CN102887836A - L-phenylglycine derivative and application thereof - Google Patents

L-phenylglycine derivative and application thereof Download PDF

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CN102887836A
CN102887836A CN2011102008377A CN201110200837A CN102887836A CN 102887836 A CN102887836 A CN 102887836A CN 2011102008377 A CN2011102008377 A CN 2011102008377A CN 201110200837 A CN201110200837 A CN 201110200837A CN 102887836 A CN102887836 A CN 102887836A
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CN102887836B (en
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杨大成
晏菊芳
范莉
陈欣
苏小燕
李华冲
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Southwest University
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract

The invention discloses an L-phenylglycine derivative shown in a formula I, wherein in the formula, R1 is an amino-protecting group, R2 is -NO2, -NH2 or -NHCO(CH2)nR4, n=1-8, R4 is hydrogen, halogen, hydroxy, acyloxy, C1-C8 alkoxy, sulfhydryl, substituted sulfhydryl, amino, substituted amino or nitrogen-containing heterocyclic group, R3 is -OR5 or NR6R7, R5 is hydrogen, C1-C8 alkyl or substituted C1-C8 alkyl, R6 and R7 independently are hydrogen, hydroxy, C1-C8 alkyl or substituted C1-C8 alkyl. The L-phenylglycine derivative provided by the invention has certain PPRE agonistic activity, and the relative PPRE agonistic activity of part of the compound reaches to 32.91 to 120.42 %. The L-phenylglycine derivative can be used for preparing a PPRE agonist and also is a good precursor molecule of anti-diabetic drugs.

Description

L-phenylglycine derivatives and application thereof
Technical field
The invention belongs to chemical field, relate to the design of novel L-phenylglycine derivatives, synthetic and anti-diabetic activity research.
Background technology
Diabetes are chronic lifelong participation diseases of a kind of serious threat human health, wherein the diabetic subject more than 90% is diabetes B, its feature main manifestations is that insulin secretion minimizing, insulin resistant and liver glucose increase, and causes the interior carbohydrate metabolism of body to get muddled.Although the medicine of diabetes is a lot, there is certain toxic side effect in most of medicine.Select natural matter cheap and easy to get, adopt relatively simple synthetic method, the antidiabetic thing of preparation novel structure remains challenge chemical and the pharmacy worker.
In recent years, Pharmaceutical Chemist is being obtained remarkable progress aspect the research diabetes B medicine, wherein as the glinides nateglinide (Nateglinide) of non-sulfonylurea Drugs Promoting Insulin Secretion, can reduce early stage level of postprandial blood sugar, the control blood glucose fluctuation has preferably development prospect.Previously studies show that some amino acid itself has the effect of lowering blood glucose, its intensity is followed successively by: arginine＞Methionin＞phenylalanine＞leucine＞Histidine＞Threonine＞tryptophane.Therefore, with amino acid derivedization or change structure, be one of effective ways that obtain stronger anti-diabetic activity molecule.Nateglinide belongs to the D-phenylalanine derivative.Studies show that the blood sugar reducing function of nateglinide is 50 times of D-phenylalanine blood sugar reducing function, but nateglinide belongs to ultrashort effect medicine, need administration every day 3～4 times and therapeutic dose large (60～120mg/ time).Therefore, nateglinide is further transformed, might be obtained than the active better antidiabetic medicine of nateglinide.And phenylglycine and phenylalanine structural similitude, the research of phenylglycine derivatives also might obtain to have the antidiabetic medicine of good hypoglycemic activity.
Summary of the invention
In view of this, one of purpose of the present invention is to provide a kind of L-phenylglycine derivatives, and two of purpose is to provide the application of above-mentioned L-phenylglycine derivatives in pharmacy field.
For achieving the above object, the invention provides following technical scheme:
1. the L-phenylglycine derivatives shown in the formula I:
Figure BDA0000076593340000011
In the formula, R 1Be amino protecting group;
R 2For-NO 2,-NH 2Or-NHCO (CH 2) nR 4, n=1～8, R 4Be hydrogen, halogen, hydroxyl, acyloxy, C1-C8 alkoxyl group, sulfydryl, substituted sulfhydryl, amino, substituted-amino or nitrogen heterocycle;
R 3For-OR 5Or NR 6R 7, R 5Be the C1-C8 alkyl of hydrogen, C1-C8 alkyl or replacement, R 6, R 7Be the C1-C8 alkyl of hydrogen, hydroxyl, C1-C8 alkyl or replacement independently.
Preferably, R 1Be in Z (benzene methoxycarbonyl), Fmoc (9-fluorenylmethyloxycarbonyl), Boc (tertbutyloxycarbonyl) or Ts (4-Methyl benzenesulfonyl base).
Preferred, R 1Be Z.
Preferably, R 2For-NO 2,-NH 2Or-NHCO (CH 2) nR 4, n=1～8, R 4Be hydrogen, halogen, hydroxyl, acyloxy, C1-C8 alkoxyl group, sulfydryl, substituted sulfhydryl, amino, substituted-amino, phthalimide-based, tetrazole-1-base, substituted tetrazole-1-base, pyrazol-1-yl, substituted pyrazolecarboxylic-1-base, benzoglyoxaline-1-base, substituted benzimidazole-1-base, benzotriazole-1-base, replacement benzotriazole-1-base, piperazine-1-base, N-substituted-piperazinyl-1-base, uridylic-1-base or substituted uracil-1-base.
Preferred, R 2For-NO 2,-NH 2Or-NHCOCH 2R 4, R 4Be hydrogen; halogen; hydroxyl; acetoxyl group; the C1-C8 alkoxyl group; sulfydryl; benzimidazolyl-2 radicals-Ji sulfydryl; amino; Fmoc-is amino; Z-is amino; N-methyl-N-ethylamino; the amine sulfonyl-phenyl is amino; phthalimide-based; tetrazole-1-base; 5-methyl tetrazole-1-base; 5-phenyl tetrazole-1-base; 5-methyl mercapto tetrazole-1-base; pyrazol-1-yl; 3，5-dimethylpyrazole-1-base; benzoglyoxaline-1-base; benzotriazole-1-base; N-amino protecting group-piperazine-1-base; N-phenylpiperazine-1-base; uridylic-1-base or methyl uracil-1-base.
Preferred again, R 2For-NO 2Or-NHCOCH 2R 4, R 4Be hydrogen, chlorine, methoxyl group, benzimidazolyl-2 radicals-Ji sulfydryl, 4-[(5-methyl isoxzzole-3-yl) sulfamyl] phenyl amino, phthalimide-based, benzotriazole-1-base or N-Boc-piperazine-1-base.
Most preferred, R 2For-NHCOCH 2R 4, R 4Be chlorine or benzotriazole-1-base.
Preferably, R 3For-OR 5Or NR 6R 7, R 5Be hydrogen, C1-C4 alkyl or benzyloxy, R 6, R 7Be hydrogen, hydroxyl, C1-C4 alkyl or hydroxyethyl independently.
Preferred, R 3For-OH ,-OCH 3Or-N (CH 3) CH 2CH 2OH.
Most preferred, R 3For-OCH 3Or-N (CH 3) CH 2CH 2OH.
2. the application of the L-phenylglycine derivatives shown in the formula I in preparation PPRE agonist.
Beneficial effect of the present invention is: the present invention's design, synthesized the novel L-phenylglycine derivatives of a class, and it has been carried out anti-diabetic activity research, the result shows, although the alpha-glucosidase of this compounds suppresses active and dipeptidyl peptidase-IV (DPP-IV) inhibition activity is all lower, but it has certain PPRE agonist activity, part of compounds (M2-b wherein, 1b, 1e, 2f, 3a, 3b, 3d, 4e, 5a and 5b, (positive control is pioglitazone 10.0 the relative agonist activity of peroxisome proliferation-activated receptors response element (PPRE) μ g/mL) reaches 32.91～120.42%, 0.78 μ g/mL), compound 2f particularly, 1b, 4e reaches more than 88%, can be used for preparing the PPRE agonist.Can effectively reduce the level of Regular Insulin and triacylglycerol in postprandial blood sugar, the blood circulation in view of known PPRE agonist such as pioglitazone, englitazone etc., thereby increase peripheral tissues to the utilization of glucose, improve insulin sensitivity, therefore, L-phenylglycine derivatives of the present invention is antidiabetic medicine guide molecule preferably still, and its development for the antidiabetic thing of high-efficiency low-toxicity is laid a good foundation.
Embodiment
In order to make the purpose, technical solutions and advantages of the present invention clearer, the below is described in detail the preferred embodiments of the present invention.
The raw material L-m-nitro glycine that uses in preferred embodiment system according to literature method (synthesising process research of the .L-m-nitro glycine such as Su Xiaoyan. Southwestern University's journal (natural science edition), 2010,32 (3): 45～49) make; Agents useful for same is commercially available, and purity is analytical pure or chemical pure.The key instrument of Characterization of The Products is as follows in the preferred embodiment: accurate micro melting point apparatus (X-6 type, Fu Kai Instr Ltd.), NMR spectrometer with superconducting magnet (AV-300 type, the U.S.), Fourier transform infrared spectrometer (Spectrum GX type, Perkin Elmer), time-of-flight mass spectrometer (Reflex type, Bruker), and high-resolution mass spectrometer (the Varian7.0T type, Varian).
The preparation of embodiment one, target compound 1
1, the preparation of intermediate M1
M1-a (R 1=Fmoc) and M1-b (R 1Chinese patent application CN 101633626A is seen in=Z) preparation.
M1-c (R 1=Ts) preparation: in the 250mL round-bottomed flask, add SM 50.0mmol and massfraction and be 10% Na 2CO 3Solution stirs and makes dissolving, the ice bath cooling, slowly drip the acetone soln 50mL of Ts-Cl 75mmol, finish, be warming up to 18 ℃ of stirring reactions, keep pH to 9～11 in the reaction process, tlc (TLC) monitoring reaction process, afterreaction finished in 4 hours, and the ice bath cooling is regulated pH to 5～6 with 2mol/L HCl, organic solvent is removed in underpressure distillation, add EtOAc 120mL, the ice bath cooling is regulated pH to 3～4 with 2mol/L HCl again, tell the EtOAc layer, water merges organic layer with EtOAc extraction 3 times, with saturated NaCl solution washing to neutrality, wash again anhydrous Na with water 1 time 2SO 4Drying, suction filtration, EtOAc is removed in the filtrate decompression distillation, resistates sherwood oil-CH 3OH mixed solvent recrystallization obtains M1-c 5.195g, yield 88.9%.
2, the preparation of intermediate M2
In round-bottomed flask, add anhydrous CH 3OH, ice bath are cooled to 0 ℃, slowly drip SOCl 2, finish 0～10 ℃ of stirring reaction A 1Hour, add again M1 in batches, be warming up to 65～75 ℃ of stirring reactions, TLC monitoring reaction process, A 2Hour afterreaction finishes, and vacuum rotary steam is closely dried, and resistates is with sherwood oil-CH 3OH mixed solvent recrystallization obtains M2.Concrete preparation condition and the results are shown in Table 1.
Preparation condition and the result of table 1M2
Figure BDA0000076593340000041
M2-a：m.p.110.5～118.7℃； 1H?NMR(DMSO-d 6，300MHz)δ：3.65(s，3H，-COO CH 3)，4.24～4.29(m，1H，CH)，4.35(d，2H， CH 2O)，5.57(d，1H，CH，J＝8.0Hz)，7.32～8.25(m，11H，Ar-H)，8.34(s，1H，Ar-H)，8.57(s，1H，-CONH-)； 13C?NMR(DMSO-d 6，75MHz)δ：46.6，52.7，57.0，66.0，120.1，122.6，123.1，123.6，125.3，127.1，127.7，130.1，134.8，138.9，140.8，143.7，147.8，155，9，170.4.
M2-b：m.p.93.8～94.9℃； 1H?NMR(DMSO-d 6，300MHz)δ：3.76(s，3H，-COO CH 3)，5.04～5.15(m，2H，Ph CH 2O)，5.49(d，1H，CH，J＝6.4Hz)，6.11(d，1H，-CONH-，J＝5.36Hz)，7.26～7.35(m，4H，Ar-H)，7.56(t，1H，Ar-H，J 1＝7.9Hz)，7.75(d，1H，Ar-H，J＝7.4Hz)，8.18～8.26(m，2H，Ar-H)； 13C?NMR(DMSO-d 6，75MHz)δ：53.3，57.2，67.4，122.0，123.5，128.2，128.3，128.5，129.8，133.3，135.7，139.0，148.5，155.2，169.9.
M2-c：m.p.88.9～96.7℃； 1H?NMR(DMSO-d 6，300MHz)δ：2.28(s，3H，CH 3)，3.51(s，3H，-COO CH 3)，5.35～5.38(m，1H，CH)，7.20(d，2H，Ar-H，J＝7.8Hz)，7.52～7.58(m，3H，Ar-H)，7.75(d，1H，Ar-H，J＝7.6Hz)，8.08(d，2H，Ar-H，J＝7.3Hz)，9.11(d，1H，-CONH-，J＝9.7Hz)； 13C?NMR(DMSO-d 6，75MHz)δ：20.9，52.8，58.5，122.2，122.9，126.5，129.2，130.0，134.4，137.8，137.9，142.7，147.8，169.3.
3, the preparation of intermediate M3
The preparation of M3-a～M3-c: in the 500mL round-bottomed flask, add M2, Zn powder, NH 4Cl and CH 3OH 40～120mL is warming up to 70～90 ℃ of stirring in water bath reactions, TLC monitoring reaction process, A 3Hour afterreaction finishes, suction filtration, filter cake CH 3OH (2 * 40mL) washings, filtrate decompression is concentrated, and drying obtains M3.Concrete preparation condition and the results are shown in Table 2.
Preparation condition and the result of table 2M3-a～M3-c
Figure BDA0000076593340000051
M3-c：m.p.175.8～180.9℃； 1H?NMR(DMSO-d 6，300MHz)δ：2.36(s，3H，CH 3)，3.38(s，3H，-COO CH 3)，4.71(d，1H，CH，J＝8.6Hz)，5.16(s，1H，NH 2)，6.35(d，2H，Ar-H，J＝7.5Hz)，6.45(d，2H，Ar-H，J＝6.9Hz)，6.88～6.94(m，1H，Ar-H)，7.34(d，2H，Ar-H，J＝7.9Hz)，7.63(d，2H，Ar-H，J＝8.0Hz).8.68(d，1H，-CONH-，J＝8.8)； 13C?NMR(DMSO-d 6，75MHz)δ：21.0，52.1，59.7，112.6，113.8，114.4，126.6，129.1，129.4，136.0，137.9，142.7，148.9，170.4.
M3-d (R 1=Fmoc) and M3-e (R 1Chinese patent application CN 101633626A is seen in=Z) preparation.
4, the preparation of target compound 1
In the round-bottomed flask of 100mL, add M3 and dry acetone 10～25mL, stir and make dissolving, add anhydrous K under the ice bath 2CO 3, slowly drip again ClCH 2The acetone soln 10mL of COCl finishes and removes ice bath, B 1℃ stirring reaction, TLC monitoring reaction process, A 4Hour afterreaction finishes, suction filtration, filter cake after washing, merging filtrate, the underpressure distillation desolventizing, resistates be crude product with column chromatography (EtOAc-PE) purifying, obtain 1.Concrete preparation condition and the results are shown in Table 3.
The preparation condition of table 31 and result
Figure BDA0000076593340000052
Figure BDA0000076593340000053
1a：m.p.119.2～123.1℃；
Figure BDA0000076593340000054
(c?1.0mg/mL，CH 3COCH 3)； 1H?NMR(DMSO-d 6，300MHz)δ：3.63(s，3H，-COO CH 3)，4.24(s，1H，CH)，4.26～4.28(d，4H， CH 2O，CO CH 2，J＝6.4Hz)，4.32(s，1H，CH)，5.24(d，1H，CH，J＝7.2Hz)，7.14(d，1H，Ar-H，J＝7.4Hz)，7.28～7.44(m，5H，Ar-H)，7.62(d，2H，Ar-H，J＝12.5Hz)，7.81(d，2H，Ar-H，J＝7.2Hz)，7.89(d，2H，Ar-H，J＝7.4Hz)，8.43(d，1H，-CONH-，J＝7.4Hz)，10.41(s，1H，-CONH-)； 13C?NMR(DMSO-d 6，75MHz)δ：43.6，46.6，52.4，58.0，66.1，118.9，119.2，120.1，123.4，125.4，127.1，127.7，129.2，137.0，138.7，140.7，143.4，156.0，164.8，171.1.
1b:m.p.149.2～150.4 ℃;
Figure BDA0000076593340000061
(c 1.0mg/mL, CH 3COCH 3); 1H NMR (DMSO-d 6, 300MHz) δ: 3.64 (s, 3H ,-COO CH 3), 4.25 (s, 2H, CO CH 2Cl), 5.06 (s, 2H, Ph CH 2O), 5.25 (d, 1H, CH, J=7.5Hz), 7.12 (d, 1H, Ar-H, J=7.6Hz), 7.30～7.36 (m, 6H, Ar-H), 7.60 (d, 2H, Ar-H, J=12.9Hz), (8.32 d, 1H ,-CONH-, J=7.4Hz), 10.40 (s, 1H ,-CONH-); 13C NMR (DMSO-d 6, 75MHz) δ: 43.6,52.3,58.0,65.8,118.8,119.3,123.3,127.8,127.9,128.4,129.2,136.9,137.0,138.7,155.9,164.8,171.1; HR ESI-MS:C 19H 19ClN 2O 5[M-H] -Calculated value 389.0910, measured value 389.0915.
Figure BDA0000076593340000062
1c：m.p.130.2～136.4℃；
Figure BDA0000076593340000063
(c?1.0mg/mL，CH 3COCH 3)； 1H?NMR(DMSO-d 6，300MHz)δ：2.35(s，3H，CH 3)，3.45(s，3H，-COO CH 3)，4.27(s，2H， CH 2Cl)，4.93(d，1H，CH，J＝8.9Hz)，6.97(d，1H，Ar-H，J＝7.6Hz)，7.22～7.32(m，3H，Ar-H)，7.49～7.54(m，2H，Ar-H)，7.62(d，2H，Ar-H，J＝8.0Hz)，8.86(d，1H，-CONH-，J＝8.9Hz)，8.88(s?1H，-CONH-，J＝10.40Hz).
1d：m.p.184.1～185.7℃；
Figure BDA0000076593340000064
(c?1.0mg/mL，CH 3COCH 3)； 1H?NMR(DMSO-d 6，300MHz)δ：4.23(s，1H，CH)，4.26～4.29(m，5H， CH 2O，CO CH 2，-CONH-)，5.13(d，1H，CH，J＝7.7Hz)，7.16(d，1H，Ar-H，J＝7.4Hz)，7.28～7.44(m，6H，Ar-H)，7.61(d，2H，Ar-H，J＝5.5Hz)，7.89(d，2H，Ar-H，J＝7.4Hz)，8.31(d，2H，Ar-H，J＝7.7Hz)，10.41(s，1H，-CONH-)，12.88(s，1H，COOH)； 13CNMR(DMSO-d 6，75MHz)δ：43.5，46.7，58.1，66.0，118.9，119.0，119.4，120.0，123.2，125.4，127.6，128.3，129.0，138.5，140.7，143.8，155.8，164.7，171.7.
Figure BDA0000076593340000065
1e: oily matter; 1H NMR (DMSO-d 6, 300MHz) δ: 3.64 (s, 3H ,-COO CH 3), 4.26 (s, 2H, CO CH 2Cl), 5.06 (s, 2H, Ph CH 2O), 5.23 (d, 1H, CH, J=7.5Hz), (7.13 d, 1H, Ar-H, J=7.6Hz), 7.32～7.34 (m, 6H, Ar-H), 7.61 (d, 2H, Ar-H, J=12.9Hz), 8.33 (d, 1H,-CONH-, J=7.4Hz), 10.42 (s, 1H,-CONH-), 11.56 (s, 1H ,-COOH).
The preparation of embodiment two, target compound 2
Figure BDA0000076593340000071
In the 250mL round-bottomed flask, add R 5X 1H or
Figure BDA0000076593340000072
DMF 2-10mL and anhydrous K 2CO 3, stir, add 1b, 25～40 ℃ of stirring reactions, TLC monitoring reaction process, A 5Hour afterreaction finishes, and adds ice NaCl solution 100mL and EtOAc 50～80mL, and the ice bath cooling is regulated pH to 5～6 with 2mol/L HCl, and (3 * 30mL) extractions merge organic layer to EtOAc, and saturated NaCl solution washing is to neutral, anhydrous Na 2SO 4Drying, suction filtration, filtrate decompression is concentrated, and column chromatographic isolation and purification obtains 2.Concrete preparation condition and the results are shown in Table 4.
The preparation condition of table 42 and result
Figure BDA0000076593340000073
Figure BDA0000076593340000081
Figure BDA0000076593340000082
2a:m.p.92.7～99.1 ℃; (c 1.0mg/mL, EtOAc); 1H NMR (CDCl 3, 300MHz) δ: 3.65 (s, 3H ,-COO CH 3), 3.92 (s, 2H, CO CH 2), 5.01～5.13 (m, 2H, Ph CH 2O), 5.33 (d, 1H, CH, J=6.9Hz), 5.94 (d, 1H ,-CONH-, J=6.9Hz), 7.07 (d, 1H, Ar-H, J=7.4Hz), 7.22～7.31 (m, 9H, Ar-H), (7.51 d, 3H, Ar-H, J=6.0Hz), 7.63 (s, 1H ,-CONH-); 13C NMR (CDCl 3, 75MHz) δ: 36.1,52.9,57.8,67.2,118.3,119.8,122.7,128.0,128.5,129.6,135.9,137.2,138.9,150.5,155.5,168.2,171.0.HRESI-MS:C 26H 24N 4O 5S[M-H] -Calculated value 503.1395, measured value 503.1401.
2b:m.p.119.2～123.1 ℃;
Figure BDA0000076593340000084
(c 1.0mg/mL, CH 3COCH 3); 1H NMR (DMSO-d 6, 300MHz) δ: 2.3 (s, 3H, CH 3), 3.63 (s, 3H ,-CO 2 CH 3), 4.49 (s, 2H, CO CH 2), 5.06 (s, 2H, Ph CH 2O), 5.22 (d, 1H, CH, J=7.1Hz), (6.40 s, 1H, Ar-H), 6.62 (d, 2H, Ar-H, J=7.9Hz), 7.08 (d, 1H, Ar-H, J=7.4Hz), 7.30～7.36 (m, 6H, Ar-H), 7.51～7.56 (m, 4H, Ar-H), 8.21 (d, 1H ,-CONH-, J=7.2Hz), 10.24 (s, 1H ,-CONH-); 13C NMR (DMSO-d 6, 75MHz) δ: 12.1,50.2,52.3,59.8,65.7,96.7,112.8,118.4,118.8,122.0,122.8,128.4,129.1,129.4,136.8,139.0,154.0,155.9,159.5,162.3,165.2,170.4,171.1; HRESI-MS:C 29H 29N 5O 8S[M+Na] +Calculated value 630.1629, measured value 630.1625.
Figure BDA0000076593340000085
2c:m.p.114.0～115.8 ℃; [α] D 20+ 17.0 (c 1.0mg/mL, EtOAc); 1H NMR (DMSO-d 6, 300MHz) δ: 3.62 (s, 3H ,-COO CH 3), 5.05 (s, 2H, Ph CH 2O), 5.20 (s, 2H, CO CH 2Cl), 5.24 (d, 1H, CH, J=7.1Hz), (7.11 d, 1H, Ar-H, J=7.4Hz), 7.19～7.35 (m, 7H, Ar-H), 7.52～7.69 (m, 5H, Ar-H), 8.24 (s, 1H, Ar-H), 8.31 (d, 1H ,-CONH-, J=6.9Hz), 10.57 (s, 1H ,-CONH-); 13C NMR (DMSO-d 6, 75MHz) δ: 30.7,52.3,58.0,65.7,110.3,119.3,122.4,123.1,127.8,128.4,129.2,134.4,136.8,137.1,138.8,143.2,145.0,155.9,165.6,171.0.HR ESI-MS:C 26H 24N 4O 5[M-H] -Calculated value 471.1674, measured value 471.1674.
2d:m.p.98.7～100.1 ℃; (c 1.0mg/mL, CH 3COCH 3); [α] D 20+ 25.0 (c 1.0mg/mL, EtOAc); 1H NMR (DMSO-d 6, 300MHz) δ: 3.64 (s, 3H ,-COO CH 3), 4.01 (s, 2H, CO CH 2), 5.07 (s, 2H, Ph CH 2O), 5.25 (d, 1H, CH, J=7.3Hz), 7.15 (d, 1H, Ar-H, J=7.3Hz), 7.32～7.95 (m, 12H, Ar-H), 8.33 (d, 1H ,-CONH-, J=7.4Hz), (8.81 d, 1H, Ar-H, J=4.9Hz), 9.89 (s, 1H ,-CONH-); 13C NMR (DMSO-d 6, 75MHz) δ: 43.4,52.3,58.1,65.7,118.9,119.2,122.7,127.7,128.4,129.0,129.4,130.0,131.7,136.8,138.2,138.9,155.9,168.0,169.1,171.1; HR ESI-MS:C 27H 23N 3O 7[M-H] -Calculated value 500.1463, measured value 500.1455.
2e:m.p.100.9～105.2 ℃;
Figure BDA0000076593340000093
(c 1.0mg/mL, EtOAc); 1H NMR (CDCl 3, 300MHz) δ: 1.48 (s, 9H, C ( CH 3) 3), 2.57 (s, 4H, CH 2, CH 2), 3.15 (s, 2H, CO CH 2), 3.52 (s, 4H, CH 2, CH 2), 3.73 (s, 3H ,-COO CH 3), 5.04～5.15 (m, 2H, Ph CH 2O), 5.35 (d, 1H, CH, J=6.7Hz), (5.90 d, 1H ,-CONH-, J=6.3Hz), 7.12 (d, 1H, Ar-H, J=7.1Hz), 7.26 (s, 1H, Ar-H), 7.35 (s, 5H, Ar-H), 7.46 (s, 1H, Ar-H), 7.69 (d, 1H, Ar-H, J=7.4Hz), 9.05 (s, 1H ,-CONH-); 13C NMR (CDCl 3, 75MHz) δ: 28.3,43.4,52.9,53.2,57.8,62.1,67.1,80.0,118.1,119.8,122.9,128.2,128.5,129.7,136.0,137.6,137.9,154.6,155.3,168.0,171.0; HR ESI-MS:C 28H 36N 4O 7[M-H] -Calculated value 539.2511, measured value 539.2511.
2f:m.p.195.4～198.7 ℃;
Figure BDA0000076593340000094
(c 1.0mg/mL, CH 3COCH 3); 1H NMR (DMSO-d 6, 300MHz) δ: 3.62 (s, 3H ,-COO CH 3), 5.06 (s, 2H, Ph CH 2O), 5.23 (d, 1H, CH, J=6.7Hz), 5.70 (s, 2H, CO CH 2Cl), 7.36～7.37 (m, 5H, Ar-H), 7.43 (d, 1H, Ar-H, J=7.5Hz), 7.56 (d, 4H, Ar-H, J=7.4Hz), 7.85 (d, 1H, Ar-H, J=8.1Hz), 8.08 (d, 1H ,-CONH-, J=8.1Hz), 8.27 (d, 1H, Ar-H, J=7.2Hz), 10.69 (s, 1H ,-CONH-); 13C NMR (DMSO-d 6, 75MHz) δ: 50.4,52.1,57.4,65.6,110.8,119.0,119.3,123.8,127.3,127.7,127.8,128.2,128.3,131.4,133.8,136.7,138.2,145.0,155.8.164.4,171.2; HRESI-MS:C 25H 23N 5O 5[M-H] -Calculated value 472.1626, measured value 472.1630.
Figure BDA0000076593340000095
2g:m.p.184.9～188.7 ℃;
Figure BDA0000076593340000096
(c 1.0mg/mL, EtOAc); 1H NMR (DMSO-d 6, 300MHz) δ: 2.67 (s, 4H, CH 2, CH 2), 3.19 (s, 6H, CO CH 2, CH 2, CH 2), 3.61 (s, 3H ,-COO CH 3), 5.06 (s, 2H, Ph CH 2O), 5.22 (d, 1H, CH, J=7.3Hz), 6.76 (t, 1H, Ar-H, J=7.0Hz), 6.94 (d, 2H, Ar-H, J=7.9Hz), 7.22 (t, 2H, Ar-H, J=7.4Hz), 7.32～7.36 (d, 7H, Ar-H, J=12.1Hz), 7.62 (d, 2H, Ar-H, J=8.1Hz), 8.25 (d, 1H,-CONH-, J=7.4Hz), 9.83 (s, 1H ,-CONH-); 13C NMR (DMSO-d 6, 75MHz) δ: 48.7,52.9,53.3,58.3,62.2,66.4,116.1,119.6,120.3,128.4,128.6,128.9,129.1,129.6,131.8,137.5,139.1,151.6,156.6,169.0,172.0; HR ESI-MS:C 29H 32N 4O 5[M+Na] +Calculated value 539.2265, measured value 539.2263.
2h:m.p.187.7～191.5 ℃;
Figure BDA0000076593340000101
(c 1.0mg/mL, EtOAc); 1H NMR (DMSO-d 6, 300MHz) δ: 3.62 (s, 3H ,-COO CH 3), 5.06 (s, 2H, Ph CH 2O), 5.24 (m, 1H, CH), 5.78 (s, 2H, CO CH 2Cl), 7.31～7.58 (m, 12H, Ar-H), 8.08～8.10 (m, 2H, Ar-H), 8.30 (d, 1H ,-CONH-, J=7.7Hz), 10.73 (s, 1H ,-CONH-); 13C NMR (DMSO-d 6, 75MHz) δ: 52.9,56.0,58.2,66.4,121.1,127.1,127.5,128.5,128.6,129.0,129.2,130.0,131.4,132.5,137.5,138.8,156.6,163.7,165.0,172.0; HR ESI-MS:C 26H 24N 6O 5[M-H] -Calculated value 499.1735, measured value 499.1738.
Figure BDA0000076593340000102
2i:m.p.156.9～159.6 ℃;
Figure BDA0000076593340000103
(c 1.0mg/mL, EtOAc); 1H NMR (DMSO-d 6, 300MHz) δ: 2.57 (s, 3H, CH 3), 3.76 (s, 3H ,-COO CH 3), 5.14 (s, 4H, Ph CH 2O, CO CH 2), 5.31 (d, 1H, CH, J=6.3Hz), 6.18 (d, 1H ,-CONH-, J=6.3Hz), 7.12 (d, 1H, Ar-H, J=7.2Hz), 7.20～7.51 (m, 7H, Ar-H), 7.62 (s, 1H, Ar-H), 8.84 (s, 1H ,-CONH-); 13C NMR (DMSO-d 6, 75MHz) δ: 8.8,49.8,53.0,57.9,67.2,118.7,120.1,123,4,127.9,128.2,128.5,129.7,136.0,137.6,137.7,155.6,162.7,170.8; HRESI-MS:C 21H 22N 6O 5[M+Na] +Calculated value 461.1544, measured value 461.1546.
2j:m.p.128.9～135.6 ℃;
Figure BDA0000076593340000104
(c 1.0mg/mL, CH 3COCH 3); 1H NMR (DMSO-d 6, 300MHz) δ: 3.63 (s, 3H ,-COO CH 3), 5.06 (s, 2H, Ph CH 2O), 5.24 (d, 1H, CH, J=7.5Hz), 5.49 (s, 2H, CO CH 2), 7.13 (d, 1H, Ar-H, J=7.5Hz), 7.31～7.36 (m, 6H, Ar-H), (7.57 d, 2H, Ar-H, J=9.3Hz), 8.33 (d, 1H ,-CONH-, J=7.5Hz), 9.43 (s, 1H, X), 10.65 (s, 1H ,-CONH-); 13C NMR (DMSO-d 6, 75MHz) δ: 50.5,52.8,58.3,60.2,66.2,119.1,119.5,123.7,128.1,128.3,128.8,129.7,137.2,137.5,138.8,145.7,156.3,164.0,171.4; HR ESI-MS:C 20H 20N 6O 5[M-H] -Calculated value 423.1422, measured value 423.1426.
Figure BDA0000076593340000105
2k:m.p.182.4～185.7 ℃;
Figure BDA0000076593340000111
(c 1.0mg/mL, EtOAc); 1H NMR (CDCl 3, 300MHz) δ: 3.74 (s, 3H ,-COO CH 3), 3.98 (s, 3H ,-S CH 3), 4.06 (s, 2H, Ph CH 2O), 5.15 (s, 2H ,-N CH 2CO), 5.35 (d, 1H ,-CONH-, J=7.01Hz), (5.90 s, 1H, CH), 7.13 (d, 1H, Ar-H, J=7.3Hz), 7.28～7.36 (m, 5H, Ar-H), 7.51 (d, 1H, Ar-H, J=7.8Hz), 7.60 (s, 1H, Ar-H), 9.45 (s, 1H, Ar-H); HR ESI-MS:C 21H 22N 6O 5S[M-H] -Calculated value 469.1300, measured value 469.1297.
2l:m.p.220.2～223.0 ℃; (c=1.0mg/mL, DMF); 1H NMR (CDCl 3, 300MHz) δ: 1.77 (s, 3H ,-CH 3), 3.63 (s, 3H ,-COOCH 3), 4.49 (s, 2H ,-COCH 2-), 5.05 (s, 2H, Ph CH 2O), 5.21 (d, 1H, J=7.8Hz ,-CONH-), (7.09 d, 1H, J=6.9Hz, Ar-H), 7.31～7.35 (m, 6H, H-1, Ar-H), 7.51～7.66 (m, 3H, Ar-H), 8.31 (d, 1H, J=7.8Hz, H-7), 10.35 (s, 1H,-CH-), 11.35 (s, 1H ,-CONHCO-); 13C NMR (DMSO-d 6, 75MHz) δ: 12.4,31.2,52.7,58.4,66.1,108.5,118.9,119.2,123.3,128.2,128.3,128.8,129.6,137.2,137.4,139.2,142.8,151.5,156.3,162.7,163.4,, 171.4; HR ESI-MS:C 24H 24N 4O 7[M-H] -Calculated value 479.1572, measured value 479.1572.
Figure BDA0000076593340000113
2m: 13C NMR (DMSO-d 6, 75MHz) δ: 11.3,13.5,31.0,52.7,58.4,66.1,105.4,119.2,119.6,123.6,125.3,128.2,128.3,128.8,129.5,137.2,137.4,139.1,156.3,165.1,166.1,171.4; HRESI-MS:C 24H 26N 4O 4[M-H] -Calculated value 449.1903, measured value 449.1906.
The preparation of embodiment three, target compound 3
Figure BDA0000076593340000114
Adding 2 and THF 10～25mL in the 100mL round-bottomed flask stir, and the ice bath cooling adds 1mol/L LiOH solution and regulates pH to 10～12, B 2℃ stirring reaction, TLC monitoring reaction process, A 6Hour afterreaction finishes, and the ice bath cooling is regulated pH to 5～6 with 2mol/L HCl, the vacuum rotary steam desolventizing, and the ice bath cooling is regulated pH to 3～4 with 2mol/L HCl, and water merges organic layer, with saturated NaCl solution washing, anhydrous Na with EtOAc extraction 3 times 2SO 4Drying, suction filtration, EtOAc is removed in the filtrate decompression distillation, obtains 3.Concrete preparation condition and the results are shown in Table 5.
The preparation condition of table 53 and result
Figure BDA0000076593340000121
Figure BDA0000076593340000122
3a:m.p.145.3～154.2 ℃; (c 1.0mg/mL, DMF); 1H NMR (DMSO-d 6, 300MHz) δ: 4.60 (s, 2H ,-CH 2-), 5.04 (s, 2H ,-Ph CH 2O), 5.09～5.18 (m, 2H ,-CH-and-SCH-), (7.12 d, 1H, Ar-H, J=7.5Hz), 7.27～7.35 (m, 8H, Ar-H), 7.42～7.65 (m, 4H, Ar-H), 8.13 (d, 1H,-NH-, J=7.8Hz), 10.46 (s, 1H,-NH-), 10.87 (s, 1H ,-COOH); HR ESI-MS:C 25H 21N 4O 5S calculated value 489.1238, measured value 489.1238.
3b：m.p.160.2-167.0℃.
Figure BDA0000076593340000124
3c：m.p.168.6～172.3℃；
Figure BDA0000076593340000125
(c?1.0mg/mL，DMF)； 1H?NMR(DMSO-d 6，300MHz)δ：3.99(s，2H，-CH 2-)，5.05(s，2H，-Ph CH 2O)，5.13(d，1H，-CH-，J＝7.5Hz)，7.11(d，1H，Ar-H，J＝7.8Hz)，7.31～7.85(m，12H，Ar-H)，8.10(d，1H，Ar-H，J＝7.8Hz，)，8.76(d，1H，-NH-，J＝5.7Hz)，9.86(s，1H，-NH-)，12.94(s，1H，-COOH).
3d：m.p.176.2～179.4℃；
Figure BDA0000076593340000126
(c?1.0mg/mL，DMF).
Figure BDA0000076593340000127
3e:m.p.150.2～154.1 ℃;
Figure BDA0000076593340000128
(c 1.0mg/mL, DMF); 1H NMR (DMSO-d 6, 300MHz) δ: 1.42 (s, 9H ,-C ( CH 3) 3), 2.04～2.09 (m, 4H ,-CH 2-), 3.02～3.23 (m, 4H ,-CO CH 2), 4.02 (s, 2H ,-CH 2-), 5.05 (s, 2H ,-Ph CH 2O), 5.13 (d, 1H ,-CH-, J=7.8Hz), (7.16 d, 1H, Ar-H, J=7.2Hz), 7.31～7.36 (m, 6H, Ar-H), 7.59～7.64 (m, 2H, Ar-H), 8.14 (d, 1H,-CONH-, J=7.8Hz), 10.48 (s, 1H,-CONH-), 10.80 (s, 1H ,-COOH); 13C NMR (DMSO-d 6, 75MHz) δ: 28.4,31.1,52.0,57.8,58.5,66.0,80.2,119.4,119.5,123.6,128.1,128.2,128.8,129.4,137.2,138.3,138.5,153.9,156.2,172.3; HRESI-MS:C 27H 34N 4O 7[M+Na] +Calculated value 549.2320, measured value 549.2327.
The preparation of embodiment four, target compound 4
Figure BDA0000076593340000131
1, the preparation of intermediate M4
The preparation of M4-a～M4-c: it is lower that cryosel is bathed cooling, to R 6X 2Slowly drip SOCl among the H 40mL 23.140g (26.3mmol), finish and stirred 0.5 hour, add again M1-b 8.255g (25.0mmol), B3 ℃ of stirring reaction, TLC monitoring reaction process, A 7Hour afterreaction finishes, suction filtration, and the concentrated crude product that obtains of filtrate decompression, with corresponding alcohol-sherwood oil mixed solvent recrystallization, acquisition M4-a～M4-c.Concrete preparation condition and the results are shown in Table 6.
Preparation condition and the result of table 6M4-a～M4-c
Figure BDA0000076593340000132
M4-d (R 6X 2=PhCH 2O) preparation: see Chinese patent application CN 101633626A.
The preparation of M4-e～M4-h: the ice bath cooling is lower, adds R in 100mL flask I 6X 2H, THF 10-20mL, DIPEA1-3mL stirred 15 minutes.Add M1-b, HOBt, THF10-20mL, DIPEA1.5-3mL and DCC in 50mL flask II, stir-activating 0.5 hour is transferred to activation solution among the flask I B again 4℃ stirring reaction, TLC monitoring reaction process, A 8Hour afterreaction finishes, suction filtration, the concentrated THF that removes of filtrate decompression adds EtOAc 55-100mL, successively with massfraction be 10% citric acid solution (3 * 45mL), the NaHCO of 0.5mol/L 3Solution (3 * 50mL), saturated NaCl solution (3 * 60mL) washing, anhydrous Na 2SO 4Drying, suction filtration, filtrate is concentrated, uses column chromatography purifying, obtains M4-e～M4-h.Concrete preparation condition and the results are shown in Table 7.
Preparation condition and the result of table 7M5-e～M5-h
Figure BDA0000076593340000141
Figure BDA0000076593340000142
M4-a：m.p.107.0～112.1℃； 1H?NMR(DMSO-d 6，300MHz)δ：1.12(t，3H，CH 3，J＝6.8Hz)，4.10～4.12(m，2H，CH 2)，5.07(s，2H，Ph CH 2O)，5.53(m，1H，CH)，7.35(s，5H，Ar-H)，7.67(t，1H，Ar-H，J＝7.9Hz，)，7.89(d，1H，Ar-H，J＝7.3Hz)，8.20(d，1H，-CONH-，J＝8.2Hz)，8.32(s，1H，Ar-H)，8.50(d，1H，Ar-H，J＝7.6Hz)； 13C?NMR(DMSO-d 6，75MHz)δ：14.3，57.6，61.8，66.3，123.0，123.5，128.2，128.3，128.8，130.5，135.2，137.1，139.2，148.2，156.3，170.3.
M4-b：m.p.106.0～107.9℃； 1H?NMR(DMSO-d 6，300MHz)δ：0.77(t，3H，CH 3，J＝6.9Hz)，1.48～1.53(m，2H，CH 2)，4.04(s，2H，O CH 2)，5.09(s，2H，Ph CH 2O)，5.57(d，1H，CH，J＝7.5Hz)，7.36(s，5H，Ar-H)，7.66～7.71(m，1H，Ar-H)，7.91(d，1H，Ar-H，J＝7.2Hz)，8.21(d，1H，-CONH-，J＝8.1Hz)，8.35(s，1H，Ar-H)，8.52(d，1H，Ar-H，J＝7.5Hz)； 13C?NMR(DMSO-d 6，75MHz)δ：170.3，156.3，148.1，139.3，137.1，135.2，130.4，128.8，128.3，128.2，123.5，123.0，67.1，66.3，57.6，21.8，10.4
Figure BDA0000076593340000143
M4-c：m.p.130.0～134.8℃； 1H?NMR(DMSO-d 6，300MHz)δ：0.79(t，3H，CH 3，J＝7.2Hz)，1.16～1.23(m，2H，CH 2)，1.46～1.50(m，2H，CH 2)，4.05～4.09(m，2H，O CH 2)，5.06(s，2H，Ph CH 2O)，5.56(d，1H，CH，J＝8.1Hz)，7.37(s，5H，Ar-H)，7.66～7.71(m，1H，Ar-H)，7.91(d，1H，Ar-H，J＝7.5Hz)，8.21(d，1H，-CONH-，J＝8.4Hz)，8.35(s，1H，Ar-H)，8.52(d，1H，Ar-H，J＝8.1Hz)； 13C?NMR(DMSO-d 6，75MHz)δ：13.8，18.8，30.4，57.6，65.4，66.3，123.0，123.5，128.2，128.3，128.8，130.4，135.2，137.1，139.3，148.1，156.3，170.3.
M4-d：m.p.120.1～123.6℃； 1H?NMR(DMSO-d 6，300MHz)δ：5.03(s，2H，CH 2)，5.06(s，2H，CH 2)，5.51(d，1H，J＝6.0Hz，CH)，6.08(d，1H，J＝3.0Hz，-CONH-)，7.18～7.71(m，12H，Ar-H)，8.19～8.22(m，2H，Ar-H)；MS?m/z：421.0([M+1] +，15％)，443.0([M+23] +，100％).
Figure BDA0000076593340000151
M4-e：
Figure BDA0000076593340000152
(c＝1.0mg/mL，EtOAc)； 1H?NMR(DMSO-d 6，300MHz)δ：2.87～2.99(m，4H，N(CH 3) CH 2CH 2OH，N(CH 3)CH 2 CH 2OH)，3.51～3.52(m，3H，CH 3)，5.04(s，2H，Ph CH 2O)，5.88(d，1H，CH，J＝7.8Hz)，7.35(s，4H，Ar-H)，7.67(d，1H，Ar-H，J＝6.0Hz)，7.85(d，1H，Ar-H，J＝7.2Hz)，8.10(d，1H，-CONH-，J＝8.1Hz)，8.16～8.23(m，2H，Ar-H)，8.27(s，1H，Ar-H).
M4-f：m.p.121.4～127.8℃； 13C?NMR(DMSO-d 6，75MHz)δ：55.8，66.2，122.2，123.2，124.0，128.1，128.3，128.8，130.4，134.3，137.2，141.1，148.1，156.1.
Figure BDA0000076593340000153
M4-g：m.p.116.2～120.0℃； 1H?NMR(DMSO-d 6，300MHz)δ：0.99(t，3H，-CH 3，J＝7.2Hz，)，3.03～3.13(m，2H，-CH 2-)，5.04(s，2H，-Ph CH 2O)，5.38(d，1H，-CH-，J＝8.4Hz)，7.31～7.37(m，5H，Ar-H)，7.62～7.68(m，1H，Ar-H)，7.87(t，1H，Ar-H，J＝8.1Hz)，8.15(d，1H，Ar-H，J＝8.6Hz)，8.24(d，1H，Ar-H，J＝8.7Hz)，8.33(s，1H，-CONH-).
M4-h：m.p.110.2～116.3℃； 1H?NMR(DMSO-d 6，300MHz)δ：2.59(d，3H，-CH 3，J＝4.2Hz)，5.04(s，2H，-Ph CH 2O)，5.38(d，1H，-CH-，J＝7.8Hz)，7.36(s，5H，Ar-H)，7.62～7.70(m，2H，Ar-H)，7.87(d，1H，-CONH-，J＝7.5Hz)，8.15～8.25(m，2H，Ar-H，J＝8.4Hz)，8.33(d，1H，-CONH-). 13CNMR(DMSO-d 6，75MHz)δ：26.1，57.9，66.2，122.4，123.0，123.9，128.2，128.7，128.9，130.3，134.4，137.2，148.1，156.1，.169.7.
2, the preparation of intermediate M5
In the 50mL round-bottomed flask, add M4 12mmol, Zn powder 130mmol, NH 4Cl 75mmol and CH 3OH 65mL, the reaction of 75 ℃ of stirring in water bath, TLC monitoring to reaction finishes, suction filtration while hot, filter cake CH 3(concentrating under reduced pressure obtains M5 to OH for 2 * 20mL) washings, merging filtrate and washing lotion.
3, the preparation of target compound 4
In the 125mL round-bottomed flask, add M5 and dry acetone 25～50mL, stir and make dissolving, add anhydrous K under the ice bath 2CO 3, slowly drip again ClCH 2The acetone soln 10-15mL of COCl finishes and removes ice bath, B 5℃ stirring reaction, TLC monitoring reaction process, A 9Hour afterreaction finishes, suction filtration, and the filtrate washing, concentrated, use column chromatography purifying, obtain 4.Concrete preparation condition and the results are shown in Table 8.
The preparation condition of table 84 and result
Figure BDA0000076593340000162
4a:m.p.83.2～84.5 ℃; 1H NMR (DMSO-d 6, 300MHz) δ: 1.13 (t, 3H, CH 3, J=6.9Hz), 4.06～4.13 (m, 2H, CH 2), 4.25 (s, 2H, CO CH 2Cl), 5.07 (s, 2H, Ph CH 2O), 5.21 (d, 1H, CH, J=7.5Hz), 7.12 (s, 1H, Ar-H), 7.30～7.36 (m, 6H, Ar-H), 7.59 (d, 2H, Ar-H, J=6.6Hz), (8.28 d, 1H ,-CONH-, J=7.5Hz), 10.38 (s, 1H ,-CONH-); 13C NMR (DMSO-d 6, 75MHz) δ: 14.4,44.0,58.5,61.4,66.1,119.2,119.6,123.6,128.2,128.3,128.8,129.5,137.3,137.4,139.1,156.1,165.1,170.9; HR ESI-MS:C 20H 21ClN 2O 5[M-H] -Calculated value 403.1066, measured value 403.1072.
4b:m.p.95.8～96.4 ℃; 1H NMR (DMSO-d 6, 300MHz) δ: 0.74～0.79 (m, 3H, CH 3), 1.49～1.56 (m, 2H ,-CH 2-), 4.02 (t, 2H, O CH 2, J=6.0Hz), 4.25 (s, 2H, CH 2Cl), 5.07 (s, 2H, Ph CH 2O), 5.22 (d, 1H, CH, J=7.2Hz), 7.14 (d, 1H, Ar-H, J=7.5Hz), 7.31～7.36 (m, 6H, Ar-H), 7.58 (d, 1H, Ar-H, J=14,1Hz), 8.29 (d, 1H ,-CONH-, J=7.5Hz), 10.39 (s, 1H ,-CONH-); 13C NMR (DMSO-d 6, 75MHz) δ: 10.4,21.8,44.0,58.3,66.1,66.8,119.6,128.1,128.3,128.7,129.5,137.2,137.4,139.0,156.4,165.1,170.9; HR ESI-MS:C 21H 23ClN 2O 5[M-H] -Calculated value 417.1223, measured value 417.1221.
Figure BDA0000076593340000171
4c：m.p.85.6～87.0℃； 1H?NMR(DMSO-d 6，300MHz)δ：0.77～0.82(t，3H，CH 3，J＝7.5Hz)，1.16～1.26(m，2H，CH 2)，1.44～1.53(m，2H，CH 2)，4.04～4.08(m，2H，O CH 2)，4.25(s，2H， CH 2Cl)，5.11(s，2H，Ph CH 2O)，5.21(d，1H，CH，J＝4.2Hz)，7.12(d，1H，Ar-H，J＝7.8Hz)，7.30～7.36(m，5H，Ar-H)，7.59(s，1H，Ar-H)，8.28(d，1H，-CONH-，J＝7.5Hz)，10.38(s，1H，-CONH-)； 13C?NMR(DMSO-d 6，75MHz)δ：13.9，18.2，30.4，44.0，58.6，65.0，66.1，119.2，119.5，123.6，128.2，128.3，129.5，137.3，139.1，156.3，165.1，171.0.
4d:m.p.126.8～131.5 ℃; 1H NMR (DMSO-d 6, 300MHz) δ: 4.25 (s, 2H, CO CH 2Cl), 5.07 (s, 2H, Ph CH 2O), 5.15 (s, 2H, Ph CH 2O), 5.29～5.32 (m, 1H, CH), 7.13 (d, 1H, Ar-H, J=7.5Hz), 7.26～7.35 (m, 11H, Ar-H), 7.34 (d, 2H, Ar-H, J=7.5Hz), (8.36 d, 1H ,-CONH-, J=7.5Hz), 10.38 (s, 1H ,-CONH-); 13C NMR (DMSO-d 6, 75MHz) δ: 44.0,58.6,66.7,128.0,128.2,128.3,128.4,128.8,129.5,136.1,137.2,139.1,156.4,165.1,170.9; HR ESI-MS:C 25H 23ClN 2O 5[M-H] -Calculated value 465.1223, measured value 465.1230.
4e:m.p.101.1～105.8 ℃; 1H NMR (DMSO-d 6, 300MHz) δ: 85～2.91 (m, 4H, N (CH 3) CH 2CH 2OH, N (CH 3) CH 2 CH 2OH), 3.45～3.48 (m, 3H, CH 3), 4.24 (s, 2H, CO CH 2Cl), 5.02 (s, 2H, Ph CH 2O), 5.52～5.67 (q, 1H, CH, J 1=7.8Hz), 7.09 (d, 1H, Ar-H, J=7.5Hz), 7.29～7.34 (m, 6H, Ar-H), (7.51 d, 1H, Ar-H, J=7.2Hz), 7.60～7.65 (m, 1H, Ar-H), 7.69 (s, 1H ,-CONH-, J=7.5Hz), 10.37 (s, 1H ,-CONH-); 13C NMR (DMSO-d 6, 75MHz) δ: 34.4,36.2,44.0,49.1,50.2,58.8,66.0,119.0,124.0,128.1,128.2,128.8,129.5,137.4,139.1,139.2,156.1,165.1,170.0; HR ESI-MS:C 21H 24ClN 3O 5[M-H] -Calculated value 432.1332, measured value 432.1326.
4f：m.p.103.1～105.9℃； 1H?NMR(DMSO-d 6，300MHz)δ：4.24(s，2H， CH 2Cl)，5.04(s，2H，Ph CH 2O)，5.14(d，1H，CH，J＝8.1Hz)，7.15(d，1H，Ar-H，J＝7.5Hz)，7.21(s，1H，Ar-H)，7.27～7.35(m，5H，Ar-H)，7.56～7.60(m，2H，Ar-H)，7.74(d，1H，-CONH-，J＝7.8Hz)，10.35(s，1H，-CONH-)； 13CNMR(DMSO-d 6，75MHz)δ：44.0，55.8，66.2，122.2，123.2，123.9，128.1，128.3，128.8，130.4，134.3，137.2，141.2，156.2，165.1，169.6.
Figure BDA0000076593340000181
4g：m.p.179.6～181.2℃； 1H?NMR(DMSO-d 6，300MHz)δ：1.00(t，3H，J＝7.2Hz，H-21)，3.02～3.10(m，2H，H-20)，4.26(s，2H，H-17)，5.03(s，2H，H-5)，5.15(d，1H，J＝7.8Hz，H-8)，7.12(d，1H，J＝7.8Hz，H-10)，7.26～7.37(m，6H，H-1，H-2，H-3，H-11)，7.55～7.58(m，2H，H-12，H-14)，7.81(d，1H，J＝8.7Hz，H-19)，8.26(d，1H，J＝8.4Hz，H-7)，10.26(s，1H，H-15)； 13C?NMR(DMSO-d 6，75MHz)δ：14.9，34.0，44.0，58.8，66.0，118.7，119.1，123.1，128.1，128.2，129.2，137.3，140.0，156.2，165.1，169.6.
4h：m.p.99.1～106.2℃； 1H?NMR(DMSO-d 6，300MHz)δ：1.00(t，3H，J＝7.2Hz，H-21)，3.02～3.10(m，2H，H-20)，4.26(s，2H，H-17)，5.03(s，2H，H-5)，5.15(d，1H，J＝7.8Hz，H-8)，7.12(d，1H，J＝7.8Hz，H-10)，7.26～7.37(m，6H，H-1，H-2，H-3，H-11)，7.55～7.58(m，2H，H-12，H-14)，7.81(d，1H，J＝8.7Hz，H-19)，8.26(d，1H，J＝8.5Hz，H-7)，10.46(s，1H，H-15)； 13C?NMR(DMSO-d 6，75MHz)δ：26.1，44.0，58.6，66.0，118.8，119.1，123.2，128.0，128.2，128.8，129.2，1347.3，138.8，139.9，156.1，165.1，170.4.
The preparation of embodiment five, target compound 5
In the 100mL round-bottomed flask, add M2-b and acetone 10～20mL, the lower anhydrous K that adds of ice bath cooling 2CO 3, slowly drip again YCH 2COCl finishes and removes ice bath, B 6℃ stirring reaction, TLC monitoring reaction process, A 10Hour afterreaction finishes, and adds saturated NaCl solution, the ice bath cooling, regulate pH to 5～6 with 2mol/L HCl, revolve to steam and remove acetone, residual solution extracts (3 * 50mL) with EtOAc, merge organic phase, with saturated NaCl solution washing (3 * 50mL), anhydrous MgSO 4Drying, suction filtration, filtrate is concentrated, uses column chromatography purifying, obtains 5.Concrete preparation condition and the results are shown in Table 9.
The preparation condition of table 95 and result
Figure BDA0000076593340000191
Figure BDA0000076593340000192
5a:m.p.125.8～128.2 ℃; 1H NMR (DMSO-d 6, 300MHz) δ: 3.03 (s, 3H ,-CO CH 3), 3.63 (s, 3H ,-COO CH 3), 5.06 (s, 2H, Ph CH 2O), 5.20 (d, 1H, CH, J=7.5Hz)), 7.05 (d, 1H, Ar-H, J=7.8Hz)) and, 7.25～7.36 (m, 6H, Ar-H), 7.57 (t, 2H, Ar-H, J 1=8.1Hz)), 8.29 (d, 1H ,-CONH-, J=7.5Hz)), 10.01 (s, 1H ,-CONH-); 13C NMR (DMSO-d 6, 75MHz) δ: 24.4,52.7,58.5,66.1,118.9,119.3,122.7,128.2,128.3,128.8,129.4,137.1,137.2,140.0,156.3,168.8,171.5; HR ESI-MS:C 19H 20N 2O 5[M+Na] +Calculated value 379.1264, measured value 379.1271.
5b：m.p.115.8～118.4℃； 1H?NMR(DMSO-d 6，300MHz)δ：3.37(s，3H，-O CH 3)，3.64(s，3H，-COO CH 3)，3.99(s，2H，CO CH 2O)，5.06(s，2H，Ph CH 2O)，5.23(d，1H，CH，J＝7.5Hz))，7.09(d，1H，Ar-H，J＝7.5Hz))，7.27～7.36(m，5H，Ar-H)，7.64(t，2H，Ar-H，J 1＝7.5Hz))，8.28(d，1H，-CONH-，J＝7.8Hz))，9.82(s，1H，-CONH-)； 13C?NMR(DMSO-d 6，75MHz)δ：52.7，58.5，59.1，66.1，72.1，119.7，120.3，123.3，128.2，128.3，128.8，129.3，137.1，137.2，139.0，156.3，168.5，171.5.
Figure BDA0000076593340000193
5f： 1H?NMR(DMSO-d 6，300MHz)δ：0.90(3H，t，J＝7.2Hz，-CH 2 CH 3)，1.55-1.63(2H，m，- CH 2CH 3)，2.26(2H，t，J＝7.2Hz，- CH 2CH 2)，3.62(3H，s，OCH 3)，5.05(2H，s，-OCH 2)，5.19(1H，d，J＝7.2Hz，-CH)，7.04(1H，d，J＝7.5Hz，Ar-H)7.35(6H，m，Ar-H)，7.57(2H，m，Ar-H)，8.26(1H，d，J＝7.5Hz，-CONH )，9.94(1H，s，-CONH)； 13C?NMR(DMSO-d 6，75MHz)δ：14.1，19.0，38.7，52.7，58.5，66.1，118.9，119.3，122.7，128.2，128.3，128.8，129.4，137.1，137.2，139.9，156.4，171.5，171.7.
The PPRE agonist activity of embodiment six, part of compounds of the present invention detects
The HepG2 cell that will infect the recombinant expression vector that contains PPRE gene and luciferase (Luc) reporter gene is inoculated in 96 orifice plates, after cellar culture spends the night, use the low sugar DMEM substratum that contains 10.00 μ g/mL testing samples instead, set up simultaneously blank (not adding sample) and positive control (adding the positive reference compound pioglitazone of 0.78 μ g/mL), continue to cultivate after 24 hours, measure chemiluminescence intensity L value and calculate exciting rate: exciting rate=[(L1 Sample-L1 Blank)/(L1 Negative-L1 Blank)]/[(L2 Sample-L2 Blank)/(L2 Negative-L2 Blank)] * 100%, wherein L1 is the chemiluminescence intensity of Photinus pyralis LUC, and L2 is the chemiluminescence intensity of internal reference renilla luciferase, and relatively exciting rate is greater than 70% sample determination EC 50Value, each diluted sample is six concentration gradients during mensuration, each concentration is established two multiple holes.Test-results sees Table 10 and table 11.
The PPRE agonist activity detected result of table 10 part of compounds
Figure BDA0000076593340000201
As can be seen from Table 10, the relative exciting rate of the PPRE of compound M2-b, 1b, 1e, 2f, 3a, 3b, 3d, 4e, 5a and 5b all reaches more than 30%, and wherein 3 the highest compounds of the relatively exciting rate of PPRE are followed successively by 4e (120.42%), 1b (105.04%) and 2f (88.65%).
(1) relatively the relatively exciting rate of PPRE of M2-a～M2-c, M3-a～M3-c, 1a～1c can find that the L-phenylglycine derivatives shown in the formula I is at R 2And R 3In the identical situation, R 1For the PPRE agonist activity of Z than R 1For Fmoc or Ts good.
(2) relatively the relatively exciting rate of PPRE of 1b, 2a～2m, 5a～5f can find that the L-phenylglycine derivatives shown in the formula I is at R 1=Z and R 3=OCH 3Situation under, R 2For-H ,-Cl ,-OCH 3, The PPRE agonist activity better.
(3) relatively the relatively exciting rate of PPRE of 3a～3e can find that the L-phenylglycine derivatives shown in the formula I is at R 1=Z and R 3In the situation of=OH, R 2For
Figure BDA0000076593340000211
The PPRE agonist activity better.
(4) relatively the relatively exciting rate of PPRE of 1b, 4a～4e can find that the L-phenylglycine derivatives shown in the formula I is at R 1And R 2In the identical situation, R 3For-OCH 3,-N (CH 3) CH 2CH 2The PPRE agonist activity of OH is better.
(5) relatively 1b can find that with the relative exciting rate of PPRE of 1e the L-phenylglycine derivatives shown in the formula I is at R 1=Z and R 2In the situation of=Cl, R 3For-OCH 3The PPRE agonist activity than R 3For-OH is good.Relatively 2a～2b can find that with the relative exciting rate of PPRE of 3a～3b, 2c～2e and 3c～3e the L-phenylglycine derivatives shown in the formula I is at R 1=Z and R 2=
Figure BDA0000076593340000212
The alpha-glucosidase of embodiment seven, part of compounds of the present invention suppresses determination of activity
Contain by the alpha-glucosidase that extracts in the rat intestinal in the 100 μ L reaction systems, 67nM sodium phosphate buffer (PH6.8) and 10.00 μ g/mL testing samples, set up simultaneously blank (not containing enzyme and sample), negative control (not containing sample) and positive control (containing the positive reference compound voglibose of 1.00 μ g/mL), 37 ℃ were reacted 10 minutes, add again 0.1M maltose, room temperature reaction 10 minutes, add again 200 μ L glucose detection reagent (company is built up in Nanjing), mixing is measured the OD value and is calculated inhibiting rate: inhibiting rate=[1-(OD in wavelength 490nm place Sample-OD Blank)/(OD Negative-OD Blank)] * 100%.Test-results sees Table 12.
The alpha-glucosidase of table 12 part of compounds suppresses the determination of activity result
Figure BDA0000076593340000213
As can be seen from Table 12, the alpha-glucosidase of the compounds of this invention inhibition activity is all lower.
The DPP-IV of embodiment eight, part of compounds of the present invention suppresses determination of activity
Contain DPP-IV (Sigma), 25mM HEPES damping fluid in the 200 μ L reaction systems and (contain 140mM NaCl, massfraction and be 1% BSA and 80mM MgCl 2) and 10.00 μ g/mL testing samples, set up simultaneously blank (not containing enzyme and sample), negative control (not containing sample) and positive control (containing the positive reference compound KR-62436 of 0.30 μ g/mL), room temperature reaction 10 minutes, add again dipeptidyl peptidase enzyme substrates GLY-PRO-GLY-GLY, room temperature reaction 25～40 minutes, measure fluorescence intensity F (excitation wavelength 355nm, emission wavelength 460nm) and calculate inhibiting rate: inhibiting rate=[1-(F Sample-F Blank)/(F Negative-F Blank)] * 100%.Test-results sees Table 13.
The DPP-IV of table 13 part of compounds suppresses the determination of activity result
Figure BDA0000076593340000221
As can be seen from Table 13, the DPP-IV of the compounds of this invention inhibition activity is all lower.
Explanation is at last, above embodiment is only unrestricted in order to technical scheme of the present invention to be described, although by invention has been described with reference to the preferred embodiments of the present invention, but those of ordinary skill in the art is to be understood that, can make various changes to it in the form and details, and not depart from the spirit and scope of the present invention that appended claims limits.

Claims (10)

1. the L-phenylglycine derivatives shown in the formula I:
Figure FDA0000076593330000011
In the formula, R 1Be amino protecting group;
R 2For-NO 2,-NH 2Or-NHCO (CH 2) nR 4, n=1-8, R 4Be hydrogen, halogen, hydroxyl, acyloxy, C1-C8 alkoxyl group, sulfydryl, substituted sulfhydryl, amino, substituted-amino or nitrogen heterocycle;
R 3For-OR 5Or NR 6R 7, R 5Be the C1-C8 alkyl of hydrogen, C1-C8 alkyl or replacement, R 6, R 7Be the C1-C8 alkyl of hydrogen, hydroxyl, C1-C8 alkyl or replacement independently.
2. the L-phenylglycine derivatives shown in the formula I according to claim 1 is characterized in that: R 1Be Z, Fmoc, Boc or Ts.
3. the L-phenylglycine derivatives shown in the formula I according to claim 2 is characterized in that: R 1Be Z.
4. the L-phenylglycine derivatives shown in the formula I according to claim 1 is characterized in that: R 4Be hydrogen, halogen, hydroxyl, acyloxy, C1-C8 alkoxyl group, sulfydryl, substituted sulfhydryl, amino, substituted-amino, phthalimide-based, tetrazole-1-base, substituted tetrazole-1-base, pyrazol-1-yl, substituted pyrazolecarboxylic-1-base, benzoglyoxaline-1-base, substituted benzimidazole-1-base, benzotriazole-1-base, replacement benzotriazole-1-base, piperazine-1-base, N-substituted-piperazinyl-1-base, uridylic-1-base or substituted uracil-1-base.
5. the L-phenylglycine derivatives shown in the formula I according to claim 4 is characterized in that: R 2For-NO 2,-NH 2Or-NHCOCH 2R 4, R 4Be hydrogen; halogen; hydroxyl; acetoxyl group; the C1-C8 alkoxyl group; sulfydryl; benzimidazolyl-2 radicals-Ji sulfydryl; amino; Fmoc-is amino; Z-is amino; N-methyl-N-ethylamino; the amine sulfonyl-phenyl is amino; phthalimide-based; tetrazole-1-base; 5-methyl tetrazole-1-base; 5-phenyl tetrazole-1-base; 5-methyl mercapto tetrazole-1-base; pyrazol-1-yl; 3，5-dimethylpyrazole-1-base; benzoglyoxaline-1-base; benzotriazole-1-base; N-amino protecting group-piperazine-1-base; N-phenylpiperazine-1-base; uridylic-1-base or methyl uracil-1-base.
6. the L-phenylglycine derivatives shown in the formula I according to claim 5 is characterized in that: R 2For-NO 2Or-NHCOCH 2R 4, R 4Be hydrogen, chlorine, methoxyl group, benzimidazolyl-2 radicals-Ji sulfydryl, 4-[(5-methyl isoxzzole-3-yl) sulfamyl] phenyl amino, phthalimide-based, benzotriazole-1-base or N-Boc-piperazine-1-base.
7. the L-phenylglycine derivatives shown in the formula I according to claim 6 is characterized in that: R 2For-NHCOCH 2R 4, R 4Be chlorine or benzotriazole-1-base.
8. the L-phenylglycine derivatives shown in the formula I according to claim 1 is characterized in that: R 3For-OR 5Or NR 6R 7, R 5Be hydrogen, C1-C4 alkyl or benzyloxy, R 6, R 7Be hydrogen, hydroxyl, C1-C4 alkyl or hydroxyethyl independently.
9. the L-phenylglycine derivatives shown in the formula I according to claim 8 is characterized in that: R 3For-OCH 3Or-N (CH 3) CH 2CH 2OH.
10. the application of the L-phenylglycine derivatives shown in the formula I claimed in claim 1 in preparation PPRE agonist.
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