CN103193695A - 3-phenyl-3-pyrrolyl pentane derivative and medical application thereof - Google Patents
3-phenyl-3-pyrrolyl pentane derivative and medical application thereof Download PDFInfo
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- 0 CCC(CC)(c1ccc(**)[n]1*)c1cc(C)c(**)cc1 Chemical compound CCC(CC)(c1ccc(**)[n]1*)c1cc(C)c(**)cc1 0.000 description 6
- USYBJGUCYZNJMP-IJHRGXPZSA-N CCC(CC)(c1ccc(C(N(CCC2)[C@@H]2C(O)=N)=O)[n]1C)c(cc1)cc(C)c1OCC(C)O Chemical compound CCC(CC)(c1ccc(C(N(CCC2)[C@@H]2C(O)=N)=O)[n]1C)c(cc1)cc(C)c1OCC(C)O USYBJGUCYZNJMP-IJHRGXPZSA-N 0.000 description 1
- SNEBILQEIZRRTL-QHCPKHFHSA-N CCC(CC)(c1ccc(C(N2[C@H](CO)CCC2)=O)[n]1C)c(cc1)cc(C)c1OCCC(C)(C)C Chemical compound CCC(CC)(c1ccc(C(N2[C@H](CO)CCC2)=O)[n]1C)c(cc1)cc(C)c1OCCC(C)(C)C SNEBILQEIZRRTL-QHCPKHFHSA-N 0.000 description 1
- RODWRQOYPPYSBC-RCCKNPSSSA-N CCC(CC)(c1ccc(C(O)=O)[n]1CC)c(cc1C)ccc1OC/C(/C(C)(C)C)=C\CO Chemical compound CCC(CC)(c1ccc(C(O)=O)[n]1CC)c(cc1C)ccc1OC/C(/C(C)(C)C)=C\CO RODWRQOYPPYSBC-RCCKNPSSSA-N 0.000 description 1
Abstract
The invention relates to the field of pharmaceutical chemistry, and in particular relates to a 3-phenyl-3-pyrrolyl pentane derivative (I) shown in the specification, wherein R1, R2, R3, R4 and R5 are defined in the specification. A pharmacodynamic experiment shows that the compound has effects of treating psoriasis and resisting tumor. The invention also discloses a preparation method of the compound.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to a class 3-phenyl-3-pyrryl pentane derivative, their preparation method and treatment psoriatic and anticancer usage.
Background technology
Vitamin D Receptor (VDR) is a kind of acceptor dependent form transcription factor that belongs to nucleus internal hormone receptor superfamily.The part of VDR, 1 α, 25-(OH)
2Vitamin D
3Be the acceptor of VDR, it is calcium phosphorus stable state in keeping body, and inducing cell differentiation and aspects such as inhibition cell proliferation and immunoregulation all play an important role.
Since 1 α, 25-(OH)
2Vitamin D
3Can act on multiple target tissue, and physiological action is also varied, it has been widely used in clinical treatment.But, use 1 α, 25-(OH)
2Vitamin D
3Exist a main side effect-hypercalcemia.In order to reduce adverse drug reaction, to 1 α, 25-(OH)
2Vitamin D
3Carry out structural modification and can obtain some analogues less to the blood calcium metabolic effect.What gone on the market has Tacalcitol ointment, calcipotriol ointment etc., and the two all is approved for the medicine treatment of psoriasis vulgaris.Some other 1 α, 25-(OH)
2Vitamin D
3Analogue referring to document: Vitamin D Analogs:Mechanism of Action of Therapeutic Applications, Curr.Med.Chem.2001,8,1661-1679.
In order to reduce this type of drug side effect, one class phenylbenzene replaces alkyl compound and is developed out, and find that it can significantly reduce it and rise the ability of blood calcium under the condition that keeps the VDR ligand activity, referring to document: Novel onsecosteroidal vitaminD mimics exert VDR-modulating activities with less calcium mobilization than1 α, 25-(OH)
2VitaminD
3, Chemistry ﹠amp; Biology1999,6,265-275. in addition, US2007105951 has announced that a class benzofurane base replaces synthetic as the VDR receptor stimulant of alkyl compound.WO2004063348 has announced that a class phenyl thienyl replaces alkyl compound synthesizing as the VDR receptor stimulant.In view of the complicacy of psoriatic and oncotherapy, this area still presses for the VDR receptor stimulant of research and development high-efficiency low-toxicity.
Summary of the invention
The invention discloses the compound of a class general formula I, show through pharmacological evaluation, compound of the present invention has stronger avidity to the VDR acceptor, and people's keratinocyte and human breast cancer cell propagation is had stronger restraining effect, and the ability of its rising blood calcium very a little less than.Therefore, the compound of general formula I of the present invention can be used for the treatment of various cancers and psoriatic in various degree.
Structural formula of compound of the present invention is as follows:
Wherein: R
1Represent hydrogen or C
1-C
5Alkyl;
R
2Representative
R
3Representative
R
4Represent hydrogen, C
1-C
5Alkyl, C
1-C
5Phenylalkyl,
Said n all represents 0,1 or 2;
R
5Represent hydrogen, C
1-C
5Hydroxyalkyl, C
1-C
5Substituted hydroxy alkyl, C
1-C
5Carboxyalkyl, C
1-C
5Replacement carboxyalkyl, C
1-C
5Methoxycarbonyl alkyl, C
1-C
5Replacement methoxycarbonyl alkyl,
C wherein
1-C
5The substituted hydroxy alkyl in substituting group be C
1-C
5Alkyl or C
1-C
5Hydroxyalkyl; C
1-C
5The replacement carboxyalkyl in substituting group be C
1-C
5Alkyl or C
1-C
5Carboxyalkyl; C
1-C
5The substituted alkoxycarbonyl alkyl in substituting group be C
1-C
5Alkyl or C
1-C
5Alkoxycarbonyl alkyl.
The pharmacy acceptable salt of general formula (I) compound has the pharmacology curative effect same with this compound.
R wherein
2The preferred oxygen that represents.
R
3Preferred representative
R
4Preferred representative
R
5Preferred 2-hydroxyethyl, the 3-hydroxypropyl, 2 (R)-hydroxypropyl, 2 (S)-hydroxypropyl, 2 (S)-1 of representing, 4-dihydroxyl butyl, 2-carboxyl base ethyl, 3-carboxyl propyl group, 2 (R)-carboxyl propyl group, 2 (S)-carboxyl propyl group, 2 (S)-1,4-dicarboxyl butyl, 2-methoxycarbonyl ethyl, 3-methoxycarbonyl propyl group, 2 (R)-methoxycarbonyl propyl group, 2 (S)-methoxycarbonyl propyl group, 2 (S)-1,4-dimethoxycarbonyl butyl,
Compound of the present invention can prepare with following method:
R wherein
1, R
2, R
3, R
4, R
5Definition is the same.
The compounds of this invention or its pharmacy acceptable salt can be made various preparations by adding pharmaceutically acceptable carrier.Clinical for oral, injection, local application etc.
The clinical used dosage of compound of the present invention is 0.001mg～1000mg/ days, also can depart from this scope according to the weight of the state of an illness or the difference of formulation.
Pharmacodynamics test proves: The compounds of this invention has excellent Vitamin D Receptor agonist activity, suppresses the activity of people's keratinocyte and human breast carcinoma tumor cell proliferation, and rise the blood calcium ability very a little less than.Compound of the present invention can be used for treating the some diseases by the Vitamin D Receptor mediation, as psoriatic, and leukemia, mammary cancer etc.
Be pharmacodynamics test and the result of part of compounds of the present invention below, the structural formula of compound code name correspondence is seen embodiment, the structural formula of positive drug:
One, short human promyelocytic leukemia cell (HL-60 cell) Analytical Chemical Experiment (test of Vitamin D Receptor agonist activity)
Experimental technique: the HL-60 cell in the vegetative period of taking the logarithm, adjusting cell density is 1 * 10
4The cell suspension of individual viable cell, setting is subjected to examination group, positive controls, negative control group according to requirement of experiment, establishes 3 parallel holes for every group, places 37 ℃ of 5%CO
2And cultivation 96h in the incubator of saturated humidity.Adding 200 μ L contains Buddhist ripple ester (TPA, final concentration is 200ngml
-1) 1%NBT solution mix, put the people and hatch 30min for 37 ℃, will remove supernatant liquor behind the cell centrifugation again, every part of sample adds the dimethyl sulfoxide (DMSO) of 150 μ L, the 20min that vibrates under the room temperature surveys the absorbance under the 570nm wavelength, after be converted into medium effective concentration.Experimental result sees Table 1:
Table 1 The compounds of this invention and contrast are to human leukemia cell's (HL-60) short Analytical Chemical Experiment:
Above-mentioned effect experiment proves that The compounds of this invention has good Vitamin D Receptor agonist activity.
Two, suppress people's immortality keratinocyte (HaCaT cell) and Michigan cancer foundation-7 breast cancer cell (MCF-7 cell) proliferation experiment
Experimental technique: the HaCaT cell in the vegetative period of taking the logarithm and MCF-7 cell, adjusting cell density is 2 * 10
4Individual/ml, be inoculated in inoculating cell suspension 200 μ L in every hole in 3 96 well culture plates; Be subjected to examination group, positive controls, negative control group; Dosing behind the cell inoculation 24h is established 3 parallel holes for every group, places 37 ℃ of 5%CO
2And cultivate in the incubator of saturated humidity, abandon supernatant after cultivating 48h respectively, every hole adds MTT and the 200 μ L DMEM nutrient solutions that 20 μ L concentration are 5mg/ml and continues to cultivate 4h, every hole adds 150 μ L dimethyl sulfoxide (DMSO) and vibrate 10min on shaking table, optical density value (D570) experiment of measuring wavelength 570nm with microplate reader repeats 3 times, after be converted into medium effective concentration.Experimental result sees Table 2:
Table 2 The compounds of this invention and contrast are to people's keratinocyte cell and human breast cancer cell proliferation inhibition test
Above-mentioned effect experiment proves that The compounds of this invention has good inhibition keratinocyte and the activity of breast cancer tumour cell proliferation.
Three, rise the blood calcium activity in the body
Experimental technique: 10 weeks were cleaned level mouse (Jiangsu University, credit number SPXK (Soviet Union) 2009-002), and mean body weight is (20 ± 2) g; Animal is divided into 10 groups at random, and every group of 6 mouse are respectively blank group (physiological saline), all the other 7 groups be control group Tacalcitol (5ug/kg), be subjected to examination group representation compound sw-22 and sw-34 (high 30mg/kg, middle 10mg/kg, low 0.5mg/kg).Experiment mice gives 40mg every day before the administration, the forage feed of 200mg phosphorus and 40 unit vitamin D, and every 3d weighs once.After raising 7d, the subcutaneous injection administration respectively of each group, administration is 7 days altogether, and blank group gives equal volume physiological saline, freely takes the photograph water under relative humidity 67% environment, ingests, and weighs 1 time in per 3 days.Experimental result is seen Fig. 1, compares * p＜0.05, * * p＜0.01 with physiological saline; Compare #p＜0.05, ##p＜0.01 with Tacalcitol.Above-mentioned pharmacodynamic experiment proves that The compounds of this invention does not have influence to calcium level.
Description of drawings
Fig. 1 rises the blood calcium aptitude tests to test in the body of compound sw-22 and sw-34
Embodiment
Embodiment 1
4-hydroxy-3-methyl methyl benzoate (2)
(50.0g 0.32mol) is dissolved in the 300mL methyl alcohol, slowly adds the 45mL vitriol oil under whipped state, is warming up to back flow reaction 6.5h after adding with 4-hydroxy-3-methyl phenylformic acid.Reaction is cooled to room temperature after finishing, and transfers about pH to 6, then with in the reaction solution impouring 1L frozen water with the 2.5M NaOH aqueous solution.With the solid filtering of separating out and use cold wash, dry pink solid 50.4g, yield: 92.3%.
1H?NMR(300MHz，CDCl
3)：7.01(1H，s)，6.98(1H，d，J＝8.5Hz)，6.50(1H，d，J＝8.5Hz)，5.40(1H，bs)，3.88(3H，s)，2.26(3H，s)。
4-benzyl oxygen base-3-methyl-toluate (3)
With compound 2 (17.0g 102mmol) is dissolved in the 200mL acetone, add successively salt of wormwood (42.3g, 306mmol), potassiumiodide (5.1g, 30.6mmol) and cylite (19.2g, 112mmol), stirring and refluxing reaction 6h.Reaction is cooled to room temperature after finishing, the elimination insolubles, and the filtrate decompression distillation gets red oil after revolving most solvents, gets pink crystal 2 5.3g, yield: 96.5% with the sherwood oil recrystallization.Fusing point: 56-58 ℃;
1H NMR (300MHz, CDCl
3) δ: 7.46-7.31 (5H, m), 7.10 (1H, s), 7.04 (1H, d, J=8.3Hz), 6.69 (1H, d, J=8.3Hz), 5.04 (2H, s), 3.88 (3H, s), 2.24 (3H, s).
3-(4-benzyloxy-3-aminomethyl phenyl)-3-amylalcohol (4)
Prepare the ethyl grignard reagent according to a conventional method.Under 0 ℃, with compound 3 (1.0g, diethyl ether solution 3.9mmol) (10mL) slowly splash into grignard reagent/diethyl ether solution (10mL, 15.6mmol) in, in about 1h, dropwise, be warming up to 25 ℃ the reaction 2h.Reaction finishes the back with the ice-water bath cooling, slowly drips saturated ammonium chloride solution and emits until no bubble.Add an amount of ethyl acetate, fully stir the back layering, tell organic layer, water layer merges organic layer with ethyl acetate extraction (10mL * 3), and with an amount of saturated common salt water washing, anhydrous sodium sulfate drying, steaming desolventizes, and gets white oily matter 0.9g, yield 89%.
1H?NMR(300MHz，CDCl
3)δ：7.49-7.28(5H，m)，7.06(1H，s)，7.03(1H，d，J＝8.3Hz)，6.79(1H，d，J＝8.3Hz)，5.04(2H，s)，2.27(3H，s)，1.77(4H，q，J＝7.5Hz)，0.97(6H，t，J＝7.5Hz)。
3 '-(4-benzyloxy-3-aminomethyl phenyl)-3 '-(5-ethoxycarbonyl pyrroles-2-yl) pentane (5)
With compound 4 (1.3g, 4.6mmol) and pyrroles-2-carboxylic acid, ethyl ester (0.7g 5.1mmol) is dissolved in the 10mL methylene dichloride, drips down 1.3mL trifluoracetic acid ether in-25 ℃, drips to finish the back and continue to stir 1h.After reaction finishes, add 10mL water, fully stir the back layering, tell organic layer, water layer dichloromethane extraction (5mL * 3), merge organic layer, with an amount of saturated common salt water washing, anhydrous sodium sulfate drying, steaming desolventizes, get yellow oil, through column chromatography purification (ethyl acetate: sherwood oil=1: 12) get yellow solid 1.35g, yield: 73.0%.Fusing point: 86-89 ℃;
1HNMR (300MHz, CDCl
3) δ: 7.49-7.28 (5H, m), 7.03 (1H, s), 7.01 (1H, d, J=8.5Hz), 6.79 (1H, d, J=8.5Hz), 6.70 (1H, d, J=2.0Hz), 6.50 (1H, d, J=2.0Hz), 5.04 (2H, s), 4.30 (2H, q, J=7.1Hz), 2.24 (3H, s), 1.97 (4H, q, J=7.3Hz), 1.32 (3H, t, J=7.1Hz), 0.67 (6H, t, J=7.3Hz).
3 '-(4-benzyloxy-3-aminomethyl phenyl)-3 '-(5-ethoxycarbonyl-1-methylpyrrole-2-yl) pentane (6a)
With compound 5 (241mg 0.6mmol) is dissolved among the 5mLDMF, under condition of ice bath, add in batches NaH (58.3mg, 1.2mmol), insulated and stirred 0.5h, (114mg 0.8mmol), reacts 1h under the room temperature to add methyl iodide then.After reaction finishes, under condition of ice bath, slowly drip 20mL water, add the 10mL ethyl acetate again, fully stir the back layering, tell organic layer, water layer ethyl acetate extraction (5mL * 3), merge organic layer, with an amount of saturated common salt water washing, anhydrous sodium sulfate drying, boil off solvent and get yellow oil 205mg, yield: 82.4%.
1H?NMR(300MHz，CDCl
3)δ：7.49-7.29(5H，m)，7.03(1H，s)，7.02(1H，d，J＝8.4Hz)，6.79(1H，d，J＝8.4Hz)，6.60(1H，d，J＝1.9Hz)，6.49(1H，d，J＝1.9Hz)，5.04(2H，s)，4.25(2H，q，J＝7.1Hz)，3.86(3H，s)，2.25(3H，s)，1.94(4H，q，J＝7.3Hz)，1.30(3H，t，J＝7.1Hz)，0.67(6H，t，J＝7.3Hz)。
3 '-(4-benzyloxy-3-aminomethyl phenyl)-3 '-(5-ethoxycarbonyl-1-N-ethyl pyrrole N--2-yl) pentane (6b)
With compound 5 (6.7g 16.5mmol) is dissolved among the 30mL DMF, under condition of ice bath, add in batches NaH (1.6g, 33.0mmol), insulated and stirred 0.5h, add then iodoethane (3.9g, 24.8mmol), 40 ℃ of following reaction 12h.After reaction finishes, under condition of ice bath, slowly drip 100mL water, add the 30mL ethyl acetate again, fully stir the back layering, tell organic layer, water layer ethyl acetate extraction (10mL * 3), merge organic layer, with an amount of saturated common salt water washing, anhydrous sodium sulfate drying, boil off solvent and get colorless oil 4.8g, yield: 66.9%.
1H?NMR(300MHz，CDCl
3)δ：7.50-7.28(5H，m)，7.04(1H，s)，7.02(1H，d，J＝8.6Hz)，6.77(1H，d，J＝8.6Hz)，6.70(1H，d，J＝2.0Hz)，6.57(1H，d，J＝2.0Hz)，5.04(2H，s)，4.32-4.20(4H，m)，2.25(3H，s)，1.95(4H，q，J＝7.0Hz)，1.35-1.26(6H，m)，0.67(6H，t，J＝7.0Hz)。
3 '-(4-hydroxy-3-methyl phenyl)-3 '-(5-ethoxycarbonyl-1-methylpyrrole-2-yl) pentane (7a)
(4.3g 10.2mmol) is dissolved in 20mL methyl alcohol, and (6.25g, 102mmol), reaction is spent the night under the room temperature condition to add Pd/C (0.43g) and ammonium formiate then successively with compound 6a.Reaction finishes back elimination insolubles, and filtrate adds the suitable quantity of water dilution, uses ethyl acetate extraction, tells organic layer, water layer merges organic layer, with an amount of saturated common salt water washing with ethyl acetate extraction (10mL * 3), anhydrous sodium sulfate drying boils off solvent and gets white solid 3.3g, yield: 97.9%.Fusing point: 78-81 ℃;
1HNMR (300MHz, CDCl
3) δ: 6.98 (1H, s), 6.96 (1H, d, J=8.3Hz), 6.70 (1H, d, J=2.0Hz), 6.69 (1H, d, J=8.3Hz), 6.49 (1H, d, J=2.0Hz), 4.25 (2H, q, J=7.1Hz), 3.85 (3H, s), 2.21 (3H, s), 1.95 (4H, q, J=7.4Hz), 1.31 (3H, t, J=7.1Hz), 0.67 (6H, t, J=7.4Hz).
3 '-(4-hydroxy-3-methyl phenyl)-3 '-(5-ethoxycarbonyl-1-N-ethyl pyrrole N--2-yl) pentane (7b)
Change 6a into 6b, the same 7a of preparation method.
White solid, yield: 97.2%.Fusing point: 72-74 ℃;
1H NMR (300MHz, CDCl
3) δ: 6.92 (1H, s), 6.88 (1H, d, J=8.6Hz), 6.63 (1H, d, J=2.1Hz), 6.60 (1H, d, J=8.6Hz), 6.50 (1H, d, J=2.1Hz), 4.25-4.06 (4H, m), 2.28 (3H, s), 1.87 (4H, q, J=7.4Hz), 1.30-1.25 (6H, m), 0.60 (6H, t, J=7.4Hz).
3 '-(4-(3,3-dimethyl-2-butanone oxygen base)-3-aminomethyl phenyl)-3 '-(5-ethoxycarbonyl-1-methylpyrrole-2-yl) pentane (8a)
With compound 7a (6.4g 19.0mmol) is dissolved in the 50mL acetone, add successively salt of wormwood (5.5g, 40.0mmol), potassiumiodide (0.5g, 3.0mmol) and a chlorine pinacolone (3.9g, 29mmol), stirring and refluxing reaction 12h.Be cooled to room temperature after reaction finishes, the elimination insolubles, yellow oil behind most solvents is revolved in the filtrate decompression distillation, through column chromatography purification (ethyl acetate: sherwood oil=1: 30) yellow oil 6.9g, yield: 83.1%.
1H?NMR(300MHz，CDCl
3)δ：7.01(1H，s)，6.97(1H，d，J＝8.5Hz)，6.68(1H，d，J＝1.9Hz)，6.50(1H，d，J＝8.5Hz)，6.49(1H，d，J＝1.9Hz)，4.84(2H，s)，4.30(2H，q，J＝7.1Hz)，3.85(3H，s)，2.26(3H，s)，1.93(4H，q，J＝7.3Hz)，1.32(3H，t，J＝7.1Hz)，1.25(9H，s)，0.65(6H，t，J＝7.3Hz)。
3 '-(4-(3,3-dimethyl butyrate ketone group oxygen base)-3-aminomethyl phenyl)-3 '-(5-ethoxycarbonyl-1-N-ethyl pyrrole N--2-yl) pentane (8b)
Change 7a into 7b, the same 8a of preparation method.
Yellow oil, yield: 86.4%.
1H?NMR(300MHz，CDCl
3)δ：7.02(1H，s)，6.97(1H，d，J＝8.5Hz)，6.68(1H，d，J＝2.0Hz)，6.56(1H，d，J＝2.0Hz)，6.51(1H，d，J＝8.5Hz)，4.84(2H，s)，4.31-4.10(4H，m)，2.26(3H，s)，1.93(4H，q，J＝7.6Hz)，1.46-1.30(6H，m)，1.28(9H，s)，0.66(6H，t，J＝7.6Hz)。
Synthesizing of 3 '-(4-(3,3-dimethyl butyrate ketone group oxygen base)-3-aminomethyl phenyl)-3 '-(5-carboxyl-1-methylpyrrole-2-yl) pentane (9a)
(1.8g 4.2mmol) is dissolved in the 20mL ethanol, adds 10mL potassium hydroxide (1.2g, aqueous solution 20.1mmol), 80 ℃ of reaction 5h with compound 8a.After reaction finishes, add 20mL water, transfer about pH to 3 with 1M HCl, use ethyl acetate extraction, tell organic layer, water layer merges organic layer, with an amount of saturated common salt water washing with ethyl acetate extraction (5mL * 3), anhydrous sodium sulfate drying, get yellow oil after boiling off solvent, through column chromatography purification (ethyl acetate: sherwood oil=1: 10) get colorless oil 1.5g, yield: 89.2%.
1H?NMR(300MHz，CDCl
3)δ：6.93(1H，s)，6.91(1H，d，J＝8.2Hz)，6.78(1H，d，J＝1.9Hz)，6.45(1H，d，J＝1.9Hz)，6.43(1H，d，J＝8.2Hz)，4.76(2H，s)，3.78(3H，s)，2.18(3H，s)，1.86(4H，q，J＝7.3Hz)，1.24(9H，s)，0.60(6H，t，J＝7.3Hz)。
3 '-(4-(3,3-dimethyl butyrate ketone group oxygen base)-3-aminomethyl phenyl)-3 '-(5-carboxyl-1-N-ethyl pyrrole N--2-yl) pentane (9b)
Change 8a into 8b, the same 9a of preparation method.
Colorless oil, yield: 87.0%.
1H?NMR(300MHz，CDCl
3)δ：7.01(1H，s)，6.97(1H，d，J＝8.5Hz)，6.85(1H，d，J＝2.0Hz)，6.60(1H，d，J＝2.0Hz)，6.51(1H，d，J＝8.5Hz)，4.84(2H，s)，4.26(2H，q，J＝7.1Hz)，2.26(3H，s)，1.93(4H，q，J＝7.3Hz)，1.41(6H，t，J＝7.1Hz)，1.28(9H，s)，0.66(6H，t，J＝7.3Hz)。
Embodiment 2
2-(5-(1-ethyl-1-(4-(2-carbonyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-picoline-2-formamido-)-methyl acetate (sw-1)
(0.3g 0.75mmol) is dissolved in 10mL DMF, adds glycine methyl ester hydrochloride (0.1g with compound 10a, 0.83mmol) and triethylamine (0.33g, 3.3mmol), stirring 10min, add successively then HOBt (0.12g, 0.91mmol) and EDCI (0.17g, 0.91mmol).Room temperature reaction spends the night.After reaction finishes, in reaction solution impouring 20mL water, use ethyl acetate extraction, tell organic layer, water layer ethyl acetate extraction (10mL * 3), merge organic layer, with an amount of saturated common salt water washing, anhydrous sodium sulfate drying boils off solvent and gets yellow oil, through column chromatography purification (ethyl acetate: sherwood oil=1: 4) get white solid 0.29g, yield: 82.1%.Fusing point: 121-122 ℃; HRMS, ESI
+, m/z:Calcd for C
27H
39N
2O
5(M+H)
+, 471.2853; Found, 471.2863;
1H NMR (300MHz, CDCl
3) δ:
1H NMR (CDCl
3, 300Hz) δ: 7.01 (1H, s), 6.98 (1H, d, J=8.5Hz), 6.50 (1H, d, J=8.5Hz), 6.45 (1H, d, J=1.8Hz), 6.18 (1H, d, J=1.8Hz), 4.833 (2H, s), 3.88 (3H, s), 3.69 (3H, s), 3.59 (2H, t, J=6.0Hz), 2.60 (2H, t, J=6.0Hz), 2.26 (3H, s), 1.91 (4H, q, J=7.3Hz), 1.26 (9H, s), 0.65 (6H, t, J=7.3Hz).
Embodiment 3
2-(5-(1-ethyl-1-(4-(2-hydroxyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-picoline-2-formamido-)-ethanol (sw-2)
With compound sw-1 (0.11g 0.23mmol) is dissolved in 10mL methyl alcohol, add in batches sodium borohydride (0.088g, 2.3mmol), room temperature reaction 0.5h.After reaction finishes, add 10mL water, use ethyl acetate extraction, tell organic layer, water layer ethyl acetate extraction (5mL * 3), merge organic layer, with an amount of saturated common salt water washing, anhydrous sodium sulfate drying boils off solvent, through column chromatography purification (ethyl acetate: sherwood oil=1: 1) get white solid 0.1g, yield: 96.2%.Fusing point: 98-100 ℃; HRMS, ESI
+, m/z:Calcd for C
26H
41N
2O
4(M+H)
+, 445.3061; Found, 445.3069;
1H NMR (500MHz, CDCl3) δ: 7.02 (1H, d, J=8.5Hz), 7.00 (1H, s), 6.70 (1H, d, J=8.5Hz), 6.49 (1H, d, J=1.9Hz), 6.21 (1H, d, J=1.9Hz), 4.09 (2H, m), 3.87 (3H, s), 3.72 (2H, m), 3.70 (1H, m), 3.46 (2H, m), 2.19 (3H, s), 1.91 (4H, q, J=7.5Hz), 1.01 (9H, s), 0.65 (6H, t, J=7.5Hz).
Embodiment 4
2-(5-(1-ethyl-1-(4-(2-carbonyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-picoline-2-formamido-)-acetic acid (sw-3)
(0.16g 0.33mmol) is dissolved in 5mL tetrahydrofuran (THF) and 1mL water, adds LiOH2H with compound sw-1
2(70mg, 1.65mmol), room temperature reaction spends the night O.After reaction finishes, add 10mL water, transfer about pH to 4 with the 1M hydrochloric acid soln, use ethyl acetate extraction, merge organic layer, anhydrous sodium sulfate drying, boil off solvent, through column chromatography purification (methylene dichloride: methyl alcohol=40: 1) get faint yellow solid 0.13g, yield: 83.9%.Fusing point: 104-105 ℃; HRMS, ESI
+, m/z:Calcd for C
26H
37N
2O
5(M+H)
+, 457.2697; Found, 457.2704;
1H NMR (500MHz, CDCl
3) δ: 7.00 (1H, s), 6.95 (1H, d, J=8.5Hz), 6.50 (1H, d, J=1.9Hz), 6.49 (1H, d, J=8.5Hz), 6.32 (1H, d, J=1.9Hz), 4.83 (2H, s), 4.07 (2H, d, J=5.3Hz), 3.85 (3H, s), 2.24 (3H, s), 1.90 (4H, q, J=7.3Hz), 1.24 (9H, s), 0.64 (6H, t, J=7.3Hz).
Embodiment 5
2-(5-(1-ethyl-1-(4-(2-hydroxyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-picoline-2-formamido-)-acetic acid (sw-4)
With compound sw-3 with compound (0.14g 0.31mmol) is dissolved in 10mL methyl alcohol, add in batches sodium borohydride (0.24g, 6.2mmol), room temperature reaction 0.5h.After reaction finishes, add 10mL water, use ethyl acetate extraction, merge organic layer, anhydrous sodium sulfate drying boils off solvent, through column chromatography purification (methylene dichloride: methyl alcohol=20: 1) get faint yellow solid 0.12g, yield: 85.1%.Fusing point: 96-98 ℃; HRMS, ESI
+, m/z:Calcd for C
26H
39N
2O
5(M+H)
+, 459.2853; Found, 459.2858;
1H NMR (500MHz, CDCl
3) δ: 6.93 (1H, s), 6.92 (1H, d, J=8.4Hz), 6.63 (1H, d, J=8.4Hz), 6.37 (1H, d, J=1.8Hz), 6.25 (1H, d, J=1.8Hz), 4.01 (2H, m), 3.92 (2H, m), 3.81 (1H, m), 3.62 (3H, s), 2.10 (3H, s), 1.92 (4H, q, J=6.8Hz), 0.96 (9H, s), 0.57 (6H, t, J=6.8Hz).
Embodiment 6
3-(5-(1-ethyl-1-(4-(2-carbonyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-picoline-2-formamido-)-methyl propionate (sw-5)
The same sw-1 of preparation method changes glycine methyl ester hydrochloride into the Beta-alanine methyl ester hydrochloride.
White solid, yield: 82.0%.Fusing point: 97-100 ℃; HRMS, ESI
+, m/z:Calcd for C
28H
41N
2O
5(M+H)
+, 485.3010; Found, 485.3016;
1H NMR (CDCl
3, 300Hz) δ: 7.01 (1H, s), 6.98 (1H, d, J=8.5Hz), 6.50 (1H, d, J=8.5Hz), 6.45 (1H, d, J=1.8Hz), 6.18 (1H, d, J=1.8Hz), 4.833 (2H, s), 3.88 (3H, s), 3.69 (3H, s), 3.59 (2H, t, J=6.0Hz), 2.60 (2H, t, J=6.0Hz), 2.26 (3H, s), 1.91 (4H, q, J=7.3Hz), 1.26 (9H, s), 0.65 (6H, t, J=7.3Hz).
Embodiment 7
3-(5-(1-ethyl-1-(4-(2-hydroxyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-picoline-2-formamido-)-propyl alcohol (sw-6)
The same sw-2 of preparation method changes sw-1 into sw-5.
White solid, yield: 98.6%.Fusing point: 80-81 ℃; HRMS, ESI
+, m/z:Calcd for C
27H
43N
2O
4(M+H)
+, 459.3217; Found, 459.3223;
1H NMR (CDCl
3, 300Hz) δ: 7.00 (1H, s), 7.01 (1H, d, J=8.3Hz), 6.70 (1H, d, J=8.3Hz), 6.50 (1H, d, J=1.4Hz), 6.19 (1H, d, J=1.4Hz), 4.11 (2H, m), 3.88 (3H, s), 3.70 (1H, m), 3.63 (2H, m), 3.48 (2H, m), 2.19 (3H, s), 1.93 (4H, q, J=7.2Hz), 1.70 (2H, m), 1.00 (9H, s), 0.65 (6H, t, J=7.2Hz).
Embodiment 8
3-(5-(1-ethyl-1-(4-(2-carbonyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-picoline-2-formamido-)-propionic acid (sw-7)
The same sw-3 of preparation method changes sw-1 into sw-5.
Faint yellow solid, yield 80.5%.Fusing point: 124-126 ℃; HRMS, ESI
+, m/z:Calcd for C
27H
39N
2O
5(M+H)
+, 471.2853; Found, 471.2859;
1H NMR (CDCl
3, 300Hz) δ: 6.98 (1H, s), 6.93 (1H, d, J=8.5Hz), 6.45 (1H, d, J=8.5Hz), 6.21 (1H, d, J=1.4Hz), 6.04 (1H, d, J=1.4Hz), 4.81 (2H, s), 3.78 (3H, s), 3.45 (2H, t, J=5.9Hz), 2.41 (2H, t, J=5.9Hz), 2.20 (3H, s), 1.87 (4H, q, J=7.2Hz), 1.23 (9H, s), 0.60 (6H, t, J=7.2Hz).
Embodiment 9
3-(5-(1-ethyl-1-(4-(2-hydroxyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-picoline-2-formamido-)-propionic acid (sw-8)
The same sw-4 of preparation method changes sw-3 into sw-7.
Faint yellow solid g, yield: 82.9%.Fusing point: 158-160 ℃; HRMS, ESI
+, m/z:Calcd for C
27H
41N
2O
5(M+H)
+, 473.3010; Found, 473.3014;
1H NMR (CDCl
3, 300Hz) δ: 6.92 (1H, s), 6.93 (1H, d, J=8.1Hz), 6.80 (1H, d, J=1.3Hz), 6.63 (1H, d, J=8.1Hz), 6.25 (1H, d, J=1.3Hz), 4.01 (2H, m), 3.81 (1H, m), 3.61 (3H, s), 3.27 (2H, t, J=5.6Hz), 2.21 (2H, t, J=5.6Hz), 2.09 (3H, s), 1.83 (4H, q, J=6.9Hz), 0.94 (9H, s), 0.57 (6H, t, J=6.9Hz).
Embodiment 10
(S)-2-(5-(1-ethyl-1-(4-(2-carbonyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-picoline-2-formamido-)-methyl propionate (sw-9)
The same sw-1 of preparation method changes glycine methyl ester hydrochloride into L-alanine methyl ester hydrochloride.
White solid, yield 89.7%.Fusing point: 92-93 ℃; HRMS, ESI
+, m/z:Calcd for C
28H
41N
2O
5(M+H)
+, 485.3010; Found, 485.3019;
1H NMR (500MHz, CDCl
3) δ: 7.02 (1H, s), 6.98 (1H, d, J=8.6Hz), 6.51 (1H, d, J=8.6Hz), 6.48 (1H, d, J=1.8Hz), 6.28 (1H, d, J=1.8Hz), 4.84 (2H, s), 4.66 (1H, m), 3.87 (3H, s), 3.75 (3H, s), 2.26 (3H, s), 1.92 (4H, q, J=6.5Hz), 1.44 (3H, d, J=7.2Hz), 1.25 (9H, s), 0.65 (6H, t, J=6.5Hz).
Embodiment 11
(S)-2-(5-(1-ethyl-1-(4-(2-hydroxyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-picoline-2-formamido-)-propyl alcohol (sw-10)
The same sw-2 of preparation method changes sw-1 into sw-9.
White solid g, yield: 95.0%.Fusing point: 88-89 ℃; HRMS, ESI
+, m/z:Calcd for C
27H
43N
2O
4(M+H)
+, 459.3217; Found, 459.3223;
1H NMR (300MHz, CDCl
3) δ: 7.02 (1H, s), 7.02 (1H, d, J=9.7Hz), 6.71 (1H, d, J=9.7Hz), 6.51 (1H, d, J=1.5Hz), 6.20 (1H, d, J=1.5Hz), 4.10 (2H, m), 3.86 (2H, m), 3.83 (1H, s), 3.69 (1H, m), 3.54 (1H, m), 2.19 (1H, s), 1.92 (4H, q, J=7.2Hz), 1.20 (3H, d, J=6.9Hz), 1.01 (9H, s), 0.65 (6H, t, J=7.2Hz).
Embodiment 12
(S)-2-(5-(1-ethyl-1-(4-(2-carbonyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-picoline-2-formamido-)-propionic acid (sw-11)
The same sw-3 of preparation method changes sw-1 into sw-9.
Faint yellow solid, yield: 84.7%.Fusing point: 148-150 ℃; HRMS, ESI
+, m/z:Calcd for C
27H
39N
2O
5(M+H)
+, 471.2853; Found, 471.2860;
1H NMR (300MHz, CDCl
3) δ: 6.93 (1H, s), 6.90 (1H, d, J=8.9Hz), 6.42 (1H, d, J=2.0Hz), 6.21 (1H, d, J=2.0Hz), 6.20 (1H, d, J=8.9Hz), 4.78 (2H, s), 4.54 (1H, m), 3.79 (3H, s), 2.18 (3H, s), 1.85 (4H, q, J=7.0Hz), 1.42 (3H, d, J=6.8Hz), 1.18 (9H, s), 0.56 (6H, t, J=7.0Hz).
Embodiment 13
(S)-2-(5-(1-ethyl-1-(4-(2-hydroxyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-picoline-2-formamido-)-propionic acid (sw-12)
The same sw-4 of preparation method changes sw-3 into sw-11.
Faint yellow solid, yield: 86.9%.Fusing point: 92-93 ℃; HRMS, ESI
+, m/z:Calcd for C
27H
41N
2O
5(M+H)
+, 473.3010; Found, 473.3016;
1H NMR (300MHz, CDCl
3) δ: 6.93 (1H, s), 6.64 (1H, d, J=8.2Hz), 6.44 (1H, d, J=1.8Hz), 6.22 (1H, d, J=1.8Hz), 6.16 (1H, d, J=8.2Hz), 4.55 (1H, m), 4.04 (1H, m), 3.80 (3H, s), 3.77 (1H, m), 3.65 (1H, m), 2.10 (3H, s), 1.85 (4H, q, J=6.8Hz), 1.41 (3H, d, J=7.0Hz), 0.94 (9H, s), 0.58 (6H, t, J=6.8Hz).
Embodiment 14
2-(5-(1-ethyl-1-(4-(2-carbonyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-ethylpyridine-2-formamido-)-methyl acetate (sw-13)
The same sw-1 of preparation method changes 10a into 10b.
White oily matter, yield: 80.5%.HRMS，ESI
+，m/z：Calcd?for?C
28H
41N
2O
5(M+H)+，485.3010；found，485.3016；
1H?NMR(300MHz，CDCl
3)δ：7.01(1H，s)，6.97(1H，d，J＝8.5Hz)，6.57(1H，d，J＝1.4Hz)，6.51(1H，d，J＝8.5Hz)，6.28(1H，d，J＝1.4Hz)，4.84(2H，s)，4.32(2H，q，J＝7.1Hz)，4.10(2H，d，J＝5.3Hz)，3.76(3H，s)，2.26(3H，s)，1.92(4H，q，J＝7.3Hz)，1.36(3H，t，J＝7.1Hz)，1.26(9H，s)，0.64(6H，t，J＝7.3Hz)。
Embodiment 15
2-(5-(1-ethyl-1-(4-(2-hydroxyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-ethylpyridine-2-formamido-)-ethanol (sw-14)
The same sw-2 of preparation method changes sw-1 into sw-13.
White solid, yield: 97.0%.Fusing point: 81-82 ℃; HRMS, ESI
+, m/z:Calcd for C
27H
43N
2O
4(M+H)
+, 459.3217; Found, 459.3217;
1H NMR (300MHz, CDCl3) δ: 7.03 (1H, d, J=8.3Hz), 7.00 (1H, s), 6.71 (1H, d, J=8.3Hz), 6.58 (1H, d, J=1.8Hz), 6.20 (1H, d, J=1.8Hz), 4.31 (2H, q, J=7.1Hz), 4.08 (1H, m), 3.86 (1H, m), 3.74 (1H, m), 3.70 (2H, m), 3.47 (2H, m), 2.04 (3H, s), 1.92 (4H, q, J=7.2Hz), 1.36 (3H, t, J=7.1Hz), 1.01 (9H, s), 0.64 (6H, t, J=7.2Hz).
Embodiment 16
2-(5-(1-ethyl-1-(4-(2-carbonyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-ethylpyridine-2-formamido-)-acetic acid (sw-15)
The same sw-3 of preparation method changes sw-1 into sw-13.
Faint yellow solid, yield: 82.2%.Fusing point: 104-106 ℃; HRMS, ESI
+, m/z:Calcd for C
27H
39N
2O
5(M+H)
+, 471.2853; Found, 471.2853;
1H NMR (300MHz, CDCl
3) δ: 6.92 (1H, s), 6.88 (1H, d, J=8.5Hz), 6.52 (1H, d, J=1.9Hz), 6.41 (1H, d, J=8.5Hz), 6.23 (1H, d, J=1.9Hz), 4.77 (2H, s), 4.21 (2H, q, J=7.1Hz), 4.00 (2H, m), 2.17 (3H, s), 1.83 (4H, q, J=7.3Hz), 1.27 (3H, t, J=7.1Hz), 1.17 (9H, s), 0.56 (6H, t, J=7.3Hz).
Embodiment 17
2-(5-(1-ethyl-1-(4-(2-hydroxyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-ethylpyridine-2-formamido-)-acetic acid (sw-16)
The same sw-4 of preparation method changes sw-3 into sw-15.
Faint yellow solid, yield: 83.9%.Fusing point: 160-162 ℃; HRMS, ESI
+, m/z:Calcd for C
27H
41N
2O
5(M+H)
+, 473.3010; Found, 473.3017;
1H NMR (300MHz, CDCl
3) δ: 7.02 (1H, d, J=8.4Hz), 6.94 (1H, s), 6.53 (1H, d, J=8.4Hz), 6.38 (1H, d, J=1.3Hz), 6.33 (1H, d, J=1.3Hz), 4.13 (2H, m), 4.01 (2H, m), 3.82 (2H, q, J=6.9Hz), 3.63 (1H, m), 2.11 (3H, s), 1.85 (4H, q, J=6.3Hz), 1.16 (3H, t, J=6.9Hz), 0.96 (9H, s), 0.57 (6H, t, J=6.3Hz).
Embodiment 18
3-(5-(1-ethyl-1-(4-(2-carbonyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-ethylpyridine-2-formamido-)-methyl propionate (sw-17)
The same sw-1 of preparation method changes 10a into 10b, and glycine methyl ester hydrochloride changes the Beta-alanine methyl ester hydrochloride into.
White oily matter, yield: 86.5%.HRMS，ESI
+，m/z：Calcd?for?C
29H
43N
2O
5(M+H)
+，499.3166；found，499.3175；
1H?NMR(CDCl
3，300Hz)δ：7.01(1H，s)，6.97(1H，d，J＝8.5Hz)，6.54(1H，d，J＝1.9Hz)，6.51(1H，d，J＝8.5Hz)，6.17(1H，d，J＝1.9Hz)，4.84(2H，s)，4.31(2H，q，J＝7.1Hz)，3.68(3H，s)，3.60(2H，t，J＝6.1Hz)，2.60(2H，t，J＝6.1Hz)，2.26(3H，s)，1.90(4H，q，J＝7.3Hz)，1.36(3H，t，J＝7.1Hz)，1.26(9H，s)，0.64(6H，t，J＝7.3Hz)。
Embodiment 19
3-(5-(1-ethyl-1-(4-(2-hydroxyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-ethylpyridine-2-formamido-)-propyl alcohol (sw-18)
The same sw-2 of preparation method changes sw-1 into sw-17.
White solid, yield: 92.9%.Fusing point: 104-106 ℃; HRMS, ESI
+, m/z:Calcd for C
28H
45N
2O
4(M+H)
+, 473.3374; Found, 473.3379;
1H NMR (CDCl
3, 300Hz) δ: 7.01 (1H, s), 7.02 (1H, d, J=8.2Hz), 6.71 (1H, d, J=8.2Hz), 6.58 (1H, d, J=1.5Hz), 6.17 (1H, d, J=1.5Hz), 4.32 (2H, q, J=6.9Hz), 4.11 (1H, m), 3.86 (1H, m), 3.70 (1H, m), 3.63 (2H, t, J=5.6Hz), 3.47 (2H, t, J=5.7Hz), 2.20 (3H, s), 1.94 (4H, q, J=7.1Hz), 1.68 (2H, m), 1.36 (3H, t, J=6.9Hz), 1.00 (9H, s), 0.65 (6H, t, J=7.1Hz).
Embodiment 20
3-(5-(1-ethyl-1-(4-(2-carbonyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-ethylpyridine-2-formamido-)-propionic acid (sw-19)
The same sw-3 of preparation method changes sw-1 into sw-17.
Faint yellow solid, yield: 89.1%.Fusing point: 90-91 ℃; HRMS, ESI
+, m/z:Calcd for C
28H
41N
2O
5(M+H)
+, 485.3010; Found, 485.3010;
1H NMR (CDCl
3, 300Hz) δ: 6.93 (1H, s), 6.89 (1H, d, J=8.5Hz), 6.49 (1H, d, J=1.9Hz), 6.40 (1H, d, J=8.5Hz), 6.11 (1H, d, J=1.9Hz), 4.77 (2H, s), 4.23 (2H, q, J=7.1Hz), 3.60 (2H, t, J=5.6Hz), 2.53 (2H, t, J=5.6Hz), 2.16 (3H, s), 1.82 (4H, q, J=7.1Hz), 1.28 (3H, t, J=7.1Hz), 1.17 (9H, s), 0.56 (6H, t, J=7.1Hz).
Embodiment 21
3-(5-(1-ethyl-1-(4-(2-hydroxyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-ethylpyridine-2-formamido-)-propionic acid (sw-20)
The same sw-4 of preparation method changes sw-3 into sw-19.
Faint yellow solid, yield: 85.4%.Fusing point: 163-166 ℃; HRMS, ESI
+, m/z:Calcd for C
28H
43N
2O
5(M+H)
+, 487.3166; Found, 487.3175;
1H NMR (CDCl
3, 300Hz) δ: 6.94 (1H, s), 6.95 (1H, d, J=8.4Hz), 6.65 (1H, d, J=8.4Hz), 6.40 (1H, d, J=1.9Hz) 6.20 (1H, d, J=1.9Hz), 4.12 (2H, q, J=6.9Hz), 4.02 (1H, m), 3.86 (1H, m), 3.65 (1H, m), 3.29 (2H, t, J=5.5Hz), 2.22 (2H, t, J=5.5Hz), 2.11 (3H, s), 1.85 (4H, q, J=6.6Hz), 1.19 (3H, t, J=6.9Hz), 0.96 (9H, s), 0.58 (6H, t, J=6.6Hz).
Embodiment 22
(S)-2-(5-(1-ethyl-1-(4-(2-carbonyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-ethylpyridine-2-formamido-)-methyl propionate (sw-21)
The same sw-1 of preparation method changes 10a into 10b, and glycine methyl ester hydrochloride changes L-alanine methyl ester hydrochloride into.
White solid, yield: 80.3%.Fusing point: 92-93 ℃; HRMS, ESI
+, m/z:Calcd for C
29H
43N
2O
5(M+H)
+, 499.3166; Found, 499.3175;
1H NMR (300MHz, CDCl
3) δ: 7.02 (1H, s), 6.97 (1H, d, J=8.7Hz), 6.56 (1H, d, J=1.5Hz), 6.51 (1H, d, J=8.7Hz), 6.26 (1H, d, J=1.5Hz), 4.85 (2H, s), 4.66 (1H, m), 4.29 (2H, q, J=6.9Hz), 3.75 (1H, s), 2.27 (3H, s), 1.90 (4H, q, J=7.2Hz), 1.45 (3H, d, J=7.2Hz), 1.35 (3H, t, J=6.9Hz), 1.26 (9H, s), 0.64 (6H, t, J=7.2Hz).
Embodiment 23
(S)-2-(5-(1-ethyl-1-(4-(2-hydroxyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-ethylpyridine-2-formamido-)-propyl alcohol (sw-22)
The same sw-2 of preparation method changes sw-1 into sw-21.
White solid, yield: 94.1%.Fusing point: 89-90 ℃; HRMS, ESI
+, m/z:Calcd for C
28H
45N
2O
4(M+H)
+, 473.3374; Found, 499.3388;
1H NMR (300MHz, CDCl
3) δ: 7.01 (1H, s), 7.02 (1H, d, J=8.1Hz), 6.72 (1H, d, J=8.1Hz), 6.58 (1H, d, J=1.5Hz), 6.18 (1H, d, J=1.5Hz), 4.31 (2H, q, J=7.1Hz), 4.11 (2H, m), 3.85 (1H, m), 3.70 (2H, m), 3.56 (1H, m), 2.20 (3H, s), 1.92 (4H, q, J=7.2Hz), 1.36 (3H, t, J=7.1Hz), 1.20 (3H, d, J=6.8Hz), 1.01 (9H, s), 0.65 (6H, t, J=7.2Hz).
Embodiment 24
(S)-2-(5-(1-ethyl-1-(4-(2-carbonyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-ethylpyridine-2-formamido-)-propionic acid (sw-23)
The same sw-3 of preparation method changes sw-1 into sw-21.
Faint yellow solid, yield: 82.5%.Fusing point: 114-117 ℃; HRMS, ESI
+, m/z:Calcd for C
28H
41N
2O
5(M+H)
+, 485.3010; Found, 485.3020;
1H NMR (300MHz, CDCl
3) δ: 6.93 (1H, s), 6.90 (1H, d, J=8.4Hz), 6.54 (1H, d, J=1.9Hz), 6.43 (1H, d, J=8.4Hz), 6.20 (1H, d, J=1.9Hz), 4.78 (2H, s), 4.53 (1H, m), 4.23 (2H, q, J=7.1Hz), 2.19 (3H, s), 1.84 (4H, q, J=7.0Hz), 1.43 (3H, d, J=7.1Hz), 1.29 (3H, t, J=7.1Hz), 1.19 (9H, s), 0.57 (6H, t, J=7.0Hz).
Embodiment 25
(S)-2-(5-(1-ethyl-1-(4-(2-hydroxyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-ethylpyridine-2-formamido-)-propionic acid (sw-24)
The same sw-4 of preparation method changes sw-3 into sw-23.
Faint yellow solid, yield: 87.8%.Fusing point: 110-111 ℃; HRMS, ESI
+, m/z:Calcd for C
28H
43N
2O
5(M+H)
+, 487.3166; Found, 487.3179;
1H NMR (300MHz, CDCl
3) δ: 7.02 (1H, d, J=8.1Hz), 7.01 (1H, s), 6.72 (1H, d, J=8.1Hz), 6.61 (1H, d, J=1.3Hz), 6.27 (1H, d, J=1.3Hz), 4.61 (1H, m), 4.31 (2H, m), 4.09 (2H, q, J=7.2Hz), 3.73 (1H, m), 2.20 (3H, s), 1.92 (4H, q, J=6.9Hz), 1.49 (3H, d, J=6.9Hz), 1.36 (3H, t, J=7.2Hz), 1.01 (9H, s), 0.65 (6H, t, J=6.9Hz).
Embodiment 26
(R)-2-(5-(1-ethyl-1-(4-(2-carbonyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-picoline-2-formamido-)-methyl propionate (sw-25)
The same sw-1 of preparation method changes glycine methyl ester hydrochloride into D-alanine methyl ester hydrochloride.
White solid, yield: 84.6%.Fusing point: 123-124 ℃; HRMS, ESI
+, m/z:Calcd for C
29H
43N
2O
5(M+H)
+, 499.3166; Found, 499.3160;
1H NMR (300MHz, CDCl
3) δ: 7.01 (1H, s), 6.98 (1H, d, J=8.6Hz), 6.52 (1H, d, J=8.6Hz), 6.48 (1H, d, J=1.8Hz), 6.27 (1H, d, J=1.8Hz), 4.85 (2H, s), 4.65 (1H, m), 3.87 (3H, s), 3.76 (3H, s), 2.26 (3H, s), 1.89 (4H, q, J=7.2Hz), 1.45 (3H, d, J=7.2Hz), 1.26 (9H, s), 0.64 (6H, t, J=7.2Hz).
Embodiment 27
(R)-2-(5-(1-ethyl-1-(4-(2-hydroxyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-picoline-2-formamido-)-propyl alcohol (sw-26)
The same sw-2 of preparation method changes sw-1 into sw-25.
White solid, yield: 89.2%.Fusing point: 89-92 ℃; HRMS, ESI
+, m/z:Calcd for C
28H
45N
2O
4(M+H)
+, 473.3374; Found, 473.3365;
1H NMR (300MHz, CDCl
3) δ: 7.02 (1H, d, J=8.4Hz), 7.00 (1H, s), 6.72 (1H, d, J=8.4Hz), 6.50 (1H, d, J=1.8Hz), 6.19 (1H, d, J=1.8Hz), 4.09 (2H, m), 3.87 (3H, s), 3.85 (1H, m), 3.68 (2H, m), 3.56 (1H, m), 2.20 (3H, s), 1.92 (4H, q, J=7.2Hz), 1.20 (3H, d, J=6.8Hz), 1.01 (9H, s), 0.65 (6H, t, J=7.2Hz).
Embodiment 28
(R)-2-(5-(1-ethyl-1-(4-(2-carbonyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-picoline-2-formamido-)-propionic acid (sw-27)
The same sw-3 of preparation method changes sw-1 into sw-25.
Faint yellow solid, yield: 82.7%.Fusing point: 120-122 ℃; HRMS, ESI
+, m/z:Calcd for C
28H
41N
2O
5(M+H)
+, 485.3010; Found, 485.3007;
1H NMR (300MHz, CDCl
3) δ: 6.95 (1H, s), 6.91 (1H, d, J=8.2Hz), 6.45 (1H, d, J=8.2Hz), 6.34 (1H, d, J=1.7Hz), 6.27 (1H, d, J=1.7Hz), 4.78 (2H, s), 4.12 (1H, m), 3.63 (3H, s), 2.19 (3H, s), 1.83 (4H, q, J=7.2Hz), 1.23 (9H, s), 1.14 (3H, d, J=6.9Hz), 0.57 (6H, t, J=7.2Hz).
Embodiment 29
(R)-2-(5-(1-ethyl-1-(4-(2-hydroxyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-picoline-2-formamido-)-propionic acid (sw-28)
The same sw-4 of preparation method changes sw-3 into sw-27.
Faint yellow solid, yield: 85.5%.Fusing point: 136-137 ℃; HRMS, ESI
+, m/z:Calcd for C
28H
43N
2O
5(M+H)
+, 487.3166; Found, 487.3167;
1H NMR (300MHz, CDCl
3) δ: 6.97 (1H, d, J=8.4Hz), 6.96 (1H, s), 6.65 (1H, d, J=8.4Hz), 6.63 (1H, d, J=1.8Hz), 6.30 (1H, d, J=1.8Hz), 4.32 (1H, m), 4.02 (2H, m), 3.83 (1H, m), 3.65 (3H, s), 2.14 (3H, s), 1.72 (4H, q, J=6.8Hz), 1.10 (3H, d, J=5.6Hz), 0.99 (9H, s), 0.60 (6H, t, J=6.8Hz).
Embodiment 30
(S)-1-(5-(1-ethyl-1-(4-(2-carbonyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-picoline-2-carbonyl)-tetramethyleneimine-2-carboxylate methyl ester (sw-29)
The same sw-1 of preparation method changes glycine methyl ester hydrochloride into the L-proline methyl ester hydrochloride.
White solid, yield: 86.3%.Fusing point: 62-64 ℃; HRMS, ESI
+, m/z:Calcd for C
30H
43N
2O
5(M+H)
+, 511.3166; Found, 511.3178;
1H NMR (300MHz, CDCl
3) δ: 7.01 (1H, s), 6.97 (1H, d, J=8.5Hz), 6.50 (1H, d, J=8.5Hz), 6.44 (1H, d, J=2.0Hz), 6.26 (1H, d, J=2.0Hz), 4.84 (2H, s), 4.12 (1H, m), 3.79 (3H, s), 3.75 (2H, m), 3.74 (3H, s), 2.32 (4H, q, J=7.2Hz), 1.98 (4H, m), 2.05 (3H, s), 1.26 (9H, s), 0.65 (6H, t, J=7.2Hz).
Embodiment 31
(S)-1-(5-(1-ethyl-1-(4-(2-hydroxyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-picoline-2-carbonyl)-tetramethyleneimine-2-methyl alcohol (sw-30)
The same sw-2 of preparation method changes sw-1 into sw-29.
White solid, yield: 88.7%.Fusing point: 70-71 ℃; HRMS, ESI
+, m/z:Calcd for C
29H
45N
2O
4(M+H)
+, 485.3374; Found, 485.3368;
1H NMR (300MHz, CDCl
3) δ: 6.98 (1H, d, J=8.2Hz), 6.97 (1H, s), 6.67 (1H, d, J=8.2Hz), 6.44 (1H, d, J=1.3Hz), 6.18 (1H, d, J=1.3Hz), 4.38 (1H, m), 4.06 (1H, m), 3.86 (2H, m), 3.69 (1H, m), 3.66 (2H, m), 3.76 (3H, s), 2.16 (3H, s), 1.89 (4H, q, J=7.1Hz), 1.85 (1H, m), 1.75 (1H, m), 1.55 (1H, m), 1.22 (1H, m), 0.96 (9H, s), 0.63 (6H, t, J=7.1Hz).
Embodiment 32
(S)-1-(5-(1-ethyl-1-(4-(2-carbonyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-picoline-2-carbonyl)-tetramethyleneimine-2-carboxylic acid (sw-31)
The same sw-3 of preparation method changes sw-1 into sw-29.
Faint yellow solid, yield: 85.6%.Fusing point: 87-88 ℃; HRMS, ESI
+, m/z:Calcd for C
29H
41N
2O
5(M+H)
+, 497.3010; Found, 497.2998;
1H NMR (300MHz, CDCl
3) δ: 6.93 (1H, s), 6.90 (1H, d, J=2.3Hz), 6.50 (1H, d, J=2.3Hz), 6.44 (1H, d, J=8.5Hz), 6.28 (1H, d, J=8.5Hz), 4.81 (2H, s), 4.65 (1H, m), 3.80 (3H, s), 3.66 (2H, m), 1.93 (4H, m), 2.21 (3H, s), 1.86 (4H, q, J=7.2Hz), 1.21 (9H, s), 0.62 (6H, t, J=7.2Hz).
Embodiment 33
(S)-1-(5-(1-ethyl-1-(4-(2-hydroxyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-picoline-2-carbonyl)-tetramethyleneimine-2-carboxylic acid (sw-32)
The same sw-4 of preparation method changes sw-3 into sw-31.
Faint yellow solid, yield: 81.0%.Fusing point: 108-109 ℃; HRMS, ESI
+, m/z:Calcd for C
29H
43N
2O
5(M+H)
+, 499.3166; Found, 499.3155;
1H NMR (300MHz, CDCl
3) δ: 7.03 (1H, d, J=8.3Hz), 7.00 (1H, s), 6.69 (1H, d, J=8.3Hz), 6.27 (1H, d, J=2.2Hz), 6.25 (1H, d, J=2.2Hz), 4.31 (1H, m), 4.10 (1H, m), 3.86 (1H, m), 3.71 (2H, m), 3.57 (3H, s), 1.85 (4H, q, J=6.9Hz), 1.80 (2H, m), 1.64 (2H, m), 2.18 (3H, s), 0.98 (9H, s), 0.65 (6H, t, J=6.9Hz).
Embodiment 34
(S)-2-(5-(1-ethyl-1-(4-(2-carbonyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-picoline-2-formamido-)-dimethyl succinate (sw-33)
The same sw-1 of preparation method changes glycine methyl ester hydrochloride into L-aspartic acid dimethyl ester hydrochloride.
White solid, yield: 84.3%.Fusing point: 57-58 ℃; HRMS, ESI
+, m/z:Calcd for C
30H
43N
2O
7(M+H)
+, 543.3065; Found, 543.3078;
1H NMR (300MHz, CDCl
3) δ: 7.01 (1H, s), 6.98 (1H, d, J=8.7Hz), 6.68 (1H, d, J=8.7Hz), 6.47 (1H, d, J=1.2Hz), 6.32 (1H, d, J=1.2Hz), 4.84 (2H, s), 4.12 (1H, m), 3.86 (3H, s), 3.77 (3H, s), 3.69 (3H, s), 3.07 (1H, m), 2.91 (1H, m), 2.32 (3H, s), 1.92 (4H, q, J=7.0Hz), 1.26 (9H, s), 0.65 (6H, t, J=7.0Hz).
Embodiment 35
(S)-2-(5-(1-ethyl-1-(4-(2-hydroxyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-picoline-2-formamido-)-butyleneglycol (sw-34)
The same sw-2 of preparation method changes sw-1 into sw-33.
White solid, yield: 90.2%.Fusing point: 80-82 ℃; HRMS, ESI
+, m/z:Calcd for C
28H
45N
2O
5(M+H)
+, 489.3323; Found, 489.3316;
1H NMR (300MHz, CDCl
3) δ: 6.94 (1H, d, J=8.6Hz), 6.93 (1H, s), 6.63 (1H, d, J=8.6Hz), 6.44 (1H, d, J=1.3Hz), 6.20 (1H, d, J=1.3Hz), 4.11 (1H, m), 4.02 (1H, m), 3.78 (3H, s), 3.75 (1H, m), 3.62 (2H, m), 3.59 (2H, m), 3.56 (1H, m), 2.11 (3H, s), 1.85 (4H, q, J=7.1Hz), 1.55 (2H, m), 0.93 (9H, s), 0.57 (6H, t, J=7.1Hz).
Embodiment 36
(S)-2-(5-(1-ethyl-1-(4-(2-carbonyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-picoline-2-formamido-)-Succinic Acid (sw-35)
The same sw-3 of preparation method changes sw-1 into sw-33.
Faint yellow solid, yield: 87.1%.Fusing point: 92-94 ℃; HRMS, ESI
+, m/z:Calcd for C
28H
39N
2O
7(M+H)
+, 515.2752; Found, 515.2740;
1H NMR (300MHz, CDCl
3) δ: 6.93 (1H, s), 6.81 (1H, d, J=2.3Hz), 6.73 (1H, d, J=2.3Hz), 6.42 (1H, d, J=8.5Hz), 6.29 (1H, d, J=8.5Hz), 4.89 (1H, m), 4.78 (2H, s), 3.75 (3H, s), 2.98 (1H, m), 2.87 (1H, m), 2.16 (3H, s), 1.84 (4H, q, J=7.2Hz), 1.17 (9H, s), 0.56 (6H, t, J=7.2Hz).
Embodiment 37
(S)-2-(5-(1-ethyl-1-(4-(2-hydroxyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-picoline-2-formamido-)-Succinic Acid (sw-36)
The same sw-4 of preparation method changes sw-3 into sw-35.
Faint yellow solid, yield: 82.3%.Mp：223-225℃；HRMS，ESI
+，m/z：Calcd?for?C
28H
41N
2O
7(M+H)
+，517.2908；found，517.2903；
1H?NMR(300MHz，CDCL
3)δ：7.00(1H，d，J＝7.9Hz)，6.97(1H，s)，6.79(1H，d，J＝7.9Hz)，6.67(1H，d，J＝2.2Hz)，6.38(1H，d，J＝2.2Hz)，4.81(1H，m)，4.29(1H，m)，4.02(1H，m)，3.77(3H，s)，3.45(1H，m)，2.50(1H，m)，2.39(1H，m)，2.12(3H，s)，1.89(4H，q，J＝6.9Hz)，0.92(9H，s)，0.59(6H，t，J＝6.9Hz)。
Embodiment 38
(R)-2-(5-(1-ethyl-1-(4-(2-carbonyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-ethylpyridine-2-formamido-)-methyl propionate (sw-37)
The same sw-1 of preparation method changes 10a into 10b, and glycine methyl ester hydrochloride changes D-alanine methyl ester hydrochloride into.
White solid, yield: 85.1%.Fusing point: 62-63 ℃; HRMS, ESI
+, m/z:Calcd for C
29H
43N
2O
5(M+H)
+, 499.3166; Found, 499.3160;
1H NMR (300MHz, CDCl
3) δ: 7.02 (1H, s), 6.97 (1H, d, J=8.5Hz), 6.56 (1H, d, J=8.5Hz), 6.51 (1H, d, J=1.8Hz), 6.26 (1H, d, J=1.8Hz), 4.85 (2H, s), 4.65 (1H, m), 4.30 (2H, q, J=7.1Hz), 3.75 (3H, s), 2.27 (3H, s), 1.92 (4H, q, J=7.0Hz), 1.45 (3H, d, J=7.2Hz), 1.35 (3H, t, J=7.1Hz), 1.26 (9H, s), 0.64 (6H, t, J=7.0Hz).
Embodiment 39
(R)-2-(5-(1-ethyl-1-(4-(2-hydroxyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-ethylpyridine-2-formamido-)-propyl alcohol (sw-38)
The same sw-2 of preparation method changes sw-1 into sw-37.
White solid, yield: 95.6%.Fusing point: 64-67 ℃; HRMS, ESI
+, m/z:Calcd for C
28H
45N
2O
4(M+H)
+, 473.3374; Found, 473.3365;
1H NMR (300MHz, CDCl
3) δ: 6.96 (1H, d, J=8.1Hz), 6.94 (1H, s), 6.63 (1H, d, J=8.1Hz), 6.52 (1H, d, J=1.7Hz), 6.12 (1H, d, J=1.7Hz), 4.24 (2H, m), 4.02 (2H, m), 3.79 (1H, m), 3.62 (2H, q, J=7.0Hz), 3.48 (1H, m), 2.13 (3H, s), 1.84 (4H, q, J=7.2Hz), 1.29 (3H, t, J=7.0Hz), 1.12 (3H, d, J=6.8Hz), 0.94 (9H, s), 0.57 (6H, t, J=7.2Hz).
Embodiment 40
(R)-2-(5-(1-ethyl-1-(4-(2-carbonyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-ethylpyridine-2-formamido-)-propionic acid (sw-39)
The same sw-3 of preparation method changes sw-1 into sw-37.
Faint yellow solid, yield: 81.5%.Fusing point: 82-84 ℃; HRMS, ESI
+, m/z:Calcd for C
28H
41N
2O
5(M+H)
+, 485.3010; Found, 485.3007;
1H NMR (300MHz, CDCl
3) δ: 6.93 (1H, s), 6.89 (1H, d, J=8.6Hz), 6.52 (1H, d, J=8.6Hz), 6.43 (1H, d, J=1.9Hz), 6.20 (1H, d, J=1.9Hz), 4.78 (2H, s), 4.52 (1H, m), 4.20 (2H, q, J=7.1Hz), 2.19 (3H, s), 1.82 (4H, q, J=7.2Hz), 1.42 (3H, d, J=7.2Hz), 1.28 (3H, t, J=7.1Hz), 1.18 (9H, s), 0.56 (6H, t, J=7.2Hz).
Embodiment 41
(R)-2-(5-(1-ethyl-1-(4-(2-hydroxyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-ethylpyridine-2-formamido-)-propionic acid (sw-40)
The same sw-4 of preparation method changes sw-3 into sw-39.
Faint yellow solid, yield: 84.1%.Fusing point: 86-87 ℃; HRMS, ESI
+, m/z:Calcd for C
28H
43N
2O
5(M+H)
+, 487.3166; Found, 487.3167;
1H NMR (300MHz, CDCl
3) δ: 7.03 (1H, d, J=8.6Hz), 7.02 (1H, s), 6.72 (1H, d, J=8.6Hz), 6.61 (1H, d, J=1.9Hz), 6.30 (1H, d, J=1.9Hz), 4.64 (1H, m), 4.31 (2H, m), 3.88 (2H, q, J=7.1Hz), 3.74 (1H, m), 2.22 (3H, s), 1.93 (4H, q, J=7.1Hz), 1.49 (3H, d, J=7.2Hz), 1.37 (3H, t, J=7.1Hz), 1.03 (9H, s), 0.66 (6H, t, J=7.1Hz).
Embodiment 42
(S)-1-(5-(1-ethyl-1-(4-(2-carbonyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-ethylpyridine-2-carbonyl)-tetramethyleneimine-2-carboxylate methyl ester (sw-41)
The same sw-1 of preparation method changes 10a into 10b, and glycine methyl ester hydrochloride changes the L-proline methyl ester hydrochloride into.
White oily matter, yield: 80.9%.HRMS，ESI
+，m/z：Calcd?for?C
31H
45N
2O
5(M+H)
+，525.3323；found，525.3330；
1H?NMR(300MHz，CDCl
3)δ：7.02(1H，s)，6.96(1H，d，J＝8.6Hz)，6.51(1H，d，J＝8.6Hz)，6.49(1H，d，J＝2.0Hz)，6.19(1H，d，J＝2.0Hz)，4.84(2H，s)，4.58(1H，m)，4.19(2H，q，J＝6.6Hz)，3.74(2H，m)，3.72(3H，s)，2.25(3H，s)，2.17(1H，m)，1.98(1H，m)，1.92(1H，m)，1.90(4H，q，J＝7.3Hz)，1.88(1H，m)，1.34(3H，t，J＝6.6Hz)，1.25(9H，s)，0.65(6H，t，J＝7.3Hz)。
Embodiment 43
(S)-1-(5-(1-ethyl-1-(4-(2-hydroxyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-ethylpyridine-2-carbonyl)-tetramethyleneimine-2-methyl alcohol (sw-42)
The same sw-2 of preparation method changes sw-1 into sw-41.
White solid, yield: 86.1%.Fusing point: 64-66 ℃; HRMS, ESI
+, m/z:Calcd for C
30H
47N
2O
4(M+H)
+, 499.3530; Found, 499.3532;
1H NMR (300MHz, CDCl
3) δ: 7.02 (1H, d, J=8.2Hz), 7.01 (1H, s), 6.72 (1H, d, J=8.2Hz), 6.54 (1H, d, J=1.8Hz), 6.18 (1H, d, J=1.8Hz), 4.40 (1H, m), 4.20 (1H, m), 4.09 (2H, q, J=7.1Hz), 3.85 (2H, m), 3.71 (1H, m), 3.69 (2H, m), 3.53 (1H, m), 2.20 (3H, s), 1.91 (4H, q, J=7.2Hz), 1.78 (1H, m), 1.75 (1H, m), 1.59 (2H, m), 1.35 (3H, t, J=7.1Hz), 1.01 (9H, s), 0.67 (6H, t, J=7.2Hz).
Embodiment 44
(S)-1-(5-(1-ethyl-1-(4-(2-carbonyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-ethylpyridine-2-carbonyl)-tetramethyleneimine-2-carboxylic acid (sw-43)
The same sw-3 of preparation method changes sw-1 into sw-41.
Faint yellow solid, yield: 81.8%.Fusing point: 94-96 ℃; HRMS, ESI
+, m/z:Calcd for C
30H
43N
2O
5(M+H)
+, 511.3166; Found, 511.3165;
1H NMR (300MHz, CDCl
3) δ: 7.00 (1H, s), 6.96 (1H, d, J=8.7Hz), 6.49 (1H, d, J=8.7Hz), 6.34 (1H, d, J=2.3Hz), 6.19 (1H, d, J=2.3Hz), 4.81 (2H, s), 4.65 (1H, m), 3.80 (3H, s), 3.66 (2H, m), 1.93 (4H, m), 2.21 (3H, s), 1.24 (9H, s), 1.13 (3H, t, J=7.0Hz), 0.61 (6H, t, J=6.8Hz).
Embodiment 45
(S)-1-(5-(1-ethyl-1-(4-(2-hydroxyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-ethylpyridine-2-carbonyl)-tetramethyleneimine-2-carboxylic acid (sw-44)
The same sw-4 of preparation method changes sw-3 into sw-43.
Faint yellow solid, yield: 84.2%.Fusing point: 104-105 ℃; HRMS, ESI
+, m/z:Calcd for C
30H
45N
2O
5(M+H)
+, 513.3323; Found, 513.3322;
1H NMR (300MHz, CDCl
3) δ: 7.00 (1H, d, J=8.5Hz), 6.99 (1H, s), 6.68 (1H, d, J=8.5Hz), 6.36 (1H, d, J=1.8Hz), 6.20 (1H, d, J=1.8Hz), 4.29 (1H, m), 4.10 (1H, m), 4.06 (2H, m), 3.84 (2H, q, J=7.0Hz), 3.70 (1H, m), 3.64 (1H, m), 2.16 (3H, s), 1.95 (1H, m), 1.88 (4H, q, J=6.8Hz), 1.89 (2H, m), 1.76 (1H, m), 1.15 (3H, t, J=7.0Hz), 1.00 (9H, s), 0.63 (6H, t, J=6.8Hz).
Embodiment 46
(S)-2-(5-(1-ethyl-1-(4-(2-carbonyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-ethylpyridine-2-formamido-)-dimethyl succinate (sw-45)
The same sw-1 of preparation method changes 10a into 10b, and glycine methyl ester hydrochloride changes L-aspartic acid dimethyl ester hydrochloride into.
White oily matter, yield: 83.4%.HRMS，ESI
+，m/z：Calcd?for?C
31H
45N
2O
7(M+H)
+，557.3221；found，557.3223；
1H?NMR(300MHz，CDCl
3)δ：7.02(1H，s)，6.98(1H，d，J＝8.5Hz)，6.66(1H，d，J＝8.5Hz)，6.54(1H，d，J＝1.8Hz)，6.31(1H，d，J＝1.8Hz)，4.95(1H，m)，4.85(2H，s)，4.28(2H，q，J＝7.1Hz)，3.77(3H，s)，3.68(3H，s)，3.01(2H，m)，2.26(3H，s)，1.92(4H，q，J＝6.9Hz)，1.35(3H，t，J＝7.1Hz)，1.26(9H，s)，0.65(6H，t，J＝6.9Hz)。
Embodiment 47
(S)-2-(5-(1-ethyl-1-(4-(2-hydroxyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-ethylpyridine-2-formamido-)-butyleneglycol (sw-46)
The same sw-2 of preparation method changes sw-1 into sw-45.
White solid, yield: 90.5%.Fusing point: 93-94 ℃; HRMS, ESI
+, m/z:Calcd for C
29H
47N
2O
5(M+H)
+, 503.3479; Found, 503.3483;
1H NMR (300MHz, CDCl
3) δ: 7.02 (1H, d, J=8.9Hz), 7.00 (1H, s), 6.71 (1H, d, J=8.9Hz), 6.58 (1H, d, J=2.0Hz), 6.26 (1H, d, J=2.0Hz), 4.30 (2H, m), 4.07 (2H, q, J=7.0Hz), 3.85 (1H, m), 3.71 (2H, m), 3.67 (1H, m), 3.62 (2H, m), 2.19 (3H, s), 1.92 (4H, q, J=7.2Hz), 1.35 (3H, t, J=7.0Hz), 1.01 (9H, s), 0.65 (6H, t, J=7.2Hz).
Embodiment 48
(S)-2-(5-(1-ethyl-1-(4-(2-carbonyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-ethylpyridine-2-formamido-)-Succinic Acid (sw-47)
The same sw-3 of preparation method changes sw-1 into sw-45.
Faint yellow solid, yield: 81.4%.Fusing point: 252-255 ℃; HRMS, ESI
+, m/z:Calcd for C
29H
41N
2O
7(M+H)
+, 529.2908; Found, 529.2906;
1H NMR (300MHz, CDCl
3) δ: 6.96 (1H, s), 6.95 (1H, d, J=8.4Hz), 6.47 (1H, d, J=8.4Hz), 6.52 (1H, d, J=1.8Hz), 6.30 (1H, d, J=1.8Hz), 4.85 (1H, m), 4.78 (2H, s), 4.24 (2H, q, J=7.1Hz), 2.95 (2H, m), 2.20 (3H, s), 1.92 (4H, q, J=6.8Hz), 1.35 (3H, t, J=7.1Hz), 1.26 (9H, s), 0.65 (6H, t, J=6.8Hz).
Embodiment 49
(S)-2-(5-(1-ethyl-1-(4-(2-hydroxyl-3,3-dimethyl-butyl oxygen base)-3-aminomethyl phenyl)-propyl group)-1-ethylpyridine-2-formamido-)-Succinic Acid (sw-48)
The same sw-4 of preparation method changes sw-3 into sw-47.
Faint yellow solid, yield: 82.0%.Fusing point: 280-284 ℃; HRMS, ESI
+, m/z:Calcd for C
29H
43N
2O
7(M+H)
+, 531.3065; Found, 531.3064;
1H NMR (300MHz, CDCl
3) δ: 6.96 (1H, s), 6.96 (1H, d, J=8.5Hz), 6.79 (1H, d, J=8.5Hz), 6.71 (1H, d, J=1.8Hz), 6.36 (1H, d, J=1.8Hz), 4.75 (1H, m), 4.25 (2H, m), 3.76 (2H, q, J=6.3Hz), 3.45 (1H, m), 2.50 (2H, m), 2.12 (3H, s), 1.90 (4H, q, J=6.0Hz), 1.22 (3H, t, J=6.3Hz), 0.92 (9H, s), 0.58 (6H, t, J=6.0Hz).
Claims (8)
1. the compound of a general formula (I) or its pharmacy acceptable salt:
Wherein: R
1Represent hydrogen or C
1-C
5Alkyl;
R
2Representative
R
3Representative
R
4Represent hydrogen, C
1-C
5Alkyl, C
1-C
5Phenylalkyl,
Or
Said n all represents 0,1 or 2;
R
5Represent hydrogen, C
1-C
5Hydroxyalkyl, C
1-C
5Substituted hydroxy alkyl, C
1-C
5Carboxyalkyl, C
1-C
5Replacement carboxyalkyl, C
1-C
5Methoxycarbonyl alkyl, C
1-C
5Replacement methoxycarbonyl alkyl,
C wherein
1-C
5The substituted hydroxy alkyl in substituting group be C
1-C
5Alkyl or C
1-C
5Hydroxyalkyl; C
1-C
5The replacement carboxyalkyl in substituting group be C
1-C
5Alkyl or C
1-C
5Carboxyalkyl; C
1-C
5The substituted alkoxycarbonyl alkyl in substituting group be C
1-C
5Alkyl or C
1-C
5Alkoxycarbonyl alkyl.
2. the compound of claim 1 or its pharmacy acceptable salt, wherein R
2Represent oxygen.
3. the compound of claim 1 or its pharmacy acceptable salt, wherein R
3Representative
Or
4. the compound of claim 1 or its pharmacy acceptable salt, wherein R
4Representative
Or
5. the compound of claim 1 or its pharmacy acceptable salt, wherein R
5Represent 2-hydroxyethyl, 3-hydroxypropyl, 2 (R)-hydroxypropyl, 2 (S)-hydroxypropyl, 2 (S)-1,4-dihydroxyl butyl, 2-carboxyl base ethyl, 3-carboxyl propyl group, 2 (R)-carboxyl propyl group, 2 (S)-carboxyl propyl group, 2 (S)-1,4-dicarboxyl butyl, 2-methoxycarbonyl ethyl, 3-methoxycarbonyl propyl group, 2 (R)-methoxycarbonyl propyl group, 2 (S)-methoxycarbonyl propyl group, 2 (S)-1,4-dimethoxycarbonyl butyl,
Or
6. pharmaceutical composition wherein contains each compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier in the claim 1 to 5.
7. the compound of each in the claim 1 to 5 or its pharmacy acceptable salt are for the preparation of the purposes of the psoriatic medicine for the treatment of.
8. the compound of each in the claim 1 to 5 or its pharmacy acceptable salt are for the preparation of the purposes of the medicine for the treatment of tumor disease.
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| CN106389433A (en) * | 2016-12-07 | 2017-02-15 | 郑州仁宏医药科技有限公司 | Application of hetrazan in preparing drug for treating psoriasis |
| CN108191733A (en) * | 2018-01-11 | 2018-06-22 | 中国药科大学 | A kind of penta alkyl compound of benzene-pyrroles, preparation method and anti-hepatic fibrosis purposes |
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