalen-1-yl) -L-methionine ester methyl ester (15-2)
The same synthesis as compound (1-4) was carried out, hydrogenolyzing compound (15-1) (480.0mg, 1.44mmol), reacting with 4-methoxybenzenesulfonyl chloride (357mg, 1.72mmol) and pyridine (348. mu.L, 4.32mmol) as starting materials to give 220mg of a white solid with a yield of 30%, m.p.98-101 ℃.1H-NMR(300MHz,CDCl3)7.88(td,J=7.2,3.2Hz,2H),7.63(d,J=2.1Hz,1H),7.61(d,J=2.1Hz,1H),7.44-7.36(m,2H),7.01(d,J=8.1Hz,1H),6.82(d,J=3.8Hz,2H),6.79(d,J=2.1Hz,1H),6.39(d,J=8.2Hz,1H),5.17(d,J=7.9Hz,1H),4.39(q,J=6.8Hz,1H),3.79(s,3H),3.77(s,3H),2.68(t,J=7.1Hz,2H),2.29-2.15(m,2H),2.11(s,3H);EI-MS m/z:475[M+H]+。
(3) (4- ((4-methoxy-N- (2-methoxy-2-oxoethyl) phenyl) sulfonamido) naphthalen-1-yl) -L-methionine methyl ester (15-3)
Starting from compound (15-2) (110.0mg, 230. mu. mol), potassium carbonate (95.4mg, 0.69mmol) and methyl bromoacetate (42.2mg, 276. mu. mol), compound (2-1) gave 100mg of a pale yellow oil in 80% yield.1H-NMR(300MHz,CDCl3)8.96(dd,J=8.7,1.2Hz,1H),8.42(d,J=8.8Hz,1H),7.93(d,J=8.4Hz,1H),7.69(ddd,J=8.7,6.9,1.2Hz,1H),7.53(ddd,J=8.3,6.8,1.2Hz,1H),6.55(d,J=8.8Hz,1H),6.23(d,J=7.6Hz,1H),4.45(dd,J=17.7,3.8Hz,1H),4.19(dd,J=17.7,12.0Hz,2H),3.81(s,3H),2.68(td,J=6.8,2.5Hz,2H),2.31(ddq,J=21.4,14.5,7.2Hz,2H),2.14(s,3H);EI-MS m/z:547[M+H]+。
(4) (4- ((N- (carboxymethyl) -4-methoxyphenyl) sulfonamido) naphthalen-1-yl) -L-methionine (I-c-5)
The same method as that of the compound (I-a-1) was carried out using the compound (15-3) (100.0mg, 183.0. mu. mol), LiOH. H2O (153.0mg, 3.7mmol) as a raw material, reacting to obtain a white solid of 75.0mg, yield 79%, m.p.95-98 ℃,1H-NMR(300MHz,DMSO-d6)12.72(br,2H),8.37-8.24(m,1H),7.97(ddd,J=16.3,7.0,3.6Hz,1H),7.61(dd,J=9.7,7.9Hz,2H),7.45(dt,J=6.6,3.6Hz,2H),7.11-7.02(m,2H),6.96(dd,J=12.8,8.2Hz,1H),6.51(d,J=8.2Hz,1H),6.26(q,J=8.4Hz,1H),4.41(dd,J=17.7,3.8Hz,1H),4.21(dd,J=17.7,12.0Hz,2H),3.84(s,3H),2.74-2.56(m,2H),2.33-2.07(m,2H),2.06(d,J=10.0Hz,3H);EI-MS m/z:519[M+H]+。
example 16:
(S) -2- ((4- ((N- (carboxymethyl) -4-methoxyphenyl) sulfonamido) naphthalen-1-yl) amino) -4- (methylsulfonyl) butanoic acid (I-c-6)
15-3 Synthesis same as example 15
(S) -methyl 2- ((4- ((4-methoxy-N- (2-methoxy-2-oxoethyl) phenyl) sulfonamido) naphthalen-1-yl) amino) -4- (methylsulfonyl) butanoate (16-1)
The compound (15-3) (400.0mg, 0.8mmol) was dissolved in dichloromethane and a dichloromethane diluent of m-chloroperoxybenzoic acid (152mg, 0.88mmol) was added dropwise under ice-bath conditions, and after the completion of the reaction monitored by TlC, column chromatography was performed to obtain 0.2g of a white solid with a yield of 43%.1H-NMR(300MHz,CDCl3)8.96(dd,J=8.7,1.2Hz,1H),8.42(d,J=8.8Hz,1H),7.93(d,J=8.4Hz,1H),7.69(ddd,J=8.7,6.9,1.2Hz,1H),7.53(ddd,J=8.3,6.8,1.2Hz,1H),6.55(d,J=8.8Hz,1H),6.23(d,J=7.6Hz,1H),5.23(m,1H),4.66(dd,J=17.7,3.8Hz,1H),4.43(m,1H)4.19(dd,J=17.7,12.0Hz,1H),3.81-3.64(m,9H),3.22(m,2H),2.88-2.95(m,3H),2.38(ddq,J=21.4,14.5,7.2Hz,2H);EI-MS m/z:579[M+H]+。
(2) (S) -2- ((4- ((N- (carboxymethyl) -4-methoxyphenyl) sulfonamido) naphthalen-1-yl) amino) -4- (methylsulfonyl) butanoic acid (I-c-6)
The same procedure as for the synthesis of Compound (I-a-1) was repeated except that Compound (16-1) (200.0mg, 346. mu. mol), LiOH. H2O (290.0mg, 6.9mmol) as a raw material, reacting to obtain 125.0mg of white solid with a yield of 52 percent, m.p.98-102 ℃,1H-NMR(300MHz,DMSO-d6)12.72(br,2H),8.37-8.24(m,1H),7.97(ddd,J=16.3,7.0,3.6Hz,1H),7.61(dd,J=9.7,7.9Hz,2H),7.45(dt,J=6.6,3.6Hz,2H),7.11-7.02(m,2H),6.96(dd,J=12.8,8.2Hz,1H),6.51(d,J=8.2Hz,1H),6.26(q,J=8.4Hz,1H),4.41(dd,J=17.7,3.8Hz,1H),4.21(dd,J=17.7,12.0Hz,2H),3.84(s,3H),3.32(m,2H),2.95(m,3H),2.38(ddq,J=21.4,14.5,7.2Hz,2H);EI-MS m/z:551[M+H]+。
example 17:
(4- ((N- (carboxymethyl) -4-methoxyphenyl) sulfonamido) naphthalen-1-yl) -L-serine (I-c-7)
1-2 Synthesis the same as in example 1
(1) O-benzyl-N- (4-nitronaphthalen-1-yl) -L-serine methyl ester (17-1)
The same procedure as for the synthesis of Compound (1-3) was repeated except that Compound (1-2) (2g, 6.22mmol), O-benzyl-L-serine methyl ester hydrochloride (1.54g, 7.46mmol), and Cs2CO3(4g,12.44mmol)、(±)-BINAP(0.58g,0.94mmol)、Pd2(dba)3(0.28g, 0.32mmol) and DIPEA (2.2ml, 12.44mmol) as starting materials to give 1.40g of a yellow oily liquid in 59% yield,1H-NMR(300MHz,CDCl3)8.98(d,J=8.8Hz,1H),8.38(d,J=8.8Hz,1H),7.90(d,J=8.5Hz,1H),7.73(ddd,J=8.6,6.9,1.3Hz,1H),7.57(ddd,J=8.4,6.9,1.4Hz,1H),7.36-7.27(m,5H),6.35(d,J=8.8Hz,1H),6.15(d,J=7.7Hz,1H),4.61(d,J=1.4Hz,2H),4.50(dt,J=7.5,3.6Hz,1H),4.08-3.93(m,2H),3.82(s,3H);EI-MS m/z:381[M+H]+。
(2) O-benzyl-N- (4- ((4-methoxyphenyl) sulfonamido) naphthalen-1-yl) -L-serine methyl ester (17-2)
In the same manner as the synthesis of compound (1-4), compound (24-1) (1.4g, 3.68mmol) was hydrogenolyzed and then reacted with 4-methoxybenzenesulfonyl chloride (914mg, 4.42mmol), pyridine (889. mu.L, 11.04mmol) as a starting material to give 1.2g of a gray solid at a yield of 63%, m.p.94-97 ℃,1H-NMR(300MHz,CDCl3)7.86(ddd,J=9.8,7.1,2.2Hz,2H),7.65-7.58(m,2H),7.45-7.37(m,2H),7.37-7.30(m,5H),7.02(d,J=8.1Hz,1H),6.83-6.77(m,2H),6.74(s,1H),6.30(d,J=8.2Hz,1H),5.37(d,J=7.4Hz,1H),4.60(d,J=3.1Hz,2H),4.37(p,J=3.9Hz,1H),3.95(qd,J=9.4,3.9Hz,2H),3.79(s,3H),3.77(s,3H);EI-MS m/z:521[M+H]+。
(3) (4- ((4-methoxyphenyl) sulfonylamino) naphthalen-1-yl) -L-serine methyl ester (17-3)
Compound (17-2) (0.8g, 1.58mmol) was dissolved in a small amount of THF, 30ml of methanol was added, and 10% palladium on carbon (168mg, 0.16mol) loaded with H was added in time2Ball at H2The reaction was heated to 50 ℃ in the ambient. TLC monitoring reaction (10h), removing palladium carbon by diatomite assisted filtration, directly making sand, obtaining gray solid 0.5g by column chromatography, yield 77%, m.p.110-113 deg.C,1H-NMR(300MHz,CDCl3)7.92-7.82(m,2H),7.64-7.58(m,2H),7.44-7.35(m,2H),6.99(d,J=8.1Hz,1H),6.83-6.77(m,3H),6.35(d,J=8.2Hz,1H),5.42(s,1H),4.31(d,J=3.8Hz,1H),4.07(d,J=3.8Hz,2H),3.82(s,3H),3.79(s,3H);EI-MS m/z:431[M+H]+。
(4) (4- ((4-methoxy-N- (2-methoxy-2-oxoethyl) phenyl) sulfonylamino) naphthalen-1-yl) -L-serine methyl ester (17-4)
As with the synthesis method of the compound (2-1), starting from the compound (17-3) (200.0mg, 465. mu. mol), potassium carbonate (193.0mg, 1.4mmol) and methyl bromoacetate (85.4mg, 558. mu. mol), 190mg of a pale yellow oil was obtained in a yield of 81%,1H-NMR(300MHz,CDCl3)8.03(ddd,J=9.8,6.8,2.2Hz,1H),7.94(dt,J=6.4,2.1Hz,1H),7.67(dd,J=9.0,2.9Hz,2H),7.54-7.45(m,2H),7.13(t,J=8.5Hz,1H),6.90(dd,J=9.1,2.7Hz,2H),6.39(t,J=7.8Hz,1H),5.52(s,1H),4.71(dd,J=17.8,1.9Hz,1H),4.35(s,1H),4.24(d,J=17.8Hz,1H),4.07(d,J=10.3Hz,2H),3.87(d,J=1.2Hz,3H),3.84(d,J=13.0Hz,3H),3.66(s,3H);EI-MS m/z:503[M+H]+。
(5) (4- ((N- (carboxymethyl) -4-methoxyphenyl) sulfonamido) naphthalen-1-yl) -L-serine (I-c-7)
The same procedure as described for the synthesis of Compound (I-a-1) was repeated except that Compound (17-4) (190mg, 378.0. mu. mol), LiOH. H2O (318.0mg, 7.6mmol) as a raw material, 143.0mg of white solid is obtained by reaction, the yield is 80%, m.p.136-139 ℃,1H-NMR(300MHz,DMSO-d6)12.76(s,2H),8.20(s,1H),8.00(d,J=16.9Hz,1H),7.69-7.54(m,2H),7.47(s,2H),7.07(s,2H),7.01-6.88(m,1H),6.29(s,1H),6.21(s,1H),4.42(d,J=18.5Hz,1H),4.26(d,J=15.1Hz,1H),4.17(s,1H),3.92(s,2H),3.84(s,3H);EI-MS m/z:475[M+H]+。
example 18:
(4- ((N- (carboxymethyl) -4-methoxyphenyl) sulfonamido) naphthalen-1-yl) -L-aspartic acid (I-c-8)
1-2 Synthesis the same as in example 1
(1) (4-Nitro-naphthalen-1-yl) -L-aspartic acid dimethyl ester (18-1)
The same method as the synthesis of the compound (1-3) was used, except that the compound (1-2) (1g, 3.11mmol), L-aspartic acid dimethyl ester hydrochloride (0.74g, 3.73mmol), and Cs2CO3(2g,6.22mmol)、(±)-BINAP(0.29g,0.47mmol)、Pd2(dba)3(0.14g,0.16mmol) and DIPEA (1.1ml,6.22mmol) as starting materials, 0.65g of a yellow oily liquid was obtained in a yield of 63%,1H-NMR(300MHz,CDCl3)9.01-8.91(m,1H),8.41(d,J=8.8Hz,1H),7.94(d,J=8.7Hz,1H),7.72(ddd,J=8.6,6.9,1.3Hz,1H),7.57(ddd,J=8.4,6.8,1.3Hz,1H),6.50(d,J=8.9Hz,1H),6.39(d,J=7.6Hz,1H),4.71(dt,J=7.6,4.9Hz,1H),3.85(s,3H),3.75(s,3H),3.08(qd,J=16.5,5.0Hz,2H);EI-MS m/z:333[M+H]+。
(2) (4- ((4-methoxyphenyl) sulfonamido) naphthalen-1-yl) -L-aspartic acid dimethyl ester (18-2)
In the same manner as the synthesis of compound (1-4), compound (18-1) (650.0mg, 1.96mmol) was hydrogenolyzed and then reacted with 4-methoxybenzenesulfonyl chloride (487mg, 2.35mmol), pyridine (474. mu.L, 5.88mmol) as a starting material to give 230mg of a white solid with a yield of 25%, m.p.147-150 ℃,1H-NMR(300MHz,CDCl3)7.90-7.84(m,2H),7.66-7.60(m,2H),7.42(ddt,J=6.6,4.2,2.2Hz,2H),7.06(d,J=8.1Hz,1H),6.83(d,J=8.9Hz,2H),6.61(s,1H),6.42(d,J=8.2Hz,1H),5.46(d,J=7.8Hz,1H),4.58(dt,J=7.6,5.4Hz,1H),3.81(s,3H),3.80(s,3H),3.73(s,3H),3.07-2.93(m,2H);EI-MS m/z:473[M+H]+。
(3) (4- ((4-methoxyphenyl) sulfonamido) naphthalen-1-yl) -L-aspartic acid (I-c-8)
The same procedure as for the synthesis of Compound (I-a-1) was repeated except that Compound (18-2) (100.0mg, 212.0. mu. mol) and LiOH. H were used2O (89.0mg, 2.12mmol) as raw material to obtain gray solid 81.0mg, yield 86%, m.p.160-163 deg.C,1H-NMR(300MHz,DMSO-d6)12.55(br,1H),9.47(s,1H),8.04(d,J=7.9Hz,1H),7.81(d,J=7.8Hz,1H),7.48(d,J=8.5Hz,2H),7.30(d,J=7.7Hz,2H),6.92(d,J=8.4Hz,2H),6.72(d,J=8.2Hz,1H),6.26(d,J=8.3Hz,1H),4.33(s,1H),3.70(s,3H),2.79(d,J=6.4Hz,2H);EI-MS m/z:445[M+H]+。
(4) (4- ((4-methoxy-N- (2-methoxy-2-oxoethyl) phenyl) sulfonamido) naphthalen-1-yl) -L-aspartic acid dimethyl ester (18-3)
In the same manner as in the synthesis of the compound (2-1), starting from the compound (18-3) (100.0mg, 250. mu. mol), potassium carbonate (103.7mg, 0.75mmol) and methyl bromoacetate (54.4mg, 300. mu. mol), 100mg of a pale yellow oil was obtained in a yield of 84%,1H-NMR(300MHz,CDCl3)8.03(s,1H),7.88(d,J=7.9Hz,1H),7.68(dd,J=8.5,6.0Hz,2H),7.54-7.47(m,2H),7.13(dd,J=8.1,5.0Hz,1H),6.92(dd,J=9.0,4.6Hz,3H),6.44-6.36(m,1H),4.71(dd,J=17.6,2.3Hz,1H),4.59(d,J=5.6Hz,1H),4.24(d,J=17.8Hz,1H),3.88(d,J=2.3Hz,3H),3.81(d,J=13.9Hz,3H),3.74(d,J=12.6Hz,3H),3.67(d,J=1.7Hz,3H),3.01(s,2H);EI-MS m/z:545[M+H]+。
example 19:
(4- ((4-methoxyphenyl) sulfonamido) naphthalen-1-yl) -L-phenylalanine (I-d-1)
Synthesis of 7-2 is completely in accordance with example 7
(3) (4- ((4-methoxyphenyl) sulfonamido) naphthalen-1-yl) -L-phenylalanine (I-d-1)
The same procedure as for the synthesis of Compound (I-a-1) was repeated except that Compound (7-2) (100.0mg, 204.1. mu. mol) and LiOH. H were used2O (86.0mg, 2.04mmol) as starting material gave 78.0mg of a white solid in 90% yield m.p.111-115 ℃.1H-NMR(300MHz,DMSO-d6)12.79(br,1H),9.53(s,1H),8.24-8.16(m,1H),7.87(dd,J=7.7,2.0Hz,1H),7.59-7.51(m,2H),7.44-7.33(m,4H),7.26(dd,J=8.2,6.6Hz,2H),7.21-7.13(m,1H),7.03-6.94(m,2H),6.75(d,J=8.2Hz,1H),6.38(s,1H),6.24(d,J=8.4Hz,1H),4.21(s,1H),3.78(s,3H),3.24-3.15(m,2H);EI-MS m/z:477[M+H]+。
Example 20:
(4- ((N- (carboxymethyl) -4-methoxyphenyl) sulfonamido) naphthalen-1-yl) -L-phenylalanine (I-d-2)
Synthesis of 7-2 is completely in accordance with example 7
(1) (4- ((N- (cyanomethyl) -4-methoxyphenyl) sulfonamido) naphthalen-1-yl) -L-phenylalanine methyl ester (20-1)
Synthesis of Compound (2-1) from Compound (7-2) (200.0mg, 408. mu. mol), potassium carbonate (166.0mg, 1.2mmol) and bromoacetonitrile (58.8mg, 490. mu. mol) gave 198mg of a gray oil in 92% yield.1H-NMR(300MHz,CDCl3)8.03(dd,J=20.4,8.1Hz,1H),7.75(d,J=8.1Hz,1H),7.71-7.64(m,2H),7.54-7.43(m,2H),7.37-7.22(m,5H),7.19-7.05(m,2H),6.91(t,J=7.3Hz,2H),6.41-6.28(m,1H),4.92(d,J=17.8Hz,1H),4.50(d,J=7.9Hz,1H),4.24(d,J=17.8Hz,1H),3.88(d,J=3.3Hz,3H),3.73(dt,J=13.7,1.7Hz,3H),3.67(t,J=3.2Hz,3H),3.33-3.18(m,2H);EI-MS m/z:530[M+H]+。
(2) (4- ((N- ((2H-tetrazol-5-yl) methyl) -4-methoxyphenyl) sulfonylamino) naphthalen-1-yl) -L-phenylalanine (I-d-2)
Compound (20-1) (198.0mg, 374. mu. mol) was dissolved in 5.0ml of DMF, and sodium azide (56mg, 1.1mmol) and finally ammonium chloride (80.0mg, 1.5mmol) were added, followed by heating to reflux. TLC (about 5h) to monitor the reaction is complete, water is added into the solution, solid is precipitated, suction filtration is carried out, the solid is dissolved by EA, 3 times of washing is carried out by 3mol/L sodium hydroxide solution, water layer is separated, a small amount of EA is used for washing 2 times, the pH value is adjusted to 2 by hydrochloric acid, solid is precipitated, suction filtration and drying are carried out, light yellow solid 88mg is obtained, the yield is 40%, and m.p.>250℃.1H-NMR(300MHz,DMSO-d6)12.54(br,2H),8.26(s,1H),7.95(s,1H),7.60(dd,J=17.2,8.4Hz,2H),7.40(dd,J=17.5,7.4Hz,4H),7.22(ddt,J=21.4,13.7,7.2Hz,3H),7.04(t,J=8.1Hz,2H),6.93(dd,J=18.2,8.2Hz,1H),6.25(dd,J=11.8,8.4Hz,1H),5.00-5.12(m,2H),4.28-4.08(m,1H),3.82(s,3H),3.25-3.20(m,2H);EI-MS m/z:559[M+H]+。
Example 21:
(4- ((N- (carboxymethyl) -4-methoxyphenyl) sulfonamido) naphthalen-1-yl) -L-phenylalanine (I-d-3)
Synthesis of 7-3 is completely in accordance with example 7
(1) (4- ((4-methoxy-N- (2-methoxy-2-oxoethyl) phenyl) sulfonamido) naphthalen-1-yl) -L-phenylalanine (I-d-3)
Dissolving the compound (7-3) (500.0mg, 0.89mmol) in 10ml methanol and 5ml water, adding hydroxylamine hydrochloride (68.4mg, 0.98mmol) and sodium hydroxide (117.6mg, 2.84mmol) under nitrogen protection, heating to reflux, reacting for 5 hours, adding water, adjusting pH to 4-5, precipitating white solid, filtering and drying to obtain 400.0mg of product with yield of 82%, m.p.203-206 ℃.1H-NMR(300MHz,DMSO-d6)12.98(br,1H),8.26(s,1H),7.95(s,1H),7.59(dd,J=17.2,8.4Hz,2H),7.40(dd,J=17.2,7.4Hz,4H),7.22(ddt,J=21.4,13.7,7.2Hz,3H),7.06(t,J=8.1Hz,2H),6.95(dd,J=18.2,8.4Hz,1H),6.25(dd,J=11.6,8.4Hz,1H),4.81-5.01(m,2H),4.18-4.08(m,1H),3.80(s,3H),3.27-3.18(m,2H);EI-MS m/z:550[M+H]+。
Example 22:
(4- ((N- (2-amino-2-oxoethyl) -4-methoxyphenyl) sulfonylamino) naphthalen-1-yl) -L-phenylalanine (I-d-4)
9-2 Synthesis is in full accordance with example 9
(1) (4- ((N- (2-amino-2-oxoethyl) -4-methoxyphenyl) sulfonylamino) naphthalen-1-yl) -L-phenylalanine methyl ester (22-1)
Synthesis of Compound (2-1) from Compound (7-2) (200.0mg, 408. mu. mol), potassium carbonate (166.0mg, 1.1mmol) and bromoacetamide (68.0mg, 490. mu. mol) as starting materials gave 180mg of a brown oil in 81% yield.1H-NMR(300MHz,CDCl3)8.03(dd,J=20.4,8.1Hz,1H),7.75(d,J=8.1Hz,1H),7.71-7.64(m,2H),7.54-7.43(m,2H),7.37-7.22(m,5H),7.19-7.05(m,2H),6.91(t,J=7.3Hz,2H),6.41-6.28(m,1H),4.62(d,J=17.3Hz,1H),4.40(d,J=7.9Hz,1H),4.14(d,J=17.8Hz,1H),3.90(d,J=3.3Hz,3H),3.76(dt,J=13.5,1.7Hz,3H),3.67(t,J=3.2Hz,3H),3.32-3.15(m,2H);EI-MS m/z:548[M+H]+。
(2) (4- ((N- (2-amino-2-oxoethyl) -4-methoxyphenyl) sulfonylamino) naphthalen-1-yl) -L-phenylalanine (I-d-4)
The same procedure as described for the synthesis of Compound (I-a-1) was repeated except that Compound (22-1) (180.0mg, 329.0. mu. mol), LiOH. H2O (138.6g, 3.3mmol) as starting material was reacted to give 148.0mg of a grey solid in 68% yield, m.p.146-149 ℃.1H-NMR(300MHz,DMSO-d6)12.74(br,1H),8.26(s,1H),7.95(s,1H),7.59(dd,J=17.2,8.4Hz,2H),7.40(dd,J=17.3,7.4Hz,4H),7.22(ddt,J=21.4,13.7,7.4Hz,3H),7.04(t,J=8.1Hz,2H),6.93(dd,J=17.2,8.2Hz,1H),6.25(dd,J=11.8,8.4Hz,1H),4.59(d,J=17.8Hz,1H),4.28-4.08(m,2H),3.82(s,3H),3.30-3.19(m,2H);EI-MS m/z:534[M+H]+。
Example 23:
(4- ((4-methoxyphenyl) sulfonamido) naphthalen-1-yl) -L-methionine (I-d-5)
15-2 Synthesis in full accordance with example 15
(1) (4- ((4-methoxyphenyl) sulfonamido) naphthalen-1-yl) -L-methionine (I-c-5)
The same procedure as for the synthesis of Compound (I-a-1) was repeated except that Compound (15-2) (100.0mg, 210.0. mu. mol) and LiOH. H were used2O (89.0mg, 2.10mmol) as starting material gave 70.0mg of a white solid in 72% yield m.p.113-116 ℃.1H-NMR(300MHz,DMSO-d6)9.57(d,J=3.2Hz,1H),8.34-8.25(m,1H),7.97-7.89(m,1H),7.63-7.56(m,2H),7.42(td,J=7.0,6.2,3.8Hz,2H),7.03(dq,J=9.8,3.0Hz,2H),6.82(d,J=8.2Hz,1H),6.27(dd,J=8.4,6.5Hz,1H),4.17(d,J=4.9Hz,1H),3.81(s,3H),2.67(td,J=13.4,7.0Hz,2H),2.29-2.11(m,2H),2.04(d,J=21.8Hz,3H);EI-MS m/z:461[M+H]+。
Example 24:
(4- ((4-methoxyphenyl) sulfonamido) naphthalen-1-yl) -L-aspartic acid (I-c-20)
Synthesis of 18-2 was the same as in example 18
(1) (4- ((4-methoxyphenyl) sulfonamido) naphthalen-1-yl) -L-aspartic acid (I-c-20)
The same procedure as for the synthesis of Compound (I-a-1) was repeated except that Compound (18-2) (100.0mg, 212.0. mu. mol) and LiOH. H were used2O (89.0mg, 2.12mmol) as starting material, giving 81.0mg of a grey solid, yield 86%, m.p.160-163 ℃,1H-NMR(300MHz,DMSO-d6)12.55(br,1H),9.47(s,1H),8.04(d,J=7.9Hz,1H),7.81(d,J=7.8Hz,1H),7.48(d,J=8.5Hz,2H),7.30(d,J=7.7Hz,2H),6.92(d,J=8.4Hz,2H),6.72(d,J=8.2Hz,1H),6.26(d,J=8.3Hz,1H),4.33(s,1H),3.70(s,3H),2.79(d,J=6.4Hz,2H);EI-MS m/z:445[M+H]+。
example 25:
(4- ((N- (carboxymethyl) -4-methoxyphenyl) sulfonamido) naphthalen-1-yl) -L-alanine (I-e-1)
1-2 Synthesis the same as in example 1
(1) (4-Nitro-naphthalen-1-yl) -L-alanine methyl ester (25-1)
Synthesized with compound (1-3) using compound (1-2) (1g, 3.11mmol), L-alanine methyl ester hydrochloride (0.52g, 3.73mmol), Cs2CO3(2g,6.22mmol)、(±)-BINAP(0.29g,0.47mmol)、Pd2(dba)3Starting from (0.14g,0.16mmol) DIPEA (1.1ml,6.22mmol), 0.40g of a yellow oily liquid was obtained in 47% yield.1H-NMR(300MHz,CDCl3)8.99(d,J=8.7Hz,1H),8.43(d,J=8.7Hz,1H),7.93(d,J=8.5Hz,1H),7.78-7.67(m,1H),7.56(dd,J=11.0,4.7Hz,1H),6.43(d,J=8.8Hz,1H),5.93(d,J=6.7Hz,1H),4.44(p,J=6.7Hz,1H),3.95-3.77(m,3H),1.71-1.60(m,3H);EI-MS m/z:275[M+H]+。
(2) (4- ((4-methoxyphenyl) sulfonamido) naphthalen-1-yl) -L-alanine methyl ester (25-2)
In the same manner as the synthesis of compound (1-4), compound (25-1) (400.0mg, 1.46mmol) was hydrogenolyzed and then reacted with 4-methoxybenzenesulfonyl chloride (363mg, 1.75mmol), pyridine (353. mu.L, 4.38mmol) as a starting material to give 200mg of a white solid with a yield of 33%, m.p.124-127 ℃.1H-NMR(300MHz,,CDCl3)7.89(dt,J=7.9,1.5Hz,2H),7.66(dd,J=9.4,2.5Hz,2H),7.51-7.43(m,2H),7.09(d,J=8.1Hz,1H),6.87(dd,J=9.3,2.4Hz,2H),6.46(s,1H),6.39(d,J=8.2Hz,1H),5.06(s,1H),4.32(d,J=6.9Hz,1H),3.85(s,3H),3.82(d,J=1.9Hz,3H),1.65(s,3H);EI-MS m/z:415[M+H]+。
(3) (4- ((4-methoxy-N- (2-methoxy-2-oxoethyl) phenyl) sulfonamido) naphthalen-1-yl) -L-alanine methyl ester (25-3)
In the same manner as in the synthesis of the compound (2-1), starting from the compound (25-2) (100.0mg, 250. mu. mol), potassium carbonate (103.7mg, 0.75mmol) and methyl bromoacetate (104.3mg, 682. mu. mol), 100mg of a pale yellow oil was obtained in 84% yield.1H-NMR(300MHz,CDCl3)8.02(s,1H),7.87(d,J=8.0Hz,1H),7.72-7.64(m,2H),7.53-7.42(m,2H),7.11(dd,J=9.9,8.2Hz,1H),6.96-6.86(m,2H),6.31(t,J=8.0Hz,1H),5.13(s,1H),4.71(d,J=17.8Hz,1H),4.32-4.20(m,2H),3.87(d,J=1.4Hz,3H),3.79(d,J=13.7Hz,3H),3.71-3.63(m,3H),1.63-1.57(m,3H);EI-MS m/z:487[M+H]+。
(4) (4- ((N- (carboxymethyl) -4-methoxyphenyl) sulfonamido) naphthalen-1-yl) -L-alanine (I-d-1)
The same procedure as for the synthesis of Compound (I-a-1) was repeated except that Compound (25-3) (100.0mg, 206.0. mu. mol), LiOH. H2O (173.0mg, 4.1mmol) was used as starting material and the reaction gave 73.0mg of a white solid in 77% yield, m.p.>250℃.1H-NMR(300MHz,DMSO-d6)12.68(br,2H),8.31(d,J=7.3Hz,1H),8.00(dd,J=19.9,7.5Hz,1H),7.73-7.57(m,2H),7.46(d,J=7.9Hz,2H),7.08(d,J=8.8Hz,2H),6.99(dd,J=15.3,8.6Hz,1H),6.54(t,J=26.4Hz,1H),6.26(t,J=8.9Hz,1H),4.45(d,J=18.4Hz,1H),4.27(d,J=13.9Hz,1H),4.21-4.13(m,1H),3.86(s,3H),1.65-1.51(m,3H);EI-MS m/z:459[M+H]+。
Example 26:
(S) -3- ((4- ((N- (carboxymethyl) -4-methoxyphenyl) sulfonamido) naphthalen-1-yl) amino) butanoic acid (I-e-2)
(1) (S) -methyl 3- ((4-nitronaphthalen-1-yl) amino) butanoate (26-1)
1-2 Synthesis the same as in example 1
The same procedure as for the synthesis of compound (1-3) was repeated except that compound (1-2) (1g, 3.11mmol) and methyl (S) -3-amino-3-phenylpropionate were used(0.58g,3.73mmol)、Cs2CO3(2g, 6.22mmol), (+ -) -BINAP (0.29g, 0.47mmol), Pd2(dba)3(0.14g, 0.16mmol), DIPEA (1.1ml,6.22mmol) as the starting material gave 0.8g of a yellow oily liquid in 89% yield,1H-NMR(300MHz,CDCl3)9.00(dd,J=8.9,1.2Hz,1H),8.28(d,J=8.9Hz,1H),8.06(dd,J=8.5,1.2Hz,1H),7.73(ddd,J=8.5,6.9,1.3Hz,1H),7.61(ddd,J=8.4,6.9,1.3Hz,1H),6.94(d,J=6.2Hz,1H),6.28(d,J=8.9Hz,1H),5.08(td,J=6.6,5.1Hz,1H),3.70(s,3H),3.05(qd,J=15.1,5.9Hz,2H),1.63-1.57(m,3H);EI-MS m/z:289[M+H]+。
(2) (S) -methyl 3- ((4- ((4-methoxyphenyl) sulfonamido) naphthalen-1-yl) amino) butanoate (26-2)
In the same manner as the synthesis of compound (1-4), compound (26-1) (0.8g, 2.78mmol) was hydrogenolyzed and then reacted with 4-methoxybenzenesulfonyl chloride (690mg, 3.33mmol), pyridine (672. mu.L, 8.34mmol) as the starting material to give 520mg of a white solid with a yield of 44%, m.p.111-114 ℃,1H-NMR(300MHz,CDCl3)7.94(dt,J=7.7,1.7Hz,2H),7.60(d,J=8.9Hz,2H),7.47(qd,J=7.0,1.5Hz,2H),7.37(ddd,J=8.5,4.7,1.7Hz,3H),7.33-7.28(m,2H),6.38(s,1H),6.18(d,J=8.3Hz,1H),5.75(s,1H),4.94(s,1H),3.81(s,3H),3.68(s,3H),2.96(dd,J=6.4,2.6Hz,2H),1.60-1.57(m,3H);EI-MS m/z:429[M+H]+。
(3) (S) -methyl 3- ((4- ((N- (carboxymethyl) -4-methoxyphenyl) sulfonamido) naphthalen-1-yl) amino) butanoate (26-3)
In the same manner as the synthesis of the compound (2-1), starting from the compound (26-2) (200.0mg, 468. mu. mol), potassium carbonate (193.5mg, 1.4mmol) and methyl bromoacetate (104.3mg, 562. mu. mol), 200mg of a pale yellow solid was obtained, the yield was 85%, m.p.105-107 ℃;1H NMR(300MHz,CDCl3)8.02(s,1H),7.87(d,J=8.0Hz,1H),7.72-7.64(m,2H),7.53-7.42(m,2H),7.11(dd,J=9.9,8.2Hz,1H),6.96-6.86(m,2H),6.31(t,J=8.0Hz,1H),5.13(s,1H),4.71(d,J=17.8Hz,1H),4.32-4.20(m,2H),3.87(d,J=1.4Hz,3H),3.79(d,J=13.7Hz,3H),3.71-3.63(m,3H),3.02(m,2H),1.63-1.57(m,3H);EI-MS m/z:501[M+H]+。
(4) (S) -3- ((4- ((N- (carboxymethyl) -4-methoxyphenyl) sulfonamido) naphthalen-1-yl) amino) butanoic acid (I-e-2)
The same procedure as for the synthesis of Compound (I-a-1) was repeated except that Compound (26-3) (200.0mg, 400.0. mu. mol), LiOH. H2O (336.0mg, 8.0mmol) as starting material, the reaction gave 167.0mg of a white solid in 88% yield, m.p.>250℃.1HNMR(300MHz,DMSO-d6)9.52(s,1H),8.25-8.19(m,1H),7.93-7.85(m,1H),7.78-7.72(m,1H),7.58(dq,J=9.8,2.9Hz,2H),7.39(td,J=6.8,6.2,3.6Hz,2H),7.20(s,1H),7.10-7.05(m,1H),7.05-6.97(m,2H),6.78(d,J=8.4Hz,1H),6.20(d,J=8.3Hz,1H),4.11-4.04(m,1H),3.79(s,3H),2.98(m,2H),1.51(d,J=7.0Hz,3H);EI-MS m/z:473[M+H]+。
Example 27:
(S) -2- ((4- ((N- (carboxymethyl) -4-methoxyphenyl) sulfonylamino) naphthalen-1-yl) amino) -2-phenylacetic acid (I-e-3)
1-2 Synthesis the same as in example 1
(1) (S) -2- ((4-nitronaphthalen-1-yl) amino) -2-phenylacetic acid methyl ester (27-1)
The same procedure as used for the synthesis of compound (1-3) was repeated except that compound (1-2) (1g, 3.11mmol), L-phenylglycine methyl ester hydrochloride (0.76g, 3.73mmol), and Cs2CO3(2g, 6.22mmol), (+ -) -BINAP (0.29g, 0.47mmol), Pd2(dba)3(0.14g, 0.16mmol), DIPEA (1.1ml,6.22mmol) as the starting material gave 0.9g of a yellow oily liquid in 83% yield,1HNMR(300MHz,CDCl3)9.00(dd,J=8.9,1.2Hz,1H),8.28(d,J=8.9Hz,1H),8.06(dd,J=8.5,1.2Hz,1H),7.73(ddd,J=8.5,6.9,1.3Hz,1H),7.61(ddd,J=8.4,6.9,1.3Hz,1H),7.42-7.29(m,5H),6.94(d,J=6.2Hz,1H),6.28(d,J=8.9Hz,1H),5.38(td,J=6.6,5.1Hz,1H),3.70(s,3H);EI-MS m/z:337[M+H]+。
(2) (S) -methyl 3- ((4- ((4-methoxyphenyl) sulfonamido) naphthalen-1-yl) amino) -3-phenylpropionate (27-2)
In the same manner as in the synthesis of compound (1-4), compound (27-1) (0.9g, 2.57mmol) was hydrogenolyzed and then subjected to hydrogenation with 4-methoxybenzenesulfonyl chloride (640mg,3.08mmol) of pyridine (691. mu.L, 8.58mmol) as starting material, 400mg of a white solid are obtained, yield 33%, m.p.98-102 ℃,1H NMR(300MHz,CDCl3)7.94(dt,J=7.7,1.7Hz,2H),7.60(d,J=8.9Hz,2H),7.47(qd,J=7.0,1.5Hz,2H),7.37(ddd,J=8.5,4.7,1.7Hz,3H),7.33-7.28(m,2H),6.82(dd,J=8.4,5.3Hz,3H),6.38(s,1H),6.18(d,J=8.3Hz,1H),5.75(s,1H),5.40(s,1H),3.81(s,3H),3.68(s,3H);EI-MS m/z:477[M+H]+。
(3) (S) -methyl 2- ((4- ((4-methoxy-N- (2-methoxy-2-oxoethyl) phenyl) sulfonylamino) naphthalen-1-yl) amino) -2-phenylacetate (27-3)
In the same manner as in the synthesis of compound (2-1), starting from compound (27-2) (200.0mg, 420. mu. mol), potassium carbonate (172.2mg, 1.26mmol) and methyl bromoacetate (77.1mg, 504. mu. mol), 200mg of a pale yellow solid was obtained in a yield of 87%, EI-MS m/z: 563[ M + H]+。
(4) (S) -2- ((4- ((N- (carboxymethyl) -4-methoxyphenyl) sulfonylamino) naphthalen-1-yl) amino) -2-phenylacetic acid (I-e-3)
The same procedure as for the synthesis of Compound (I-a-1) was repeated except that Compound (27-3) (200.0mg, 364.0. mu. mol), LiOH. H2O (302.2mg, 7.2mmol) as starting material gave 166.0mg of a white solid in 88% yield, m.p.>250℃.1HNMR(300MHz,DMSO-d6)12.53(br,2H),8.41-8.30(m,1H),8.01-7.84(m,1H),7.62-7.55(m,1H),7.55-7.40(m,5H),7.36-7.12(m,3H),7.08-7.02(m,1H),6.97-6.91(m,1H),6.83(dd,J=23.5,8.3Hz,1H),6.22(t,J=8.0Hz,1H),5.4(d,J=7.1Hz,1H),4.36(dd,J=17.7,15.7Hz,1H),4.14(dd,J=17.7,3.4Hz,1H),3.81(d,J=12.5Hz,3H),EI-MS m/z:521[M+H]+。
Example 28:
(R) -3- ((4- ((N- (carboxymethyl) -4-methoxyphenyl) sulfonamido) naphthalen-1-yl) amino) -3-phenylpropionic acid (I-e-4)
1-2 Synthesis the same as in example 1
(1) (S) -3- ((4-nitronaphthalen-1-yl) amino) -3-phenylpropionic acid methyl ester (28-1)
The same procedure as for the synthesis of compound (1-3) was repeated except that compound (1-2) (1g, 3.11mmol), (R) -methyl 3-amino-3-phenylpropionate (0.52g, 3.73mmol), and Cs2CO3(2g,6.22mmol)、(±)-BINAP(0.29g,0.47mmol)、Pd2(dba)3(0.14g,0.16mmol) and DIPEA (1.1ml,6.22mmol) as starting materials to give 1.0g of a yellow oily liquid in a yield of 90%,1H-NMR(300MHz,CDCl3)9.00(dd,J=8.9,1.2Hz,1H),8.28(d,J=8.9Hz,1H),8.06(dd,J=8.5,1.2Hz,1H),7.73(ddd,J=8.5,6.9,1.3Hz,1H),7.61(ddd,J=8.4,6.9,1.3Hz,1H),7.42-7.29(m,5H),6.94(d,J=6.2Hz,1H),6.28(d,J=8.9Hz,1H),5.08(td,J=6.6,5.1Hz,1H),3.70(s,3H),3.05(qd,J=15.1,5.9Hz,2H);EI-MS m/z:351[M+H]+。
(2) (S) -methyl 3- ((4- ((4-methoxyphenyl) sulfonamido) naphthalen-1-yl) amino) -3-phenylpropionate (28-2)
In the same manner as the synthesis of compound (1-4), compound (28-1) (1.0g, 2.86mmol) was hydrogenolyzed and then reacted with 4-methoxybenzenesulfonyl chloride (710mg, 3.43mmol), pyridine (691. mu.L, 8.58mmol) as a starting material to give 700mg of a white solid with a yield of 50%, m.p.107-110 ℃,1H-NMR(300MHz,CDCl3)7.94(dt,J=7.7,1.7Hz,2H),7.60(d,J=8.9Hz,2H),7.47(qd,J=7.0,1.5Hz,2H),7.37(ddd,J=8.5,4.7,1.7Hz,3H),7.33-7.28(m,2H),6.82(dd,J=8.4,5.3Hz,3H),6.38(s,1H),6.18(d,J=8.3Hz,1H),5.75(s,1H),4.94(s,1H),3.81(s,3H),3.68(s,3H),2.96(dd,J=6.4,2.6Hz,2H);EI-MS m/z:491[M+H]+。
(3) (S) -methyl 3- ((4- ((4-methoxy-N- (2-methoxy-2-oxoethyl) phenyl) sulfonamido) naphthalen-1-yl) amino) -3-phenylpropionate (28-3)
In the same manner as the synthesis of the compound (2-1), starting from the compound (28-2) (200.0mg, 408. mu. mol), potassium carbonate (169.2mg, 1.22mmol) and methyl bromoacetate (104.3mg, 682. mu. mol), 200mg of a pale yellow oil was obtained in a yield of 87%,1H-NMR(300MHz,CDCl3)7.98(dt,J=7.7,1.7Hz,2H),7.62(d,J=8.9Hz,2H),7.49(qd,J=7.0,1.5Hz,2H),7.35(ddd,J=8.5,4.7,1.7Hz,3H),7.35-7.24(m,2H),6.80(dd,J=8.4,5.3Hz,3H),6.37(s,1H),6.18(d,J=8.3Hz,1H),5.77(s,1H),4.50(s,1H),4.39(d,J=5.6Hz,1H),4.24(d,J=17.8Hz,1H),3.81(s,3H),3.80(s,3H),3.73(s,3H),2.96(dd,J=6.4,2.6Hz,2H);EI-MS m/z:563[M+H]+。
(4) (S) -3- ((4- ((N- (carboxymethyl) -4-methoxyphenyl) sulfonamido) naphthalen-1-yl) amino) -3-phenylpropionic acid (I-e-4)
The same procedure as described for the synthesis of Compound (I-a-1) was repeated except that Compound (28-3) (200.0mg, 356.0. mu. mol), LiOH. H2O (298.2mg, 7.1mmol) was used as starting material and the reaction gave 165.0mg of a white solid in 87% yield, m.p.>250℃.1H-NMR(300MHz,DMSO-d6)12.53(br,2H),8.41-8.30(m,1H),8.01-7.84(m,1H),7.62-7.55(m,1H),7.55-7.40(m,5H),7.36-7.12(m,3H),7.08-7.02(m,1H),6.97-6.91(m,1H),6.83(dd,J=23.5,8.3Hz,1H),6.22(t,J=8.0Hz,1H),4.94(d,J=7.1Hz,1H),4.36(dd,J=17.7,15.7Hz,1H),4.14(dd,J=17.7,3.4Hz,1H),3.81(d,J=12.5Hz,3H),3.09(dt,J=17.2,8.9Hz,1H),2.72(dt,J=15.7,4.8Hz,2H);EI-MS m/z:535[M+H]+。
Example 29: examples of the drug action
The activation effect of the naphthyl sulfonamide amino acid derivatives prepared in examples 1-28 on Nrf2 was determined, respectively.
1. Fluorescence polarization-based Keap1-Nrf2 protein-protein interaction inhibition experiment (FP experiment)
The instrument used for FP experiments is a SpectraMax Multi-Mode Microplate Reader (Molecular Devices), and the wavelengths of the excitation light and the emission light of the instrument are selected according to the corresponding fluorophores. Experimental work was performed using Corning 3676384 well plates. The reaction system in the well plate was 40. mu.L. This contained 10. mu.L of 4nM FITC-9merNrf2 polypeptide fluorescent probe, 10. mu.L of 12nM Keap1Kelch domain protein solution and 20. mu.L of the corresponding concentration of inhibitor. The positive control used 20. mu.L of 100nM Nrf2 nonapeptide (Ac-LDEETGEFL-OH) + 10. mu.L of probe + 10. mu.L of protein solution, the negative control used 10. mu.L of probe + 10. mu.L of protein solution + 20. mu.L of HEPES buffer, and the blank control used 10. mu.L of probe + 30. mu.L of HEPES buffer. Mix well at room temperature and incubate for 30 minutes before testing. In the experiment, the fluorescent group of the probe is fluorescein, the wavelength of the excitation light is 485nm, and the wavelength of the emission light is 535 nm. In this study, the milli-offset (mP) values were calculated using the fluorescence intensities in the horizontal and vertical directions (F ║ and F vert) to reflect the change in polarized light. The method for calculating the inhibition rate of the inhibitor at a certain concentration comprises the following steps:
inhibition rate%obs-Pmin)/(Pmax-Pmin))×100。
Pmax、PminAnd PobsRepresenting the polarization values of Keap1 and the fluorescent probe well, the fluorescence probe well, and the inhibitor-containing well, respectively. Calculation of IC of Compounds Using concentration-inhibition Rate curves of inhibitors50(results are shown in the table below).
2. ARE luciferase reporter gene assay
In vitro cell culture
HepG2 cells (obtained by transfection using the antibiotic Response Reporter plasmid purchased from QIAGEN according to the given guidelines) transfected with the ARE luciferase Reporter gene-containing plasmid were cultured in RPMI-1640 medium containing 10% fetal bovine serum at 37 ℃ under 5% CO2Culturing under the condition.
(1) HepG2-ARE-C8 cells in logarithmic growth phase were treated with 0.25% pancreatic digest to a concentration of 4X 105The cell suspension of (3). 100. mu.L of each of the solutions was added to a 96-well microplate and incubated overnight.
(2) The test compound was prepared in a medium at 2-fold the desired concentration, and 100. mu.L of t-butylhydroquinone (tBHQ) was added to the corresponding wells, respectively, as a positive control and DMSO as a negative control. The 96-well enzyme-linked plate added with the compound is placed at 37 ℃ and 5% CO2And (5) incubating for 12h under the conditions of constant temperature and saturated humidity.
(3) And preparing a 5X lysate in the luciferase detection kit into a 1X lysate for later use.
(4) And taking out the 96-well enzyme label plate, sucking out the culture medium from the wells, washing the cells by using 1XPBS buffer solution, and sucking out the PBS buffer solution after washing. Add 25 or 30. mu.L of 1X cell lysate per well and lyse on ice for 15 min. After the lysis, standing for 3-5min, and sucking 20 μ L of the supernatant lysate to add into the corresponding 96-well white enzyme label plate.
(5) The white ELISA plate is placed in a Thermo Scientific luminoskaxcent chemiluminescence micropore reading instrument, 100 mu L of luciferase detection reagent (prepared by uniformly mixing 1 bottle of luciferase detection substrate in a luciferase detection kit and 1 bottle of luciferase detection buffer solution) is added into each hole before testing, and reading is carried out within 1min after the detection reagent is added.
The results are shown in the following table.
The data show that the compound provided by the invention has good Keap1-Nrf2 protein-protein interaction (PPI) inhibition activity, so that the compound has good Nrf2 excitation effect; in luciferase reporter gene experiments, the compounds provided by the invention all show good induction activity, and are expected to be developed into Nrf2 excitant for anti-inflammation.
In conclusion, the compound containing amino acids and a monosulfonamide structure provided by the invention can interfere with the combination of Keap1-Nrf2 and activate Nrf2, so that inflammatory injury is reduced, the inflammatory microenvironment is improved, and the compound has potential anti-inflammatory activity. One skilled in the art knows that Nrf2 activators can be used to inhibit the inflammatory response of diseases (ref: protective role of Nrf2 in inflammation-related diseases, pharmaceutical biotechnology, 2013, stage 4), therefore, the compounds provided by the present invention can be used to prepare anti-inflammatory drugs for the treatment of numerous inflammation-related diseases, including Chronic Obstructive Pulmonary Disease (COPD), alzheimer's disease, parkinson's disease, atherosclerosis, Chronic Kidney Disease (CKD), diabetes, intestinal inflammation, rheumatoid arthritis, etc.
The above-described embodiments are intended to be illustrative of the nature of the invention, but those skilled in the art will recognize that the scope of the invention is not limited to the specific embodiments.
Claims (3)
2. a pharmaceutically acceptable salt of the naphthyl sulfonamide amino acid derivative of claim 1.
3. Use of the naphthyl sulfonamide amino acid derivative of claim 1, or a pharmaceutically acceptable salt thereof, for the preparation of an Nrf2 activator.
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