CN100480234C - N-(N-benzoyl-phenylalanyl)-phenylalanine dipeptide derivative, and preparing method and use thereof - Google Patents
N-(N-benzoyl-phenylalanyl)-phenylalanine dipeptide derivative, and preparing method and use thereof Download PDFInfo
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- CN100480234C CN100480234C CNB2006102010164A CN200610201016A CN100480234C CN 100480234 C CN100480234 C CN 100480234C CN B2006102010164 A CNB2006102010164 A CN B2006102010164A CN 200610201016 A CN200610201016 A CN 200610201016A CN 100480234 C CN100480234 C CN 100480234C
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- nmr
- dmso
- benzoyl
- phenylalanyl
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- 108010016626 Dipeptides Proteins 0.000 title claims abstract description 14
- XHHGICRKFOUSQV-VXKWHMMOSA-N (2s)-2-[[(2s)-2-benzamido-3-phenylpropanoyl]amino]-3-phenylpropanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)C=1C=CC=CC=1)C1=CC=CC=C1 XHHGICRKFOUSQV-VXKWHMMOSA-N 0.000 title claims abstract description 13
- 238000000034 method Methods 0.000 title abstract description 11
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- 239000003814 drug Substances 0.000 claims abstract description 15
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- 239000000460 chlorine Substances 0.000 claims description 30
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 claims description 17
- 238000002360 preparation method Methods 0.000 claims description 17
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 14
- 208000002672 hepatitis B Diseases 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 12
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 150000002431 hydrogen Chemical class 0.000 claims description 6
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- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
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- 229910052731 fluorine Inorganic materials 0.000 claims description 3
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- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
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- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 16
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- 239000000203 mixture Substances 0.000 description 7
- GTVVZTAFGPQSPC-QMMMGPOBSA-N (2s)-2-azaniumyl-3-(4-nitrophenyl)propanoate Chemical compound OC(=O)[C@@H](N)CC1=CC=C([N+]([O-])=O)C=C1 GTVVZTAFGPQSPC-QMMMGPOBSA-N 0.000 description 6
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- NPKISZUVEBESJI-AWEZNQCLSA-N N-benzoyl-L-phenylalanine Chemical compound C([C@@H](C(=O)O)NC(=O)C=1C=CC=CC=1)C1=CC=CC=C1 NPKISZUVEBESJI-AWEZNQCLSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- NPKISZUVEBESJI-UHFFFAOYSA-N Nalpha-benzoyl-L-phenylalanine Natural products C=1C=CC=CC=1C(=O)NC(C(=O)O)CC1=CC=CC=C1 NPKISZUVEBESJI-UHFFFAOYSA-N 0.000 description 1
- 241000237502 Ostreidae Species 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- 241000473945 Theria <moth genus> Species 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- RYCTYVDERZWBDC-AADKRJSRSA-N [N+](=O)([O-])C1=CC=C(C=C1)C([C@@H](N)C)O Chemical compound [N+](=O)([O-])C1=CC=C(C=C1)C([C@@H](N)C)O RYCTYVDERZWBDC-AADKRJSRSA-N 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 239000012675 alcoholic extract Substances 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 239000003636 conditioned culture medium Substances 0.000 description 1
- 235000019628 coolness Nutrition 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000007336 electrophilic substitution reaction Methods 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- 125000004672 ethylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C(*)=O 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229940030980 inova Drugs 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical class OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 1
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 1
- 229960001627 lamivudine Drugs 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- VXYFARNRGZWHTJ-FVGYRXGTSA-N methyl (2s)-2-amino-3-(4-hydroxyphenyl)propanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CC1=CC=C(O)C=C1 VXYFARNRGZWHTJ-FVGYRXGTSA-N 0.000 description 1
- BTHMRXRBXYHLRA-FVGYRXGTSA-N methyl (2s)-2-amino-3-(4-nitrophenyl)propanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CC1=CC=C([N+]([O-])=O)C=C1 BTHMRXRBXYHLRA-FVGYRXGTSA-N 0.000 description 1
- SWVMLNPDTIFDDY-FVGYRXGTSA-N methyl (2s)-2-amino-3-phenylpropanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CC1=CC=CC=C1 SWVMLNPDTIFDDY-FVGYRXGTSA-N 0.000 description 1
- NLWBJPPMPLPZIE-UHFFFAOYSA-N methyl 4-(bromomethyl)benzoate Chemical compound COC(=O)C1=CC=C(CBr)C=C1 NLWBJPPMPLPZIE-UHFFFAOYSA-N 0.000 description 1
- QSSJZLPUHJDYKF-UHFFFAOYSA-N methyl 4-methylbenzoate Chemical compound COC(=O)C1=CC=C(C)C=C1 QSSJZLPUHJDYKF-UHFFFAOYSA-N 0.000 description 1
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- XWEMGJQQCSSGPN-BDYUSTAISA-N n-[(2s)-3-[4-[2-(dimethylamino)ethoxy]phenyl]-1-[[(2s)-1-hydroxy-3-phenylpropan-2-yl]amino]-1-oxopropan-2-yl]benzamide Chemical compound C1=CC(OCCN(C)C)=CC=C1C[C@@H](C(=O)N[C@H](CO)CC=1C=CC=CC=1)NC(=O)C1=CC=CC=C1 XWEMGJQQCSSGPN-BDYUSTAISA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 235000020636 oyster Nutrition 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 125000000405 phenylalanyl group Chemical group 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- ZRVUAXXSASAVFG-QRPNPIFTSA-M sodium;(2s)-2-amino-3-phenylpropanoate Chemical compound [Na+].[O-]C(=O)[C@@H](N)CC1=CC=CC=C1 ZRVUAXXSASAVFG-QRPNPIFTSA-M 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
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Abstract
The invention relates to an N-(N-benzoyl-phenylalanyl)-phenylalanine dipeptide derivative and the preparing method and use thereof, comprising its racemic forms or optical isomers, its pharmaceutically acceptable salts or hydrates, and the drug combinations of it and one or multiple pharmaceutically acceptable carriers and excipients or thinners, where a compound can inhibit HBV activity and less has other toxicity and side-effects, and is a quasi-nonnucleoside antivirus drug, able to be used to prepare drugs of curing virus infection, especially anti-HBV and anti-HIV (human immunodeficiency virus) drugs.
Description
Technical field: the invention belongs to the pharmaceutical chemistry technical field, relate to N-(N-benzoyl-phenylalanyl)-phenylalanine dipeptide derivative and preparation method thereof with and in the particularly application in hepatitis B virus (HBV) infection medicine of preparation treatment viral infection.
Technical background: hepatitis B virus (Hepatitis B Virus, HBV) infecting is one of global principal disease that influences human health, and the whole world has the person of chronic HBV infection more than 400,000,000 at present, and wherein about 75% is distributed in the Asian-Pacific area.The prognosis mala of chronic hepatitis B can develop into liver cirrhosis and primary hepatocarcinoma, and the whole world is annual to have 1,000,000 people to die from hepatitis b virus infected relative disease approximately, accounts for the 9th of the disease cause of the death.
Covalently closed circular DNA (covalently closed circular.DNA, cccDNA) be the existence form of HBV DNA in host cell nuclear, be hbv replication and the template of transcribing, existing medicine is to cccDNA unrestraint effect in examining, make that its long-term existence is difficult to remove in nucleus, thereby cause that HBV DNA is sustainable to be duplicated.And cause the generation of HBV virus mutation strain in the long-term prescription process easily, sudden change as HBV archaeal dna polymerase YMDD (tyrosine-methionine(Met)-aspartic acid-aspartic acid), the sudden change of Pre-S gene etc.) and patient's reasons such as immunological tolerance, cause present antiviral therapy only effective to the sub-fraction patient, make that up to the present the mankind also do not find a kind of really effective Perfected process in tackling the process of hepatitis B virus infection.From the molecular biological knowledge of hepatitis B virus, be conceived to hepatitis B virus recursive copying mechanism, adopt cooperation of multiple sciences, screen the original new drug of the different mechanisms of action and action mode and control duplicating of hepatitis B virus, remove hepatitis B virus in the body, suppress the generation of virus mutation strain, avoiding " knock-on " phenomenon after the drug withdrawal is the pharmaceutical chemists direction of capturing from now on.On this research direction, separation and Extraction anti-hepatitis B virus activities composition and carry out structural modification from known natural phant with stronger anti-hepatitis B virus activities, finding the comparatively ideal medicine of curative effect, carry out a large amount of synthetic then, is the important channel of anti-hepatic-B virus medicine research.
Goal of the invention: for developing the anti-hepatic-B virus medicine of new and effective low toxicity; the inventor is to separate [the N-(N-benzoyl-L-phenylalanyl)-O-ethanoyl-L-phenylalaninol of the monomer with anti-hepatitis B virus activities that obtains from Miao ethnic group's medicine Herba Dichodrae (Dichondra repens Forst.); obtained patent of invention; the patent No.: 02160309.X] be parent; it is carried out structural modification and improvement and design; synthesized-N-(N-benzoyl-phenylalanyl)-phenylalanine dipeptide derivative of series structure novelty; and institute's synthetic compound carried out biological activity test; the anti-hepatitis B virus activities of having found the part derivative is better than parent compound; and less other toxic side effect that occurs; thereby this compounds has been carried out comparatively deep research, finished the present invention.
Summary of the invention:
The present invention relates to the compound of structure shown in general formula I and its preparation method and application, comprise (2S, 2 ' S), (2S, 2 ' R), (2R, 2 ' S) or (2R, 2 ' R) any stereoisomer or its raceme or optically active isomer or its mixture, or its pharmacy acceptable salt or hydrate, (I) is as follows for general formula:
General formula (I)
Wherein:
R
1And R
3Represent respectively hydrogen, fluorine, chlorine or bromine ,-NO
2,-NH
2,-CN ,-NHR ,-NRR ' ,-NHCOR ,-OH, (4-OH, 3-CH
2NRR ') ,-OCOR ,-OR ,-NHCO (CH
2)
nCOOH ,-O (CH
2)
nNRR ' ,-O (CH
2)
nCOOR or-O (CH
2)
nCOOH;
R
2Be hydrogen, C
1-C
6Alkyl, fluorine, chlorine or bromine ,-NO
2,-NH
2,-CN ,-NHR ,-NRR ' ,-NHCOR ,-OH ,-OCOR ,-OR ,-NHCO (CH
2)
nCOOH ,-O (CH
2)
nNRR ' ,-O (CH
2)
nCOOH ,-CH
2NRR ',
COOH or-COOR;
R
4Be CH
2OH, COOR, CH
2OCOR, CH
2OCO (CH
2)
2COOH or COONa;
X is CH or N;
R
1, R
2And R
3Can be respectively single or multiple substituting groups, and be in contraposition and an ortho position and a position on the phenyl ring respectively;
R, the identical or different C of R ' representative
1-C
6Straight or branched alkyl, or C
3-C
7Cycloalkyl;
N is 1 to 4 integer;
Described alkyl and cycloalkyl can be by 1-2 optional replacements of substituting group that is selected from hydroxyl, nitro, halo, cyano group, trifluoromethyl.
Compound according to the present invention can be used as activeconstituents and is used to prepare the hepatitis b virus infected medicine of treatment; the present invention includes pharmaceutical composition; said composition contains the N-shown in the general formula (I) (N-benzoyl-phenylalanyl)-phenylalanine dipeptide derivative; or its pharmacy acceptable salt or hydrate be as activeconstituents, and pharmaceutically acceptable vehicle.Described pharmaceutically acceptable vehicle is meant any thinner, auxiliary or carrier that can be used for pharmaceutical field.Compound of the present invention can be used in combination with other activeconstituentss, as long as they do not produce other disadvantageous effects, and for example anaphylaxis etc.
Drug regimen of the present invention can be mixed with some kinds of formulations, wherein contains some vehicle commonly used in the pharmaceutical field; For example, oral preparation (as tablet, capsule, solution or suspension); Injectable preparation (as injectable solution, suspension or powder injection); Topical formulations (for example ointment or solution).
The carrier that is used for pharmaceutical composition of the present invention is the available common type of pharmaceutical field, comprising: the tackiness agent that oral preparations is used, lubricant, disintegrating agent, solubility promoter, thinner, stablizer, suspension agent, non-pigment, the agent of sedan-chair flavor etc.; The sanitas that injectable formulation is used, solubility promoter, stablizer etc.; The matrix that local application's preparation is used, thinner, lubricant sanitas etc.Pharmaceutical preparation can oral administration or parenteral mode (as intravenously, subcutaneous, intraperitoneal or part) administration, if some drugs is the unsettled enteric coated tablets that is made under the stomach condition.
Following synthetic route I and synthetic route II have described the preparation method of general formula of the present invention (I) compound.
Synthetic route I
(I-a).HNO
3/H
2SO
4，rt.；(I-b).MeOH，SOCl
2，rt.；(I-c).NaBH
4/H
2O，0-10℃；
(I-a) with L-phenylalanine (perhaps L-tyrosine) as raw material, (volume ratio is: nitric acid: sulfuric acid=1.2: 1) in room temperature it is carried out nitration reaction, can obtain Compound I-1 (productive rate :～95%) to adopt nitration mixture; (I-b) reaction flask that 90ml methyl alcohol will be housed places cryosel to bathe fully cooling and stirring, drips 9.5ml (132mmol) thionyl chloride (SOCl
2).After dropwising, reaction rises to room temperature, adds the Compound I-1 of 100mmol, stirring at room 2.5h, water-bath backflow 30min.Decompression and solvent recovery is to doing, the gained residue with methyl alcohol-ether mixed solvent recrystallization get final product crystalloid Compound I-2 (productive rate :～85%); (I-c) get NaBH
41.13g (30mmol) be dissolved in the 15ml water, cryosel is bathed cooling, stirs in the aqueous solution that slowly is added drop-wise to the Compound I-2 that 15ml contains 9.2mmol down, after the reaction nature rises to room temperature (needing 2h approximately), spends the night in room temperature reaction again.Next day, (3 * 50ml) extractive reaction liquid merged methacrylate layer, successively with saturated NaHCO with ethyl ester
3(20ml), saturated sodium-chloride (20ml) washs anhydrous Na SO
4Drying, decompression and solvent recovery to do pale yellow powder shape intermediate compound I-3 (productive rate :～70%).
(I-d) .SOCl
2, reflux; (I-e) .2.0M NaOH (aq.);
R
2Be hydrogen, C
1-C
6Alkyl, halo ,-NO
2
(I-d) get benzoic acid derivative I-4 and add in the thionyl chloride and dissolve, be back to no hydrogen chloride gas and emit, the evaporated under reduced pressure solvent promptly gets Benzoyl chloride derivative I-5; (I-e) Benzoyl chloride derivative I-5 is joined place the ice bath refrigerative to dissolve the sodium hydroxide solution of L-phenylalanine, the reaction nature rises to and continues reaction 2h, the purified intermediate compound I-7 (productive rate :～90%) that promptly gets of products therefrom under the room temperature.
(I-f).DCC，DMAP，CH
2Cl
2，rt.；(I-g).1.0M?NaOH，rt.；
R
1For hydrogen ,-NO
2Or-OH
R
2Be hydrogen, C
1-C
6Alkyl, halo ,-NO
2,-NH
2,-CN ,-NHCOR ,-OH etc.
(I-f) with benzoic acid derivative I～8 of 10mmol and the L-L-Tyrosine methyl ester of 10mmol or derivative I-9, the dicyclohexyl two carbimide (DCC of phenylalanine methyl ester, 2.47g, 12mmol), to Dimethylamino pyridine (DMAP, 200mg, as catalyzer) be mixed in the reaction flask, inject anhydrous CH
2Cl
2150ml reacts on stirred overnight at room temperature under the nitrogen protection.Remove by filter dicyclohexylurea (DCU) (DCU) precipitation that reaction produces next day, filtrate is reclaimed solvent to doing the purified intermediate compound I-10 (productive rate :～95%) that promptly gets of product; (I-g) intermediate 10 of getting 10mmol adds the sodium hydroxide 1.2ml room temperature hydrolysis 2h of 1.0M with an amount of anhydrous alcohol solution, and product purification promptly gets intermediate compound I-11 (productive rate :～95%).
(I-h) isobutyl chlorocarbonate (IBCF), N-methylmorpholine (NMM) ,-5-10 ℃
(I-h) (NMM, 23.0mmol) mixed dissolution is in 50ml exsiccant CH with N-methylmorpholine with aforementioned synthetic intermediate compound I-12 (1.0mmol), I-13 (1.05mmol)
2Cl
2In, cryosel is bathed (5 ℃) cooling down, and (IBCF 1.07mmol), continues stirring reaction 30min again after dropwising to drip isobutyl chlorocarbonate.Add a little termination reaction of water, decompression and solvent recovery is to doing, and the gained solid is complete with an amount of EtOAc dissolving, successively with distilled water, dilute hydrochloric acid, distilled water, 5%NaHCO
3With saturated NaCl solution washing, anhydrous sodium sulfate drying, the reclaim under reduced pressure ethyl acetate is to doing, and the gained residue is promptly to get target product (productive rate :～65%) through recrystallization.
Synthetic route II
(II-a) (t-BuOCO)
2O, 1.0M NaOH, TBAB; (II-b) CH
2Cl
2, isobutyl chlorocarbonate (IBCF), N-methylmorpholine (NMM) ,-5-10 ℃;
(II-c)TFA，CH
2Cl
2，rt，2h；(II-d)DCC，DMAP，CH
2Cl
2，rt.
(II-a) to get L-phenylalanine derivative 10.0mmol and be dissolved in the 20ml1.0M NaOH solution, add. tert-Butyl dicarbonate is { (t-BuOCO)
2O}10.05mmol and Tetrabutyl amonium bromide (Tetrabutyl ammonium bromide, TBAB, 1.0g), stirred overnight at room temperature.Next day with concentrated hydrochloric acid conditioned reaction liquid to pH2-3, ethyl acetate extraction, methacrylate layer washs with saturated sodium-chloride, again through anhydrous sodium sulfate drying, decompression and solvent recovery promptly gets intermediate II-2 (productive rate :～98%) to doing; (II-b) its operation steps is similar to (I-h) operation, is prepared into intermediate II-4 (productive rate: 88%)
(II-c) getting synthetic gained intermediate II-4 sample of preceding-step dissolves with trifluoroacetic acid (TFA), stirring at room 2h, it is an amount of to add water in reaction flask, be adjusted to alkalescence (pH11-12) with yellow soda ash, ethyl acetate extraction, organic phase is difficult the aqueous sodium persulfate drying, decompression and solvent recovery to do white waxy solid sample II-5 (productive rate :～65%).
(II-d) with aforementioned synthetic intermediate II-5 (10mmol) and self-control benzoic acid derivative II-6 (10mmol), DCC (2.47g, 12mmol), DMAP (200mg is as catalyzer) is mixed in the reaction flask, injects anhydrous CH
2Cl
2200ml reacts on stirred overnight at room temperature under the nitrogen protection.Product promptly gets target product (productive rate :～90%) through extraction and recrystallization purifying.
Wherein synthetic route I is applicable to R
2Be hydrogen, C
1-C
6Alkyl, halo ,-NO
2,-CN ,-NHCOR ,-OH ,-OCOR ,-derivative of OR etc. is synthetic:
Synthetic route II is applicable to R
2For-CH
2NRR ',
Derivatives such as-COOR are synthetic.
Select isonicotinic acid derivatives to replace the reaction raw materials of benzoic acid derivative as synthetic route I, can synthesize the middle X of preparation general formula (I) is the derivative of N.
Select suitable reaction substrate respectively; phenylformic acid as L-phenylalanine, D-phenylalanine, L-tyrosine, D-tyrosine, various different substituted benzene L-Ala, various different substituted benzene Propanolamines, various replacements; by synthetic route I or synthetic route II and to derivative carry out the conversion and the replacement of group, for example: nitroreduction be the acidylate of phenolic hydroxyl group on the replacement of amino, aromatic ring amino (through the diazotization intermediate) and acidylate and alkylation etc., the phenyl ring and alkylation or and other electrophilic reagent (as ClCH
2(CH
2)
nNRR ', ClCH
2(CH
2)
nCOOR) replacements etc. can be synthesized N-(N-benzoyl-phenylalanyl)-phenylalanine dipeptide derivative of general formula (I) representative.
The anti-hepatitis B virus activities result of part gained derivative:
Adopt its external anti-hepatitis B virus activities of 2.2.1.5 cell tests.
Test philosophy
With the 2.2.15 cell is the hepatitis B poisonous carrier, and working sample suppresses the ability that hepatitis B virus carries out dna replication dna and produces HBsAg, HBeAg.
Test material and method
A. cell strain: 2.2.15 cell.
B. sample preparation: sample faces with before being dissolved in DMSO and is made into proper concn, makes 3 times of dilutions, totally 8 extent of dilution with nutrient solution during detection.
C. positive control drug: lamivudine (3TC), produce by Glaxo Wellcome company.
D. main agents: hepatitis B virus e antigen and s antigen are put inspection-free test agent box; a
32PdCTP;
E. testing method: 2.2.15 cell kind 96 well culture plates, add sample and positive control drug respectively by above extent of dilution after 36 hours, establish cell control well simultaneously, change the nutrient solution that contains different weaker concn samples after the dosing after 96 hours respectively, the 8th day respectively collecting cell supernatant and 2.2.15 cell after dosing, adopt the RIA method to detect the secretory volume of HBsAg, HBeAg in the cell conditioned medium, the method for dot blot detects HBV dna replication dna degree in the cell, calculates IC respectively
50And SI.
Test result sees Table 1:
The external anti-hepatitis B virus activities test result of table 1 part derivative
(the continuous external anti-hepatitis B virus activities test result of table 1 part derivative)
Experimental result in the anti-duck hepatovirus body of embodiment 75 gained compounds:
Date of test: the 7-8 month in 2006, experimental technique omits, and test result sees Table 2.
Table 2 embodiment 75 gained compounds in the duckling body to restraining effect and the effect of DHBV-DNA
Annotate: self compares (1) in (pairing):
aP＜0.05;
bP＜0.01; (2) (in groups) compares between the group:
cP＜0.05;
dP＜0.01
Compared with prior art; the invention provides N-(N-benzoyl-phenylalanyl)-phenylalanine dipeptide derivative and its preparation method of a series of novel structures; and institute's synthetic compound carried out biological activity test; the anti-hepatitis B virus activities of having found the part derivative is good and less other toxic side effect that occurs than parent compound; thereby this compounds has been carried out comparatively deep research, reached purpose of the present invention.
Embodiment:
Embodiment is intended to set forth rather than limit the scope of the invention.The gained compound is measured it with 400MHz nuclear magnetic resonance analyser (INOVA type, band nanogram trace probe, Varian Inc.)
1H spectrum and
13The C spectrum; Hewlett-Packard's HP-5973 mass spectrograph is measured its molecular weight; Agents useful for same is analytical pure or chemical pure.
(1) preparation of representative reactions intermediate:
1.1 4-nitro-L-phenylalanine (4-nitro-L-phenylalanine, numbering: M-05)
Reagent and reaction conditions: HNO
3/ H
2SO
4(1.4:1.1), rt, 5h
Experimental implementation: get L-phenylalanine 16.5g (100mmol) and be dissolved in 50ml 85% H
2SO
4In, stir and down it dropwise to be added pre-configured and be cooled to the dense HNO of room temperature
3-dense H
2SO
4(V/V:1.4/1.1) in the nitration mixture, stirring at room reaction 5h, reaction solution is regulated pH2-3 with 40% NaOH, produce a large amount of precipitations, filter and be precipitated to neutrality, decompression oven dry and promptly get 4-nitro-L-phenylalanine (4-nitro-L-phenylalanine numbers: M-05) sample 20g (95.2%) with water washing.
Using the used mixed acid nitrification agent of reaction instead rare nitric acid (30%), is that raw material can synthetic intermediate 3-nitro-L-tyrosine with L-tyrosine.
1.2 4-nitro-L-phenylalaninol (4-nitro-L-phenvlalanol, numbering: M-12)
Reagent and reaction conditions: (a) MeOH, SOCl
2, rt, 2.5h, backflow 30min; (b) NaBH
4/ H
2O, reaction is spent the night
Experimental implementation: (a) reaction flask that 90ml methyl alcohol will be housed places cryosel to bathe fully cooling and stirring, drips 9.5ml (132mmol) thionyl chloride (SOCl
2).After dropwising, reaction rises to room temperature, adds 4-nitro-L-phenylalanine (4-nitro-L-phenylalanine, numbering: M-05) 100mmol, stirring at room 2.5h, water-bath backflow 30min.Decompression and solvent recovery is to doing, and the gained residue can obtain pale yellow powder shape 4-nitro-L-phenylalanine methyl ester hydrochloride (numbering: M-06) sample 22.1g (productive rate: 85.0%) with methyl alcohol-ether mixed solvent recrystallization; (b) get NaBH
41.13g (30mmol) be dissolved in the 15ml water, cryosel is bathed cooling, stirs slowly to be added drop-wise to down in the aqueous solution that 15ml contains 2.4g (9.2mmol) M-06, after the reaction nature rises to room temperature (needing 2h approximately), spends the night in room temperature reaction again.Next day, (3 * 50ml) extractive reaction liquid merged methacrylate layer, successively with saturated NaHCO with ethyl ester
3(20ml), saturated sodium-chloride (20ml) washs anhydrous Na SO
4Drying, decompression and solvent recovery to do pale yellow powder shape sample 1.23g, identify the consistent (productive rate: 68.2%) of its structure through wave spectrum with the M-12 structure.
By similar synthetic method, select the L-phenylalanine respectively, L-tyrosine is raw material, can prepare L-phenylalanine methyl ester hydrochloride, L-tyrosine methyl ester hydrochloride, L-phenylalaninol, L-junket ammonia alcohol is as further synthetic raw material.
1.3 4-chloro-acetyl chloride yl benzoic acid { 4-(2-chloroacetamido) benzoic acid}
Reagent and reaction conditions: 1.0M NaOH (aq.) ,-5 ℃, 2h is again in stirred overnight at room temperature
Experimental implementation: get 4-benzaminic acid 13.7g (100mmol) and be dissolved among the 220ml1.0M NaOH, put-5 ℃ of coolings in the cryosel bath, and dropping chloroacetyl chloride 2-chloroacetyl chloride (12ml, 0.15mol), dropwise the back and continue reaction 2h, rise to the stirring at room reaction again and spend the night.Next day, to pH1-2, filtering-depositing was washed to nearly neutrality with concentrated hydrochloric acid conditioned reaction liquid, and oven dry promptly gets white powder 4-chloro-acetyl chloride yl benzoic acid { 4-(2-chloroacetamido) benzoic acid} sample 15.58g (productive rate: 73.0%)
1.4 2-chloro-N, and N-dimethyl amine hydrochloride (2-chloro-N, N-dimethylethanaminehydrochloride)
Reagent and reaction conditions: SOCl
2, CHCl
3, backflow 4h
Experimental implementation: get the 2-dimethylamino-ethanol 2-(dimethylamino)-ethanol} (5ml, 0.05mol) and 20mlCHCl
3Mix, stirring at room drips SOCl
2(4.3ml 0.06mol), dropwises after (needing 2h approximately) water-bath backflow 3h again, and decompression and solvent recovery is dissolved in residue among the 100ml EtOH to doing, filter and remove insoluble impurities, the filtrate evaporate to dryness, again with the gained solid dispersed in 100ml CH
2Cl
2In, agitation as appropriate is filtered, and precipitation is with The addition of C H
2Cl
2Washing is dried, and promptly gets the intermediate 2-chloro-N of white powder, N-dimethyl amine hydrochloride sample 6.18g (productive rate: 85.8%).
1.5 M-25's is synthetic
Reagent and reaction conditions: (a) NBS, ABIN, CCl
4, backflow 12h; (b) NH (CH
3)
2Bian Cl, K
2CO
3, KI, anhydrous EtOH, rt, reaction is spent the night; (c) 1.0M HCl (aq.), backflow 8h
Experimental implementation: (4.5g 30mmol), is dissolved in 60ml exsiccant CCl (a) to get methyl p-methyl benzoate
4In, add NBS (6.6g, 36.9mmol) and Diisopropyl azodicarboxylate (azobisisobutyronitrile, ABIN 12mg), place oil bath backflow 12h under the argon shield with reaction flask.Remove by filter the precipitation that reaction produces, filtrate decompression reclaims solvent to doing, and promptly gets oyster white oily matter 4-brooethyl-methyl benzoate (methyl 4-bromomethylbenzoate, numbering: M-23) 8.58g (theoretical yield 6.87g); (b) get NH (CH
3)
2HCl (6.11g, 75mmol), K
2CO
3(17.25g, 125mmol) and KI (1.66g 10mmol) mixes in the 50ml dehydrated alcohol, nitrogen protection drips M-23 (50mmol) down, the stirring at room reaction is spent the night, and handle reaction solution next day through abstraction purification, promptly get colorless oil 4-dimethyl aminomethyl methyl benzoate; (C) get the back products therefrom with 1.0M HCl dissolving back hydrolysis 8h, vacuum distillation recovered solvent, oven dry promptly gets the 4-dimethyl aminomethyl benzoate hydrochlorate (numbering: M-25) sample of pale powder shape.
Can synthesize the intermediate of array structure down by the method for above-mentioned synthetic M-25
(2) the synthetic preparation of target product
Embodiment 01:N-(N-benzoyl-L-phenylalanyl)-L-phenylalanine methyl ester
Reagent and reaction conditions: (a) 2.0M NaOH (aq.), Benzoyl chloride ,-5 ℃ of to rt, 3h, 93%; (b) CH
2Cl
2, isobutyl chlorocarbonate (isobutyl chloroformate, IBCF), N-methylmorpholine (N-methylmorpholine, HMM) ,-5 ℃
Experimental implementation: (a) 1.65g L-phenylalanine (10.0mmol) is dissolved in the 11ml 2.0M sodium hydroxide solution, cryosel is bathed cooling, stirs to drip Benzoyl chloride 10.0mmol down.Dropwise, again reaction is risen to and continue reaction 2h under the room temperature, reactant is regulated pH5-6 with 1.8ml (21.6mmol) concentrated hydrochloric acid, the precipitation that produces after filtration, water washing is to neutral, drying, the N-benzoyl-L-phenylalanine that promptly gets white powder (is numbered: M-03) sample 2.50g (productive rate: 93.0%); (b) (NMM, 23.0mmol) mixed dissolution is in 50ml exsiccant CH with N-methylmorpholine with preceding step synthetic intermediate M-03 (1.0mmol), M-01 (1.05mmol)
2Cl
2In, cryosel is bathed (5 ℃) cooling down, drip isobutyl chlorocarbonate (IBCF, 1.07mmol), continue after dropwising to stir 2h (TLC detection reaction process) again, add a little termination reaction of water, decompression and solvent recovery is to doing, the gained solid is complete with an amount of EtOAc dissolving, successively with distilled water, dilute hydrochloric acid, distilled water, 5%NaHCO
3With saturated NaCl solution washing; anhydrous sodium sulfate drying; the reclaim under reduced pressure ethyl acetate is to doing, and the gained residue promptly gets N-(N-benzoyl-L-phenylalanyl)-L-phenylalanine methyl ester { N-(N-benzoyl-L-phenylalanyl)-L-phenylalanine methyl ester} crystallized sample 280mg (productive rate: 65.0%) of white needles with re-crystallizing in ethyl acetate.
Spectroscopic data: EI-MS m/z:430 (M
+), 283,240,128,114,72,59 (100), 43;
1H-NMR (CDCl
3, 400MHz) δ: 7.68 (2H, d, J=7.6Hz, H-3 ", 7 "), 7.51 (1H, m, H-5 "), 7.42 (2H, t, H-4 ", 6 "), 7.31-7.13 (8H, m, H-5; 9,6,8,5 ', 9 ', 6 ', 8 '), 6.97 (2H; m, H-7,7 '), 6.76 (1H, d, J=7.4Hz, NHCO), 6.37 (1H; d, J=7.6Hz, NHCO), 4.85 (1H, m, H-2), 4.77 (1H, m; H-2 '), 3.70 (3H, s, OMe), 3.23-2.94 (4H, m, H-3,3 ');
13C-NMR (CDCl
3, 100MHz) δ: 171.3 (C-1), 170.4 (C-1 '), 167.0 (C-1 "), 136.4 (C-4); 135.5 (C-4 '), 133.6 (C-2 "), 131.8 (C-5 "), 129.4 (C-6,8); 129.1 (C-6 ', 8 '), 128.7 (C-4 ", 6 "), 128.6 (C-5; 9), 128.5 (C-5 ', 9 '), 127.1 (C-3 ", 7 "), 127.0 (C-7,7 '), 54.5 (C-2); 53.4 (C-2 '), 52.3 (C-COMe), 38.0 (C-3), 37.8 (C-3 ').
According to the synthetic method that is similar to embodiment 1, select suitable reaction raw materials and intermediate, can make the derivative of embodiment 02～18 respectively.
Embodiment 02:N-(N-benzoyl-L-phenylalanyl)-L-phenylalaninol
Spectroscopic data:
1H-NMR (CDCl
3, 400MHz) δ: 7.72 (2H, d, J=8.0Hz, H-3 ", 7 "), 7.53 (1H, t, J=7.2Hz, H-5 "), 7.44 (2H, t; H-4 ", 6 "), 7.35-7.07 (10H, m, H-5-9,5 '-9 '); 6.80 (1H, d, J=7.6Hz, NHCO), 5.92 (1H, d; J=7.6Hz, NHCO), 4.77 (1H, m, H-2), 4.10 (1H; m, H-2 '), 3.42 (2H, m, H-1 '); 3.27 (1H, dd, J=5.6,13.6Hz, H-3a), 3.04 (1H, dd, J=9.2,13.6Hz, H-3b), 2.77 (1H, dd, J=7.6,13.6Hz, H-3a), 2.68 (1H, dd, J=6.8,13.6Hz, H-3 ' is b); M (EI) m/z:402 (M
+), 384,311,252,224 (100), 92.
Embodiment 03:N-(N-4-fluoro-benzoyl-L-phenylalanyl)-L-phenylalanine methyl ester
Spectroscopic data:
1H-NMR (CDCl
3, 400MHz) δ: 7.69-7.72 (2H, m, H-3 ", 7 "), 7.07-7.28 (10H, m, H-5-9,5 '-9 '), 6.96-6.98 (2H, m, H-4 ", 6 "), 6.80 (1H, d, J=7.6Hz, NH), 6.34 (1H, d, J=7.6Hz, NH), 4.76-4.84 (2H, m, H-2,2 '), 3.70 (3H, s, OCH
3), 2.98-3.18 (4H, m, H-3,3 '),
13C-NMR (CDCl
3, 100MHz) δ: 171.24 (s), 170.41 (s), 165.97 (2 * s), 136.28 (s), 135.44 (s), 129.47 (s), 129.38 (4 * d), 129.11 (2 * d), 128.69 (2 * d), 128.55 (2 * d), 127.11 (2 * d), 115.74 (d), 115.52 (d), 54.56 (d), 53.44 (d), 52.38 (q), 38.13 (t), 37.82 (t) MS (EI) m/z:448 (M
+), 416,389,357,309,286,270,242,218,180,162,147,131,123 (100), 120,95,91,77,41,28.15.
Embodiment 04:N-(N-benzoyl-L-phenylalanyl)-L-L-Tyrosine methyl ester,
Spectroscopic data: mp 184.0-186.0 ℃,
1H-NMR (DMSO, 400MHz) δ: 9.18 (1H, s, Ar-OH), 8.52 (1H, d, J=8.4Hz, NHCO), 8.40 (1H, d, J=7.6Hz, NHCO), 7.77 (2H, d, J=7.6Hz, H-3 ", 7 "), 7.50 (1H, t, H-5 "), 7.42 (2H, t, H-4 ", 6 "); 7.33 (2H, d, J=7.2Hz, H-5,9), 7.24 (2H; t, H-6,8), 7.16 (1H, t, H-7); 6.99 (2H, d, J=8.4Hz, H-5 ', 9 '), 6.62 (2H; d, J=8.4Hz, H-6 ', 8 '), 4.74 (1H, m; H-2), 4.45 (1H, m, H-2 '), 3.60 (3H, s, OMe), 3.11-2.84 (4H, m, H-3,3 ');
13C-NMR (DMSO, 100MHz) δ: 171.8 (C-1), 171.5 (C-1 '), 166.2 (C-1 "), 156.0 (C-7 '); 138.2 (C-4), 134.0 (C-2 "), 131.1 (C-5 "), 129.9 (C-5 '; 9 '), 129.1 (C-6,8), 128.0 (* 2); 127.9 (* 2), 127.3 (C-3 ", 7 "), 126.8 (C-7); 126.1 (C-4 '), 115.0 (C-6 ', 8 '), 54.4 (C-2); 53.9 (C-2 '), 51.7 (C-OMe), 36.9 (C-3), 35.9 (C-3 ').
Embodiment 05:N-(N-3-methyl-benzoyl-L-phenylalanyl)-L-phenylalaninol
Spectroscopic data: N-(N-3-methyl-benzoyl-L-phenylalanyl)-L-phenylalanol, mp177.0-178.5 ℃,
1H-NMR (DMSO, 400MHz) δ: 8.44 (1H, d, J=8.4Hz, NHCO), 7.89 (1H, d, J=8.4Hz, NHCO), 7.59-7.56 (2H, m, H-3 ", 7 "), 7.32-7.10 (12H, m, H-5 ", 6 ", H-5-9,5 '-9 '), 4.83 (1H, t, CH
2OH), 4.67 (1H, m, H-2), 3.88 (1H, m, H-2 '), 3.33-3.23 (2H, m, H-1), 3.04-2.91 (2H, m, H-3), 2.85 (1H, dd, J=5.6,13.6Hz, H-3 ' is a), 2.65 (1H, dd, J=8.0,13.6Hz, H-3 ' b), 2.33 (3H, s, Ar-CH
3);
13C-NMR (DMSO, 100MHz) δ: 171.0 (C-1), 166.2 (C-1 "), 139.0 (C-4 '), 138.5 (C-4); 137.5 (C-4 "), 134.1 (C-2 "), 131.9 (C-5 "), 129.3 (* 3, C-6 ', 8 ', 6 "), 128.13 (* 4, C-5 ', 9 '; C-6,8), 128.07 (* 2, C-5,9); 128.0 (C-3 "), 126.2 (C-7 '), 126.0 (C-7), 124.6 (C-7 "), 62.2 (C-1 '); 54.8 (C-2), 52.5 (C-2 '), 33.3,36.5,21.0 (ArCH
3).
Embodiment 06:N-(N-benzoyl-4-nitro-L-phenylalanyl)-L-phenylalaninol
Spectroscopic data: mp 196.0-199.0 ℃,
1H-NMR (DMSO, 400MHz) δ: 8.62 (1H, d, J=8.4Hz, NHCO), 8.12 (2H, d, J=8.8Hz, H-6,8), 8.05 (1H, d, J=8.8Hz, NHCO), 7.78 (2H, d, J=6.4Hz, H-3 ", 7 "), 7.59 (2H, d, J=8.4Hz, H-5,9), 7.51 (1H, t, H-5 "); 7.43 (2H, t, H-4 ", 6 "), 7.26-7.12 (5H; m, H-5 '-9 '), 4.85 (1H, t, OH); 4.76 (1H, m, H-2), and 3.89 (1H, m; H-2 '), 3.32-3.26 (2H, m, H-1 '), 3.19-3.07 (2H; m, H-3), 2.92-2.81 (2H, m, H-3 ');
13C-NMR (DMSO, 100MHz) δ: 170.5 (C-1), 166.1 (C-1 "), 145.0 (C-7), 146.2 (C-4); 139.0 (C-4 '), 133.8 (C-2 "), 131.4 (C-5 "), 130.5 (C-5,9); 129.2 (C-6 ', 8 '), 128.2 (C-4 ", 6 "); 128.1 (C-5 ', 9 '), 127.4 (C-3 ", 7 "); 125.9 (C-7 '), 123.2 (C-6,8), 62.2 (C-1 '); 54.3 (C-2 '), 52.6 (C-2), 37.1 (C-3 '), 34.9 (C-3).
Embodiment 07:N-(N-4-chloro-benzoyl-L-phenylalanyl)-L-phenylalaninol
Spectroscopic data: mp 211.5-214.0 ℃,
1H-NMR (DMSO, 400MHz) δ: 8.63 (1H, d, J=8.4Hz, NHCO), 7.93 (1H, d, J=8.0Hz, NHCO), 7.81 (2H, d, J=8.0Hz, H-3 ", 7 "), 7.51 (2H, d, J=8.0Hz, H-4 ", 6 "), 7.12-7.31 (10H, m, H-5-9,5 '-9 '), 4.82 (1H, s, OH), 4.68 (H, m, H-2), 3.90 (1H, m, H-2 '), 3.29-3.39 (2H, m, H-1 '), 2.49-3.01 (4H, m, H-3,3 ')
13C-NMR (DMSO, 100MHz) δ: 170.9 (C-1), 165.1 (C-1 "), 139.0 (C-4); 138.1 (C-4 '), 136.2 (C-5 "), 132.4 (C-2 "); 129.4 (* 2), 129.2 (* 2), 128.3 (* 2); 128.09 (* 2), 128.07 (* 2), 126.2; 125.9,62.2 (C-1 '), 54.9 (C-2); 52.5 (C-2 '), 37.3 (C-3), 36.4 (C-3 ') .M (EI) m/z:436 (M
+), 406,345,327,303,286,258,190,139 (100), 120,111,104,91,73,57,43,28.
Embodiment 08:N-(N-2-chloro-benzoyl-L-phenylalanyl)-L-phenylalaninol
Spectroscopic data:
1H-NMR (CDCl
3, 400MHz) δ: 7.15-7.40 (14H, m, H-5-9,5-9 ', 4 " 7 "), 4.59-4.82 (1H, m, H-2), 4.07-4.10 (1H, m, H-2 '), 3.41-3.42 (2H, m, 1 '), 2.71-3.17 (4H, m, H-3,3 '),
13C-NMR (CDCl
3, 100MHz) δ: 172.81 (s), 169.53 (s), 139.61 (s), 138.42 (s), 137.02 (s), 132.27 (d), 131.96 (s), 130.92 (d), 130.45 (2 * d), 130.43 (2 * d), 130.01 (d), 129.46 (2 * d), 129.42 (2 * d), 127.96 (d), 127.80 (d), 127.33 (d), 63.73 (t), 56.55 (d), 54.14 (d), 38.93 (t), 37.87 (t) MS (EI) m/z:436 (M
+), 418,406,345,327,303,286,258,190,139 (100), 120,104,91,73,60,43,28,18.
Embodiment 09:N-(N-3-methyl-benzoyl-L-phenylalanyl)-L-phenylalanine methyl ester
Spectroscopic data: mp:190.0-192.0 ℃,
1H-NMR (CDCl
3, 400MHz) δ: 7.51 (1H, s, H-3 "), 7.46 (1H, d, J=4.4Hz; H-7 "), and 7.31-7.23 (6H, m, H-5 ", 6 ", H-6,8,6 ', 8 '), 7.16-7.11 (4H, m, H-5,9, H-5 ', 9 '), 6.99-6.95 (2H, m, H-7,7 '), 6.68 (1H, d, J=8.0Hz, NHCO), 7.89 (1H, d, J=7.4Hz, NHCO), 4.80 (2H, m, H-2,2 '), 3.70 (3H, s, OCH
3), 3.23-2.93 (4H, m, H-3,3 '), 2.39 (3H, s, Ar-CH
3);
13C-NMR (CDCl
3, 100MHz) δ: 171.2 (C-1), 170.3 (C-1 '), 167.2 (C-1 "); 138.4 (C-4 "), 136.4 (C-4), 135.5 (C-4 '), 133.5 (C-2 "); 132.6 (C-5 "), 129.4 (* 2), 129.1 (* 2), 128.7 (* 2), (128.5 * 2), 128.4 (C-6 "), 127.7 (C-3 "), 127.0 (* 2, C-7,7 '), 124.0 (C-7 "); 54.4 (C-2), 53.4 (C-2 '), 52.4 (OCH
3), 38.0,37.8.
Embodiment 10:N-(N-2-chloro-benzoyl-L-phenylalanyl)-L-phenylalanine methyl ester
Spectroscopic data: mp:152.5-153.5 ℃,
1H-NMR (CDCl
3, 400MHz) δ: 7.51 (1H, d, J=8.0Hz, H-7 "), 7.35-7.34 (2H, m; H-4 ", 5 "), 7.30-7.17 (9H, m, H-5,6,8; 9,5 ', 6 ', 8 ', 9 ', 6 "), 6.97-6.95 (2H, m, H-7,7 '), 6.75 (1H, d, J=7.6Hz, NHCO), 6.30 (1H, d, J=7.6Hz, NH), 4.85 (1H, m, H-2), 4.78 (1H, m, H-2), 3.67 (3H, s, OCH
3), 3.20-3.00 (4H, m, H-3,3 ');
13C-NMR (CDCl
3, 100MHz) δ: 171.2,169.9,166.1,136.2,135.5,134.1,131.6,130.8,130.3,130.2,129.4 (* 2), (129.2 * 2), 128.7 (* 2), 128.6 (* 2), 127.14,127.12,127.0,54.9,53.4,52.3,37.9,37.8.M (EI) m/z:464 (M
+), 432,373,309,302,286,258,218,180,162,147,139 (100), 131,120,112,102,97,91,83,73,60,44,28.
Embodiment 11:N-(N-2-chloro-benzoyl-L-phenylalanyl)-L-L-Tyrosine methyl ester
Spectroscopic data: mp 164.5-167.0 ℃,
1H-NMR (DMSO, 400MHz) δ: 9.27 (1H, s, Ar-OH), 8.60 (1H, d, J=8.4Hz, NHCO), 8.40 (1H, d, J=7.2Hz, NHCO), 7.42-7.14 (9H, m, H-4 " 7 ", H-5-9), 7.03 (2H, d, J=8.4Hz, H-5 ', 9 '), 6.67 (2H, d, J=8.4Hz, H-6 ', 8 '), 4.75 (1H, m, H-2), 4.46 (1H, m, H-2 '), 3.08-2.79 (4H, m, H-3,3 ');
13C-NMR (DMSO, 100MHz) δ: 171.9 (C-1), 171.1 (C-1 '), 166.0 (C-1 "), 156.1 (C-7 '); 137.8 (C-4), 136.4 (C-5 "), 130.8 (C-3 "), 130.1 (C-5 ', 9 '); 130.0 (C-2 "), 129.2 (4 "), 129.2 (C-6,8); 128.9 (7 "), 128.0 (C-5,9), 126.9 (C-6 "; C-4 '), 126.3 (C-7), 115.1 (C-6 ', 8 '); 54.0 (C-2), 51.8 (C-2 '), 37.2,36.0.
Embodiment 12:N-(N-benzoyl-4-nitro-L-phenylalanyl)-L-phenylalanine methyl ester
Spectroscopic data: mp 202.0-204.5 ℃,
1H-NMR (CDCl
3, 400MHz) δ: 8.09 (2H, d, J=8.8Hz, H-6,8), 7.71 (2H, d, J=7.6Hz, H-3 ", 7 "), 7.54 (1H, t, H-5 "), 7.43 (2H, t; H-4 ", 6 "), 7.38 (2H, d, J=8.8Hz, H-5,9), 7.13 (3H; m, H-6 '-8 '), 6.99 (2H, m, H-5 ', 9 '), 6.93 (1H; br, NHCO), 6.56 (1H, br, NHCO), 4.94 (1H, m; H-2), 4.80 (1H, m, H-2 '), 3.73 (3H, s, OCH
3), 3.29 (1H, dd, J=7.2,13.6Hz, H-3 ' a), 3.22 (1H, dd, J=5.6,14.0Hz, H-3 ' b), 3.09 (1H, dd, J=5.6,14.0Hz, H-3a), 3.01 (1H, dd, J=6.4,14.0Hz, H-3b);
13C-NMR (CDCl
3, 100MHz) δ: 171.3 (C-1), 169.8 (C-1 '), 167.1 (C-1 "), 147.0 (C-7); 144.1 (C-4), 135.2 (C-4 '), 133.1 (C-2 "), 132.2 (C-5 "); 130.3 (C-5,9), 129.0 (C-6 ', 8 '); 128.7 (C-5 ', 9 '), 128.6 (C-4 ", 6 "); 127.2 (C-7 '), 127.0 (C-3 ", 7 "), 123.7 (C-6; 8), 54.0 (C-2), 53.2 (C-2 '), 52.5 (OCH
3), 38.0,37.8.
Embodiment 13:N-(N-4-methyl-benzoyl-L-phenylalanyl)-L-phenylalaninol
Spectroscopic data: mp 200.0-202.0 ℃,
1H-NMR (DMSO, 400MHz) δ: 8.39 (1H, d, J=8.8Hz, NHCO), 7.86 (1H, d, J=8.8Hz, NHCO), 7.68 (2H, d, J=8.0Hz, H-3 ", 7 "), 7.29-7.11 (12H, m, H-4 ", 6 ", H-5 '-9 ', 5-9), 4.81 (1H, t, OH), 4.65 (1H, m, H-2), 3.88 (1H, m, H-2 '), 3.33-3.24 (2H, m, H-1 '), 3.03-2.90 (2H, m, H-3), 2.84 (1H, dd, J=6.0,13.6Hz, H-3 ' is a), 2.65 (1H, dd, J=8.0,13.6Hz, H-3 ' b), 2.33 (3H, s, Ar-CH
3);
13C-NMR (DMSO, 100MHz) δ: 171.0 (C-1), 166.0 (C-1 "), 141.2 (C-5 "), 139.0 (C-4 '), 138.4 (C-4), 131.3 (C-2 "), 129.2 (* 4, C-6,8; C-6 ', 8 '), 128.7 (C-4 ", 6 "), 128.1 (C-5 '; 9 '), 128.0 (C-5,9), 127.5 (C-3 ", 7 "); 126.2 (C-7), 125.9 (C-7 '), 62.2 (C-1 '), 54.8 (C-2 '); 52.5 (C-2), 37.3,36.4,21.0 (Ar-CH
3).
Embodiment 14:N-(N-benzoyl-4-nitro-L-phenylalanyl)-L-L-Tyrosine methyl ester
Spectroscopic data: mp 200.0-202.0 ℃,
1H-NMR (DMSO, 400MHz) δ: 9.27 (1H, s, Ar-OH), 8.67 (1H, d, J=8.4Hz, NHCO), 8.57 (1H, d, J=7.2Hz, NHCO), (8.13 2H, d, J=8.4Hz, H-6,8), 7.76 (2H, d, J=7.2Hz, H-3 ", 7 "), 7.62 (2H, d, J=8.4Hz, H-5,9), 7.51 (1H, t, H-5 "); 7.43 (2H, t, H-4 ", 6 "), 7.00 (2H, d; J=8.0Hz, H-5 ', 9 '), 6.63 (2H, d, J=8.0Hz; H-6 ', 8 '), 4.83 (1H, m, H-2); 4.42 (1H, m, H-2 '), 3.57 (3H, s; OMe), 3.22-2.84 (4H, m, H-3,3 ');
13C-NMR (DMSO, 100MHz) δ: 171.9 (C-1), 171.2 (C-1 '), 166.3 (C-1 "), 156.1 (C-7 '); 146.8 (C-7), 146.2 (C-4), 133.8 (C-2 "), 131.4 (C-5 "), 130.6 (C-5; 9), 130.4 (C-4 '), 130.1 (C-5 ', 9 '), 128.3 (C-4 ", 6 "), 127.4 (C-3 ", 7 "), 122.2 (C-6; 8), 115.1 (C-6 ', 8 '), 54.2 (C-2); 50.0 (C-2 '), 51.9 (C-OMe), 36.8 (C-3), 35.9 (C-3 ').
Embodiment 15:N-(N-benzoyl-4-nitro-L-phenylalanyl)-4-nitro-L-phenylalanine methyl ester
Spectroscopic data: mp 220.0-221.5 ℃,
1H-NMR (DMSO, 400MHz) δ: 8.57 (1H, d, J=8.0Hz, NHCO), 8.52 (1H, d, J=8.8Hz, NHCO), 8.04 (2H, d, J=8.4Hz, H-6 ', 8 '), 7.73 (2H, d, J=7.6Hz, H-3 ", 7 "), 7.49 (3H, m, H-5 ", H-5 ', 9 '), 7.41 (2H; t, H-4 ", 6 "), 7.31 (2H, d, J=7.2Hz, H-5,9); 7.23 (2H, t, H-6,8), 7.14 (1H, t, H-7), 4.70 (1H; m, H-2), 4.62 (1H, m, H-2 '), 3.61 (3H, s, OCH
3), 3.25-2.90 (4H, m, H-3,3 ');
13C-NMR (DMSO, 100MHz) δ: 171.6 (C-1), 171.4 (C-1 '), 166.2 (C-1 "); 146.3 (C-7 '), 145.5 (C-4 '), 138.3 (C-4), 133.9 (C-2 "), 131.4 (C-5 "), 130.6 (C-5 ', 9 '), 129.2 (C-6; 8), 128.2 (* 2), 128.1 (* 2), 127.4 (C-3 ", 7 "), 126.3 (C-7 '), 123.2 (C-6 ', 8 '); 54.5 (C-2), 52.9 (C-2 '), 52.1 (OCH
3), 36.8,36.2.
Embodiment 16:N-(N-benzoyl-L-phenylalanyl)-4-nitro-L-phenylalaninol
Spectroscopic data: mp 192.0-195.0 ℃,
1H-NMR (DMSO, 400MHz) δ: 8.46 (1H, d, J=8.4Hz, NHCO), 7.97 (2H, d, J=8.0Hz, H-6 ', 8 '), 7.92 (1H, d, J=8.8Hz, NHCO), 7.76 (2H, d, J=8.0Hz, H-3 ", 7 "), 7.52-7.40 (5H, m, H-4 " 6 ", H-5 ', 9 '), 7.29 (2H, d, J=7.2Hz, H-5,9), 7.23 (2H, t, H-6,8), 7.14 (1H, t, H-7), 4.89 (1H, t, OH), 4.63 (1H, m, H-2), (4.97 1H, m, H-2 '), 3.36-3.27 (2H, m, H-1 '), 3.05-2.72 (4H, m, H-3,3 ');
13C-NMR (DMSO, 100MHz) δ: 171.0 (C-1), 166.1 (C-1 "), 147.6 (C-7 '); 145.8 (C-4 '), 138.4 (C-4), 133.9 (C-2 "), 131.4 (C-5 "); 130.5 (C-5 ', 9 '), 129.2 (C-6,8); 128.2 (* 2), 128.0 (* 2), 127.3 (C-3 ", 7 "); 126.2 (C-7 '), 123.0 (C-6 ', 8 '), 62.6 (C-1 ') 54.8 (C-2); 51.9 (C-2 '), 37.0,36.4.
Embodiment 17:N-(N-4-methyl-benzoyl-L-phenylalanyl)-L-L-Tyrosine methyl ester
Spectroscopic data: mp 207.0-208.5 ℃,
1H-NMR (DMSO, 400MHz) δ: 9.24 (1H, s, Ar-OH), 8.45 (2H, m, NHCO * 2), 7.68 (2H, d, J=8.0Hz, H-3 ", 7 "), 7.33 (2H, d, J=7.2Hz, H-5,9), 7.22 (4H, m, H-4 ", 6 ", H-6,8) and, 7.14 (1H, t, H-7), 7.00 (2H, d, J=8.0Hz, H-5 ', 9 '), 6.63 (2H, d, J=8.0Hz, H-6 ', 8 '), 4.73 (1H, m, H-2), 4.42 (1H, m, H-2 '), 3.57 (3H, s, OCH
3), 3.08-2.87 (4H, m, H-3,3 '), 2.32 (3H, s, Ar-CH
3);
13C-NMR (DMSO, 100MHz) δ: 172.0,171.7,166.1 (C-1 "), 156.1 (C-7 '); 141.2 (C-5 "), 138.4 (C-4), 131.2 (C-2 "), 130.1 (C-5 '; 9 '), 129.2 (C-6,8), 128.7 (C-4 ", 6 "), 128.0 (C-5,9), 127.4 (C-3 ", 7 "), 127.0 (C-4 '), 126.2 (C-7), 115.1 (C-6 '; 8 '), 54.5 (C-2), 54.1 (C-2 '), 51.8 (OCH
3), 36.9 (C-3), 35.9 (C-3 '), 21.0 (Ar-CH
3).
Embodiment 18:N-(N-4-methyl-benzoyl-4-nitro-L-phenylalanyl)-L-L-Tyrosine methyl ester
Spectroscopic data: mp 213.0-215.0 ℃,
1H-NMR (DMSO, 400MHz) δ: 9.31 (1H, s, Ar-OH), 8.61-8.57 (2H, m, NHCO * 2), 8.12 (2H, d, J=8.8Hz, H-6,8), 7.67 (2H, d, J=7.6Hz, H-3 "; 7 "), 7.60 (2H, d, J=8.8Hz, H-5,9), 7.23 (2H, d, J=8.0Hz, H-4 ", 6 "), 7.00 (2H, d, J=8.4Hz, H-5 ', 9 '), 6.63 (2H, d, J=8.0Hz, H-6 ', 8 '), 4.81 (1H, m, H-2), 4.41 (1H, m, H-2 '), 3.56 (3H, s, OCH
3), 3.21-3.06 (2H, m, H-3 '), and 2.94-2.84 (2H, m, H-3), 2.32 (3H, s, Ar-CH
3):
13C-NMR (DMSO, 100MHz) δ: 172.0 (C-1), 171.3 (C-1 '), 166.2 (C-1 "), 156.1 (C-7 '); 146.9 (C-7), 146.2 (C-4), 141.3 (C-5 "), 131.0 (C-2 "); 130.6 (C-5,9), 130.1 (C-5 ', 9 '); 128.8 (C-4 ", 6 "), 127.4 (C-3 ", 7 "); 126.9 (C-4 '), 123.2 (C-6,8), 115.1 (C-6 '; 8 '), 54.2,53.9,51.9 (OCH
3), 36.8,35.9,21.0 (Ar-CH
3).
Embodiment 19:N-(N-4-chloro-benzoyl-L-tyrosyl)-L-phenylalaninol
Reagent and reaction conditions: (1) DCC, DMAP, 4-chloro-benzoic acid, CH
2Cl
2, rt.Overnight; (2) 1.0MNaOH, rt, 2h; (3) CH
2Cl
2Isobutyl chlorocarbonate (IBCF), N-methylmorpholine (NMM),-5 ℃ of experimental implementation: (1) takes by weighing 2.31g (10mmol) and 4-chloro-benzoic acid 1.57g (10mmol), DCC (2.47g with intermediate M-29,12mmol), DMAP (200mg, as catalyzer) be mixed in the reaction flask, inject anhydrous CH
2Cl
2150ml reacts on stirred overnight at room temperature under the nitrogen protection.Remove by filter dicyclohexylurea (DCU) (DCU) precipitation of reaction generation next day, filtrate is reclaimed solvent to doing, and the gained solids dissolves fully with ethyl acetate 100ml, successively with distilled water, dilute hydrochloric acid (40ml), distilled water, 5% NaHCO
3(40ml) with saturated NaCl solution (40ml) washing, anhydrous sodium sulfate drying, the reclaim under reduced pressure ethyl acetate promptly gets the intermediate M-75-OMe sample 3.18g (productive rate: 95.3%) of white foam shape to doing; (2) get preceding-step synthetic M-75-OMe sample 3.10g (9.29mmol) in 100ml CHCl
3In dissolving fully, (2 * 20ml) strip twice to it, and combining water layer is regulated its pH2-3 with concentrated hydrochloric acid behind the stirring at room 2h, and (2 * 30ml) extracting twice merge methacrylate layer, anhydrous Na with EtOAc to add 1.0M NaOH
2SO
4Drying reclaims solvent, and the decompression oven dry gets weak yellow foam shape intermediate M-75 sample 2.82g (productive rate: 95.1%); (3) according to the similar experimental implementation method of the synthesis step (b) of embodiment 1, the synthetic target product that obtains white powder.
Spectroscopic data: mp 217.0-219.0 ℃,
1H-NMR (DMSO, 400MHz) δ: 9.15 (1H, s, Ar-OH), 8.54 (1H, d, J=8.4Hz, NHCO), 7.87 (1H, d, J=8.4Hz, NHCO), 7.81 (2H, d, J=8.4Hz, H-3 "; 7 "), 7.53 (2H, d, J=8.4Hz, H-4 "; 6 "), 7.25-7.12 (5H, m, H-5 '-9 '), 7.07 (2H, d, J=8.0Hz, H-5,9), 6.60 (2H, d, J=8.0Hz, H-6,8), 4.80 (1H, s, OH), 4.57 (1H, m, H-2), (3.88 1H, m, H-2 '), 3.35-3.24 (2H, m, H-1 '), 2.95-2.60 (4H, m, H-3,3 ');
13C-NMR (DMSO, 100MHz) δ: 170.9 (C-1), 164.9 (C-1 "), 155.7 (C-7); 139.0 (C-5 "), 136.1 (C-4 '), 132.9 (C-4), 130.1 (C-5,9), 129.4 (* 2), 129.2 (* 2), 128.33, (128.28 * 2), 128.1 (* 2), 125.9 (C-7 '), 114.8 (C-6,8), 62.2 (C-1 '), 55.2 (C-2), (52.5 C-2 '), 36.5,36.4.
According to the synthetic method that is similar to embodiment 19, select suitable reaction raw materials and intermediate, make the derivative of embodiment 20～48 respectively.
Embodiment 20:N-(N-4-chloro-benzoyl-L-tyrosyl)-L-phenylalanine methyl ester
Spectroscopic data: mp 203.5-205.0 ℃,
1H-NMR (DMSO, 400MHz) δ: 9.16 (1H, s, Ar-OH), 8.61 (1H, d, J=8.4Hz, NHCO), 8.53 (1H, d, J=8.8Hz, NHCO), 7.79 (2H, d, J=8.4Hz, H-3 "; 7 "), 7.52 (2H, d, J=8.4, H-4 ", 6 "), 7.26-7.18 (5H, m, H-5 '-9 '), 7.10 (2H, d, J=8.4Hz, H-5,9), (6.61 2H, d, J=8.4Hz, H-6,8), 4.64 (1H, m, H-2), 4.49 (1H, m, H-2 '), 3.58 (3H, s, OCH
3), 3.03-2.80 (4H, m, H-3,3 ');
13C-NMR (DMSO, 100MHz) δ: 171.8,171.7,165.1 (C-1 "); 155.7 (C-7), 137.0 (C-4 '), 136.1 (C-5 "), 132.8 (C-2 "); 130.1 (C-5,9), 129.4 (* 2), 129.1 (* 2; C-4), 128.3 (* 4), 126.6 (C-7 '); 114.8 (C-6,8), 54.9 (C-2); 53.7 (C-2 '), 51.9 (C-OMe), 36.5 (* 2).
Embodiment 21:N-(N-benzoyl-L-tyrosyl)-L-phenylalaninol
Spectroscopic data: mp 216.0-217.5 ℃,
1H-NMR (DMSO, 400MHz) δ: 9.18 (1H, s, Ar-OH), 8.42 (1H, d, J=8.4Hz, NHCO), 7.86 (1H, d, J=8.4Hz, NHCO), 7.77 (2H, d, J=6.8Hz, H-3 ", 7 "), 7.49 (1H, t, H-5 "), 7.43 (2H, t, H-4 ", 6 "), 7.21-7.11 (5H, m, H-5 '-9 '), 7.07 (2H; d, J=8.4Hz, H-5,9), 6.59 (2H; d, J=8.4Hz, H-6,8), 4.84 (1H; t, OH), 4.56 (1H, m, H-2); 3.87 (1H, m, H-2 '), 3.34-3.22 (2H, m; H-1 '), 2.91-2.61 (4H, m, H-3,3 ');
13C-NMR (DMSO, 100MHz) δ: 171.2 (C-1), 166.1 (C-1 "), 155.7 (C-7), 139.1 (C-4 '); 134.2 (C-2 "), 131.4 (C-5 "), 130.2 (C-5,9), 129.3 (C-6 '; 8 '), 128.4 (C-4), 128.2 (C-4 ", 6 "); 128.1 (C-5 ', 9 '), 127.5 (C-3 ", 7 "); 126.0 (C-7 '), 114.9 (C-6,8), 62.3 (C-1 '); 55.3 (C-2), 52.6 (C-2 '), 36.6,36.5.
Embodiment 22:N-(N-2-chloro-benzoyl-L-tyrosyl)-L-phenylalaninol
Spectroscopic data: mp 168.0-169.0 ℃,
1H-NMR (DMSO, 400MHz) δ: 9.19 (1H, s, Ar-OH), 8.50 (1H, d, J=8.4Hz, NHCO), 7.78 (1H, d, J=8.8Hz, NHCO), 7.46-7.16 (9H, m, H-4 " 7 ", H-5 '-9 '), (7.04 2H, d, J=8.4Hz, H-5,9), 6.65 (2H, d, J=8.4Hz, H-6,8), 4.83 (1H, t, OH), 4.56 (1H, m, H-2), 3.91 (1H, m, H-2 '), 3.34-3.24 (2H, m, H-1 '), and 2.91-2.85 (2H, m, H-3), 2.74-2.63 (2H, m, H-3 ');
13C-NMR (DMSO, 100MHz) δ: 170.5 (C-1), 165.8 (C-1 "), 155.7 (C-7), 139.0 (C-4 '); 136.5 (C-5 "), 130.8 (C-4), 130.2 (C-5,9), 130.0 (C-2 "), 129.6 (C-3 "), 129.2 (C-6 ', 8 '), 128.9 (C-4 "), 128.1 (C-5 ', 9 '), 127.9 (C-7 "), 126.9 (C-6 "), 125.9 (C-7 '), 114.5 (C-6,8); 62.1 (C-1 '), 54.8 (C-2), 52.3 (C-2 '), 36.8.36.4.
Embodiment 23:N-(N-2-chloro-benzoyl-L-tyrosyl)-L-phenylalanine methyl ester
Spectroscopic data: mp 175.5-177.5 ℃,
1H-NMR (DMSO, 400MHz) δ: 9.20 (1H, s, Ar-OH), 8.52 (1H, d, J=8.8Hz, NHCO), 8.43 (1H, d, J=8.0Hz, NHCO), (7.46-7.16 9H, m, H-4 " 7 ", H-5 '-9 '), 7.07 (2H, d, J=8.4Hz, H-5,9), 6.66 (2H, d, J=8.4Hz, H-6,8), 4.64 (1H, m, H-2), 4.53 (1H, m, H-2 '), 3.59 (3H, s, OCH
3), 3.07-2.67 (4H, m, H-3,3 ');
13C-NMR (DMSO, 100MHz) δ: 171.8 (C-1), 171.2 (C-1 '), 165.9 (C-1 "), 155.8 (C-7); 137.0 (C-4 '), 136.4 (C-5 "), 130.8 (C-4), 130.2 (C-5,9), 130.0 (C-2 "), 129.6 (C-3 "), 129.2 (C-6,8), 128.9 (C-4 "), 128.3 (C-5 ', 9 '); 127.8 (C-7 "), 126.9 (C-6 "), 126.6 (C-7 '), 114.8 (C-6 '; 8 '), 54.4 (C-2), 53.8 (C-2 '), 51.9 (OCH
3), 36.7,36.5.
Embodiment 24:N-(N-4-fluoro-benzoyl-L-tyrosyl)-L-phenylalaninol
Spectroscopic data: mp 194.5-195.5 ℃,
1H-NMR (DMSO, 400MHz) δ: 9.18 (1H, s, Ar-OH), 8.51 (1H, d, J=8.4Hz, NHCO), and 7.90-7.87 (3H, m, NHCO, H-3 ", 7 "), 7.31-7.00 (6H, m, H-4 ", 6 ", 5 ', 9 ', 5,9), (6.63 2H, d, J=8.4Hz, H-6,8), 4.83 (1H, t, OH), 4.60 (1H, m, H-2), 3.90 (1H, m, H-2 '), (3.38-3.23 2H, m, H-1 '), 2.95-2.56 (4H, m, H-3,3 ');
13C-NMR (DMSO, 100MHz) δ: 171.3,171.1,165.0 (C-1 "); 162.7 (C-5 "), 155.7 (C-7), 139.1 (C-4 '), 130.1 (C-4), (130.0 C-5,9), 129.2 (C-6 ', 8 '), 128.4 (C-2 "), 128.1 (C-5 ', 9 '), 125.9 (C-7 '); 115.2 (* 2), 115.0 (* 2), 114.8 (C-6,8); 69.8 (C-1 '), 55.2 (C-2), 52.5 (C-2 '), 36.5.36.4.
Embodiment 25:N-(N-4-fluoro-benzoyl-L-tyrosyl)-L-phenylalanine methyl ester
Spectroscopic data: mp 186.5-189.0 ℃,
1H-NMR (DMSO, 400MHz) δ: 9.20 (1H, s, Ar-OH), 8.55 (2H, m, NHCO?), 7.86 (2H, m, H-3 ", 7 "), 7.30-7.13 (7H, m, H-4 ", 6 ", 5 '-9 '), 7.04 (2H, d, J=8.4, H-5,9), 7.02 (2H, d, J=8.4, H-6,8), 4.64 (1H, m, H-2), 4.50 (1H, m, H-2 '), 3.59 (3H, s, OCH
3), 3.09-2.79 (4H, m, H-3,3 ');
13C-NMR (DMSO, 100MHz) δ: 171.84,171.79,165.1 (C-1 "), 162.7 (C-5 "), 155.7 (C-7), 137.1 (C-4 '), 130.55s, 130.52s, 130.13 (C-4), (130.09 C-5,9), 130.04d, 129.1 (C-6 ', 8 '), 128.3 (C-5 ', 9 '), 126.6 (C-7 '), 115.2d, 115.0d, 114.8 (C-6,8), 54.9 (C-2), (53.7 C-2 '), 51.9 (OMe), 36.6,36.2.
Embodiment 26:N-(N-4-methyl-benzoyl-L-tyrosyl)-L-phenylalaninol
Spectroscopic data: mp 193.0-195.0 ℃,
1H-NMR (DMSO, 400MHz) δ: 9.17 (1H, s, ArNHCO), 8.36 (1H, d, J=8.4Hz, NHCO), 7.88 (1H, d, J=8.4Hz, NHCO), 7.72 (2H, d, J=8.0Hz, H-3 ", 7 "), 7.26-7.00 (9H, m, H-4 "; 6 ", H-5,9, H-5 '-9 '), 6.61 (2H, d, J=8.4Hz, H-6,8), 4.83 (1H, t, OH), 4.58 (1H, m, H-2), (3.88 1H, m, H-2 '), 3.36-3.25 (2H, m, H-1 '), 2.93-2.62 (4H, m, H-3,3 '), 2.34 (3H, s, Ar-CH
3);
13C-NMR (DMSO, 100MHz) δ: 171.2 (C-1), 165.9 (1 "), 155.7 (C-7), 141.1 (5 "), (139.1 C-4 '), 131.4 (C-2 "), 130.1 (C-5,9), 129.2 (C-6 '; 8 '), 128.7 (C-4 ", 6 "), 128.4 (C-4), 128.1 (C-5 '; 9 '), 127.5 (C-3 ", 7 "), 125.9 (C-7 '); 114.8 (C-6,8), 62.2 (C-1 '), 55.2 (C-2); 52.5 (C-2 '), 36.5,36.4,21.0 (Ar-CH
3).
Embodiment 27:N-(N-4-hydroxyl-benzoyl-L-phenylalanyl)-L-phenylalaninol
Spectroscopic data: mp 223.0-225.0 ℃,
1H-NMR (DMSO, 400MHz) δ: 9.98 (1H, s, Ar-OH), 8.22 (1H, d, J=8.8Hz, NHCO), 7.83 (1H, d, J=8.4Hz, NHCO), 7.66 (2H, d, J=8.8Hz, H-3 ", 7 "), 7.29-7.09 (10H, m, H-5-9,5 '-9 '), 6.76 (2H, d, J=8.4Hz, H-4 ", 6 "), 4.80 (1H, t, J=5.2Hz, OH), 4.62 (1H, m, H-2), (3.87 1H, m, H-2 '), 3.34-3.22 (2H, m, H-1 '), and 3.02-2.92 (2H, m, H-3), 2.84 (1H, dd, J=5.6,13.6Hz, H-3 ' a), 2.64 (1H, dd, J=8.0,13.6, Hz, H-3 ' is b);
13C-NMR (DMSO, 100MHz) δ: 171.2 (C-1) 165.8 (C-1 "), 160.2 (C-5 "), 139.0 (C-4 '), 138.5 (C-4), 129.4 (C-3 ", 7 "), 129.23 (C-6 ', 8 '), (129.21 C-6,8), 128.09 (C-5 ', 9 '), (128.03 C-5,9), 126.2 (C-7), 125.9 (C-7 '), 124.7 (C-2 "), 114.7 (C-4 ", 6 "), 62.2 (C-1 '); 54.7 (C-2), 52.5 (C-2 '), 37.2 (C-3 '), 36.5 (C-3).
Embodiment 28:N-(N-4-hydroxyl-benzoyl-L-phenylalanyl)-L-phenylalanine methyl ester
Spectroscopic data: mp 151.0-153.0 ℃,
1H-NMR (DMSO, 400MHz) δ: 9.96 (1H, s, Ar-OH), 8.44 (1H, d, J=7.2Hz, NHCO), 8.24 (1H, d, J=8.0Hz, NHCO), 7.64 (2H, d, J=8.4Hz, H-3 ", 7 "), 7.31-7.12 (10H, m, H-5-9,5 '-9 '), 6.75 (2H, d, J=8.8Hz, H-4 ", 6 "), 4.69 (1H, m, H-2), 3.49 (1H, m, H-2 '), 3.57 (3H, s, OCH
3), 3.06-2.88 (4H, m, H-3,3 ');
13C-NMR (DMSO, 100MHz) δ: 171.8 (C-1,1 '), 165.9 (C-1 "); 160.2 (C-5 "), 139.4 (C-4), 137.0 (C-4 '), 129.4 (C-3 "; 7 "), 129.17 (* 2), 129.13 (* 2), 128.3 (C-5 ', 9 '), 128.0 (C-5,9), 126.6 (C-7 '), 126.2 (C-7), 124.7 (C-2 "), 114.7 (C-4 ", 6 "); 54.4 (C-2), 53.7 (C-2 '), 51.8 (OCH
3), 36.9,36.6.
Embodiment 29:N-(N-benzoyl-3-nitro-L-tyrosyl)-L-phenylalanine methyl ester
Spectroscopic data: mp 201.0-202.5 ℃,
1H-NMR (DMSO, 400MHz) δ: 8.61-8.56 (2H, m, NHCO * 2), 7.91 (1H, s, H-5), 7.76 (2H, d, J=8.4Hz, H-3 ", 7 "), 7.51-7.41 (5H, m, H-9,4 " 6 ", ArOH), 7.26-7.18 (5H, m, H-5 '-9 '), 7.03 (1H, d, J=8.4Hz, H-8), 4.70 (1H, m, H-2), 4.50 (1H, m, H-2 '), 3.57 (3H, s, OCH
3), 3.07-2.87 (4H, m, H-3,3 ');
13C-NMR (DMSO, 100MHz) δ: 171.8,171.3,166.3 (C-1 "), 150.8 (C-7); 137.0 (C-4 '), 136.4 (C-9), 136.1 (C-6), 133.9 (C-2 "), 131.4 (C-5 "), 129.5 (C-4), 129.1 (C-6 ', 8 '); 128.3 (C-5 ', 9 '), 128.2 (C-4 ", 6 "); 127.4 (C-3 ", 7 "), 126.6 (C-7 '), 125.4 (C-5); 118.8 (C-8), 54.4 (C-2), 53.8 (C-2 '), 51.9 (OCN
3), 36.6,35.6.
Embodiment 30:N-(N-4-nitro-benzoyl-L-tyrosyl)-L-phenylalanine methyl ester
Spectroscopic data: mp 212.0-214.0 ℃,
1H-NMR (DMSO, 400MHz) δ: 9.17 (1H, s, Ar-OH), 8.89 (1H, d, J=8.4Hz, NHCO), 8.60 (1H, d, J=7.2Hz, NHCO), 8.29 (2H, d, J=8.4Hz, H-4 "; 6 "), 7.99 (2H, d, J=8.8Hz, H-3 ", 7 "), 7.26-7.18 (5H, m, H-5 '-9 '), 7.11 (2H, d, J=8.0Hz, H-5,9), (6.61 2H, d, J=8.4Hz, H-6,8), 4.68 (1H, m, H-2), 4.49 (1H, m, H-2 '), 3.57 (3H, s, OCH
3), 3.08-2.78 (4H, m, H-3,3 ');
13C-NMR (DMSO, 100MHz) δ: 171.9,171.5,164.5 (C-1 "), 155.8 (C-7); 149.1 (C-5 "), 139.7 (C-2 "), 137.1 (C-4 '), 130.1 (C-5; 9), 129.1 (C-6 ', 8 '), 128.9 (C-3 ", 7 "), 128.3 (C-5 ', 9 '), 128.1 (C-4); 126.6 (C-7 '), 123.5 (C-4 ", 6 "), 114.9 (C-6; 8), 55.1 (C-2), 53.8 (C-2 '), 51.9 (OCH
3), 36.5,36.3.
Embodiment 31:N-(N-4-methyl-benzoyl-L-tyrosyl)-L-phenylalanine methyl ester
Spectroscopic data: mp 190.0-192.5 ℃,
1H-NMR (DMSO, 400MHz) δ: 9.14 (1H, s, Ar-OH), 8.46 (1H, d, J=7.2Hz, NHCO), 8.36 (1H, d, J=8.4Hz, NHCO), 7.67 (2H, d, J=8.8Hz, H-3 ", 7 "), and 7.27-7.14 (7H, m, H-5 '-9 ', H-4 "; 6 "), 7.09 (2H, d, J=8.4Hz, H-5,9), 6.60 (2H, d, J=8.4Hz, H-6,8), 4.63 (1H, m, H-2), (4.48 1H, m, H-2 '), 3.57 (3H, s, OCH
3), 3.06-2.78 (4H, m, H-3,3 '), 2.33 (3H, s, Ar-CH
3);
13C-NMR (DMSO, 100MHz) δ: 171.9 (s * 2, C-1,1 '), 166.0 (C-1 "); 155.7 (C-7), 141.2 (C-5 "), 137.O (C-4 '), 131.3 (C-2 "), 130.1 (C-5; 9), 129.1 (C-6 ', 8 '), 128.7 (C-4 ", 6 "), 128.33 (C-4), 128.28 (C-5 ', 9 '); 127.4 (C-3 ", 7 "), 126.6 (C-7 '), 114.8 (C-6; 8), 54.8 (C-2), 53.7 (C-2 '), 51.9 (OCH
3), 36.6,36.2,21.0 (Ar-CH
3).
Embodiment 32:N-(N-3-nitro-benzoyl-L-tyrosyl)-L-phenylalaninol
Spectroscopic data: mp 225.5-227.0 ℃,
1H-NMR (DMSO, 400MHz) δ: 9.15 (1H, s, Ar-OH), 8.92 (1H, d, J=8.0Hz, NHCO), 8.62 (1H, s, H-3 "), 8.37 (1H; d, J=8.0Hz, H-5 "), 8.22 (1H, d, J=7.6Hz, H-7 "), 7.94 (1H, d, J=8.0Hz; NHCO), 7.76 (1H, t, H-6 "), 7.21-7.08 (7H, m, H-5 '-9 ', H-5,9), 6.61 (2H, d, J=8.0Hz, H-6,8), 4.80 (1H, t, OH), 4.64 (1H, m, H-2), (3.89 1H, m, H-2 '), 3.33-3.25 (2H, m, H-1 '), 2.96-2.62 (4H, m, H-3,3 ');
13C-NMR (DMSO, 100MHz) δ: 170.7 (C-1), 163.9 (C-1 "), 155.7 (C-7), 147.6 (C-4 "), (139.0 C-4 '), 135.6 (C-2 "), 133.9 (C-7 "), 130.1 (C-5,9), 130.0 (C-6 "), 129.1 (C-6 ', 8 '), 128.2 (C-4); 128.0 (C-5 ', 9 '), 125.8 (C-7 ', C-5 "), 122.2 (C-3 "), 114.8 (C-6,8), 62.2 (C-1 '); 55.3 (C-2), 52.5 (C-2 '), 36.5,36.4.
Embodiment 33:N-(N-benzoyl-L-tyrosyl)-L-phenylalanine methyl ester
Spectroscopic data: mp 200.0-202.0 ℃,
1H-NMR (DMSO, 400MHz) δ: 9.19 (1H, s, Ar-OH), 8.52-8.47 (2H, m, NHCO * 2), 7.76 (2H, d, J=6.8Hz, H-3 ", 7 "), 7.50 (1H, t, H-5 "), 7.43 (2H, t, H-4 ", 6 "), 7.25-7.18 (5H, m; H-5 '-9 '), 7.10 (2H, d, J=8.4Hz, H-5,9), 6.61 (2H; d, J=8.4Hz, H-6,8), 4.63 (1H, m, H-2); 3.78 (1H, m, H-2 '), 3.57 (3H, s, OCH
3), 3.07-2.78 (4H, m, H-3,3 ');
13C-NMR (DMSO, 100MHz) δ: 171.93,171.89,166.2 (C-1 "), 155.7 (C-7); 137.1 (C-4 '), 134.1 (C-2 "), 131.4 (C-5 "), 130.2 (C-5,9); 129.2 (C-6 ', 8 '), 128.4 (* 3, C-4 ", 6 ", C-4), 128.3 (C-5 ', 9 '); 127.5 (C-3 ", 7 "), 126.7 (C-7 '), 114.9 (C-6; 8), 54.9 (C-2), 53.8 (C-2 '), 52.0 (OCH
3), 36.6,36.2.
Embodiment 34:N-[N-(4-acetylaminohydroxyphenylarsonic acid benzoyl)-L-phenylalanyl]-the L-phenylalanine methyl ester
Spectroscopic data: mp:208.0-209.5,
1H-NMR (DMSO, 400MHz) δ: 10.16 (1H, s, ArNHCO), 8.51 (1H, d, J=7.2Hz, NHCO), 8.40 (1H, d, J=8.4Hz, NHCO), 7.73 (2H, d, J=8.8Hz, H-3 ", 7 "), 7.61 (2H, d, J=8.8Hz, H-4 ", 6 "), 7.33-7.14 (10H, m, H-5-9,5 '-9 '), 4.72 (1H, m, H-2), 4.50 (1H, m, H-2 '), 3.57 (3H, s, OCH
3), 3.07-2.90 (4H, m, H-3,3 '), 2.05 (3H, CH
3CO);
13C-NMR (DMSO, 100MHz) δ: 171.9,171.8,168.7 (ArNHCO), 165.6 (C-1 "), 142.0 (C-5 "), 138.4 (C-4), 137.0 (C-4 '), (129.2 * 2), 129.1 (* 2), 128.3 (* 4), 128.2 (C-2 "), 128.1 (* 2), 126.6 (C-7 '); 126.2 (C-7), 118.0 (C-4 ", 6 "); 54.4 (C-2), 53.7 (C-2 '), 51.9 (OCH
3), 37.0 (C-3), 36.6 (C-3 '), 24.1 (CH
3CO).
Embodiment 35:N-[N-(4-chloro acetylamino-benzoyl)-L-phenylalanyl]-the L-phenylalaninol
Spectroscopic data:
1H-NMR (DMSO, 400MHz) δ: 10.55 (1H, s, ArNHCO), 8.42 (1H, d, J=8.4Hz, NHCO), 7.90 (1H, d, J=8.0Hz, NH-CO), 7.81 (2H, d, J=8.8Hz, H-3 ", 7 "), 7.66 (2H, d, J=8.8Hz, H-4 ", 6 "), 7.33-7.12 (10H, m, H-5-9,5 '-9 '), 4.83 (1H, t, OH), 4.68 (1H, m, H-2), 4.31 (2H, COCH
2Cl), 3.91 (1H, m, H-2 '), 3.36-3.26 (2H, m, H-1 '), 3.06-2.93 (2H, m, H-3), 2.88 (1H, dd, J=6.0,13.6Hz, H-3 ' a), 2.68 (1H, dd, J=7.6,13.6Hz, H-3 ' is b);
13C-NMR (DMSO, 100MHz) δ: 171.0 (C-1), 165.4 (C-1 "), 165.0 (ArNHCO), 141.1 (C-5 "), (139.0 C-4 '), 138.4 (C-4), 129.2 (* 4, C-6,8,6 ', 8 '), 129.1 (C-2 "), 128.4 (C-3 ", 7 "), 128.1 (* 2), 128.0 (* 2), 126.2 (C-7); 125.9 (C-7 '), 118.4 (C-4 ", 6 "), 62.2 (C-1 '); 54.8 (C-2), 52.5 (C-2 '), 37.3 (C-3), 36.4 (C-3 ').
Embodiment 36:N-[N-(4-acetylaminohydroxyphenylarsonic acid benzoyl)-L-phenylalanyl]-the L-L-Tyrosine methyl ester
Spectroscopic data: mp 215.5-217.0 ℃,
1H-NMR (DMSO, 400MHz) δ: 10.23 (1H, s, ArNHCO), 9.26 (1H, s, ArOH), 8.47-8.43 (2H, m, NHCO * 2), 7.73 (2H, d, J=8.4Hz, H-3 ", 7 "), 7.62 (2H, d, J=8.4Hz, H-4 ", 6 "), 7.32 (2H, d, J=7.2Hz, H-5,9), 7.23 (2H, t, H-6,8), 7.14 (1H, t, H-7), 6.99 (2H, d, J=8.4Hz, H-5 ', 9 '), 6.62 (2H, d, J=8.0Hz, H-6 ', 8 '), 4.71 (1H, m, H-2), 4.40 (1H, m, H-2 '), 3.56 (3H, s, OCH
3), 3.07-2.86 (4H, m, H-3,3 '), 2.05 (3H, CH
3CO);
13C-NMR (DMSO, 100MHz) δ: 172.0,171.7,168.7 (ArNHCO), 165.7 (C-1 "); 156.1 (C-7 '), 142.0 (C-5 "), 138.4 (C-4), 130.1 (C-5 ', 9 '), (129.2 C-6,8), 128.3 (C-3 ", 7 "), (128.2 C-4 '), 128.0 (C-5,9), 127.0 (C-2 "); 126.2 (C-7), 117.9 (C-4 ", 6 "), 115.1 (C-6 '; 8 '), 54.5 (C-2), 54.1 (C-2 '), 51.8 (OCH
3), 36.9 (C-3), 35.9 (C-3 '), 24.1 (CH
3CO).
Embodiment 37:N-[N-(4-propionamido-benzoyl)-L-phenylalanyl]-the L-phenylalanine methyl ester
Spectroscopic data: mp 225.0-227.0 ℃,
1H-NMR (DMSO, 400MHz) δ: 10.09 (1H, s, ArNHCO), 8.52 (1H, d, J=7.6Hz, NHCO), 8.40 (1H, d, J=8.4Hz, NHCO), 7.74 (2H, d, J=8.4Hz, H-3 ", 7 "), 7.64 (2H, d, J=8.8Hz, H-4 ", 6 "), 7.34-7.13 (10H, m, H-5-9,5 '-9 '), 4.73 (1H, m, H-2), 4.52 (1H, m, H-2 '), 3.59 (3H, s, OCH
3), 3.08-2.91 (4H, m, H-3,3 '), 2.35 (2H, q, J=7.2Hz, COCH
2CH
3), 1.08 (3H, t, J=7.6Hz, COCH
2CH
3);
13C-NMR (DMSO, 100MHz) δ: 172.4,171.82,171.78,165.7 (C-1 "); 142.1 (C-5 "), 138.4 (C-4), 137.0 (C-4 '), 129.2 (* 2), (129.1 * 2), 128.3 (* 4, C-3 ", 7 ", 5 ', 9 '), 128.1 (C-2 "), 128.0 (C-5; 9), 126.6 (C-7), 126.2 (C-7 '), 118.0 (C-4 ", 6 "), 54.4 (C-2), 53.7 (C-2 '), 51.9 (OCH
3), 36.9 (C-3), 36.6 (C-3 '), 29.6 (COCH
2CH
3), 9.5 (COCH
2CH
3).
Embodiment 38:N-[N-(4-propionamido-benzoyl)-L-phenylalanyl]-4-nitro-L-phenylalanine methyl ester
Spectroscopic data: mp 221.0-223.0 ℃,
1H-NMR (DMSO, 400MHz) δ: 10.14 (1H, s, ArNHCO), 8.61 (1H, d, J=7.2Hz, NHCO), 8.42 (1H, d, J=8.4Hz, NHCO), 9.05 (2H, d, J=8.0Hz, H-6 ', 8 '), 7.72 (2H, d, J=7.6Hz, H-3 ", 7 "), 7.63 (2H, d, J=8.4Hz, H-5 ', 9 '), 7.51 (2H, d, J=8.0Hz, H-4 ", 6 "), (7.31 2H, d, J=7.2Hz, H-5,9), (7.23 2H, t, H-6,8), 7.14 (1H, t, J=7.2Hz, H-7), 4.68-4.59 (2H, m, H-2,2 '), 3.61 (3H, s, OCH
3), 3.25-2.90 (4H, m, H-3,3 '), 2.34 (2H, q, J=7.6Hz, COCH
2CH
3), 1.07 (3H, t, J=7.6Hz, COCH
2CH
3);
13C-NMR (DMSO, 100MHz) δ: 172.4 (ArNHCO), 171.8 (C-1), 171.4 (C-1 '), 165.7 (C-1 "); 146.3 (C-7 '), 145.5 (C-4 '), 142.2 (C-5 "), 138.3 (C-4), 130.6 (C-5 ', 9 '), 129.2 (C-6,8), 128.3 (C-3 "; 7 "), 128.1 (C-5,9), 128.0 (C-2 "); 126.3 (C-7), 123.2 (C-6 ', 8 '), 117.9 (C-4 ", 6 "), 54.5 (C-2), 52.9 (C-2 '), 52.1 (OCH
3), 36.8 (C-3), 36.2 (C-3 '), 29.6 (COCH
2CH
3), 9.6 (COCH
2CH
3).
Embodiment 39:N-[N-(4-acetylaminohydroxyphenylarsonic acid benzoyl)-L-phenylalanyl]-the L-phenylalaninol
Spectroscopic data: mp 193.0-195.0 ℃,
1H-NMR (DMSO, 400MHz) δ: 10.16 (1H, s, ArNHCO), 8.39 (1H, d, J=8.4Hz, NHCO), 8.26 (1H, d, J=8.4Hz, NHCO), 7.76 (2H, d, J=8.4Hz, H-3 ", 7 "), 7.62 (2H, d, J=8.8Hz, H-4 ", 6 "), 7.32-7.13 (10H, m, H-5-9,5 '-9 '), 4.70 (1H, m, H-2), 4.17 (1H, m, H-2 '), 3.64 (1H, dd, J=4.8,11.2Hz, H-1 ' a), 3.52 (1H, dd, J=7.0,11.2Hz, H-1 ' b), 3.05-2.78 (4H, m, H-3,3 '), 2.06 (3H, CH
3CO);
13C-NMR (DMSO, 100MHz) δ: 171.4 (C-1), 168.7 (ArNHCO), 165.6 (C-1 "); 142.0 (C-5 "), 138.3 (C-4), 137.8 (C-4 '), 129.2 (* 4), (128.3 * 4), 128.2 (C-2 "), 128.0 (C-3 ", 7 "); 126.4 (C-7), 126.2 (C-7 '), 118.0 (C-4 ", 6 "); 54.7 (C-2), 51.5 (C-1 '), 46.8 (C-2 '); 37.3 (C-3), 37.0 (C-3 '), 24.1 (CH
3CO).
Embodiment 40:N-[N-(4-acetylaminohydroxyphenylarsonic acid benzoyl)-L-tyrosyl]-the L-phenylalaninol
Spectroscopic data: mp 220.5-223.0 ℃,
1H-NMR (DMSO, 400MHz) δ: 10.17 (1H, s, ArNHCO), 9.14 (1H, s, ArOH), 8.28 (1H, d, J=8.0Hz, NHCO), 7.83 (1H, d, J=8.4Hz, NHCO), 7.76 (2H, d, J=8.8Hz, H-3 ", 7 "), 7.63 (2H, d, J=8.4Hz, H-4 ", 6 "), 7.22-7.07 (7H, m, H-5,9,5 '-9 '), 6.61 (2H, d, J=8.0Hz, H-6,8), 4.81 (1H, t, OH), 4.57 (1H, m, H-2), 3.88 (1H, m, H-2 '), 3.34-3.25 (2H, m, H-1 '), 2.91-2.50 (4H, m, H-3,3 '), 2.07 (3H, CH
3CO);
13C-NMR (DMSO, 100MHz) δ: 171.2 (C-1), 168.7 (ArNHCO), 165.5 (C-1 "), 155.7 (C-7); 142.0 (C-5 "), 139.0 (C-4 '), 130.1 (C-5,9), 129.2 (6 ', 8 '), 128.4 (C-4,2 "), 128.3 (C-5 ', 9 '); 128.1 (C-3 ", 7 "), 125.9 (C-7 '), 117.9 (C-4 ", 6 "); 114.8 (C-6,8), 62.2 (C-1 '), 55.1 (C-2); 52.4 (C-2 '), 36.5,36.4,24.2 (CH
3CO).
Embodiment 41:N-[N-(4-acetylaminohydroxyphenylarsonic acid benzoyl)-L-tyrosyl]-the L-phenylalanine methyl ester
Spectroscopic data: mp 225.0-226.0 ℃,
1H-NMR (DMSO, 400MHz) δ: 10.18 (1H, s, ArNHCO), 9.16 (1H, s, ArOH), 8.48 (1H, d, J=7.2Hz, NHCO), 8.34 (1H, d, J=8.4Hz, NHCO), 7.75 (2H, d, J=8.8Hz, H-3 ", 7 "), 7.63 (2H, d, J=8.8Hz, H-4 "; 6 "), 7.26-7.17 (5H, m, 5 '-9 '), 7.11 (2H, d, J=8.4Hz, H-5,9), 6.63 (2H, d, J=8.4Hz, H-6,8), 4.64 (1H, m, H-2), 4.50 (1H, m, H-2 '), 3.58 (3H, s, OCH
3), 3.08-2.79 (4H, m, H-3,3 '), 2.07 (3H, CH
3CO);
13C-NMR (DMSO, 100MHz) δ: 171.9,171.8,168.7 (ArNHCO), 165.5 (C-1 "); 155.7 (C-7), 142.0 (C-5 "), 137.0 (C-4 '), 130.1 (C-5,9), 129.1 (6 ', 8 '), 128.4 (C-4,2 "), 128.3 (* 4; C-5 ', 9 ', 3 ", 7 "); 126.6 (C-7 '), 117.9 (C-4 ", 6 "), 114.8 (C-6; 8), 54.8 (C-2), 53.7 (C-2 '), 51.9 (OCH
3), 36.6,36.2,24.1 (CH
3CO).
Embodiment 42:N-[N-(4-chloro acetylamino-benzoyl)-L-phenylalanyl]-the L-phenylalanine methyl ester
Spectroscopic data: mp 222.5-224.5 ℃,
1H-NMR (DMSO, 400MHz) ε: 10.64 (1H, s, ArNHCO), 8.57 (1H, d, J=7.6Hz, NHCO), 8.50 (1H, d, J=8.4Hz, NHCO), 7.78 (2H, d, J=8.4Hz, H-3 ", 7 "), 7.65 (2H, d, J=8.8Hz, H-4 ", 6 "), 7.34-7.14 (10H, m, H-5-9,5 '-9 '), 4.74 (1H, m, H-2), 4.51 (1H, m, H-2 '), 4.31 (2H, s, NHCOCH
2Cl), 3.59 (3H, s, OCH
3), 3.09-2.92 (4H, m, H-3,3 ');
13C-NMR (DMSO, 100MHz) δ: 171.9,171.8,165.6 (C-1 "), 165.0 (ArNHCO); 141.2 (C-5 "), 138.4 (C-4), 137.1 (C-4 '), 129.2 (C-6,8), 129.1 (C-6 ', 8 '), 129.0 (C-2 "), 128.4 (C-3 ", 7 "), 128.3 (C-5 ', 9 '), 128.1 (C-5; 9), 126.6 (C-7 '), 126.2 (C-7), 118.4 (C-4 ", 6 "), 54.5 (C-2), 53.8 (C-2 '), 51.9 (OCH
3), 43.6 (COCH
2Cl), 37.0 (C-3), 36.6 (C-3 ').
Embodiment 43:N-(the different nicotinoyl of N--L-phenylalanyl)-L-phenylalaninol
Spectroscopic data: N-(N-4-pyridinyl-formyl-L-phenylalanyl)-L-phenylalanol, mp 199.0-201.0 ℃,
1H-NMR (DMSO, 400MHz) δ: 8.83 (1H, d, J=8.8Hz, NHCO), 8.69 (2H, d, J=6.4Hz, H-4 ", 6 "), 7.96 (1H, d, J=8.0Hz, NHCO), 7.66 (2H, d, J=6.0Hz, H-3 ", 7 "), 7.31-7.11 (10H, m, H-5-9,5 '-9 '), 4.81 (1H, t, J=5.2Hz, OH), 4.68 (1H, m, H-2), (3.89 1H, m, H-2 '), 3.35-3.25 (2H, m, H-1 '), 3.04 (1H, dd, J=4.4,14.0Hz, H-3a), 2.95-2.83 (2H, m, H-3b, 3 ' a), 2.65 (1H, dd, J=7.6,13.2Hz, H-3 ' is b);
13C-NMR (DMSO, 100MHz) δ: 170.5 (C-1), 164.5 (C-1 "), 150.1 (C-4 ", 6 "); 141.0 (C-2 "), 139.0 (C-4 '), 138.2 (C-4), 129.2 (* 4, C-6,8,6 ', 8 '), 128.1 (* 4, C-5,9,5 ', 9 '), 126.3 (C-7), (125.9 C-7 '), 121.4 (C-3 ", 7 "), 62.2 (C-l '), 54.8 (C-2), 52.5 (C-2 '), 37.3 (C-3), 36.4 (C-3 ').
Embodiment 44:N-(the different nicotinoyl of N--L-phenylalanyl)-L-phenylalanine methyl ester
Spectroscopic data: mp 174.0-175.0 ℃, 1H-NMR (CDCl3,400MHz) δ: 8.71 (2H, d, J=6.0Hz, H-4 "; 6 "), 7.52 (2H, d, J=5.6Hz, H-3 ", 7 "), 7.31-7.17 (8H, m, H-5,6,8,9,5 ', 6 ', 8 ', 9 '), 7.07 (1H, br, NHCO), 6.99-6.97 (2H, m, H-7,7 '), 6.30 (1H, br, NHCO), 4.86-4.75 (2H, m, H-2,2 '), 3.72 (3H, s, OCH3), 3.20 (1H, dd, J=6.0,14.0Hz, H-3a), 3.14-3.08 (2H, m, H-3b, 3 ' a), 2.97 (1H, dd, J=7.6,13.6Hz, H-3 ' is b); 13C-NMR (CDCl3,100MHz) δ: 171.2 (C-1), 170.0 (C-1 '), 165.0 (C-1 "), 150.6 (C-4 ", 6 "), 140.7 (C-2 "), 136.0,135.3,129.3 (C-6 ', 8 '), 129.0 (C-6,8), 128.7 (C-5 ', 9 '), 128.6 (C-5,9), 127.24,127.19,120.8 (C-3 ", 7 "), 54.6 (C-2), (53.5 C-2 '), 52.4 (OCH3), 38.2 (C-3), 37.8 (C-3 ').
Embodiment 45:N-(the different nicotinoyl of N--L-phenylalanyl)-4-nitro-L-phenylalanine methyl ester
Spectroscopic data: mp 224.5-225.5,1H-NMR (CDCl3,400MHz) δ: 8.77 (2H, s, H-4 ", 6 "), 8.06 (2H, d, J=8.0Hz, H-6 ', 8 '), 7.54 (2H, s, H-3 ", 7 "), 7.29-7.19 (7H, m, H-5-9,5 ', 9 '), 6.86 (1H, br, NHCO), 6.29 (1H, br, NHCO), 4.79 (2H, m, H-2,2 '), 3.72 (3H, s, OCH
3), 3.21-3.08 (4H, m, H-3,3 ');
13C-NMR (DMSO, 100MHz) δ: 170.5 (C-1), 170.1 (C-1 '), 165.2 (C-1 "); 150.7 (C-4 ", 6 "), 147.1 (C-7 '), 143.2 (C-4 '); 140.4 (C-2 "), 135.7 (C-4), 130.1 (C-5 ', 9 '), (129.2 C-6,8), 128.9 (C-5,9), 124.4 (C-7), 123.7 (C-6 ', 8 '), 120.7 (C-3 "; 7 "), 54.8 (C-2 '), 53.0 (C-2), 52.7 (OCH
3), 38.1 (C-3 '), 37.1 (C-3).
Embodiment 46:N-(the different nicotinoyl of N--L-phenylalanyl)-L-L-Tyrosine methyl ester
Spectroscopic data: mp 216.0-217.0,
1H-NMR (DMSO, 400MHz) δ: 9.26 (1H, s, Ar-OH), 8.91 (1H, d, J=8.8Hz, NHCO), 8.70 (2H, d, J=5.2Hz, H-4 "; 6 "), 8.57 (1H, d, J=7.6Hz, NHCO), 7.66 (2H, d, J=5.2Hz, H-3 ", 7 "), 7.35 (2H, d, J=7.6Hz, H-5,9), 7.25 (2H, t, H-6,8), 7.16 (1H, t, H-7), 7.02 (2H, d, J=8.0Hz, H-5 ', 9 '), 6.64 (2H, d, J=8.0Hz, H-6 ', 8 '), 4.78 (1H, m, H-2), 4.44 (1H, m, H-2 '), 3.59 (3H, s, OCH
3), 3.12-2.85 (4H, m, H-3,3 ');
13C-NMR (DMSO, 100MHz) δ: 172.0 (C-1), 171.3 (C-1 '), 164.7 (C-1 "); 156.1 (C-7 '), 150.2 (C-4 ", 6 "), 140.9 (C-2 "), 138.1 (C-4), 130.1 (C-5 ', 9 '), 129.2 (C-6,8), 128.1 (C-5,9), 127.0 (C-4 '), 126.3 (C-7), 121.4 (C-3 ", 7 "), 115.1 (C-6 ', 8 '), 54.5 (C-2), 54.2 (C-2 '), 51.9 (OCH
3), 37.0 (C-3), 35.8 (C-3 ').
Embodiment 47:N-(the different nicotinoyl of N--L-tyrosyl)-L-phenylalaninol
Spectroscopic data: mp 210.0-212.0 ℃,
1H-NMR (DMSO, 400MHz) δ: 9.17 (1H, s, ArOH), 8.79 (1H, d, J=8.4Hz, NHCO), 8.71 (2H, d, J=5.6Hz, H-4 "; 6 "), 7.95 (1H, d, J=8.0Hz, NHCO), 7.69 (2H, d, J=5.6Hz, H-3 ", 7 "), 7.23-7.09 (7H, m, H-5,9,5 '-9 '), 6.63 (2H, d, J=8.4Hz, H-6,8), 4.82 (1H, t, OH), 4.62 (1H, m, H-2), (3.90 1H, m, H-2 '), 3.37-3.27 (2H, m, H-1 '), 2.96-2.79 (3H, m, H-3,3 ' a), 2.66 (1H, dd, J=8.0,13.6Hz, H-3 ' is b);
13C-NMR (DMSO, 100MHz) δ: 171.7 (C-1), 164.5 (C-1 "), 155.7 (C-7), 150.2 (C-4 ", 6 "), 141.1 (C-2 "), 139.0 (C-4 '), 130.1 (C-5,9), 129.2 (C-6 ', 8 '), 128.2 (C-4), 128.1 (C-5 ', 9 '), 125.9 (C-7 '), 121.4 (C-3 "; 7 "), 114.9 (C-6,8), 62.3 (C-1 '), 55.3 (C-2), 52.5 (C-2 '), 36.6,36.4.
Embodiment 48:N-(the different nicotinoyl of N--L-tyrosyl)-L-phenylalanine methyl ester
Spectroscopic data: mp 206.5-209.0 ℃,
1H-NMR (DMSO, 400MHz) δ: 9.17 (1H, s, ArOH), 8.82 (1H, d, J=8.8Hz, NHCO), 8.70 (2H, d, J=5.6Hz, H-4 ", 6 "), 8.59 (1H, d, J=7.6Hz, NHCO), 7.67 (2H, d, J=5.6Hz, H-3 ", 7 "), 7.27-7.18 (5H, m, H-5 '-9 '), 7.12 (2H, d, J=8.4Hz, H-5,9), (6.63 2H, d, J=8.4Hz, H-6,8), 4.68 (1H, m, H-2), 4.50 (1H, m, H-2 '), 3.59 (3H, s, OCH
3), 3.09-2.77 (4H, m, H-3,3);
13C-NMR (DMSO, 100MHz) δ: 171.8 (C-1), 171.4 (C-1 '), 164.6 (C-1 "); 155.7 (C-7), 150.2 (C-4 ", 6 "), 141.0 (C-2 "), (137.1 C-4 '), 130.1 (C-5,9), 129.1 (C-6 ', 8 '), 128.3 (C-5 ', 9 '), 128.1 (C-4), (126.6 C-7 '), 121.4 (C-3 ", 7 "), 114.9 (C-6,8), 54.9 (C-2), 53.8 (C-2 '), 51.9 (OCH
3), 38.9,36.5.
Embodiment 49:N-[N-(4-dimethyl aminomethyl-benzoyl)-L-phenylalanyl]-the L-phenylalaninol
Reagent and reaction conditions: (a) (t-BuOCO)
2O, 1.0M NaOH, TBAB; (b) CH
2Cl
2, isobutyl chlorocarbonate (IBCF), N-methylmorpholine (NMM) ,-5 ℃; (c) TFA, CH
2Cl
2, rt, 2h
Experimental implementation: (1.65g 10.0mmol) is dissolved in the 20ml 1.0M NaOH solution, adds tert-Butyl dicarbonate { (t-BuOCO) (a) to get the L-phenylalanine
2O} (2.289g, 10.05mmol) and Tetrabutyl amonium bromide (Tetrabutyl ammonium bromide, TBAB, 1.0g), stirred overnight at room temperature.Next day with concentrated hydrochloric acid conditioned reaction liquid to pH2-3, ethyl acetate 60ml extraction, saturated sodium-chloride (2? 0ml) washing, anhydrous sodium sulfate drying, decompression and solvent recovery promptly gets colorless oil sample N-BOC-L-phenylalanine (N-BOC-L-Phe) 2.63g (productive rate: 99%) to doing; (b) synthesis step (b) of its operation steps and embodiment 1 is similar, is prepared into the intermediate M-32 (productive rate: 88%) of white powder; (c) getting synthetic gained M-32 sample of preceding-step dissolves with trifluoroacetic acid (TFA), stirring at room 2h, it is an amount of to add water in reaction flask, be adjusted to alkalescence (pH11-12) with yellow soda ash, ethyl acetate extraction, organic phase is difficult the aqueous sodium persulfate drying, decompression and solvent recovery to do white waxy solid sample M-33 (productive rate: 65.8%).
Reagent and reaction conditions: CH
2Cl
2, DCC, DMAP, rt.
Experimental implementation: with aforementioned synthetic intermediate M-25 (10mmol) and M-33 (10mmol), DCC (2.47g, 12mmol), DMAP (200mg is as catalyzer) is mixed in the reaction flask, injects anhydrous CH
2Cl
2200ml reacts on stirred overnight at room temperature under the nitrogen protection.Product promptly gets white waxy solid product 1 (productive rate: 89%) through extraction and recrystallization purifying.
Spectroscopic data:
N-(N-(4-dimethylamino-methyl-benzoyl)-L-phenylalanyl)-L-phenylalanol，mp?196.5-198.0℃，
1H-NMR(DMSO，400MHz)δ：8.46(1H，d，J＝8.8Hz，NHCO)，7.87(1H，d，J＝8.4Hz，NHCO)，7.75(2H，d，J＝8.0Hz，H-3″，7″)，7.34(2H，d，J＝8.0Hz，H-4″，6″)，7.30-7.10(10H，m，H-5′-9′，5-9)，4.81(1H，t，OH)，4.67(1H，m，H-2)，3.87(1H，m，H-2′)，3.43(2H，s，ArCH
2N(CH
3)
2)，3.34-3.25(2H，m，H-1′)，3.02-2.93(2H，m，H-3)，2.84(1H，dd，J＝5.6，13.6Hz，H-3′a)，2.65(1H，dd，J＝8.4，13.6Hz，H-3′b)，1.14(6H，s，ArCH
2N(CH
3)
2)；
13C-NMR(DMSO，100MHz)δ：171.0(C-1)，165.9(C-1″)，143.0(C-5″)，139.0(C-4′)，138.4(C-4)，132.8(C-2″)，129.2(？，C-6，8，6′，8′)，128.5(C-4″，6″)，128.1(C-5′，9′)，128.0(C-5，9)，127.4(C-3″，7″)，126.2(C-7)，125.9(C-7′)，62.8(ArCH
2N(CH
3)
2)，62.2(C-1′)，54.8(C-2)，52.5(C-2′)，44.9(ArCH
2N(CH
3)
2)，37.2，36.4。
According to the synthetic method that is similar to embodiment 49, select suitable reaction raw materials and intermediate, make the derivative of embodiment 50～53 respectively.
Embodiment 50:N-{N-[4-(1-pyrrolidyl) methyl-benzoyl]-the L-phenylalanyl }-the L-phenylalaninol
Spectroscopic data: mp 164.0-165.0 ℃,
1H-NMR (DMSO, 400MHz) δ: 8.44 (1H, d, J=8.0Hz, NHCO), 7.87 (1H, d, J=8.4Hz, NHCO), 7.74 (2H, d, J=8.4Hz, H-3 ", 7 "), 7.35 (2H, d, J=8.0Hz, H-4 "; 6 "), 7.31-7.09 (10H, m, H-5 '-9 ', 5-9), 4.81 (1H, t, OH), 4.67 (1H, m, H-2), 3.88 (1H, m, H-2 '), 3.58 (2H, s, ArCH
2N＜), 3.34-3.24 (2H, m, H-1 '), 3.04-2.91 (2H, m, H-3), 2.85 (1H, dd, J=5.6,13.6Hz, H-3 ' a), 2.65 (1H, dd, J=8.0,13.6Hz, H-3 ' b), 2.40 (4H, s, ArCH
2N (CH
2)
2), 1.67 (4H, s,〉NCH
2CH
2CH
2CH
2N＜);
13C-NMR (DMSO, 100MHz) δ: 171.0 (C-1), 165.9 (C-1 "), 143.0 (C-5 "), (139.0 C-4 '), 138.4 (C-4), 132.6 (C-2 "), 129.2 (* 4; C-6,8,6 ', 8 '); 128.14 (C-4 ", 6 "), 128.08 (C-5 ', 9 '); 128.04 (C-5,9), 127.4 (C-3 ", 7 "); 126.2 (C-7), 125.9 (C-7 '), 62.2 (C-1 '), 59.2 (ArCH
2N＜), 54.8 (C-2), 53.5 (ArCH
2N (CH
2)
2), 52.5 (C-2 '), 37.2,36.4,23.1 (〉 NCH
2CH
2CH
2CH
2N＜).
Embodiment 51:N-{N-[4-(4-morpholinyl) methyl-benzoyl]-the L-phenylalanyl }-the L-phenylalaninol
Spectroscopic data: mp 183.0-184.5 ℃,
1H-NMR (DMSO, 400MHz) δ: 8.45 (1H, d, J=8.4Hz, NHCO), 7.87 (1H, d, J=8.0Hz, NHCO), 7.76 (2H, d, J=7.6Hz, H-3 ", 7 "), 7.37 (2H, d, J=7.6Hz, H-4 "; 6 "), 7.31-7.10 (10H, m, H-5 '-9 ', 5-9), 4.81 (1H, t, OH), 4.69 (1H, m, H-2), 3.89 (1H, m, H-2 '), 3.57 (4H, s ,-CH
2OCH
2-), 3.48 (2H, s, ArCH
2N＜), 3.34-3.25 (2H, m, H-1 '), 3.05-2.92 (2H, m, H-3), 2.86 (1H, dd, J=5.2,13.6Hz, H-3 ' a), 2.66 (1H, dd, J=8.0,13.6Hz, H-3 ' b), 2.34 (4H, s, ArCH
2N (CH
2)
2);
13C-NMR (DMSO, 100MHz) δ: 170.9 (C-1), 165.9 (C-1 "); 141.4 (C-5 "), 139.0 (C-4 '), 138.4 (C-4), 132.8 (C-2 "), 129.19 (* 2), 129.17 (* 2); 128.6 (C-4 ", 6 "), 128.06 (* 2); 128.01 (* 2), 127.4 (C-3 ", 7 "); 126.2 (C-7), 125.9 (C-7 '), 66.2 (CH
2OCH
2-), 62.2 (C-1 '), 61.96 (ArCH
2N＜), 54.7 (C-2), 53.2 (ArCH
2N (CH
2)
2), 52.5 (C-2 '), 37.2,36.4.
Embodiment 52:N-[N-(4-ethoxycarbonyl-benzoyl)-L-phenylalanyl]-the L-phenylalaninol
Spectroscopic data: mp 188.0-189.5 ℃,
1H-NMR (DMSO, 400MHz) δ: 8.74 (1H, d, J=8.4Hz, NHCO), 8.02 (2H, d, J=8.0Hz, H-4 ", 6 "), 7.97 (1H, d, J=8.4Hz, NHCO), 7.91 (2H, d, J=8.4Hz, H-3 "; 7 "), 7.33-7.11 (10H, m, H-5-9,5 '-9 '), 4.82 (1H, t, OH), 4.71 (1H, m, H-2), 4.34 (2H, q, J=7.2Hz, OCH
2CH
3), 3.90 (1H, m, H-2 '), 3.35-3.26 (2H, m, H-1 '), 3.07-2.92 (2H, m, H-3), 2.87 (1H, dd, J=5.6,13.6Hz, H-3 ' a), 2.67 (1H, dd, J=8.0,13.6Hz, H-3 ' b), 1.34 (3H, t, OCH
2CH
3);
13C-NMR (DMSO, 100MHz) δ: 171.8 (C-1), 165.2 (* 2, C-1 ", ArCOOCH
2CH
3), 139.0 (C-4 '), 138.3 (C-4), 138.1 (C-2 "); 132.1 (C-5 "), 129.2 (* 4, C-6,8,6 ', 8 '), 129.0 (C-4 "; 6 "), 128.08 (* 2), 128.05 (* 2), 127.8 (C-3 ", 7 "), 126.2 (C-7), (125.9 C-7 '), 62.2 (C-1 '), 61.0 (OCH
2CH
3), 54.9 (C-2), 52.5 (C-2 '), 37.3 (C-3), 36.4 (C-3 '), 14.2 (OCH
2CH
3).
Embodiment 53:N-[N-(2-carboxyl-benzoyl)-4-acetylaminohydroxyphenylarsonic acid L-phenylalanyl]-L-phenylalaninol sodium salt
Spectroscopic data: Sodium N-(N-2-carboxybenzoyl-L-phenylalanyl)-L-phenylalanol,
1H-NMR (DMSO, 400MHz) δ: 9.20 (1H, d, J=7.2Hz, H-4 "), 8.50 (1H; d, J=8.8Hz, H-7 "), 7.76 (1H, m, H-6 "); 7.33-7.19 (12H, m, H-5-9,5 '-9 ', NHCO * 2), 6.65 (1H; m, H-5 "), 4.48-4.39 (2H, m, H-2,2 '), 3.80 (1H, br, OH), 3.45-3.27 (2H, m, H-1 '), 2.8 δ-2.70 (4H, m, H-3,3 ');
13C-NMR (DMSO, 100MHz) δ: 170.98,170.94,168.6 (C-1 "), 139.6; 139.5,138.4,138.2,129.3 (* 2, C-4 ", 7 "), 129.3 (C-6,8), 129.0 (C-6 ', 8 '); 128.2 (C-5,9), 128.0 (C-5 ', 9 '), 127.7 (C-5 "), 126.0,125.92,125.87,61.0 (C-1 '), 54.7,54.0,36.6,36.2.
Embodiment 54:N-(N-benzoyl-4-acetylaminohydroxyphenylarsonic acid L-phenylalanyl)-O-ethanoyl-L-phenylalaninol
Reagent and reaction conditions: (a) MeOH, H
2, Pd/C (20%), rt., 3h; (b) Ac
2O, and pyridine (pyridine, pyr.), rt., 5h
Experimental implementation: (a) get aforementioned (embodiment 5) synthetic compound 1 sample 1.788g (4mmol) and be dissolved among the 100ml MeOH, the Pd/C 21mg of adding 20% after the degassing is handled, and with behind the air in the hydrogen exchange reaction system, with hydrogen balloon sealed reaction system, spend the night in the stirring at room reaction.Remove by filter the Pd/C catalyzer next day, filtrate decompression reclaims solvent to doing, and promptly gets compound 2 crude products of 1.876g white powder, the reaction that this product is directly used in down-goes on foot without warp-step purifying.(b) get-go on foot synthetic gained compound 2 crude product 469mg (＜1.0mmol) in the 5ml pyridine dissolving fully, stirring at room slowly drips diacetyl oxide (Ac
2O) 2ml, room temperature reaction 5h, the diacetyl oxide of adding dehydrated alcohol 5ml decomposing excessive, decompression and solvent recovery is to doing, and the gained solid is complete with an amount of EtOAc dissolving, successively with distilled water, 5% NaHCO
3With saturated NaCl solution washing, anhydrous sodium sulfate drying, the reclaim under reduced pressure ethyl acetate is to doing, and the gained residue promptly gets white powder product 300mg (60.0%) with re-crystallizing in ethyl acetate.
Spectroscopic data: mp 236.0-237.5 ℃,
1H-NMR (DMSO, 400MHz) δ: 9.84 (1H, s, ArNHCO), 8.49 (1H, d, J=8.4Hz, NHCO), 8.15 (1H, d, J=8.4Hz, NHCO), 7.80 (2H, d, J=7.6Hz, H-3 ", 7 "), 7.52 (1H, t, H-5 "), 7.47-7.43 (4H, m, H-4 ", 6 ", H-6,8), 7.24-7.15 (7H, m; H-5 '-9 ', H-5,9), 4.63 (1H, m; H-2), 4.18 (1H, m, H-2 '), 4.02 (1H; dd, J=4.8,11.2Hz, H-1 ' a), 3.87 (1H; dd, J=7.2,11.2Hz, H-1 ' b), 2.96-2.77 (4H; m, H-3,3 '), 1.99 (3H, CH
3CO), 1.98 (3H, CH
3CO);
13C-NMR (DMSO, 100MHz) δ: 171.2 (C-1), 170.3 (OCOCH
3), 168.1 (ArNHCOCH
3), 166.1 (C-1 "), 138.0 (C-7), 137.6 (C-4 '); 134.1 (C-2 "), 132.8 (C-4), 131.3 (C-5 "), 129.3 (C-5; 9), 129.2 (C-6 ', 8 '), 128.23 (* 2); 128.18 (* 2), 127.4 (C-3 ", 7 "), 126.2 (C-7 '); 118.6 (C-6,8), 64.6 (C-1 '), 55.0 (C-2); 49.1 (C-2 '), 36.7 (C-3 '), 36.6 (C-3), 24.0 (NHCOCH
3), 20.6 (OCOCH
3).
According to the synthetic method that is similar to embodiment 54, select suitable reaction raw materials and intermediate, make the derivative of embodiment 55～70 respectively.
Embodiment 55:N-(N-benzoyl-L-phenylalanyl)-O-ethanoyl-L-phenylalaninol
Spectroscopic data: mp 186-187 ℃, [Dan 20D-35.71 (0.028, CHCl
3) .IR (KBr) cm
-1: 3314,1725,1661,1631,1533,746,698.EI-MS m/z:444,384,353,311,269,252,224,172,131,105 (100), 91,77,60.
1H-NMR (CDCl
3, 400MHz) δ: 7.69 (2H, d, J=8.0Hz, H-3 ", 7 "), 7.50 (1H, t, H-5 "), 7.42 (2H, t, H-4 ", 6 "), 7.30-7.06 (10H, m, H-5-9, H-5 '-9 '), 6.76 (1H; d, J=7.6Hz, NHCO), 5.97 (1H, d, J=8.4Hz; NHCO), 4.77 (1H, m, H-2), 4.34 (1H, m; H-2 '), 3.93 (1H, dd, J=5.2,11.6Hz, H-1 ' is a); 3.81 (1H, dd, J=4.0,11.2Hz, H-1 ' b), 3.22 (1H; dd, J=5.6,13.6Hz, H-3a), 3.06 (1H, dd, J=8.4,13.6Hz, H-3b), 2.75 (2H, m, H-3 '), 2.03 (3H, s, CH
3CO);
13C-NMR (CDCl
3, 400MHz) δ: 170.6 (C-1), 170.2 (COCH
3), 167.1 (C-1 "), 136.7 (C-4), 136.6 (C-4 '), 133.6 (C-2 "), 131.9 (C-5 "), 129.3 (C-6,8), 129.1 (C-6 ', 8 '); 128.7 (C-4 ", 6 "), 128.6 (C-5,9); 128.5 (C-5 ', 9 '), 127.1 (C-3 ", 7 "); 127.0 (C-7 '), 126.7 (C-7), 64.5 (C-1 '), 54.9 (C-2); 49.4 (C-2 '), 38.4 (C-3), 37.4 (C-3 '), 20.77 (COCH
3).
Embodiment 56:N-(N-benzoyl-L-phenylalanyl)-O-(3-carboxyl-propionyl)-L-phenylalaninol
Spectroscopic data:
1H-NMR (CDCl
3, 400MHz) δ: 8.61 (1H, d, J one .6Hz, NHCO) 7.71 (2H, d, H-3 "; 7 "), 7.50 (1H, t, 5 "), 7.40 (2, t, H-4 ", 6 "), 7.31-7.08 (10H, m, H-5-9,5 '-9 '), 6.47 (1H; d, J=8.0Hz, NHCO), 5.12 (1H, m, H-2); 4.32 (1H, m, H-2 '), 4.15-3.94 (2H, dd * 2, H-3 '); 3.05-3.01 (2H, m, H-3), 2.70-2.58 (4H, m ,-OCOCH2CH2CO-);
Embodiment 57:N-(N-benzoyl-ethanoyl-L-phenylalanyl)-L-phenylalanine methyl ester
Spectroscopic data: mp 221.0-222.0 ℃, ℃,
1H-NMR (DMSO, 400MHz) δ: 9.84 (1H, s, ArNHCO), 8.52 (2H, m, NHCO * 2), 7.76 (2H, d, J=7.6Hz, H-3 ", 7 "), 7.51 (1H, t, H-5 "), 7.46-7.42 (4H, m, H-4 ", 6 ", H-6,8), 7.26-7.17 (7H, m, H-5 '-9 '; H-5,9), 4.71 (1H, m, H-2), 4.51 (1H; m, H-2 '), 3.59 (3H, s, OCH
3), 3.09-2.85 (4H, m, H-3,3 '), 1.99 (3H, CH
3CO);
13C-NMR (DMSO, 100MHz) δ: 171.9,171.7,168.1 (ArNHCOCH
3), 166.2 (C-1 "), 137.6 (C-7), 137.1 (C-4 '); 134.0 (C-2 "), 132.8 (C-4), 131.3 (C-5 "), 129.4 (C-5; 9), 129.1 (C-6 ', 8 '), 128.3 (C-4 ", 6 "), 128.2 (C-5 ', 9 '), 127.4 (C-3 ", 7 "), 126.6 (C-7 '), 118.6 (C-6,8); 54.6 (C-2), 53.8 (C-2 '), 51.9 (OCH
3), 36.6,36.4,24.0 (COCH
3).
Embodiment 58:N-(N-benzoyl-L-phenylalanyl)-4-amino-L-phenylalanine methyl ester hydrochloride
Spectroscopic data: mp 173.0-175.0 ℃,
1H-NMR (DMSO, 400MHz) δ: 10.25 (br, ArNH
2HCl), 8.69 (1H, d, J=7.6Hz, NHCO), 8.62 (1H, d, J=8.8Hz, NHCO), 7.77 (2H, d, J=6.8Hz, H-3 ", 7 "), 7.51-7.14 (12H, m, H-4 " 6 ", H-5-9, H-5 ', 9 ', 6 ', 8 '), 4.71 (1H, m, H-2), 4.50 (1H, m, H-2 '), 3.58 (3H, s, OCH
3), 3.11-2.82 (4H, m, H-3,3 ');
13C-NMR (DMSO, 100MHz) δ: 171.9,171.7,166.3 (C-1 "); 138.4 (C-4), 137.2 (C-7 '), 134.0 (C-2 "), 131.4 (C-5 "); 130.6 (C-4 '), 130.6 (C-5 ', 9 '), 129.3 (C-6; 8), 128.3 (* 2), 128.1 (* 2), 127.5 (C-3 ", 7 "), 126.3 (C-7 '), 123.1 (C-6 ', 8 '); 54.8 (C-2), 53.7 (C-2 '), 52.1 (OCH
3), 37.0,35.9.
Embodiment 59:N-(N-benzoyl-L-phenylalanyl)-4-acetylaminohydroxyphenylarsonic acid L-phenylalanine methyl ester
Spectroscopic data: mp 228.0-229.5 ℃,
1H-NMR (DMSO, 400MHz) δ: 9.95 (1H, s, ArNHCO), 8.60 (1H, d, J=8.8Hz, NHCO), 8.57 (1H, d, J=7.6Hz, NHCO), 7.77 (2H, d, J=6.8Hz, H-3 ", 7 "), 7.53-7.14 (12H, m, H-4 " 6 ", H-5-9, H-5 ', 9 ', 6 ', 8 '), 4.74 (1H, m, H-2), 4.47 (1H, m, H-2 '), 3.59 (3H, s, OCH
3), 3.09-2.91 (4H, m, H-3,3 '), 2.02 (3H, s, COCH
3);
13C-NMR (DMSO, 100MHz) δ: 171.9,171.7,168.2 (ArNHCOCH
3), 166.2 (C-1 "), 138.4 (C-4), 138.0 (C-7 '); 134.0 (C-2 "), 131.4 (C-4 '), 131.3 (C-5 "), 129.4 (C-5 '; 9 '), 129.2 (C-6,8), 128.2 (C-4 ", 6 "), 128.1 (C-5,9), 127.4 (C-3 ", 7 "), 126.2 (C-7), 118.8 (C-6 ', 8 '); 54.6 (C-2), 53.9 (C-2 '), 51.9 (OCH
3), 37.0,36.1,24.0 (COCH
3).
Embodiment 60:N-[N-(4-methyl-benzoyl)-L-phenylalanyl]-4-acetylaminohydroxyphenylarsonic acid L-phenylalanine methyl ester
Spectroscopic data: mp 221.5-222.0 ℃,
1H-NMR (DMSO, 400MHz) δ: 9.91 (1H, s, ArNHCO), 8.53 (1H, d, J=7.6Hz, NHCO), 8.48 (1H, d, J=8.8Hz, NHCO), 7.68 (2H, d, J=8.8Hz, H-3 "; 7 "), 7.48 (2H, d, J=8.8Hz, H-6 ', 8 '), 7.34 (2H, d, J=7.6Hz, H-5,9), 7.24 (4H, m, H-4 ", 6 ", H-6,8), 7.16 (3H, m, H-5 ', 9 ', H-7), 4.74 (1H, m, H-2), 4.48 (1H, m, H-2 '), 3.59 (3H, s, OCH
3), 3.09-2.91 (4H, m, H-3,3 '), 2.33 (3H, s, Ar-CH
3), 2.02 (3H, s, COCH
3);
13C-NMR (DMSO, 100MHz) δ: 171.9,171.8,168.1 (ArNHCO), 166.1 (C-1 "); 141.2 (C-5 "), 138.4 (C-4), 138.0 (C-7 '), 131.4 (C-2 "), 131.2 (C-4 '); 129.4 (C-5 ', 9 '), 129.2 (C-6,8), 128.7 (C-4 ", 6 "), 128.0 (C-5,9), 127.5 (C-3 ", 7 "); 126.2 (C-7), 118.9 (C-6 ', 8 '), 54.5 (C-2); 53.9 (C-2 '), 37.0,36.1,24.0 (NHCOCH
3), 21.0 (Ar-CH
3).
Embodiment 61:N-{N-[4-(3-carboxyl-propionamido)-benzoyl]-the L-phenylalanyl }-the L-phenylalaninol
Spectroscopic data:
1H-NMR (DMSO, 400MHz) δ: 12.18 (1H, COOH), 10.21 (1H, s, ArNHCO), 8.38 (1H, d, J=8.4Hz, NHCO), 7.88 (1H, d, J=8.4Hz, NHCO), 7.77 (2H, d, J=8.8Hz, H-3 "; 7 "), 7.64 (2H, d, J=8.4Hz, H-4 ", 6 "), 7.31-7.11 (10H, m, H-5-9,5 '-9 '), 4.82 (1H, t, OH), 4.67 (1H, m, H-2), 3.90 (1H, m, H-2 '), 3.35-3.24 (2H, m, H-1 '), 3.05-2.91 (2H, m, H-3), 2.86 (1H, dd, J=5.6,13.6Hz, H-3 ' a), 2.66 (1H, dd, J=8.0,13.6, Hz, H-3 ' b), 2.61-2.50 (4H, m, ArNHCOCH
2CH
2COOH);
13C-NMR (DMSO, 100MHz) δ: 173.9 (COOH), 171.1 (ArNHCO), 170.6 (C-1), 165.6 (C-1 "), 142.0 (C-5 "), (139.0 C-4 '), 138.5 (C-4), 129.23 (* 2), (129.21 * 2), 128.4 (C-3 ", 7 "), 128.2 (C-2 "), 128.1 (* 2), 128.0 (* 2); 126.2 (C-7); 125.9 (C-7 '), 117.9 (C-4 ", 6 "); 62.2 (C-1 '); 54.8 (C-2), 52.5 (C-2 '), 37.2 (C-3 '); 36.5 (C-3), 31.1 (ArNHCOCH
2CH
2COOH), 28.7 (ArNHCOCH
2CH
2COOH).
Embodiment 62:N-{N-[4-(3-carboxyl-propionamido)-benzoyl]-the L-phenylalanyl }-L-phenylalanine methyl
Spectroscopic data:
1H-NMR (DMSO, 400MHz) δ: 12.21 (1H, br, COOH), 10.22 (1H, s, ArNHCO), 8.55 (1H, d, J=7.6Hz, NHCO), 8.43 (1H, d, J=8.8Hz, NHCO), 7.74 (2H, d, J=8.8Hz, H-3 ", 7 "), 7.63 (2H, d, J=8.4Hz, H-4 ", 6 "), 7.34-7.13 (10H, m, H-5-9,5 '-9 '), 4.73 (1H, m, H-2), (4.51 1H, m, H-2 '), 3.59 (3H, s, OCH
3), 3.07-2.91 (4H, m, H-3,3 '), 2.59-2.50 (4H, m, ArNHCOCH
2CH
2COOH);
13C-NMR (DMSO, 100MHz) δ: 173.9 (COOH), 171.9,171.8,170.6,165.7 (C-1 "), 142.0 (C-5 "), 138.4 (C-4), 137.4 (C-4 '), 129.2 (C-6,8), 129.2 (C-6 ', 8 '), 128.4 (C-3 ", 7 "), 128.3 (C-5 ', 9 '), 128.12 (C-2 "), 128.07 (C-5; 9), 126.6 (C-7 '), 126.2 (C-7), 117.9 (C-4 ", 6 "), 54.4 (C-2), 53.8 (C-2 '), 51.9 (OCH
3), 36.9 (C-3 '), 36.6 (C-3), 31.1 (ArNHCOCH
2CH
2COOH), 28.7 (ArNHCOCH
2CH
2COOH).
Embodiment 63:N-(N-benzoyl-O-ethanoyl-3-acetylaminohydroxyphenylarsonic acid L-tyrosyl)-L-phenylalanine methyl ester
Spectroscopic data:
1H-NMR (DMSO, 400MHz) δ: 9.34 (1H, s, ArNHCO), 8.58-8.53 (2H, m, NHCO * 2), 7.85 (1H, s, H-5), 7.77 (2H, d, J=8.8Hz, H-3 "; 7 "), 7.51 (1H, t, H-5 "), 7.43 (2H, t, H-4 ", 6 "), 7.25-7.19 (5H, m, H-5 '-9 '), 7.09 (1H, d, J=8.0Hz; H-8), 7.99 (1H, d, J=8.0Hz, H-9), 4.70 (1H, m; H-2), 4.51 (1H, m, H-2 '), 3.59 (3H, s, OCH
3), 3.08-2.89 (4H, m, H-3,3 '), 2.24 (3H, s, OCOCH
3), 2.05 (3H, s, NHCOCH
3);
13C-NMR (DMSO, 100MHz) δ: 171.8,171.7,169.0,166.4 (C-1 "); 140.1 (C-7), 137.0 (C-4 '), 135.8 (C-6), 134.2 (C-2 "), 131.3 (C-5 "); 130.1 (C-4), 129.1 (C-6 ', 8 '), 128.3 (C-5 '; 9 '), 128.2 (C-4 ", 6 "), 127.5 (C-3 ", 7 "), 126.6 (C-7 '), 125.3,124.7; 122.4 (C-5), 54.5 (C-2), 53.8 (C-2 '), 51.9 (OCH
3), 36.6,36.5,23.6 (NHCOCH
3), 21.1 (OCOCH
3).
Embodiment 64:N-(N-benzoyl-L-phenylalanyl)-4-propionamido-L-phenylalanine methyl ester
Spectroscopic data: mp 244.5-246.0 ℃,
1H-NMR (DMSO, 400MHz) δ: 9.89 (1H, s, ArNHCO), 8.60-8.57 (2H, m, NHCO * 2), 7.76 (2H, d, J=7.6Hz, H-3 ", 7 "), 7.51-7.47 (3H, m, H-5 ", H-6 '; 8 '), 7.41 (2H, t, H-4 ", 6 "), 7.32 (2H, d; J=7.6Hz, H-5,9), 7.33 (2H, t, H-6,8); 7.15-7.13 (3H, m, H-7, H-5 ', 9 '), 4.73 (1H, m; H-2), 4.46 (1H, m, H-2 '), 3.57 (3H, s, OCH
3), 3.08-2.92 (4H, m, H-3,3 '), 2.28 (2H, q, J=7.6, Hz, NHCOCH
2CH
3), 1.05 (3H, t, J=7.6Hz, NHCOCH
2CH
3);
13C-NMR (DMSO, 100MHz) δ: 171.96,171.93,171.8,166.3 (C-1 "); 138.4 (C-4), 138.1 (C-7 '), 134.1 (C-2 "), 131.4 (C-5 ", C-4 '); 129.4 (C-5 ', 9 '), 129.2 (C-6,8); 128.2 (C-4 ", 6 "), 128.1 (C-5,9); 127.5 (C-3 ", 7 "), 126.3 (C-7), 118.9 (C-6 '; 8 '), 54.7 (C-2), 54.0 (C-2 '), 51.9 (OCH
3), 37.O, 36.1,29.6 (NHCOCH
2CH
3), 9.8 (NHCOCH
2CH
3).
Embodiment 65:N-[N-(4-dimethylamino methyl-benzoyl)-L-phenylalanyl]-O-ethanoyl-L-phenylalaninol
Spectroscopic data:
1H-NMR (CDCl
3, 400MHz) δ: 7.68 (2H, d, J=8.4Hz, H-3 ", 7 "), 7.40 (2H, d, J=8.0Hz, H-4 ", 6 "), 7.30-7.06 (10H, m, H-5 '-9 ', 5-9), 6.76 (1H, br, NHCO), 6.07 (1H, br, NHCO), 4.78 (1H, m, H-2), 4.35 (1H, m, H-2 '), 3.92 (1H, dd, J=4.8,11.6Hz, H-1 ' a), 3.81 (1H, dd, J=4.0,11.6Hz, H-1 ' b), 3.49 (2H, s, ArCH
2N (CH
3)
2), 3.22 (1H, dd, J=5.6,13.6Hz, H-3a), 3.06 (1H, dd, J=8.4,13.2Hz, H-3b), 2.76-2.73 (2H, m, H-3 '), 2.26 (6H, s, ArCH
2N (CH
3)
2), 2.03 (3H, s, COCH
3);
13C-NMR (CDCl
3, 100MHz) δ: 170.8 (C-1), 170.2 (OCOCH
3), 166.9 (C-1 "), 143.0 (C-5 "), 136.7,136.6,132.5 (C-2 "), 129.3 (* 4, C-6; 8,6 ', 8 '), 129～(C-4 ", 6 "), 128.7 (C-5 ', 9 '), 128.5 (C-5; 9), 127.1 (C-3 ", 7 "), 126.7 (C-7; 7 '), 64.5 (C-1 '), 63.8 (ArCH
2N (CH
3)
2), 54～(C-2), 49.3 (C-2 '), 45.3 (ArCH
2N (CH
3)
2), 38.4,37.4,20.8 (OCOCH
3).
Embodiment 66:N-[N-(4-dimethylamino methyl-benzoyl)-L-phenylalanyl]-O-propionyl-L-phenylalaninol
Spectroscopic data:
1H-NMR (CDCl
3, 400MHz) δ: 7.70 (2H, d, J=8.0Hz, H-3 ", 7 "), 7.44 (2H, d, J=7.6Hz, H-4 ", 6 "), 7.30-7.06 (10H, m, H-5 '-9 ', 5-9), 6.83 (1H, br, NHCO), 6.13 (1H, br, NHCO), 4.78 (1H, m, H-2), 4.34 (1H, m, H-2 '), 3.93 (1H, dd, J=5.2,11.6Hz, H-1 ' is a), 3.85-3.81 (1H, m, H-1 ' b), 3.59 (2H, s, ArCH
2N (CH
3)
2), 3.22 (1H, dd, J=7.0,13.6Hz, H-3a), 3.06 (1H, dd, J=8.4,13.6Hz, H-3b), 2.80-2.70 (2H, m, H-3 '), 2.33 (6H, s, ArCH
2N (CH
3)
2), 2.29 (2H, q, J=7.6, COCH
2CH
3), 1.13 (3H, t, J=7.6, COCH
3);
13C-NMR (CDCl
3, 100MHz) δ: 173.9 (OCOCH
2CH
3), 169.9 (C-1), 166.5 (C-1 "), 143.0 (C-5 "), 136.4,136.2,132.6 (C-2 "), 129.2 (C-6; 8), 128.9 (C-6 ', 8 '), 128.8 (C-4 ", 6 "), 128.4 (C-5 ', 9 '), 128.2 (C-5; 9), 126.9 (C-3 ", 7 "), 126.7 (C-7); 126.4 (C-7 '), 64.0 (C-1 '), 63.4 (ArCH
2N (CH
3)
2), 54.6 (C-2), 49.1 (C-2 '), 44.6 (ArCH
2N (CH
3)
2), 38.1,37.1,27.0 (OCOCH
2CH
3), 8.7 (OCOCH
2CH
3).
Embodiment 67:N-{N-[4-(4-morpholinyl) methyl-benzoyl]-the L-phenylalanyl }-O-propionyl-L-phenylalaninol
Spectroscopic data:
1H-NMR (DMSO, 400MHz) δ: 8.68 (1H, d, J=8.0Hz, NHCO), 8.30 (1H, d, J=7.6Hz, NHCO), 7.78 (2H, d, J=8.4Hz, H-3 ", 7 "), 7.36 (2H, d, J=8.0Hz, H-4 ", 6 "), 7.31-7.13 (10H, m, H-5 '-9 ', 5-9), 4.65 (1H, m, H-2), 4.18 (1H, m, H-2 '), 4.03 (1H, dd, J=4.8,11.2Hz, H-1 ' a), 3.87 (1H, dd, J=6.8,11.2Hz, H-1 ' b), 3.57 (4H, t, J=4.4Hz ,-CH
2OCH
2-), 3.49 (2H, s, ArCH
2N＜), 2.96 (2H, d, J=7.2Hz, H-3), 2.79 (2H, d, J=6.8Hz, H-3 '), 2.34 (4H, s, ArCH
2N (CH
2)
2), 2.26 (2H, q, J=7.6Hz, COCH
2CH
3), 0.98 (3H, t, J=7.6Hz, COCH
2CH
3);
13C-NMR (DMSO, 100MHz) δ: 173.5 (COEt), 171.3 (C-1), 165.9 (C-1 "); 142.3 (C-5 "), 138.4 (C-4), 138.1 (C-4 '), 132.8 (C-2 "); 129.2 (* 2), 129.1 (* 2), 128.5 (C-4 ", 6 "); 128.2 (C-5,9), 128.0 (C-5 '; 9 '), 127.4 (C-3 ", 7 "); 126.2 (C-7,7 '), 66.2 (CH
2OCH
2-), 64.5 (C-1 '), 62.0 (ArCH
2N＜), 55.1 (C-2), 53.2 (ArCH
2N (CH
2)
2), 49.2 (C-2 '), 37.2,36.6,26.7 (COCH
2CH
3), 8.9 (COCH
2CH
3).
Embodiment 68:N-[N-(4-methyl-benzoyl)-4-acetylaminohydroxyphenylarsonic acid L-phenylalanyl]-O-ethanoyl-L-L-Tyrosine methyl ester
Spectroscopic data: mp 222.0-223.0 ℃,
1H-NMR (DMSO, 400MHz) δ: 9.84 (1H, s, ArNHCO), 8.55 (1H, d, J=7.2Hz, NHCO), 8.42 (1H, d, J=8.4Hz, NHCO), 7.69 (2H, d, J=8.0Hz, H-3 "; 7 "), 7.44 (2H, d, J=8.4Hz, H-6,8), 7.27-7.23 (6H, m, H-5,9,5 ', 9 ', 4 ", 6 "), 6.98 (2H, d, J=8.4Hz, H-6 ', 8 '), 4.71 (1H, m, H-2), 4.52 (1H, m, H-2 '), 3.59 (3H, s, OCH
3), 3.07-2.86 (2H, m, H-3,3), 2.34 (3H, s, Ar-CH
3), 2.24 (3H, s, OCOCH
3), 1.99 (3H, s, NHCOCH
3);
13C-NMR (DMSO, 100MHz) δ: 171.4 (* 2, C-1,1 '), 169.2 (ArOCO), 168.1 (ArNHCO), 166.0 (C-1 "), 149.2 (C-7 '), 141.2 (C-5 "), 137.6 (C-7), (134.5 C-4 '), 132.8 (C-4), 131.2 (C-2 "), 130.1 (C-5 ', 9 '); 129.4 (C-5,9), 128.7 (C-4 ", 6 "), 127.4 (C-3 ", 7 "), 121.6 (C-6 ', 8 '), 118.7 (C-6; 8), 54.5 (C-2), 53.7 (C-2 '), 51.9 (OCH
3), 36.5,35.9,24.0 (OCOCH
3), 21.0 (ArCH
3), 20.9 (NHCOCH
3).
Embodiment 69:N-(N-benzoyl-L-phenylalanyl)-4-ethanoyl-L-phenylalaninol
Spectroscopic data: mp 235.5-238.0 ℃,
1H-NMR (DMSO, 400MHz) δ: 9.85 (1H, s, ArNHCO), 8.54 (1H, d, J=8.0Hz, NHCO), 7.95 (1H, d, J=8.4Hz, NHCO), 7.77 (2H, d, J=7.6Hz, H-3 ", 7 "), 7.50 (1H, t, H-5 "), 7.44-7.40 (4H, m, H-4 " 6 ", 6 '; 8 '), 7.31 (2H, d, J=7.6Hz, H-5,9); 7.23 (1H, t, H-6,8), 7.15-7.12 (3H, m; H-7,5 ', 9 '), 4.84 (1H, t, OH); 4.67 (1H, m, H-2), 3.86 (1H, m; H-2 '), 3.34-3.27 (2H, m, H-1 '), 3.05-2.92 (2H, m, H-3), 2.79 (1H, dd, J=6.0,13.2Hz, H-3 ' a), 2.61 (1H, dd, J=7.6,13.2Hz, H-3 ' b), 2.00 (3H, s, COCH
3);
13C-NMR (DMSO, 100MHz) δ: 171.0 (C-1), 168.1 (ArNHCO), 166.2 (C-1 "), 138.5 (C-4), 137.4 (C-7 '); 134.1 (C-2 "), 133.5 (C-4 '), 131.3 (C-5 "); 129.4 (C-5 ', 9 '), 129.2 (C-6; 8), 128.2 (C-4 ", 6 "); 128.1 (C-5,9), 127.4 (C-3 ", 7 "), 126.2 (C-7 '), 118.8 (C-6 '; 8 '), 62.1 (C-1 '), 55.0 (C-2); 52.6 (C-2 '); 37.4 (C-3), 35.8 (C-3 '), 24.0 (COCH
3).
Embodiment 70:N-[N-(4-chloro-benzoyl)-4-propionamido-L-phenylalanyl]-the L-phenylalanine methyl ester
Spectroscopic data:
1H-NMR (DMSO, 400MHz) δ: 9.75 (1H, s, ArNHCO), 8.52 (2H, m, NHCO * 2), 7.78 (2H, m, H-3 ", 7 "), 7.53-7.42 (4H, m, H-4 ", 6 ", 6,8), 7.24-7.19 (7H, m, H-5,9, H-5 '-9 '), 4.70 (1H, m, H-2), 4.51 (1H, m, H-2 '), 3.59 (3H, s, OCH
3), 3.09-2.87 (4H, m, H-3,3 '), 2.26 (2H, q, J=7.6Hz, COCH
2CH
3), 1.05 (3H, t, J=7.6Hz, COCH
2CH
3),
13C-NMR (DMSO, 100MHz) δ: 171.83,171.77,166.1 (ArNHCO), 165.1 (C-1 "); 137.6 (C-7), 137.0 (C-4 '), 136.1 (C-5 "), 134.0 (C-4), 132.7 (C-2 "); 129.4 (C-3 ", 7 "), 129.1 (C-6 ', 8 '); 128.3 (C-4 ", 6 "), 128.2 (C-5,9); 127.4 (C-5 ', 9 '), 126.6 (C-7 '), 118.7 (C-6; 8), 54.6,53.7,51.9 (OCH
3), 36.6,36.4,29.5 (COCH
2CH
3), 9.73 (COCH
2CH
3).
Embodiment 71:N-(N-benzoyl-L-phenylalanyl)-O-methyl-L-L-Tyrosine methyl ester
Reagent and reaction conditions: CH
3I, K
2CO
3, DMF, rt., reaction is spent the night
Experimental implementation: get aforementioned (seeing embodiment 3) synthetic compound 1 sample 446mg (1.0mmol) and be dissolved in the 5ml dry DMF, add the 276mg anhydrous K
2CO
3(2.0mmol), under argon shield, with 160 Cheng allusion quotation ethane (CH
3CH
2I 2.0mmol) injects reaction flask, and the stirring at room reaction is spent the night.Next day reactant is scattered in the Na of 70ml EtOAc and 30ml 10%
2CO
3In the water solution system, extracting and demixing, (2 * 20ml) washings add an amount of anhydrous Na to organic layer with saturated sodium-chloride
2SO
4Drying is filtered, filtrate through decompression and solvent recovery to do white powder sample 468mg, identify that through wave spectrum its structure and project organization compound 2-cause (productive rate: 98.7%).
Spectroscopic data: mp 170.0-172.0 ℃,
1H-NMR (CDCl
3, 400MHz) δ: 7.69 (2H, d, J=7.6Hz, H-3 ", 7 "), 7.51 (1H, t, H-5 "), 7.42 (2H, t, H-4 ", 6 "), 7.31-7.20 (5H; m, H-5-9), 6.86 (2H, d, J=8.4Hz, H-5 ', 9 '); 6.76 (1H, br, NHCO), 6.66 (2H, d, J=8.4Hz, H-6 '; 8 '), 6.29 (1H, br, NHCO), 4.84 (1H, m, H-2); 4.72 (1H, m, H-2 '), 3.90 (2H, m, ArOCH
2CH
3), 3.70 (3H, s, OMe), 3.21 (1H, dd, J=6.0,14.0Hz, H-3 ' is a), 3.12 (1H, dd, J=7.6,14.0Hz, H-3 ' b), 3.02 (1H, dd, J=5.6,13.6Hz, H-3a), 2.90 (1H, dd, J=6.4,13.6Hz, H-3b), 1.36 (3H, t, ArOCH
2CH
3);
13C-NMR (CDCl
3, 100MHz) δ: 171.7 (C-1), 170.6 (C-1 '), 167.3 (C-1 "); 158.3 (C-7 '), 136.7 (C-4), 133.9 (C-2 "), 132.2 (C-5 "); 130.4 (C-5 ', 9 '), 129.8 (C-6,8); 129.0 (* 2), 128.9 (* 2), 127.5 (C-4 '); 127.4 (C-7), 127.3 (C-3 ", 7 "); 114.8 (C-6 ', 8 '), 63.5 (ArOCH
2CH
3), 54.8 (C-2), 53.8 (C-2 '), 52.7 (C-OMe), 38.4 (C-3), 37.3 (C-3 '), 15.1 (ArOCH
2CH
3).
Employing is similar to the synthetic method of embodiment 71, selects suitable idoalkane, reaches self-control intermediate 2-chloro-N, and N-dimethyl amine hydrochloride etc. carries out electrophilic substitution reaction as reaction raw materials to phenyl ring hydroxyl or amino in the aforementioned part embodiment compound; Perhaps select dimethylamine, diethylamine, tetramethyleneimine or morphine quinoline etc. as nucleophilic reagent to containing the compound (RNHCOCH of chloro group
2Cl) the chlorine atom replaces in, makes the derivative of embodiment 72～84 respectively.
Embodiment 72:N-(N-benzoyl-L-phenylalanyl)-O-normal-butyl-L-L-Tyrosine methyl ester
Spectroscopic data: mp 177.0-178.0 ℃,
1H-NMR (CDCl
3, 400MHz) δ: 7.69 (2H, d, J=7.6Hz, H-3 ", 7 "), 7.51 (1H, t, H-5 "), 7.42 (2H, t, H-4 ", 6 "), 7.31-7.23 (5H; m, H-5-9), 6.85 (2H, d, J=8.4Hz, H-5 ', 9 '); 6.76 (1H, br, NHCO), 6.66 (2H, d, J=8.4Hz, H-6 '; 8 '), 6.31 (1H, br, NHCO), 4.83 (1H, m, H-2); 4.72 (1H, m, H-2 '), 3.82 (2H, m, ArOCH
2CH
2CH
2CH
3), 3.70 (3H, s, OMe), 3.21 (1H, dd, J=5.6,14.0Hz, H-3 ' is a), 3.12 (1H, dd, J=7.2,13.6Hz, H-3 ' b), 3.01 (1H, dd, J=5.6,14.0Hz, H-3a), 2.90 (1H, dd, J=6.8,14.0Hz, H-3b), 1.70 (2H, m, ArOCH
2CH
2CH
2CH
3), 1.45 (2H, m, ArOCH
2CH
2CH
2CH
3), 0.96 (2H, t, J=7.6Hz, ArOCH
2CH
2CH
2CH
3);
13C-NMR (CDCl
3, 100MHz) δ: 171.4 (C-1), 170.3 (C-1 '), 167.0 (C-1 "); 158.2 (C-7 '), 136.4 (C-4), 133.6 (C-2 "), 131.8 (C-5 "); 130.1 (C-5 ', 9 '), 129.4 (C-6,8); 128.7 (C-5,9), 128.6 (C-4 ", 6 "); 127.04 (C-4 ', C-7), 127.01 (C-3 ", 7 "); 114.5 (C-6 ', 8 '), 63.5 (ArOCH
2CH
2CH
2CH
3), 54.5 (C-2), 53.5 (C-2 '), 52.3 (OMe), 38.1 (C-3), 36.9 (C-3 '), 31.3 (ArOCH
2CH
2CH
2CH
3), 19.2 (ArOCH
2CH
2CH
2CH
3), 13.8 (ArOCH
2CH
2CH
2CH
3).
Embodiment 73:N-(N-benzoyl-L-phenylalanyl)-O-ethyl-L-tyrosine
Spectroscopic data:
1H-NMR (DMSO, 400MHz) δ: 12.85 (1H, br, COOH), 8.55 (1H, d, J=8.4Hz, NHCO), 8.24 (1H, d, J=8.0Hz, NHCO), 7.76 (2H, d, J=7.6Hz, H-3 ", 7 "), 7.52 (1H, t, H-5 "), 7.43 (2H, t, H-4 ", 6 "); 7.33 (2H, d, J=7.6Hz, H-5,9); 7.23 (2H, t, J=7.6Hz, H-6,8); 7.15-7.10 (3H, m, J=8.4Hz, H-7, H-5 '; 9 '), 6.70 (2H, d, J=8.4Hz, H-6 '; 8 '), 4.73 (1H, m, H-2), 4.41 (1H, m, H-2 '), 3.87 (2H, m, ArOCH
2CH
3), 3.10-2.84 (4H, m, H-3 ', 3), 1.26 (3H, t, ArOCH
2CH
3);
13C-NMR (DMSO, 100MHz) δ: 172.9 (C-1 '), 171.4 (C-1), 166.2 (C-1 "); 157.2 (C-7 '), 138.4 (C-4), 134.0 (C-2 "), 131.4 (C-5 "); 130.2 (C-5 ', 9 '), 129.2 (C-6,8); 129.0 (C-4 '), 128.2 (C-4 ", 6 "), 128.1 (C-5; 9), 127.4 (C-3 ", 7 "), 126.2 (C-7); 114.1 (C-6 ', 8 '), 62.8 (ArOCH
2CH
3), 54.5 (C-2 '), 53.8 (C-2), 36.8 (C-3), 35.9 (C-3 '), 14.7 (ArOCH
2CH
3).
Embodiment 74:N-(N-benzoyl-L-phenylalanyl)-O-normal-butyl-L-tyrosine sodium salt
Spectroscopic data:
1H-NMR (DMSO, 400MHz) δ: 8.82 (1H, d, J=8.4Hz, NHCO), 7.78 (2H, d, J=7.2Hz, H-3 ", 7 "), 7.51-7.47 (2H, m, H-5 ", NHCO), 7.41 (2H; t, H-4 ", 6 "), 7.30 (2H, d; J=7.6Hz, H-5,9), 7.22 (2H, t; H-6,8), 7.12 (1H, t, H-7); 6.99 (2H, d, J=8.4Hz, H-5 ', 9 '); 6.55 (2H, d, J=8.0Hz, H-6 ', 8 '), 4.57 (1H, m, H-2), 3.94 (1H, m, H-2 '), 3.75 (2H, t, J=6.4Hz, ArOCH
2CH
2CH
2CH
3), 3.12-2.85 (4H, m, H-3,3 '), 1.61 (2H, m, ArOCH
2CH
2CH
2CH
3), 1.37 (2H, m, ArOCH
2CH
2CH
2CH
3), 0.89 (2H, t, J=7.6Hz, ArOCH
2CH
2CH
2CH
3);
13C-NMR (DMSO, 100MHz) δ: 172.5 (C-1 '), 169.6 (C-1), 166.0 (C-1 "); 156.6 (C-7 '), 138.7 (C-4), 134.1 (C-2 "), 131.0 (C-5 "); 130.9 (C-4 '), 130.5 (C-5 ', 9 '), 128.9 (C-6; 8), 127.93,127.87; 127.3 (C-3 ", 7 "), 125.9 (C-7); 113.4 (C-6 ', 8 '), 66.8 (ArOCH
2CH
2CH
2CH
3), 55.4,55.3,36.6,36.3,30.7 (ArOCH
2CH
2CH
2CH
3), 18.6 (ArOCH
2CH
2CH
2CH
3), 13.5 (ArOCH
2CH
2CH
2CH
3).
Embodiment 75:N-[N-benzoyl-O-(2-dimethylamino-ethyl)-L-tyrosyl]-L-phenylalaninol hydrochloride
Spectroscopic data: mp 158.5-161.0 ℃,
1H-NMR (DMSO, 400MHz) δ: 10.57 (1H, br, CH
2CH
2N
+H (CH
3)
2Cl
-), 8.57 (1H, d, J=8.4Hz, NHCO), 8.03 (1H, br, NHCO), 7.83 (2H, d, J=7.6Hz, H-3 ", 7 "), 7.52 (1H, t, H-5 "), 7.45 (2H, t, H-4 ", 6 "), 7.28-7.11 (7H; m, H-5 '-9 ', H-5,9), 6.88 (2H, d, J=8.8Hz; H-6,8), 4.88 (1H, br, OH), 4.63 (1H; m, H-2), 4.28 (2H, t, J=4.8Hz, ArOCH
2CH
2N (CH
3)
2HCl), 3.89 (1H, m, H-2 '), 3.44 (2H, t, J=4.8Hz, ArOCH
2CH
2N (CH
3)
2HCl), 3.34-3.27 (2H, m, H-1 '), 3.00-2.85 (3H, m, H-3,3 ' a), 2.79 (6H, s, N (CH
3)
2), 2.71-2.66 (1H, dd, J=8.0,13.6Hz, 3 ' b);
13C-NMR (DMSO, 100MHz) d:171.0 (C-1), 166.0 (C-1 "), 156.0 (C-7), 139.1 (C-4 '); 134.0 (C-2 "), 131.3 (C-5 ", C-4), 130.3 (C-5,9); 129.2 (C-6 ', 8 '), 128.2 (C-4 ", 6 "), 128.1 (C-5 '; 9 '), 127.5 (C-3 ", 7 "), 125.9 (C-7 '); 114.2 (C-6,8), 62.2,62.1; 55.2 (* 2), 52.6 (C-2 '), 42.7 (* 2), 36.4 (* 2).
Embodiment 76:N-[N-4-(dimethylamino-kharophen)-benzoyl-L-phenylalanyl]-the L-phenylalaninol
Spectroscopic data: mp 162.5-164.0 ℃,
1H-NMR (DMSO, 400MHz) δ: 9.94 (1H, s, ArNHCO), 8.39 (1H, d, J=8.8Hz, NHCO), 7.89 (1H, d, J=8.4Hz, NHCO), 7.77 (2H, d, J=8.8Hz, H-3 ", 7 "), 7.73 (2H, d, J=8.8Hz, H-4 "; 6 "), 7.31-7.11 (10H, m, H-5-9,5 '-9 '), 4.82 (1H, t, OH), 4.67 (1H, m, H-2), 3.89 (1H, m, H-2 '), 3.35-3.24 (2H, m, H-1 '), 3.09 (2H, COCH
2N＜), and 3.07-2.91 (2H, m, H-3), 2.86 (1H, dd, J=5.6,13.6Hz, H-3 ' a), 2.66 (1H, dd, J=7.6,13.6Hz, H-3 ' b), 2.28 (6H, s ,-N (CH
3)
2);
13C-NMR (DMSO, 100MHz) δ: 171.0 (C-1), 169.1 (ArNHCO), 165.5 (C-1 "); 141.4 (C-5 "), 139.0 (C-4 '), 138.5 (C-4), 129.2 (* 4,4C-6,8,6 ', 8 '), 128.6 (C-2 "), 128.2 (C-3 ", 7 "), 128.1 (* 2); 128.0 (* 2), 126.2 (C-7), 125.9 (C-7 '); 118.5 (C-4 ", 6 "), 63.3 (COCH
2N＜), 62.2 (C-1 '), 54.8 (C-2), 52.5 (C-2 '), 45.4 (* 2 ,-N (CH
3)
2), 37.3 (C-3), 36.4 (C-3 ').
Embodiment 77:N-[N-4-(2-dimethylamino-oxyethyl group)-benzoyl-L-phenylalanyl]-the L-phenylalaninol
Spectroscopic data:
1H-NMR (CDCl
3, 400MHz) δ: 7.67 (2H, d, J=8.8Hz, H-3 "; 7 "), 7.31-7.07 (10H, m, H-5-9,5 '-9 '), 6.92 (2H, d, J=8.8Hz, H-4 ", 6 "), 6.78 (1H, d, J=7.6Hz, NHCO), 6.28 (1H, d, J=8.0Hz, NHCO), 4.80 (1H, m, H-2), 4.11-4.07 (3H, m, ArOCH
2, H-2 '), 3.42 (2H, m, H-1 '), 3.23 (1H, dd, J=6.4,13.6Hz, H-3a), 3.06 (1H, dd, J=8.4,13.6Hz, H-3b), 2.80-2.66 (4H, m, H-3 ', CH
2N (CH
3)
2), 2.34 (6H, s ,-N (CH
3)
2);
13C-NMR (CDCl
3, 100MHz) δ: 171.0 (C-1), 166.8 (C-1 "), 161. (C-5 "), 137.4 (C-4), 136.8 (C-4 '), 129.3 (C-3 ", 7 "), (129.1 C-6,8), 128.9 (C-6 ', 8 '), 128.8 (C-5 ', 9 '), 128.5 (C-5,9), 127.1 (C-7), 126.5 (C-7 '), 125.8 (C-2 "); 114.4 (C-4 ", 6 "), 66.2 (ArOCH
2), 63.4 (C-1 '), 58.1 (CH
2N (CH
3)
2), 55.1 (C-2), 52.9 (C-2 '), 45.9 (N (CH
3)
2), 38.6 (C-3 '), 36.8 (C-3).
Embodiment 78:N-[N-4-(2-dimethylamino-oxyethyl group)-benzoyl-L-phenylalanyl]-the L-phenylalanine methyl ester
Spectroscopic data:
1H-NMR (CDCl
3, 400MHz) δ: 7.64 (2H, d, J=8.8Hz, H-3 ", 7 "), 7.30-6.95 (10H, m, H-5-9,5 '-9 '), 6.92 (2H, d, J=8.8Hz, H-4 ", 6 "), 6.58 (1H, d, J=7.6Hz, NHCO), 6.35 (1H, d, J=7.2Hz, NHCO), 4.83-4.76 (2H, m, H-2,2 '), 4.10 (2H, t, J=6.0Hz, ArOCH
2), 3.70 (3H, s, OCH
3), 3.21-2.93 (4H, m, H-3,3 '), 2.75 (2H, t, J=6.0Hz, CH
2N (CH
3)
2), 2.35 (6H, s ,-N (CH
3)
2);
13C-NMR (CDCl
3, 100MHz) δ: 171.3 (C-1), 170.5 (C-1 '), 166.6 (C-1 "); 161.7 (C-5 "), 136.4 (C-4), 135.5 (C-4 '), 129.4 (C-3 "; 7 "), 129.1 (C-6,8), 128.8 (C-6 ', 8 '), 128.7 (C-5 ', 9 '), 128.5 (C-5,9), 127.0 (C-7,7 '), 125.9 (C-2 "); 114.3 (C-4 ", 6 "), 66.1 (ArOCH
2), 58.1 (CH
2N (CH
3)
2), 54.4 (C-2), 53.4 (C-2 '), 52.3 (OCH
3), 45.9 (N (CH
3)
2), 38.0,37.8.
Embodiment 79:N-(N-benzoyl-L-phenylalanyl)-O-methyl-L-tyrosine sodium salt
Spectroscopic data:
1H-NMR (DMSO, 400MHz) δ: 8.81 (1H, d, J=8.4Hz, NHCO), 7.78 (2H, d, J=7.2Hz, H-3 "; 7 "), 7.48 (2H, m, H-5 ", NHCO), 7.42 (2H, t, H-4 ", 6 "), 7.30 (2H, d, J=8.4Hz, H-5,9), 7.22 (2H, t; H-6,8), 7.13 (1H, t, H-7), 7.01 (2H, d, J=8.4Hz; H-5 ', 9 '), 6.57 (2H, d, J=8.4Hz, H-6 ', 8 '), 4.57 (1H; m, H-2), 3.95 (1H, m, H-2 '), 3.59 (3H, s, ArOCH
3), 3.13-2.86 (4H, m, H-3,3 ');
13C-MR (DMSO, 100MHz) δ: 172.7 (C-1 '), 169.9 (C-1), 166.2 (C-1 "); 157.3 (C-7 '), 138.9 (C-4), 134.1 (C-2 "), 131.3 (C-5 "); 131.0 (C-4 '), 130.7 (C-5 ', 9 '), 129.1 (C-6; 8), 128.2 (C-4 ", 6 "), 128.1 (C-5; 9), 127.4 (C-3 ", 7 "), 126.1 (C-7); 112.9 (C-6 ', 8 '), 55.6 (* 2), 54.7 (ArOCH
3), 36.7,36.3.
Embodiment 80:N-[N-benzoyl-O-carboxymethyl-L-tyrosyl]-L-phenylalaninol sodium salt
Spectroscopic data:
1H-NMR (DMSO, 400MHz) δ: 8.65 (1H, br, NHCO), 8.30 (1H, br, NHCO), 7.82 (2H, d, J=8.0Hz, H-3 ", 7 "), 7.50 (1H, t, H-5 "), 7.43 (2H, t, H-4 ", 6 "), 7.23-7.17 (5H, m; H-5 '-9 '), 7.12 (2H, d, J=8.0Hz, H-5,9), 6.69 (2H; d, J=8.4Hz, H-6,8), 5.17 (1H, br, OH); 4.59 (1H, m, H-2), 4.08 (2H, s, ArOCH
2COONa), 3.87 (1H, m, H-2 '), 3.33-3.27 (2H, m, H-1 '), 2.93-2.66 (4H, m, H-3,3 ');
13C-NMR (DMSO, 100MHz) δ: 171.2 (C-1, COONa), 166.0 (C-1 "); 157.4 (C-7), 139.2 (C-4 '), 134.2 (C-2 "), 131.2 (C-5 "); 129.7 (C-5,9), 129.4 (C-4), 129.2 (C-6 '; 8 '), 128.1 (C-4 ", 6 "), 128.0 (C-5 '; 9 '), 127.4 (C-3 ", 7 "), 125.8 (C-7 '); 114.0 (C-6,8), 67.8 (ArOCH
2COONa), 62.1 (C-1 '), 55.5 (C-2), 52.6 (C-2 '), 36.4 (C-3,3 ').
Embodiment 81:N-[N-4-(dimethylamino-kharophen)-benzoyl-L-phenylalanyl]-the L-phenylalanine methyl ester
Spectroscopic data: mp 192.5-194.0 ℃,
1H-NMR (DMSO, 400MHz) δ: 9.92 (1H, s, ArNHCO), 8.52 (1H, d, J=7.6Hz, NHCO), 8.41 (1H, d, J=8.4Hz, NHCO), 7.71 (4H, m, H-3 ", 7 ", 4 ", 6 "), 7.33-7.14 (10H, m, H-5-9,5 '-9 '), 4.72 (1H, m, H-2), 4.50 (1H, m, H-2 '), 3.57 (3H, s, OCH
3), 3.07 (2H, s, NHCOCH
2N＜), 3.06-2.89 (4H, m, H-3,3 '), 2.26 (6H, s ,-N (CH
3)
2);
13C-NMR (DMSO, 100MHz) δ: 172.5,172.4,169.8 (ArNHCO), 165.3 (C-1 "), 142.1 (C-5 "), 139.0 (C-4), 137.7 (C-4 '), (129.83 C-6,8), 129.78 (C-6 ', 8 '), 129.1 (C-2 "), 128.9 (C-5 ', 9 '), 128.8 (C-3 ", 7 "), 128.7 (C-5,9), 127.2 (C-7 '); 126.9 (C-7), 119.1 (C-4 ", 6 "), 63.9 (COCH
2N＜), 55.1 (C-2), 54.4 (C-2 '), 52.5 (OHH
3), 46.0 (N (CH
3)
2), 37.6 (C-3), 37.2 (C-3 ').
Embodiment 82:N-{N-[4-(1-pyrrolidyl) acetylaminohydroxyphenylarsonic acid benzoyl]-the L-phenylalanyl }-the L-phenylalanine methyl ester
Spectroscopic data:
1H-NMR (DMSO, 400MHz) δ: 9.93 (1H, s, ArNHCO), 8.53 (1H, d, J=7.2Hz, NHCO), 8.43 (1H, d, J=8.8Hz, NHCO), 7.75 (2H, d, J=8.8Hz, H-3 ", 7 "), 7.69 (2H, d, J=8.8Hz, H-4 ", 6 "), 7.34-7.15 (10H, m, H-5-9,5 '-9 '), 4.74 (1H, m, H-2), 4.52 (1H, m, H-2 '), 3.59 (3H, s, OCH
3), 3.26 (2H, COCH
2N＜), 3.07-2.94 (4H, m, H-3,3 '), 2.59 (4H, m, COCH
2N (CH
2)
2), 1.74 (4H, m,〉NCH
2CH
2CH
2CH
2N＜);
13C-NMR (DMSO, 100MHz) δ: 171.8,171.7,169.2 (ArNHCO), 165.6 (C-1 "), 141.4 (C-5 "), 138.3 (C-4), (137.0 C-4 '), 129.2 (* 2), 129.1 (* 2), 128.5 (C-2 "), 128.3 (* 2), 128.2 (* 2); 128.0 (* 2), 126.6 (C-7 '), 126.2 (C-7); 118.5 (C-4 ", 6 "), 59.5 (COCH
2N＜), 54.4 (C-2), 53.73 (C-2 '), 53.69 (COCH
2N (CH
2)
2), 51.9 (OCH
3), 36.9 (C-3), 36.6 (C-3 '), 23.5 (〉 NCH
2CH
2CH
2CH
2N＜).
Embodiment 83:N-[N-benzoyl-4-(3-carboxyl-propionamido)-L-phenylalanyl]-the L-phenylalaninol
Spectroscopic data:
1H-NMR (DMSO, 400MHz) δ: 11.31 (1H, s, ArNHCO), 8.96 (1H, d, J=8.4Hz, NHCO), 8.37 (1H, d, J=8.0Hz, NHCO), 7.79 (2H, m, H-3 "; 7 "), 7.46 (2H, m, H-4 ", 6 "), (7.40 2H, d, J=8.4Hz, H-6,8), (7.24-7.11 7H, m, H-5 '-9 ', H-5,9), 5.05 (1H, br, OH), 4.58 (1H, m, H-2), 3.87 (1H, m, H-2 '), 3.36-2.95 (2H, m, H-1 '), 2.94-2.65 (4H, m, H-3, H-3 '), 2.33 (2H, m, CH
2COONa), 2.21 (2H, t, ArNHCOCH
2),
13C-NMR (DMSO, 100MHz) δ: 176.1 (CH
2COONa), 172.0 (ArNHCOCH
2), 171.1 (C-1), 165.0 (C-1 "), 139.2 (C-4 '), 138.0 (C-7); 135.9 (C-5 "), 132.9 (C-4), 132.3 (C-2 "), 129.34 (C-3 ", 7 "); 129.30 (C-5,9), 129.2 (C-6 ', 8 '), 128.2 (C-4 ", 6 "), 128.0 (C-5 ', 9 '), 125.8 (C-7 '); 118.3 (C-6,8), 62.2 (C-1 '), 55.6 (C-2); 52.6 (C-2 '), 36.8,36.4,34.6 (CH
2COONa), 33.9 (ArNHCOCH
2).
Embodiment 84:N-(N-benzoyl-4-dimethylamino-L-phenylalanyl)-L-phenylalaninol
Spectroscopic data:
1H-NMR (DMSO, 400MHz) δ: 7.74 (2H, d, J=7.2Hz, H-3 ", 7 "), 7.52 (1H, t, H-5 "), 7.43 (2H, t, H-4 ", 6 "), 7.21-7.08 (7H, m, H-5 '-9 '; H-5,9), 6.90 (1H, d, J=7.2Hz, NHCO), 6.62 (2H; d, J=8.4Hz, H-6,8), 5.96 (1H, d, J=7.6Hz; NHCO), 4.70 (1H, m, H-2), 4.09 (1H, m, H-2 '); 3.49-3.35 (2H, m, H-1 '), 3.32 (4H, q, J=7.2Hz, N (CH
2CH
3)
2), 3.19 (1H, dd, J=5.6,13.2Hz, H-3a), 2.88 (1H, dd, J=9.2,13.6Hz, H-3b), 2.77 (1H, dd, J=7.6,13.6Hz, H-3 ' a), 2.68 (1H, dd, J=7.2,13.6Hz, H-3 ' b), 2.18 (1H, t, OH), 1.14 (6H, t, J=7.2Hz, N (CH
2CH
3)
2);
13C-NMR (DMSO, 100MHz) δ: 171.1 (C-1), 167.1 (C-1 "), 146.9 (C-7); 137.4 (C-4 '), 133.7 (C-2 "), 131.8 (C-5 "), 130.2 (C-5; 9), 129.1 (C-6 ', 8 '), 128.6 (* 2); 128.5 (* 2), 127.1 (C-3 ", 7 "), 126.5 (C-7 '); 122.7 (C-4), 111.9 (C-6,8), 63.4 (C-1 '); 55.5 (C-2), 52.8 (C-2 '), 44.3 (N (CH
2CH
3)
2), 37.9 (C-3 '), 36.8 (C-3), 12.5 (N (CH
2CH
3)
2).
Embodiment 85:N-(N-benzoyl-L-phenylalanyl)-L-tyrosine and sodium salt thereof
Reagent and reaction conditions: (a) NaOH, DMF, rt, 5h; (b) NaOH/EtOH-CHCl
3
Experimental implementation: (a) get aforementioned (seeing embodiment 3) synthetic compound 1 sample 2.0mmol and in the mixed solvent of 5ml DMF and 10mlEtOH, dissolve fully, stir and add 5M NaOH solution 1ml down, room temperature reaction spends the night, the gained reaction solution is distributed to 150ml EtOAc and 50ml 10% Na with it after regulating pH2-3 with concentrated hydrochloric acid
2CO
3In the aqueous solution, extracting and demixing, organic layer is with saturated sodium-chloride 2 * 30ml washing, anhydrous sodium sulfate drying, decompression and solvent recovery promptly gets N-(N-benzoyl-L-phenylalanyl)-L-tyrosine (compound 2) sample 674mg (productive rate: 78.0%) of white powder to doing; (b) get the synthetic gained compound 2 sample 235mg (0.48mmol) of back in 10ml EtOH and 5ml CHCl
3Mixed solvent in dissolving fully; stir and drip 1.0M NaOH solution 0.48ml down; room temperature reaction spends the night; reclaim solvent to doing; the gained solids promptly gets N-(N-benzoyl-L-the phenylalanyl)-L-tyrosine sodium salt 133mg (productive rate: 61.2%) of white powder with re-crystallizing in ethyl acetate.
Spectroscopic data: N-(N-benzoyl-L-phenylalanyl)-L-tyrosine,
1H-NMR (DMSO, 400MHz) δ: 12.75 (COOH), 9.22 (1H, s, Ar-OH), 8.55 (1H, d, J=8.4Hz, NHCO), 8.23 (1H, d, J=7.6Hz, NHCO), 7.76 (2H, d, J=7.6Hz, H-3 ", 7 "), 7.51 (1H, t, H-5 "), 7.43 (2H, t, H-4 ", 6 "), 7.34 (2H, d, J=7.2Hz, H-5,9); 7.24 (2H, t, H-6,8), 7.15 (1H, t; H-7), 7.02 (2H, d, J=8.4Hz, H-5 ', 9 '); 6.61 (2H, d, J=8.4Hz, H-6 ', 8 '); 4.74 (1H, m, H-2 '), 4.38 (1H, m; H-2), 3.11-2.82 (4H, m, H-3,3 ');
13C-NMR (DMSO, 100MHz) δ: 172.9 (C-1 '), 171.5 (C-1), 166.3 (C-1 "), 156.0 (C-7 '); 138.4 (C-4), 134.0 (C-2 "), 131.3 (C-5 "), 130.1 (C-5 ', 9 '); 129.2 (C-6,8), 128.2 (C-4 ", 6 "); 128.0 (C-5,9), 127.4 (C-3 ", 7 "); 127.3 (C-4 '), 126.2 (C-7), 115.0 (C-6 ', 8 '); 54.6 (C-2 '), 53.9 (C-2), 36.9 (C-3), 35.9 (C-3 ').
Employing is similar to the working method of embodiment 85, and the acylate of carboxyl ester in the part of compounds in the previous embodiment or alcoholic extract hydroxyl group is hydrolyzed and the preparation of sodium salt etc., makes the derivative of embodiment 86～106 respectively.
Embodiment 86:N-(N-benzoyl-L-phenylalanyl)-L-phenylalanine
Spectroscopic data:
1H-NMR (DMSO, 400MHz) δ: 12.81 (1H, br, COOH), 8.53 (1H, d, J=8.4Hz, NHCO), 8.31 (1H, d, J=8.0Hz, NHCO), 7.74 (2H, d, J=7.6Hz, H-3 ", 7 "), 7.46 (1H, t, H-5 "); 7.40 (2H, t, H-4 ", 6 "), 7.33-7.12 (10H, m; H-5-9,5 '-9 '), 4.72 (1H, m, H-2), 4.46 (1H; m, H-2 '), 3.10-2.90 (4H, m, H-3,3 ');
13C-NMR (DMSO, 100MHz) δ: 172.8 (C-1 '), 171.5 (C-1), 166.2 (C-1 "), 138.4 (C-4); 137.4 (C-4 '), 134.0 (C-2 "), 131.3 (C-5 "), 129.2 (* 4, C-6; 8, C-6 ', 8 '), 128.2 (* 4, C-4 ", 6 ", C-5 ', 9 '), 128.1 (C-5,9); 127.4 (C-3 ", 7 "), 126.5 (C-7 '), 126.2 (C-7); 54.6 (C-2), 53.6 (C-2 '), 36.9 (C-3), 36.7 (C-3 ').
Embodiment 87:N-(N-benzoyl-4-acetylaminohydroxyphenylarsonic acid L-phenylalanyl)-L-phenylalanine
Spectroscopic data: mp 233.5-235.5 ℃,
1H-NMR (DMSO, 400MHz) δ: 9.84 (1H, s, ArNHCO), 8.46 (1H, d, J=8.4Hz, NHCO), 7.89 (1H, d, J=8.0Hz, NHCO), 7.79 (2H, d, J=7.6Hz, H-3 ", 7 "), 7.52 (1H, t, H-5 "); 7.47-7.42 (4H, m, H-4 ", 6 ", H-6; 8), 7.23-7.11 (7H, m, H-5 '-9 ', H-5; 9), 4.83 (1H, t, OH), 4.64 (1H; m, H-2), 3.90 (1H, m, H-2 '); 3.34-3.25 (2H, m, H-1 '), 3.00-2.64 (4H, m, H-3,3 '), 1.99 (3H, CH
3CO);
13C-NMR (DMSO, 100MHz) δ: 170.9 (C-1), 168.0 (ArNHCOCH
3), 166.0 (C-1 "), 139.0 (C-7), 137.5 (C-4 '); 134.1 (C-2 "), 132.9 (C-4), 131.3 (C-5 "), 129.4 (C-5; 9), 129.2 (C-6 ', 8 '), 128.2 (* 2); 128.1 (* 2), 127.4 (C-3 ", 7 "), 125.9 (C-7 '); 118.6 (C-6,8), 62.2 (C-1 '), 54.9 (C-2); 52.5 (C-2 '), 36.7 (C-3 '), 36.4 (C-3), 24.0 (NHCOCH
3).
Embodiment 88:N-(N-benzoyl-4-nitro-L-phenylalanyl)-L-phenylalanine
Spectroscopic data:
1H-NMR (DMSO, 400MHz) δ: 12.85 (1H, COOH), 8.54 (1H, d, J=8.8Hz, NHCO), 8.42 (1H, d, J=8.4Hz, NHCO), 8.14 (2H, d, J=8.8Hz, H-6,8), 7.77 (2H, d, J=6.8Hz, H-3 ", 7 "), 7.63 (2H, d, J=8.4Hz, H-5,9), 7.52 (1H, t, H-5 "), 7.45 (2H, t, H-4 ", 6 "), 7.26-7.18 (5H, m, H-5 '-9 '), 4.85 (1H, m, H-2); 4.49 (1H, m, H-2 '), 3.24-2.94 (4H, m, H-3,3 ');
13C-NMR (DMSO, 100MHz) δ: 172.7 (C-1 '), 171.0 (C-1), 166.3 (C-1 "), 146.8 (C-7); 146.2 (C-4), 137.4 (C-4 '), 133.8 (C-2 "), 131.4 (C-5 "), 130.5 (C-5; 9), 129.2 (C-6 ', 8 '), 128.2 (* 4, C-4 ", 6 ", 5 ', 9 '), 127.4 (C-3 ", 7 "), 126.5 (C-7 '), 123.2 (C-6,8); 53.9 (C-2 '), 53.6 (C-2), 36.8,36.6.
Embodiment 89:N-(N-benzoyl-L-phenylalanyl)-4-acetylaminohydroxyphenylarsonic acid L-phenylalanine
Spectroscopic data:
1H-NMR (DMSO, 400MHz) δ: 12.80 (1H, br, COOH), 9.87 (1H, s, ArNHCO), 8.55 (1H, d, J=8.4Hz, NHCO), 8.32 (1H, d, J=8.0Hz, NHCO), 7.75 (2H, d, J=7.2Hz, H-3 ", 7 "), 7.51-7.13 (12H, m, H-4 " 6 ", H-5-9, H-5 ', 9 ', 6 ', 8 '), 4.73 (1H, m, H-2), 4.44 (1H, m, H-2 '), 3.10-2.88 (4H, m, H-3,3 '), 2.02 (3H, s, COCH
3);
13C-NMR (DMSO, 100MHz) δ: 172.9 (C-1 '), 171.6 (C-1), 168.1 (ArNHCOCH
3), 166.3 (C-1 "), 138.5 (C-4), 137.9 (C-7 '), 134.1 (C-2 "), (131.8 C-4 '), 131.3 (C-5 "), 129.4 (C-5 ', 9 '); 129.2 (C-6,8), 128.2 (C-4 ", 6 "); 128.1 (C-5,9), 127.4 (C-3 ", 7 "); 126.3 (C-7 '), 118.8 (C-6 ', 8 '), 54.6 (C-2); 53.7 (C-2 '), 37.0 (C-3), 36.1 (C-3 '), 24.0 (COCH
3).
Embodiment 90:N-(N-4-methyl-benzoyl-L-phenylalanyl)-4-acetylaminohydroxyphenylarsonic acid L-phenylalanine
Spectroscopic data:
1H-NMR (DMSO, 400MHz) δ: 10.02 (1H, s, ArNHCO), 8.70 (1H, d, J=8.4Hz, NHCO), 7.64 (2H, d, J=8.0Hz, H-3 ", 7 "), 8.49 (1H, d, J=6.4Hz, NHCO), 7.33-7.27 (4H, m, H-6 ', 8 ', H-5,9), 7.21-7.17 (4H, m, H-4 ", 6 ", H-6,8) and, 7.10 (1H, t, H-7), 7.00 (2H, d, J=8.4Hz, H-5 ', 9 '), 4.50 (1H, m, H-2), (3.95 1H, m, H-2 '), 3.12-2.88 (4H, m, H-3,3 '), 2.29 (3H, s, Ar-CH
3), 1.94 (3H, s, COCH
3);
13C-NMR (DMSO, 100MHz) δ: 172.8 (C-1 '), 170.1 (C-1), 168.0 (ArNHCO), 166.2 (C-1 "); 141.1 (C-5 "), 139.0 (C-4), 137.2 (C-7 '), 133.6 (C-2 "), 131.3 (C-4 '); 129.9 (C-5 ', 9 '), 129.1 (C-6,8), 128.7 (C-4 ", 6 "), 128.1 (C-5,9), 127.5 (C-3 ", 7 "); 126.1 (C-7), 118.5 (C-6 ', 8 '), 55.9 (C-2 '); 55.5 (C-2 '), 36.9,36.5,23.9 (NHCOCH
3), 21.0 (Ar-CH
3).
Embodiment 91:N-(N-4-hydroxyl-benzoyl-L-phenylalanyl)-L-phenylalanine sodium salt
Spectroscopic data:
1H-NMR (DMSO, 400MHz) δ: 8.45 (1H, d, J=8.4Hz, NHCO), 7.62 (2H, d, J=8.4Hz, H-3 ", 7 "), 7.44 (1H, br, NHCO), 7.29-7.05 (10H, m, H-5-9,5 '-9 '), 6.76 (3H, m, ArOH, H-4 ", 6 "), 4.50 (1H, m, H-2), 4.02 (1H, m, H-2 '), 3.11-2.92 (4H, m, H-3,3 ');
13C-NMR (DMSO, 100MHz) δ: 170.2 (C-1,1 '), 166.0 (C-1 "), 160.6 (C-5 "), 139.1,139.0,129.8 (C-3 ", 7 "), 129.4 (C-6,8), 129.1 (C-6 ', 8 '), 128.1 (C-5 ', 9 '), 127.5 (C-5,9), 126.1 (C-7), (125.5 C-7 '), 124.5 (C-2 "), 114.7 (C-4 ", 6 "); 55.7 (C-2 '), 55.4 (C-2), 37.2,36.8.
Embodiment 92:N-[N-4-(3-carboxyl-propionamido)-benzoyl-L-phenylalanyl]-L-phenylalanine sodium salt
Spectroscopic data:
1H-NMR (DMSO, 400MHz) δ: 11.38 (1H, s, ArNHCO), 9.92 (1H, br, ArOH), 8.60 (1H, d, J=8.0Hz, NHCO), 7.73 (2H, d, J=8.8Hz, H-3 "; 7 "), 7.62 (2H, d, J=8.4Hz, H-4 "; 6 "), 7.50 (1H, d, J=6.0Hz, NHCO), 7.13-7.05 (7H, m, H-5-9,5 ', 9 '), (6.62 2H, d, J=8.4Hz, H-6,8), 4.45 (1H, m, H-2), 4.04 (1H, m, H-2 '), 3.14-2.79 (4H, m, H-3,3 '), 2.46 (2H, t, J=6.4Hz, ArNHCOCH
2CH
2COONa), 2.27 (2H, t, J=6.0Hz, ArNHCOCH
2CH
2COONa);
13C-NMR (DMSO, 100MHz) δ: 176.4 (COONa), 173.2,172.7,170.4,165.7 (C-1 "); 156.0 (C-7), 142.4 (C-5 "), 139.0 (C-4 '), (129.9 C-5,9), 129.8 (C-6 ', 8 '), 128.5 (C-4), 128.3 (C-5 ', 9 '), 127.9 (C-2 "), 127.5 (C-3 ", 7 "), 125.5 (C-7 '), 117.8 (C-4 ", 6 "), 115.0 (C-6,8); 56.1 (C-2), 55.4 (C-2 '), 37.3 (C-3 '); 36.5 (C-3), 34.4,33.5.
Embodiment 93:N-(N-benzoyl-L-tyrosyl)-L-phenylalanine
Spectroscopic data:
1H-NMR (DMSO, 400MHz) δ: 12.79 (1H, br, COOH), 9.12 (1H, s, Ar-OH), 8.44 (1H, d, J=8.8Hz, NHCO), 8.26 (1H, d, J=7.6Hz, NHCO), 7.73 (2H, d, J=6.8Hz, H-3 ", 7 "), 7.48 (1H, t, H-5 "), 7.41 (2H, t; H-4 ", 6 "), 7.25-7.13 (5H, m, H-5 '-9 '); 7.09 (2H, d, J=8.4Hz, H-5,9); 6.58 (2H, d, J=8.4Hz, H-6,8); 4.61 (1H, m, H-2), 4.43 (1H, m; H-2 '), 3.08-2.76 (4H, m, H-3,3 ');
13C-NMR (DMSO, 100MHz) δ: 172.8 (C-1 '), 171.7 (C-1), 166.2 (C-1 "), 155.7 (C-7); 137.4 (C-4 '), 134.1 (C-2 "), 131.3 (C-5 "), 130.1 (C-5,9); 129.2 (C-6 ', 8 '), 128.4 (C-4), 128.2 (* 4, C-4 ", 6 ", C-5 ', 9 '), 127.4 (C-3 ", 7 "), 126.5 (C-7 '), 114.9 (C-6,8); 55.0 (C-2), 53.5 (C-2 '), 36.7,36.2.
Embodiment 94:N-(N-benzoyl-L-phenylalanyl)-4-propionamido-L-phenylalanine
Spectroscopic data:
1H-NMR (DMSO, 400MHz) δ: 12.78 (1H, br, COOH), 9.81 (1H, s, ArNHCO), 8.56 (1H, d, J=8.4Hz, NHCO), 8.33 (1H, d, J=8.0Hz, NHCO), 7.75 (2H, d, J=7.2Hz, H-3 ", 7 "), 7.50-7.48 (3H, m, H-5 ", H-6 '; 8 '), 7.42 (2H, t, H-4 ", 6 "), 7.34 (2H; d, J=7.2Hz, H-5,9), 7.23 (2H, t; H-6,8), 7.17-7.12 (3H, m, H-7, H-5 '; 9 '), 4.73 (1H, m, H-2), 4.44 (1H; m, H-2 '), 3.10-2.86 (4H, m, H-3,3 '), 2.28 (2H, q, J=7.6Hz, NHCOCH
2CH
3), 1.06 (3H, t, J=7.6Hz, NHCOCH
2CH
3);
13C-NMR (DMSO, 100MHz) δ: 172.9 (C-1 '), 171.9,171.6,166.3 (C-1 "); 138.5 (C-4), 138.0 (C-7 '), 134.1 (C-2 "), 131.7 (C-4 '), 131.3 (C-5 "); 129.4 (C-5 ', 9 '), 129.2 (C-6,8), 128.2 (C-4 ", 6 "), 128.1 (C-5,9), 127.5 (C-3 ", 7 "); 126.3 (C-7), 118.9 (C-6 ', 8 '), 54.7 (C-2); 53.7 (C-2 '), 37.0,36.1,29.6 (NHCOCH
2CH
3), 9.8 (NHCOCH
2CH
3).
Embodiment 95:N-(N-benzoyl-L-tyrosyl)-4-acetylaminohydroxyphenylarsonic acid L-phenylalanine sodium salt
Spectroscopic data:
1H-NMR (DMSO, 400MHz) δ: 9.95 (1H, s, ArNHCO), 9.47 (1H, s, ArOH), 8.86 (1H, d, J=8.4Hz, NHCO), 7.78-7.74 (3H, m, H-3 ", 7 ", NHCO), 7.48 (3H, m, H-6 ', 8 ', H-5 "), 7.34 (2H; t, H-4 ", 6 "), 7.08 (2H, d; J=8.4Hz, H-5,9), 7.01 (2H, d; J=8.8Hz, H-5 ', 9 '), 6.61 (2H, d; J=8.4Hz, H-6,8), 4.44 (1H, m; H-2), 3.95 (1H, m, H-2 '), 3.09-2.78 (4H, m, H-3,3 '), 1.97 (3H, CH
3CO);
13C-NMR (DMSO, 100MHz) δ: 172.6 (C-1 '), 170.0 (C-1), 168.0 (ArNHCO), 165.3 (C-1 "); 155.8 (C-7), 137.2 (C-7 '), 136.0 (C-2 "), 133.6 (C-4 '), 132.9 (C-5 "); 130.0 (C-5,9), 129.9 (C-5 ', 9 '), 129.4 (C-4 ", 6 "), 128.7 (C-4), 128.3 (C-3 ", 7 "); 118.4 (6 ', 8 '), 115.0 (C-6,8); 56.4 (C-2 '), 55.5 (C-2), 36.5,36.1.23.9 (CH
3CO).
Embodiment 96:N-(N-4-methyl-benzoyl-L-tyrosyl)-4-acetylaminohydroxyphenylarsonic acid L-phenylalanine
Spectroscopic data:
1H-NMR (DMSO, 400MHz) δ: 12.79 (1H, br, COOH), 9.86 (1H, s, ArNHCO), 9.14 (1H, s, Ar-OH), 8.36 (1H, d, J=8.8Hz, NHCO), 8.23 (1H, d, J=7.6Hz, NHCO), 7.66 (2H, d, J=8.0Hz, H-3 ", 7 "), 7.44 (2H, d, J=8.4Hz, H-6 ', 8 '), 7.23 (2H, d, J=7.6Hz, H-4 ", 6 "), 7.14 (2H, d, J=8.4Hz, H-5 ', 9 '), 7.10 (2H, d, J=8.4Hz, H-5,9), (6.60 2H, d, J=8.4Hz, H-6,8), 4.61 (1H, m, H-2), 4.41 (1H, m, H-2 '), 3.00-2.82 (4H, m, H-3,3 '), 2.32 (3H, s, Ar-CH
3), 2.01 (3H, s, COCH
3);
13C-NMR (DMSO, 100MHz) δ: 172.8 (C-1 '), 171.7 (C-1), 168.1 (ArNHCO), 166.0 (C-1 "); 155.7 (C-7), 141.2 (C-5 "), 137.8 (C-7 '), 131.8 (C-4 '), 131.3 (C-2 "); 130.1 (C-5,9), 129.4 (C-5 ', 9 '); 128.7 (C-4 ", 6 "), 128.5 (C-4), 127.4 (C-3 ", 7 "), 118.8 (C-6 ', 8 '), 114.8 (C-6; 8), 55.0 (C-2), 53.6 (C-2 '), 52.1 (OCH
3), 36.2 (t * 2), 24.0 (COCH
3), 21.0 (Ar-CH
3).
Embodiment 97:N-(N-4-chloro-benzoyl-L-phenylalanyl)-L-phenylalanine
Spectroscopic data:
1H-NMR (DMSO, 400MHz) d:12.83 (1H, br, COOH), 8.67 (1H, d, J=8.4Hz, NHCO), 8.39 (1H, d, J=8.0Hz, NHCO), 7.79 (2H, d, J=8.8Hz, H-3 ", 7 "), 7.53 (2H, m, H-4 ", 6 "), 7.34-7.13 (10H, m, H-5-9,5 '-9 '), 4.75 (1H, m, H-2), 4.48 (1H, m, H-2 '), 3.13-2.88 (4H, m, H-3,3 ')
13C-NMR (DMSO, 100MHz) δ: 172.8 (C-1 '), 171.5 (C-1), 165.1 (C-1 "); 138.4 (C-4), 137.4 (C-4 '), 136.2 (C-5 "), 132.7 (C-2 "), 129.4 (* 2), 129.2 (* 4); 128.3 (* 2), 128.2 (* 2), 128.1 (* 2); 126.5,126.3,54.6 (C-2); 53.6 (C-2 '), 36.9,36.6.
Embodiment 98:N-(N-4-chloro-benzoyl-L-phenylalanyl)-L-phenylalanine sodium salt
Spectroscopic data:
1H-NMR (DMSO, 400MHz) δ: 8.92 (1H, br, NHCO), 7.79 (2H, d, J=8.8Hz, H-3 ", 7 "), 7.51 (3H, m, H-4 ", 6 ", NHCO), 7.31-7.05 (10H, m, H-5-9,5 '-9 '), 4.52 (1H, m, H-2), (3.90 1H, m, H-2 '), 3.13-3.09 (2H, m, H-3), 2.98-2.89 (2H, m, H-3 ')
13C-NMR (DMSO, 100MHz) δ: 179.0 (C-1 '), 169.7 (C-1), 165.1 (C-1 "); 139.3 (C-4), 138.8 (C-4 '), 136.0 (C-5 "), 132.8 (C-2 "); 129.8 (* 2), 129.4 (* 2), 129.1 (* 2); 128.2 (* 2), 128.1 (* 2), 127.4 (* 2); 126.1,125.4,55.9 (C-2); 55.5 (C-2 '), 37.2,36.8.
Embodiment 99:N-(N-2-chloro-benzoyl-L-phenylalanyl)-L-phenylalanine
Spectroscopic data:
1H-NMR (DMSO, 400MHz) δ: 12.82 (1H, br, COOH), 8.56 (1H, d, J=8.4Hz, NHCO), 8.23 (1H, d, J=7.6Hz, NHCO), 7.43-7.12 (14H, m, H-5-9, H-4 " 7 ", H-5 '-9 '), 4.74 (1H, m, H-2), 4.52 (1H, m, H-2 '), 3.14-2.78 (4H, m, H-3,3 ');
13C-NMR (DMSO, 100MHz) δ: 172.6 (C-1 '), 170.9 (C-1), 165.9 (C-1 "), 137.8 (C-4); 137.3 (C-4 '), 136.4 (C-5 "), 130.7 (C-3 "), 129.9 (C-2 "), 129.5 (C-4 "), 129.21 (C-6 ', 8 '), 129.17 (C-6; 8), 128.8 (C-7 "), 128.2 (C-5,9), 128.0 (C-5 ', 9 '), 126.8 (C-6 "), 126.5 (C-7); 126.2 (C-7 '), 54.1,53.5,37.2.36.8.
Embodiment 100:N-(N-4-nitro-benzoyl-L-tyrosyl)-L-phenylalanine
Spectroscopic data:
1H-NMR (DMSO, 400MHz) δ: 9.19 (1H, br, Ar-OH), 8.90 (1H, d, J=8.8Hz, NHCO), 8.42 (1H, d, J=7.6Hz, NHCO), 8.30 (2H, d, J=8.8Hz, H-4 "; 6 "), 7.99 (2H, d, J=8.8Hz, H-3 ", 7 "), 7.27-7.18 (5H, m, H-5 '-9 '), 7.13 (2H, d, J=8.4Hz, H-5,9), 6.63 (2H, d, J=8.4Hz, H-6,8), 4.70 (1H, m, H-2), (4.47 1H, m, H-2 '), 3.14-2.80 (4H, m, H-3,3 ');
13C-NMR (DMSO, 100MHz) δ: 172.9 (C-1 '), 171.4 (C-1), 164.5 (C-1 "), 155.8 (C-7); 149.1 (C-5 "), 139.7 (C-2 "), 137.6 (C-4 '), 130.1 (C-5,9); 129.2 (C-6 ', 8 '), 128.9 (C-3 ", 7 "); 128.2 (C-5 ', 9 '), 128.2 (C-4), 126.5 (C-7 '); 123.5 (C-4 ", 6 "), 114.9 (C-6,8); 55.2 (C-2), 53.7 (C-2 '), 36.6,36.3.
Embodiment 101:N-(N-4-acetylaminohydroxyphenylarsonic acid benzoyl-L-phenylalanyl)-L-phenylalanine
Spectroscopic data:
1H-NMR (DMSO, 400MHz) δ: 12.82 (1H, br, COOH), 10.16 (1H, s, ArNHCO), 8.42 (1H, d, J=8.4Hz, NHCO), 8.32 (1H, d, J=8.0Hz, NHCO), 7.73 (2H, d, J=8.8Hz, H-3 ", 7 "), 7.62 (2H, d, J=8.8Hz, H-4 ", 6 "), 7.34-7.14 (10H, m, H-5-9,5 '-9 '), 4.72 (1H, m, H-2), 4.47 (1H, m, H-2 '), 3.12-2.91 (4H, m, H-3,3 '), 2.06 (3H, CH
3CO);
13C-NMR (DMSO, 100MHz) δ: 172.8 (C-1 '), 171.6 (C-1), 168.7 (ArNHCO), 165.7 (C-1 "), 142.0 (C-5 "), 138.5 (C-4), 137.4 (C-4 '), 129.4 (C-6,8), 129.2 (C-6 ', 8 '), 128.3 (C-3 ", 7 "), 128.2 (C-2 "); 128.2 (C-5 ', 9 '), 128.1 (C-5; 9), 126.5 (C-7 '), 126.2 (C-7); 117.9 (C-4 ", 6 "), 54.5 (C-2); 53.6 (C-2 '); 36.9 (C-3), 36.7 (C-3 '), 24.1 (CH
3CO).
Embodiment 102:N-(the different nicotinoyl of N--L-phenylalanyl)-L-tyrosine
Spectroscopic data:
1H-NMR (DMSO, 400MHz) δ: 12.78 (1H, br, COOH), 9.23 (1H, s, Ar-OH), 8.89 (1H, d, J=8.8Hz, NHCO), 8.70 (2H, m, H-4 ", 6 "), 8.36 (1H, d, J=8.0Hz, NHCO), 7.65 (2H, d, J=5.2Hz, H-3 ", 7 "), (7.34 2H, d, J=6.8Hz, H-5,9), 7.25 (2H, t, H-6,8), 7.16 (1H, t, H-7), 7.03 (2H, d, J=8.4Hz, H-5 ', 9 '), 6.62 (2H, d, J=8.0Hz, H-6 ', 8 '), 4.77 (1H, m, H-2), 4.38 (1H, m, H-2 '), 3.13-2.82 (4H, m, H-3,3 ');
13C-NMR (DMSO, 100MHz) δ: 172.9 (C-1 '), 171.1 (C-1), 164.7 (C-1 "), 156.0 (C-7 '); 150.2 (C-4 ", 6 "), 140.9 (C-2 "), 138.2 (C-4), 130.1 (C-5 ', 9 '), 129.2 (C-6,8), (128.1 C-5,9), 127.4 (C-4 '), 126.3 (C-7), 121.4 (C-3 ", 7 "), 115.0 (C-6 ', 8 '), 54.6 (C-2), 54.0 (C-2 '), 37.0 (C-3), 35.8 (C-3 ').
Embodiment 103:N-(N-4-acetylaminohydroxyphenylarsonic acid benzoyl-L-phenylalanyl)-L-tyrosine
Spectroscopic data:
1H-NMR (DMSO, 400MHz) δ: 12.77 (1H, br, COOH), 10.18 (1H, s.ArNHCO), 9.23 (1H, s, ArOH), 8.43 (1H, d, J=8.4Hz, NHCO), 8.24 (1H, d, J=7.6Hz, NHCO), 7.73 (2H, d, J=8.8Hz, H-3 ", 7 "), 7.63 (2H, d, J=8.8Hz, H-4 ", 6 "), 7.34 (2H, d, J=7.2Hz, H-5,9), 7.24 (2H, t, H-6,8), 7.15 (1H, t, H-7), 7.02 (2H, d, J=8.4Hz, H-5 ', 9 '), 6.61 (2H, d, J=8.8Hz, H-6 ', 8 '), 4.72 (1H, m, H-2), 4.39 (1H, m, H-2 '), 3.10-2.84 (4H, m, H-3,3 '), 2.07 (3H, CH
3CO);
13C-NMR (DMSO, 100MHz) δ: 172.9 (C-1 '), 171.5 (C-1), 168.7 (ArNHCO), 165.7 (C-1 "), 156.0 (C-7 '); 142.0 (C-5 "), 138.5 (C-4), 130.1 (C-5 ', 9 '), 129.2 (C-6,8), 128.3 (C-3 ", 7 "), 128.2 (C-4 '), (128.0 C-5,9), 127.3 (C-2 "); 126.2 (C-7), 118.0 (C-4 ", 6 "); 115.0 (C-6 ', 8 '), 54.5 (C-2); 53.9 (C-2 '); 36.9 (C-3), 36.0 (C-3 '), 24.1 (CH
3CO).
Embodiment 104:N-(N-4-propionamido-benzoyl-L-phenylalanyl)-L-phenylalanine
Spectroscopic data:
1H-NMR (DMSO, 400MHz) δ: 12.81 (1H, br, COOH), 10.09 (1H, s, ArNHCO), 8.40 (1H, d, J=8.4Hz, NHCO), 8.31 (1H, d, J=7.6Hz, NHCO), 7.73 (2H, d, J=9.2Hz, H-3 ", 7 "), 7.63 (2H, d, J=8.8Hz, H-4 ", 6 "), 7.34-7.13 (10H, m, H-5-9,5 '-9 '), 4.72 (1H, m, H-2), 4.48 (1H, m, H-2 '), 3.11-3.05 (2H, m, H-3), 2.99-2.91 (2H, m, H-3 '), 2.34 (2H, q, J=7.6Hz, COCH
2CH
3), 1.08 (3H, t, J=7.6Hz, COCH
2CH
3);
13C-NMR (DMSO, 100MHz) δ: 172.8 (C-1 '), 172.4,171.6,165.7 (C-1 "); 142.1 (C-5 "), 138.5 (C-4), 137.4 (C-4 '), 129.2 (* 4, C-6,8,6 ', 8 '), 128.3 (C-3 ", 7 "), 128.2 (C-5 ', 9 '), 128.1 (C-2 "), 128.0 (C-5,9); 126.5 (C-7), 126.2 (C-7 '), 118.0 (C-4 ", 6 "), 54.5 (C-2); 53.5 (C-2 '), 36.9 (C-3), 36.6 (C-3 '), 29.6 (COCH
2CH
3), 9.5 (COCH
2CH
3).
Embodiment 105:N-(N-4-acetylaminohydroxyphenylarsonic acid benzoyl-L-tyrosyl)-L-phenylalanine
Spectroscopic data:
1H-NMR (DMSO, 400MHz) δ: 12.79 (1H, br, COOH), 10.16 (1H, s, ArNHCO), 9.14 (1H, s, ArOH), 8.32 (1H, d, J=8.8Hz, NHCO), 8.27 (1H, d, J=7.6Hz, NHCO), 7.73 (2H, d, J=8.4Hz, H-3 ", 7 "), 7.62 (2H, d, J=8.4Hz, H-4 ", 6 "), 7.25-7.17 (5H, m, 5 '-9 '), 7.11 (2H, d, J=8.4Hz, H-5,9), 6.61 (2H, d, J=8.8Hz, H-6,8), 4.62 (1H, m, H-2), 4.46 (1H, m, H-2 '), 3.11-2.73 (4H, m, H-3,3 '), 2.07 (3H, CH
3CO);
13C-NMR (DMSO, 100MHz) δ: 172.8 (C-1 '), 171.8 (C-1), 168.7 (ArNHCO), 165.6 (C-1 "); 155.7 (C-7), 142.0 (C-5 "), 137.4 (C-4 '), 130.1 (C-5,9), 129.2 (6 ', 8 '), 128.4 (C-4,2 "), 128.3 (C-3 ", 7 "), 128.2 (C-5 ', 9 '), 126.5 (C-7 '), 117.9 (C-4 ", 6 "), 114.8 (C-6,8), 54.9 (C-2); 53.5 (C-2 '), 36.7,36.2,24.2 (CH
3CO).
Embodiment 106:N-(the different nicotinoyl of N--L-tyrosyl)-4-nitro-L-phenylalanine
Spectroscopic data:
1H-NMR (DMSO, 400MHz) δ: 12.96 (1H, br, COOH), 9.17 (1H, s, ArOH), 8.79 (1H, d, J=8.4Hz, NHCO), 8.69 (2H, d, J=5.6Hz, H-4 ", 6 "), 8.50 (1H, d, J=8.4Hz, NHCO), 8.08 (2H, d, J=8.8Hz, H-6 ', 8 '), 7.65 (2H, m, H-3 ", 7 "), 7.52 (2H, d, J=8.4Hz, H-5 ', 9 '), 7.11 (2H, d, J=8.8Hz, H-5,9), 6.62 (2H, d, J=8.4Hz, H-6,8), 4.67-4.54 (2H, m, H-2,2 '), 3.26 (1H, dd, J=5.2,13.6Hz, H-3 ' a), 3.08 (1H, dd, J=9.2,13.6Hz, H-3 ' b), 2.98-2.73 (2H, m, H-3);
13C-NMR (DMSO, 100MHz) δ: 172.4 (C-1 '), 171.3 (C-1), 164.5 (C-1 "), 155.8 (C-7); 150.2 (C-4 ", 6 "), 146.2 (C-7 '), 145.9 (C-4 '); 140.9 (C-2 "), 130.6 (C-5 ', 9 '), 130.1 (C-5,9), 128.1 (C-4), 123.2 (C-6 ', 8 '), 121.3 (C-3 ", 7 "), 114.9 (C-6,8), 55.0 (C-2), 52.9 (C-2 '), 36.3,36.1.
Claims (5)
- [claim 1] N-(N-benzoyl-phenylalanyl)-phenylalanine dipeptide derivative is characterized in that: the compound of structure shown in general formula I, or its pharmacy acceptable salt or hydrate;
General formula (I)WhereinR 1For hydrogen ,-NH 2, CH 2NRR ' ,-NRR ' ,-NHCOR, (4-OH, 3-CH 2NRR ') ,-OCOR ,-OR ,-NHCO (CH 2) nCOOH ,-O (CH 2) nNRR ' ,-O (CH 2) nCOOR or-O (CH 2) nCOOH;R 2Be hydrogen, C 1-C 6Alkyl, fluorine, chlorine or bromine ,-NO 2,-NH 2,-CN ,-NRR ' ,-NHCOR ,-OH ,-OCOR ,-OR ,-NHCO (CH 2) nCOOH ,-O (CH 2) nN RR ' ,-O (CH 2) nCOOH ,-CH 2NRR ',COOH or-COOR;
R 3For hydrogen ,-NH 2, CH 2NRR ' ,-NRR ' ,-NHCOR ,-OH, (4-OH, 3-CH 2NRR ') ,-OCOR ,-OR ,-NHCO (CH 2) nCOOH ,-O (CH 2) nNRR ' ,-O (CH 2) nCOOR or-O (CH 2) nCOOH;X is CH or N;R 1, R 2, R 3Be not hydrogen and R simultaneously 1, R 2, R 3When being N for H and X simultaneously, R 4Be CH 2OH, COOR, CH 2OCOR, CH 2OCO (CH 2) 2COOH or COONa; R 1, R 2, R 3When being CH for H and X simultaneously, R 4Be COOR or CH 2OCO (CH 2) 2COOH;R 1, R 2And R 3Can be respectively single or multiple substituting groups, and be in contraposition and an ortho position and a position on the phenyl ring respectively;R, the identical or different C of R ' representative 1-C 6Straight or branched alkyl, or C 3-C 7Cycloalkyl;N is 1 to 4 integer. - [claim 2] wants 1 described N-(N-benzoyl-phenylalanyl)-phenylalanine dipeptide derivative according to right, it is characterized in that: described alkyl and cycloalkyl can be replaced by the substituting group of 1-2 hydroxyl, nitro, halo, cyano group, trifluoromethyl.
- [claim 3] wants the preparation method of 1 described N-(N-benzoyl-phenylalanyl)-phenylalanine dipeptide derivative as right, it is characterized in that:Synthetic route I is as follows:
(I-a) dicyclohexyl two carbimides, to Dimethylamino pyridine, CH 2Cl 2, room temperature; (I-b) 1.0MNaOH, room temperature;
(I-c) isobutyl chlorocarbonate, N-methylmorpholine ,-5～10 ℃. - [claim 4] wants the preparation method of 1 described N-(N-benzoyl-phenylalanyl)-phenylalanine dipeptide derivative as right, it is characterized in that:Synthetic route II is as follows:
(II-a) (t-BuOCO) 2O, 1.0MNaOH, Tetrabutyl amonium bromide; (II-b) CH 2Cl 2, isobutyl chlorocarbonate, N-methylmorpholine ,-5～10 ℃; (II-c) trifluoroacetic acid, CH 2Cl 2, room temperature, 2h; (II-d) dicyclohexyl two carbimides, to Dimethylamino pyridine, CH 2Cl 2, room temperature. - The application of [claim 5] N-as claimed in claim 1 (N-benzoyl-phenylalanyl)-phenylalanine dipeptide derivative in the medicine of preparation treatment hepatitis B virus infection; it is characterized in that: described N-(N-benzoyl-phenylalanyl)-phenylalanine dipeptide derivative or its pharmacy acceptable salt are prepared into suitable form of administration, can add additives or vehicle.
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| CN102186804A (en) * | 2008-10-20 | 2011-09-14 | 克塞诺波特公司 | Methods of synthesizing a levodopa ester prodrug |
| CN101445467B (en) * | 2008-12-30 | 2013-01-23 | 浙江九洲药业股份有限公司 | Chemical synthesis method of N-(4-chlorobenzoyl)-tyramine |
| CN102466659A (en) * | 2010-11-15 | 2012-05-23 | 天津药物研究院 | Method for detecting N-(N-benzoyl- phenylalanyl)-phenylalanine dipeptide derivative |
| CN103508921B (en) * | 2012-06-21 | 2015-09-30 | 贵州百灵企业集团制药股份有限公司 | A kind of preparation method of phenylalaninol compound |
| CN103508920B (en) * | 2012-06-21 | 2016-03-02 | 贵州百灵企业集团制药股份有限公司 | A kind of preparation method and its usage of optical isomer of phenylalaninol compound |
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| CN111909051B (en) * | 2020-08-07 | 2022-12-27 | 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) | N- [ 4-phenyl-3- (benzoylamino) -1, 1-trifluoro-butyl-2-yl ] -phenylalaninol derivative and preparation method and application thereof |
| CN112500308B (en) * | 2020-10-28 | 2023-10-03 | 澳门科技大学 | Golden amide alcohol ester and fluorinated derivative thereof, and preparation method and application thereof |
| CN114853629B (en) * | 2021-02-03 | 2023-06-13 | 沈阳农业大学 | Dipeptide compound and preparation method and application thereof |
| CN114470150B (en) * | 2021-12-13 | 2022-12-27 | 完美（广东）日用品有限公司 | Application of chicken-derived small molecular peptide in preparation of product for preventing and improving liver injury and secondary symptoms thereof and product |
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