CN101215276B - N,N'-substituted phenylpropylamino acid phenylpropylaminoalcohols esters derivatives and preparation method thereof - Google Patents
N,N'-substituted phenylpropylamino acid phenylpropylaminoalcohols esters derivatives and preparation method thereof Download PDFInfo
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- CN101215276B CN101215276B CN 200810010040 CN200810010040A CN101215276B CN 101215276 B CN101215276 B CN 101215276B CN 200810010040 CN200810010040 CN 200810010040 CN 200810010040 A CN200810010040 A CN 200810010040A CN 101215276 B CN101215276 B CN 101215276B
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- alcohol ester
- phenylpropyl alcohol
- phenylalanine
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- 0 CC(C)(C)OC(NCCC(C)(CC(C)(C)*)*C(O)=*)=O Chemical compound CC(C)(C)OC(NCCC(C)(CC(C)(C)*)*C(O)=*)=O 0.000 description 4
- LFKDJXLFVYVEFG-UHFFFAOYSA-N CC(C)(C)OC(N)=O Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 2
Abstract
The invention belongs to the medical technology field, providing an N, N'-substituted styrene-acrylate amino acid styrene-acrylate amino alcohol esters derivative and the preparation process. The invention further discloses racemate or optical isomer or salt available on pharmacology or salvation of N, N'-substituted styrene-acrylate amino acid styrene-acrylate amino alcohol esters derivative and medicine compound which contains the compound, and the structural formula is showed as followed. N, N'-substituted styrene-acrylate amino acid styrene-acrylate amino alcohol ester compound and salt available on pharmacology in the invention which are used as active components can be prepared into formulation which is needed in clinics through combining with excipient available in clinics, thereby being used to cure tumor, especially breast cancer.
Description
Technical field:
The invention belongs to medical technical field, relate to N, N '-substituted phenylpropylamino acid phenylpropylaminoalcesters esters derivatives and preparation method thereof, definite saying relates to N, its raceme of N '-substituted phenylpropylamino acid phenylpropylaminoalcesters esters derivatives or optically active isomer or its pharmacy acceptable salt or solvate and the pharmaceutical composition and preparation method thereof and the application of these compounds in the medicine of preparation treatment tumour, especially mammary cancer that contain described compound.
Background technology:
Tumour is the chronic disease of serious harm human life health, and its incidence and lethality rate are constantly raising year by year, have followed the second that cardiovascular disorder becomes lethal disease afterwards closely.
And the mammary cancer common malignant tumour that is the women, in the first place that its sickness rate of many countries and regions has occupied women's malignant tumour.Sickness rate at Chinese Breast Cancer rises year by year, and in big cities such as Beijing, Shanghai, mammary cancer has leapt to first of women's Cancer Mortality.
Therefore, develop the medicine for the treatment of cancer, especially mammary cancer of the high-efficiency low-toxicity with independent intellectual property right extremely urgent.
A.M.Clark extracts from aspergillus flavipes first and isolates that (S)-N-benzoyl phenylalanine-(Lloydia 1977,40 (2), 146-51) for (S)-2-benzamide base-3-phenylpropyl alcohol ester.Extract from the moulds such as penicillium megasporum, P.brevicompactum, P.canadense successively afterwards and obtain this compound; Also separate from the plants such as Grangea maderaspatana, Medicago polymorpha, Anaphalis subumbellata, Artemisia anomala, Croton hieronymi and obtain.In addition; (S)-N-benzoyl phenylalanine that extraction obtains from patrinia scabra Bunge first such as Gu Zhengbing-(S)-2-acetamido-3-phenylpropyl alcohol ester also belongs to N; N '-substituted phenylpropylamino acid phenylpropylaminoalcesters esters structural compounds (Chinese Chemical Letters; 2002; 13,957).
Pei-Lin Wu etc. has carried out preliminary study to the activity of (S)-N-benzoyl phenylalanine-(S)-2-benzamide base-3-phenylpropyl alcohol ester.Tested respectively it in the activity of vitro inhibition people cancer of the stomach, nasopharyngeal carcinoma, lung cancer and mammary cancer by using Nugc-3, HONE-1, A549 and MCF-7 cell strain, find that it has activity for cancer of the stomach, nasopharyngeal carcinoma, show than strong inhibitory activity (Chem.Pharm.Bull.2004 for lung cancer and mammary cancer, 52 (3), 345-349).
The prior art result of study shows N, and it is active that N '-substituted phenylpropylamino acid phenylpropylaminoalcesters esters structural compounds compounds has antitumor particularly anti-breast cancer, so the value of furtheing investigate is arranged.
Summary of the invention:
The objective of the invention is to seek and develop the N with good anti-tumor activity, N '-substituted phenylpropylamino acid phenylpropylaminoalcesters esters derivatives.
Another object of the present invention is to provide N, the application of N '-substituted phenylpropylamino acid phenylpropylaminoalcesters esters derivatives in the preparation antitumor drug.
N of the present invention, N '-substituted phenylpropylamino acid phenylpropylaminoalcesters esters derivatives are a kind of compounds with general formula I constitutional features, the compound of general formula I, and its raceme or optically active isomer, or its pharmacy acceptable salt and solvate:
Wherein, R
1, R
2Be hydrogen independently; Aryl; The C1-C of straight or branched
10Alkyl; The C5-C6 cycloalkyl; R
3, R
4Be hydrogen independently, the C1-C10 alkyl of straight or branched; The C5-C6 cycloalkyl; The C1-C10 alkyloyl of straight or branched, C5-C6 cycloalkanes acyl group, aroyl; 4-hetaroylpyrazol; The C2-C10 alkenyl, the C2-C10 alkynyl; R
5, R
6Be hydrogen independently, the C1-C10 alkyl of straight or branched; The C5-C6 cycloalkyl; Aryl; Heteroaryl; The C2-C10 alkenyl, the C2-C10 alkynyl;
n
1, n
2, n
3Be 0 or 1
X can be Sauerstoffatom, nitrogen-atoms or sulphur atom;
Y can be O, S, N-R
7
In a preferred embodiment of the invention, compound of Formula I of the present invention is represented (S, the S) configurational isomer of general formula I I, or its pharmacy acceptable salt or solvate,
Wherein, be connected in N (R
3, R
5) and N (R
4, R
6) carbon atom be (S, S) configuration
R
1, R
2Be hydrogen independently; Aryl; The C1-C10 alkyl of straight or branched; The C5-C6 cycloalkyl; R
3, R
4Be hydrogen independently, the C1-C10 alkyl of straight or branched; The C5-C6 cycloalkyl; The C1-C10 alkyloyl of straight or branched, C5-C6 cycloalkanes acyl group, aroyl; 4-hetaroylpyrazol; The C2-C10 alkenyl, the C2-C10 alkynyl; R
5, R
6Be hydrogen independently, the C1-C10 alkyl of straight or branched; The C5-C6 cycloalkyl; Aryl; Heteroaryl; The C2-C10 alkenyl, the C2-C10 alkynyl;
n
1, n
2, n
3Be 0 or 1
X can be Sauerstoffatom, nitrogen-atoms or sulphur atom;
Y can be O, S, N-R
7
In a preferred embodiment of the invention, compound of Formula I of the present invention is represented (S, the R) configurational isomer of general formula III, or its pharmacy acceptable salt or solvate,
Wherein, be connected in N (R
3, R
5) and N (R
4, R
6) carbon atom be (S, R) configuration
R
1, R
2Be hydrogen independently; Aryl; The C1-C10 alkyl of straight or branched; The C5-C6 cycloalkyl;
R
3, R
4Be hydrogen independently, the C1-C10 alkyl of straight or branched; The C5-C6 cycloalkyl; The C1-C10 alkyloyl of straight or branched, C5-C6 cycloalkanes acyl group, aroyl; 4-hetaroylpyrazol; The C2-C10 alkenyl, the C2-C10 alkynyl;
R
5, R
6Be hydrogen independently, the C1-C10 alkyl of straight or branched; The C5-C6 cycloalkyl; Aryl; Heteroaryl; The C2-C10 alkenyl, the C2-C10 alkynyl;
n
1, n
2, n
3Be 0 or 1
X can be Sauerstoffatom, nitrogen-atoms or sulphur atom;
Y can be O, S, N-R7
In a preferred embodiment of the invention, compound of Formula I of the present invention is represented (R, the R) configurational isomer of general formula I V, or its pharmacy acceptable salt or solvate,
Wherein, be connected in N (R
3, R
5) and N (R
4, R
6) carbon atom be (R, R) configuration
R
1, R
2Be hydrogen independently; Aryl; The C1-C10 alkyl of straight or branched; The C5-C6 cycloalkyl; R
3, R
4Be hydrogen independently, the C1-C10 alkyl of straight or branched; The C5-C6 cycloalkyl; The C1-C10 alkyloyl of straight or branched, C5-C6 cycloalkanes acyl group, aroyl; 4-hetaroylpyrazol; The C2-C10 alkenyl, the C2-C10 alkynyl; R
5, R
6Be hydrogen independently, the C1-C10 alkyl of straight or branched; The C5-C6 cycloalkyl; Aryl; Heteroaryl; The C2-C10 alkenyl, the C2-C10 alkynyl;
n
1, n
2, n
3Be 0 or 1
X can be Sauerstoffatom, nitrogen-atoms or sulphur atom;
Y can be O, S, N-R
7
In a preferred embodiment of the invention, compound of Formula I of the present invention is represented (R, the S) configurational isomer of general formula V, or its pharmacy acceptable salt or solvate,
Wherein, be connected in N (R
3, R
5) and N (R
4, R
6) carbon atom be (R, S) configuration
R
1, R
2Be hydrogen independently; Aryl; The C1-C10 alkyl of straight or branched; The C5-C6 cycloalkyl; R
3, R
4Be hydrogen independently, the C1-C10 alkyl of straight or branched; The C5-C6 cycloalkyl; The C1-C10 alkyloyl of straight or branched, C5-C6 cycloalkanes acyl group, aroyl; 4-hetaroylpyrazol; The C2-C10 alkenyl, the C2-C10 alkynyl; R
5, R
6Be hydrogen independently, the C1-C10 alkyl of straight or branched; The C5-C6 cycloalkyl; Aryl; Heteroaryl; The C2-C10 alkenyl, the C2-C10 alkynyl;
n
1, n
2, n
3Be 0 or 1
X can be Sauerstoffatom, nitrogen-atoms or sulphur atom;
Y can be O, S, N-R
7
Wherein, N-R
7In R
7C1-C10 alkyl for straight or branched; The C5-C6 cycloalkyl; Aryl; Heteroaryl;
As mentioned above, wherein, R
1, R
2Be phenyl or hydroxyl-substituted base; Methyl; Cyclopentyl; R
3, R
4Be hydrogen; Methyl; Phenyl, replaced by one or more groups on its phenyl ring, described group is selected from, methyl, methoxyl group, fluorine, chlorine, bromine, hydroxyl, acetoxyl group, benzyloxy, trifluoromethyl, cyano group, nitro, amino, acetylamino, sulfydryl, methyl mercapto, ethyl sulfydryl, methylsulfonyl, carboxyl, carboxyl methyl; 4-pyridyl, 3-pyridyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrryl, 3-pyrryl, 4-piperidyl-N-Z; Alpha-Naphthyl, betanaphthyl; Pentamethylene base, cyclohexyl; Formyl radical; Benzoyl, replaced by one or more groups on its phenyl ring, described group is selected from, methyl, methoxyl group, fluorine, chlorine, bromine, hydroxyl, acetoxyl group, benzyloxy, trifluoromethyl, cyano group, nitro, amino, acetylamino, sulfydryl, methyl mercapto, ethyl sulfydryl, methylsulfonyl, carboxyl, carboxyl methyl; 4-pyridine formyl radical, 3-pyridine formyl radical, 2-furancarbonyl, 3-furancarbonyl, 2-Thenoyl, 3-Thenoyl, 2-pyrroyl group, 3-pyrroyl group, 4-piperidine formyl base-N-Z; Alpha-Naphthyl formyl radical, betanaphthyl formyl radical; Cyclopentyl formyl radical, cyclohexyl formyl radical; R
5, R
6Be the hydrogen methyl; Phenyl, replaced by one or more groups on its phenyl ring, described group is selected from, methyl, methoxyl group, fluorine, chlorine, bromine, hydroxyl, acetoxyl group, benzyloxy, trifluoromethyl, cyano group, nitro, amino, acetylamino, sulfydryl, methyl mercapto, ethyl sulfydryl, methylsulfonyl, carboxyl, carboxyl methyl; 4-pyridyl, 3-pyridyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrryl, 3-pyrryl, 4-piperidyl-N-Z; Alpha-Naphthyl, betanaphthyl; Pentamethylene base, cyclohexyl;
Wherein, the Z in 4-piperidyl-N-Z is the C1-C10 alkyl of straight or branched; The C1-C10 alkyloyl, C5-C6 cycloalkanes acyl group, aroyl; 4-hetaroylpyrazol; The C2-C10 alkenyl, the C2-C10 alkynyl;
R
3, R
5Can couple together and form a saturated ring system that contains 2-5 carbon atom; R
3, R
5Couple together morpholine ring, pyridine ring, piperidine ring, the piperazine ring that also can form replacement, its substituting group is the C1-C10 alkyl of straight or branched
R
4, R
6Can couple together and form a saturated ring system that contains 2-5 carbon atom; R
4, R
6Couple together morpholine ring, pyridine ring, piperidine ring, the piperazine ring that also can form replacement, its substituting group is the C1-C10 alkyl of straight or branched;
Due to the N according to following formula I-V of the present invention, N '-substituted phenylpropylamino acid phenylpropylaminoalcesters esters compound has antitumor action, therefore it clinically can be as preparation antitumor drug, particularly following cancer, as mammary cancer, lung cancer, liver cancer, leukemia etc.
Compound of the present invention can be used as activeconstituents and is used for the treatment of cancer, suffers from the compound of the present invention of the patient significant quantity of cancer, can reach the purpose of this disease for the treatment of.
Pharmaceutical composition of the present invention is the N with following formula I, and the compound of N '-replacement phenylpropyl alcohol amino acid phenylpropyl alcohol aminoalcohol ester or its pharmacy acceptable salt are as activeconstituents.Compound of the present invention can be mixed and made into the medicinal compositions that needs clinically with pharmaceutically acceptable thinner, auxiliary and/or carrier.
When pharmaceutical composition of the present invention is applied to it to be mixed with several formulation when clinical, as: oral preparations (as tablet, capsule, lozenge, solution or suspension); Injectable preparation (as injectable solution or suspension, or injectable dried powder, add water for injection to use immediately before injection); Topical formulations (as ointment or solution).
The carrier that is used for pharmaceutical composition of the present invention is the available common vector of pharmaceutical field, comprising: the tackiness agent that oral preparations is used, lubricant, disintegrating agent, solubility promoter, thinner, stablizer, suspension agent, non-pigment, correctives etc.; The sanitas that injectable formulation is used, solubilizing agent, stablizer etc.; The matrix that topical formulations is used, thinner, lubricant, sanitas etc.Pharmaceutical preparation can oral administration or parenteral mode (for example intravenously, subcutaneous, intraperitoneal or part) administration, if some drugs is unsettled under the stomach condition, it can be mixed with enteric coated tablets.
Following synthetic route A-D has described the preparation of compound of Formula I of the present invention, and all raw materials are all by organic chemistry filed ordinary method preparation or commercially available.All final compound of the present invention is all to prepare by the following method or by similar method.
According to formula I-V compound of the present invention, in route A,
R
1Be hydrogen; Aryl; The C1-C10 alkyl of straight or branched; The C5-C6 cycloalkyl;
R
2Be hydrogen; Aryl; The C1-C10 alkyl of straight or branched; The C5-C6 cycloalkyl;
R
3Be hydrogen, the C1-C10 alkyl of straight or branched; The C5-C6 cycloalkyl;
R
4C1-C10 alkyl for hydrogen or straight or branched;
R
5Be formyl radical; Ethanoyl; Benzoyl, replaced by one or more groups on its phenyl ring, described group is selected from, methyl, methoxyl group, fluorine, chlorine, bromine, hydroxyl, acetoxyl group, benzyloxy, trifluoromethyl, cyano group, nitro, amino, acetylamino, sulfydryl, methyl mercapto, ethyl sulfydryl, methylsulfonyl, carboxyl, carboxyl methyl; 4-pyridine formyl radical, 3-pyridine formyl radical, 2-furancarbonyl, 3-furancarbonyl, 2-Thenoyl, 3-Thenoyl, 2-pyrroyl group, 3-pyrroyl group, 4-piperidine formyl base-N-Z; Alpha-Naphthyl formyl radical, betanaphthyl formyl radical; Cyclopentyl formyl radical, cyclohexyl formyl radical; Methylsulfonyl, p-toluenesulfonyl; Wherein, Z is the C1-C10 alkyl of straight or branched; The C1-C10 alkyloyl, C5-C6 cycloalkanes acyl group, aroyl; 4-hetaroylpyrazol; The C2-C10 alkenyl, the C2-C10 alkynyl
R
6Be phenyl, replaced by one or more groups on its phenyl ring, described group is selected from, methyl, methoxyl group, fluorine, chlorine, bromine, hydroxyl, acetoxyl group, benzyloxy, trifluoromethyl, cyano group, nitro, amino, acetylamino, sulfydryl, methyl mercapto, ethyl sulfydryl, methylsulfonyl, carboxyl, carboxyl methyl; 4-pyridyl, 3-pyridyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrryl, 3-pyrryl, 4-piperidyl-N-Z; Alpha-Naphthyl, betanaphthyl; Pentamethylene base, cyclohexyl; Formyl radical; Benzoyl, replaced by one or more groups on its phenyl ring, described group is selected from, methyl, methoxyl group, fluorine, chlorine, bromine, hydroxyl, acetoxyl group, benzyloxy, trifluoromethyl, cyano group, nitro, amino, acetylamino, sulfydryl, methyl mercapto, ethyl sulfydryl, methylsulfonyl, carboxyl, carboxyl methyl; 4-pyridine formyl radical, 3-pyridine formyl radical, 2-furancarbonyl, 3-furancarbonyl, 2-Thenoyl, 3-Thenoyl, 2-pyrroyl group, 3-pyrroyl group, 4-piperidine formyl base-N-Z; Alpha-Naphthyl formyl radical, betanaphthyl formyl radical; Cyclopentyl formyl radical, cyclohexyl formyl radical; Methylsulfonyl, p-toluenesulfonyl;
Wherein, Z is the C1-C10 alkyl of straight or branched; The C1-C10 alkyloyl, C5-C6 cycloalkanes acyl group, aroyl; 4-hetaroylpyrazol; The C2-C10 alkenyl, the C2-C10 alkynyl
Y is Sauerstoffatom, sulphur atom;
X can be Sauerstoffatom, nitrogen-atoms or sulphur atom
n
1, n
2Be 0 or 1
With the phenylalanine of N-BOC protection and derivative and the phenylalaninol of N-replacement and derivative and the N of phenylalaninol of phenylalanine, N '-dicyclohexylcarbodiimide is dissolved in non-protonic solvent or non-polar organic solvent in the lump.Described solvent is given an example: tetrahydrofuran (THF), methyl-sulphoxide, DMF, dioxane, toluene, methylene dichloride or trichloromethane.Holding temperature 0-100 ℃, preferred 10-70 ℃, more preferably 20-50 ℃, reaction for some time, for example reacted 3-24 hour.Obtain the derivative of the phenylalanine phenylalaninol ester of N-BOC protection-N '-replacement; slough the BOC blocking group with trifluoroacetic acid at a certain temperature; temperature of reaction is 0-100 ℃, preferred 10-70 ℃, more preferably 20-50 ℃, reaction for some time, for example reacts 3-24 hour.Gained deprotection product is under the condition take organic bases as acid binding agent; organic bases is given an example: pyridine, triethylamine, diethylamine, dimethylamine or piperidines; with suitable R5-Cl at a certain temperature temperature of reaction be 0-100 ℃, preferred 10-70 ℃, more preferably 20-50 ℃; reaction for some time; for example reacted 3-24 hour, reaction obtains formula I-V compound.
Route A
According to formula I-V compound of the present invention, in route B,
R
3Be hydrogen, the C1-C10 alkyl of straight or branched; The C5-C6 cycloalkyl;
R
4C1-C10 alkyl for hydrogen or straight or branched;
R
5Be formyl radical; Ethanoyl; Benzoyl, replaced by one or more groups on its phenyl ring, described group is selected from, methyl, methoxyl group, fluorine, chlorine, bromine, hydroxyl, acetoxyl group, benzyloxy, trifluoromethyl, cyano group, nitro, amino, acetylamino, sulfydryl, methyl mercapto, ethyl sulfydryl, methylsulfonyl, carboxyl, carboxyl methyl; 4-pyridine formyl radical, 3-pyridine formyl radical, 2-furancarbonyl, 3-furancarbonyl, 2-Thenoyl, 3-Thenoyl, 2-pyrroyl group, 3-pyrroyl group, 4-piperidine formyl base-N-Z; Alpha-Naphthyl formyl radical, betanaphthyl formyl radical; Cyclopentyl formyl radical, cyclohexyl formyl radical; Methylsulfonyl, p-toluenesulfonyl;
Wherein, Z is the C1-C10 alkyl of straight or branched; The C1-C10 alkyloyl, C5-C6 cycloalkanes acyl group, aroyl; 4-hetaroylpyrazol; The C2-C10 alkenyl, the C2-C10 alkynyl
R
6Be phenyl, replaced by one or more groups on its phenyl ring, described group is selected from, methyl, methoxyl group, fluorine, chlorine, bromine, hydroxyl, acetoxyl group, benzyloxy, trifluoromethyl, cyano group, nitro, amino, acetylamino, sulfydryl, methyl mercapto, ethyl sulfydryl, methylsulfonyl, carboxyl, carboxyl methyl; 4-pyridyl, 3-pyridyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrryl, 3-pyrryl, 4-piperidyl-N-Z; Alpha-Naphthyl, betanaphthyl; Pentamethylene base, cyclohexyl; Formyl radical; Benzoyl, replaced by one or more groups on its phenyl ring, described group is selected from, methyl, methoxyl group, fluorine, chlorine, bromine, hydroxyl, acetoxyl group, benzyloxy, trifluoromethyl, cyano group, nitro, amino, acetylamino, sulfydryl, methyl mercapto, ethyl sulfydryl, methylsulfonyl, carboxyl, carboxyl methyl; 4-pyridine formyl radical, 3-pyridine formyl radical, 2-furancarbonyl, 3-furancarbonyl, 2-Thenoyl, 3-Thenoyl, 2-pyrroyl group, 3-pyrroyl group, 4-piperidine formyl base-N-Z; Alpha-Naphthyl formyl radical, betanaphthyl formyl radical; Cyclopentyl formyl radical, cyclohexyl formyl radical; Methylsulfonyl, p-toluenesulfonyl;
Wherein, Z is the C1-C10 alkyl of straight or branched; The C1-C10 alkyloyl, C5-C6 cycloalkanes acyl group, aroyl; 4-hetaroylpyrazol; The C2-C10 alkenyl, the C2-C10 alkynyl;
Y is Sauerstoffatom, sulphur atom;
X can be Sauerstoffatom, nitrogen-atoms or sulphur atom
n
1, n
2Be 0 or 1
n
4, n
5Be 1-5.
With the phenylalanine of N-BOC protection-O-benzyl protection and derivative and the phenylalaninol of N-replacement-O-benzyl protection and derivative and the N of phenylalaninol of phenylalanine, N '-dicyclohexylcarbodiimide is dissolved in non-protonic solvent or non-polar organic solvent in the lump.Described solvent is given an example: tetrahydrofuran (THF), methyl-sulphoxide, DMF, dioxane, toluene, methylene dichloride or trichloromethane.Holding temperature 0-100 ℃, preferred 10-70 ℃, more preferably 20-50 ℃, reaction for some time, for example reacted 3-24 hour.Obtain the derivative of the phenylalanine phenylalaninol ester of N-BOC protection-N '-replacement; slough the BOC blocking group with trifluoroacetic acid at a certain temperature; temperature of reaction is 0-100 ℃, preferred 10-70 ℃, more preferably 20-50 ℃, reaction for some time, for example reacts 3-24 hour.gained deprotection product is under the condition take organic bases as acid binding agent, organic bases is given an example: pyridine, triethylamine, diethylamine, dimethylamine or piperidines, with suitable R5-Cl at a certain temperature temperature of reaction be 0-100 ℃, preferred 10-70 ℃, more preferably 20-50 ℃, reaction for some time, for example reacted 3-24 hour, obtain the product of benzyl protection, under the catalysis of palladium carbon, slough benzyl with hydrogen under normal pressure, temperature of reaction is 0-100 ℃ at a certain temperature, preferred 10-70 ℃, more preferably 20-60 ℃, reaction for some time, for example reacted 3-10 hour, reaction obtains formula I-V compound.
Route B
According to formula I-V compound of the present invention, in route C,
R
3Be hydrogen, the C1-C10 alkyl of straight or branched; The C5-C6 cycloalkyl;
R
4Be hydrogen, the C1-C10 alkyl of straight or branched; The C5-C6 cycloalkyl;
Y is Sauerstoffatom, sulphur atom;
X can be Sauerstoffatom, nitrogen-atoms or sulphur atom
n
1, n
2Be 0 or 1
n
6, n
8Be 1-8
n
7, n
9Be 1-5
With the phenylalanine of N-BOC protection and derivative and the phenylalaninol of N-(O-benzyl) acylations protection and derivative and the N of phenylalaninol of phenylalanine, N '-dicyclohexylcarbodiimide is dissolved in non-protonic solvent or non-polar organic solvent in the lump.Described solvent is given an example: tetrahydrofuran (THF), methyl-sulphoxide, DMF, dioxane, toluene, methylene dichloride or trichloromethane.Holding temperature 0-100 ℃, preferred 10-70 ℃, more preferably 20-50 ℃, reaction for some time, for example reacted 3-24 hour.Obtain the derivative of the phenylalanine phenylalaninol ester of N-BOC protection-N '-replacement; slough the BOC blocking group with trifluoroacetic acid at a certain temperature; temperature of reaction is 0-100 ℃, preferred 10-70 ℃, more preferably 20-50 ℃, reaction for some time, for example reacts 3-24 hour.Gained deprotection product is under the condition take organic bases as acid binding agent, and organic bases is given an example: pyridine, triethylamine, diethylamine, dimethylamine or piperidines, and with suitable
Temperature of reaction at a certain temperature
Be 0-100 ℃, preferred 10-70 ℃, more preferably 20-50 ℃, reaction for some time, for example reacted 3-24 hour, the product that obtains under the catalysis of palladium carbon, is sloughed benzyl with hydrogen under normal pressure, temperature of reaction is 0-100 ℃, preferred 10-70 ℃, more preferably 20-60 ℃ at a certain temperature, reaction for some time, for example to react 3-10 hour, reaction obtains formula I-V compound.
Route C
According to formula I-V compound of the present invention, in route D,
R
1Be hydrogen; Aryl; The C1-C10 alkyl of straight or branched; The C5-C6 cycloalkyl;
R
2Be hydrogen; Aryl; The C1-C10 alkyl of straight or branched; The C5-C6 cycloalkyl;
A is hydrogen; Aryl; The C1-C10 alkyl of straight or branched;
Y is Sauerstoffatom, sulphur atom;
X can be Sauerstoffatom, nitrogen-atoms or sulphur atom
n
1, n
2Be 0 or 1
With the phenylalanine of N-BOC protection and derivative and the phenylalaninol of N-BOC protection and derivative and the N of phenylalaninol of phenylalanine, N '-dicyclohexylcarbodiimide is dissolved in non-protonic solvent or non-polar organic solvent in the lump.Described solvent is given an example: tetrahydrofuran (THF), methyl-sulphoxide, DMF, dioxane, toluene, methylene dichloride or trichloromethane.Holding temperature 0-100 ℃, preferred 10-70 ℃, more preferably 20-50 ℃, reaction for some time, for example reacted 3-24 hour.Obtain N; the derivative of the phenylalanine phenylalaninol ester of N '-BOC protection is sloughed the BOC blocking group with trifluoroacetic acid at a certain temperature, and temperature of reaction is 0-100 ℃, preferred 10-70 ℃, more preferably 20-50 ℃; reaction for some time, for example reacted 3-24 hour.Gained deprotection product is under the organic bases effect, and organic bases is given an example: pyridine, triethylamine, diethylamine, dimethylamine or piperidines, and with A-N-(CH
2CH
2Cl)
2Temperature of reaction is 0-100 ℃, preferred 10-70 ℃, more preferably 20-50 ℃ at a certain temperature, reaction for some time, for example to react 3-24 hour, and reaction obtains formula I compound.
Route D
Advantage of the present invention is: in order to develop efficient antitumor drug.The contriver is to N, N '-substituted phenylpropylamino acid phenylpropylaminoalcesters esters compound has carried out broad research, a plurality of structural points are modified and transformed, the N that has synthesized a series of novel structures, N '-substituted phenylpropylamino acid phenylpropylaminoalcesters esters derivatives and process In Vitro Anti T47D and MDA-MB231 activity of tumor cells shaker test, find that this compounds has good anti-tumor activity, thereby completed the present invention.Compound according to the present invention can be used as activeconstituents for the preparation of the medicine for treating tumor thing, and following cancer particularly is as mammary cancer, lung cancer, liver cancer, leukemia etc.
The subordinate list explanation:
Table 1 is the inhibiting measurement result of the present invention to T47D and MDA-MB231 tumour cell
Embodiment:
Following embodiment will better understand compound of the present invention and their preparation, and these embodiment are intended to set forth rather than limit the scope of the invention.
Embodiment 1:(S)-N-(2-furancarbonyl)-phenylalanine-(S)-2-benzamide base-3-phenylpropyl alcohol ester (STM-YL-1)
Steps A: the preparation of (S)-N-tertiary butyl oxycarbonyl phenylalanine-(S)-2-benzamide base-3-phenylpropyl alcohol ester (1):
With 4.24g N-BOC-L-phenylalanine and 3.3g N, N '-dicyclohexylcarbodiimide is dissolved in the chloroform of 50mL, and at room temperature stirs 1 hour.Under this condition, splash into the 3.02g N-benzoyl of 50mL chloroform dilution-L-phenylalaninol.Drip and finish, room temperature continues to stir 4 days.Crude product gets white solid 5.1g, fusing point: 138-140 ℃, yield: 65% through column chromatography purifying (the oil mystery: ethyl acetate, volume ratio are 10: 1).ESI-MS m/z:525[M+Na]
+。
Step B:(S)-1-((S)-2-benzamide base-benzene propoxy-)-1-oxygen-3-phenyl the third ammonia fluoroform sulphonate (2)
0.3g (1) and 1.5mL trifluoroacetic acid are at room temperature stirred 4h jointly, remove solvent under reduced pressure, obtain white solid 0.18g, yield: 80%; Mp 149-150 ℃.ESI-MS m/z:517.2[M+1]
+。
Step C:(S)-N-(2-furancarbonyl)-phenylalanine-(S)-2-benzamide base-3-phenylpropyl alcohol ester
Gained 0.18g (2) are dissolved in the 200mL pyridine, dropwise splash into 60 μ L 2-furans Benzoyl chlorides under room temperature, drip and finish, continue reaction and spend the night.Under decompression, steam the pyridine except 2/3 volume, surplus solution pours in frozen water, separates out white precipitate, and suction filtration obtains the 0.23g white solid.Yield: 90%.
1H-NMR(CDCl
3,δppm):6.61-7.95(m,18H),6.35(s,1H),6.24(s,1H),4.81-4.83(m,1H),4.57-4.59(m,1H),4.47-4.49(m,1H),4.22-4.26(m,1H),3.29-3.35(m,2H),2.93-2.95(m,2H)。
Embodiment 2:(R)-N-(2-furancarbonyl)-phenylalanine-(S)-2-benzamide base-3-phenylpropyl alcohol ester (STM-YL-2)
Steps A: the preparation of (R)-N-tertiary butyl oxycarbonyl phenylalanine-(S)-2-benzamide base-3-phenylpropyl alcohol ester (1):
With 4.24g N-BOC-D-phenylalanine and 3.3g N, N '-dicyclohexylcarbodiimide is dissolved in the chloroform of 50mL, and at room temperature stirs 1 hour.Under this condition, splash into the 3.02g N-benzoyl of 50mL chloroform dilution-L-phenylalaninol.Drip and finish, room temperature continues to stir 4 days.Crude product gets white solid 5.1g through column chromatography purifying (the oil mystery: ethyl acetate, volume ratio are 10: 1), yield: 65%, and fusing point: 138-140 ℃.
Step B:(R)-1-((S)-2-benzamide base-benzene propoxy-)-1-oxygen-3-phenyl the third ammonia fluoroform sulphonate (2)
0.3g (1) and 1.5mL trifluoroacetic acid are at room temperature stirred 4h jointly, and solvent is divided exactly in decompression, obtains white solid 0.18g, yield: 80%; Mp 149-150 ℃.
Step C:(R)-N-(2-furancarbonyl)-phenylalanine-(S)-2-benzamide base-3-phenylpropyl alcohol ester
Gained 0.18g (2) are dissolved in the 200mL pyridine, dropwise splash into 60 μ L 2-furans Benzoyl chlorides under room temperature, drip and finish, continue reaction and spend the night.Under decompression, steam the pyridine except 2/3 volume, surplus solution pours in frozen water, separates out white precipitate, and suction filtration obtains the 0.23g white solid.Yield: 90%.
1H-NMR(CDCl
3,δ ppm):6.61-7.95(m,18H),6.35(s,1H),6.24(s,1H),4.81-4.83(m,1H),4.57-4.59(m,1H),4.47-4.49(m,1H),4.22-4.26(m,1H),3.29-3.35(m,2H),2.93-2.95(m,2H)。
Embodiment 3:(R)-N-(2-furancarbonyl)-phenylalanine-(R)-2-benzamide base-3-phenylpropyl alcohol ester (STM-YL-3)
Steps A: the preparation of (R)-N-tertiary butyl oxycarbonyl phenylalanine-(R)-2-benzamide base-3-phenylpropyl alcohol ester (1):
With 4.24g N-BOC-D-phenylalanine and 3.3g N, N '-dicyclohexylcarbodiimide is dissolved in the chloroform of 50mL, and at room temperature stirs 1 hour.Under this condition, splash into the 3.02g N-benzoyl of 50mL chloroform dilution-D-phenylalaninol.Drip and finish, room temperature continues to stir 4 days.Crude product gets white solid 5.1g through column chromatography purifying (sherwood oil: ethyl acetate, volume ratio are 10: 1), yield: 65%, and fusing point: 138-140 ℃.
Step B:(R)-1-((R)-2-benzamide base-benzene propoxy-)-1-oxygen-3-phenyl the third ammonia fluoroform sulphonate (2)
0.3g (1) and 1.5mL trifluoroacetic acid are at room temperature stirred 4h jointly, and solvent is divided exactly in decompression, obtains white solid 0.18g, yield: 80%; Mp 149-150 ℃.
Step C:(R)-N-(2-furancarbonyl)-phenylalanine-(R)-2-benzamide base-3-phenylpropyl alcohol ester
Gained 0.18g (2) are dissolved in the 200mL pyridine, dropwise splash into 60 μ L 2-furans Benzoyl chlorides under room temperature, drip and finish, continue reaction and spend the night.Under decompression, steam the pyridine except 2/3 volume, surplus solution pours in frozen water, separates out white precipitate, and suction filtration obtains the 0.23g white solid.Yield: 90%.
1H-NMR(CDCl
3,δppm):6.61-7.95(m,18H),6.35(s,1H),6.24(s,1H),4.81-4.83(m,1H),4.57-4.59(m,1H),4.47-4.49(m,1H),4.22-4.26(m,1H),3.29-3.35(m,2H),2.93-2.95(m,2H)。
Embodiment 4:(S)-N-(2-furancarbonyl)-phenylalanine-(R)-2-benzamide base-3-phenylpropyl alcohol ester (STM-YL-4)
Steps A: the preparation of (S)-N-tertiary butyl oxycarbonyl phenylalanine-(R)-2-benzamide base-3-phenylpropyl alcohol ester (1):
With 4.24g N-BOC-L-phenylalanine and 3.3g N, N '-dicyclohexylcarbodiimide is dissolved in the chloroform of 50mL, and at room temperature stirs 1 hour.Under this condition, splash into the 3.02g N-benzoyl of 50mL chloroform dilution-D-phenylalaninol.Drip and finish, room temperature continues to stir 4 days.Crude product gets white solid 5.1g through column chromatography purifying (sherwood oil: ethyl acetate, volume ratio are 10: 1), yield: 65%, and fusing point: 138-140 ℃.
Step B:(S)-1-((R)-2-benzamide base-benzene propoxy-)-1-oxygen-3-phenyl the third ammonia fluoroform sulphonate (2)
0.3g (1) and 1.5mL trifluoroacetic acid are at room temperature stirred 4h jointly, and solvent is divided exactly in decompression, obtains white solid 0.18g, yield: 80%; Mp 149-150 ℃.
Step C:(S)-N-(2-furancarbonyl)-phenylalanine-(R)-2-benzamide base-3-phenylpropyl alcohol ester
Gained 0.18g (2) are dissolved in the 200mL pyridine, dropwise splash into 60 μ L 2-furans Benzoyl chlorides under room temperature, drip and finish, continue reaction and spend the night.Under decompression, steam the pyridine except 2/3 volume, surplus solution pours in frozen water, separates out white precipitate, and suction filtration obtains the 0.23g white solid.Yield: 90%.
1H-NMR(CDCl
3,δppm):6.61-7.95(m,18H),6.35(s,1H),6.24(s,1H),4.81-4.83(m,1H),4.57-4.59(m,1H),4.47-4.49(m,1H),4.22-4.26(m,1H),3.29-3.35(m,2H),2.93-2.95(m,2H)。
The compounds process for production thereof of 5-20 is with embodiment 1-4.
Embodiment 5:(S)-N-(3-pyridine formyl radical)-phenylalanine-(S)-2-benzamide base-3-phenylpropyl alcohol ester (STM-YL-5)
1H-NMR(DMSO-d6,δppm):9.19(s,1H),9.01(s,1H),8.70(s,1H),8.32(s,1H),7.17-7.76(m,17H),4.70(m,1H),4.44(m,1H),4.07-4.18(m,2H),3.18-3.22(m,1H),3.04-3.13(m,1H),2.85(m,2H)
Embodiment 6:(R)-N-(3-pyridine formyl radical)-phenylalanine-(S)-2-benzamide base-3-phenylpropyl alcohol ester (STM-YL-6)
1H-NMR(DMSO-d6,δppm):9.19(s,1H),9.01(s,1H),8.70(s,1H),8.32(s,1H),7.17-7.76(m,17H),4.70(m,1H),4.44(m,1H),
4.07-4.18(m,2H),3.18-3.22(m,1H),3.04-3.13(m,1H),2.85(m,2H)
Embodiment 7:(R)-N-(3-pyridine formyl radical)-phenylalanine-(R)-2-benzamide base-3-phenylpropyl alcohol ester (STM-YL-7)
1H-NMR(DMSO-d6,δppm):9.19(s,1H),9.01(s,1H),8.70(s,1H),8.32(s,1H),7.17-7.76(m,17H),4.70(m,1H),4.44(m,1H),4.07-4.18(m,2H),3.18-3.22(m,1H),3.04-3.13(m,1H),2.85(m,2H)
Embodiment 8:(S)-N-(3-pyridine formyl radical)-phenylalanine-(R)-2-benzamide base-3-phenylpropyl alcohol ester (STM-YL-8)
1H-NMR(DMSO-d6,δppm):9.19(s,1H),9.01(s,1H),8.70(s,1H),8.32(s,1H),7.17-7.76(m,17H),4.70(m,1H),4.44(m,1H),4.07-4.18(m,2H),3.18-3.22(m,1H),3.04-3.13(m,1H),2.85(m,2H)
Embodiment 9:(S)-N-(4-pyridine formyl radical)-phenylalanine-(S)-2-benzamide base-3-phenylpropyl alcohol ester (STM-YL-9)
1H-NMR(DMSO-d6,δppm):9.19(s,1H),8.68(s,2H),8.32(s,1H),7.17-7.76(m,17H),4.70(m,1H),4.44(m,1H),4.07-4.18(m,2H),3.18-3.22(m,1H),3.04-3.13(m,1H),2.85(m,2H)
Embodiment 10:(R)-N-(4-pyridine formyl radical)-phenylalanine-(S)-2-benzamide base-3-phenylpropyl alcohol ester (STM-YL-10)
1H-NMR(DMSO-d6,δppm):9.19(s,1H),8.68(s,2H),8.32(s,1H),7.17-7.76(m,17H),4.70(m,1H),4.44(m,1H),4.07-4.18(m,2H),3.18-3.22(m,1H),3.04-3.13(m,1H),2.85(m,2H)
Embodiment 11:(R)-N-(4-pyridine formyl radical)-phenylalanine-(R)-2-benzamide base-3-phenylpropyl alcohol ester (STM-YL-11)
1H-NMR(DMSO-d6,δppm):9.19(s,1H),8.68(s,2H),8.32(s,1H),7.17-7.76(m,17H),4.70(m,1H),4.44(m,1H),4.07-4.18(m,2H),3.18-3.22(m,1H),3.04-3.13(m,1H),2.85(m,2H)
Embodiment 12:(S)-N-(4-pyridine formyl radical)-phenylalanine-(R)-2-benzamide base-3-phenylpropyl alcohol ester (STM-YL-12)
1H-NMR(DMSO-d6,δppm):9.19(s,1H),8.68(s,2H),8.32(s,1H),7.17-7.76(m,17H),4.70(m,1H),4.44(m,1H),4.07-4.18(m,2H),3.18-3.22(m,1H),3.04-3.13(m,1H),2.85(m,2H)
Embodiment 13:(S)-N-(2-Thenoyl)-phenylalanine-(S)-2-benzamide base-3-phenylpropyl alcohol ester (STM-YL-13)
1H-NMR(CDC1
3,δppm):7.06-7.95(m,18H),6.56(s,1H),6.43(s,1H),4.80-4.83(m,1H),4.55-4.57(m,1H),4.48-4.51(m,1H),4.22-4.26(m,1H),3.30-3.35(m,2H),2.93-2.95(m,2H)。
Embodiment 14:(R)-N-(2-Thenoyl)-phenylalanine-(S)-2-benzamide base-3-phenylpropyl alcohol ester (STM-YL-14)
1H-NMR(CDCl
3,δppm):7.06-7.95(m,18H),6.56(s,1H),6.43(s,1H),4.80-4.83(m,1H),4.55-4.57(m,1H),4.48-4.51(m,1H),4.22-4.26(m,1H),3.30-3.35(m,2H),2.93-2.95(m,2H)。
Embodiment 15:(R)-N-(2-Thenoyl)-phenylalanine-(R)-2-benzamide base-3-phenylpropyl alcohol ester (STM-YL-15)
1H-NMR(CDCl
3,δppm):7.06-7.95(m,18H),6.56(s,1H),6.43(s,1H),4.80-4.83(m,1H),4.55-4.57(m,1H),4.48-4.51(m,1H),4.22-4.26(m,1H),3.30-3.35(m,2H),2.93-2.95(m,2H)。
Embodiment 16:(S)-N-(2-Thenoyl)-phenylalanine-(R)-2-benzamide base-3-phenylpropyl alcohol ester (STM-YL-16)
1H-NMR(CDCl
3,δppm):7.06-7.95(m,18H),6.56(s,1H),6.43(s,1H),4.80-4.83(m,1H),4.55-4.57(m,1H),4.48-4.51(m,1H),4.22-4.26(m,1H),3.30-3.35(m,2H),2.93-2.95(m,2H)。
Embodiment 17:(S)-N-(1-benzyloxycarbonyl-4-piperidine formyl base)-phenylalanine-(S)-2-benzamide base-3-phenylpropyl alcohol ester (STM-YL-17)
1H-NMR(CDCl
3,δppm):7.08-7.95(m,20H),6.56(s,1H),6.43(s,1H),5.34(S,2H),4.80-4.83(m,1H),4.55-4.57(m,1H),4.48-4.51(m,1H),4.22-4.26(m,1H),3.39(t,4H),3.29-3.32(m,2H),2.93-2.95(m,2H),2.44-2.46(m,1H),1.76-1.87(m,4H)
Embodiment 18:(R)-N-(1-benzyloxycarbonyl-4-piperidine formyl base)-phenylalanine-(S)-2-benzamide base-3-phenylpropyl alcohol ester (STM-YL-18)
1H-NMR(CDCl
3,δppm):7.08-7.95(m,20H),6.56(s,1H),6.43(s,1H),5.34(S,2H),4.80-4.83(m,1H),4.55-4.57(m,1H),4.48-4.51(m,1H),4.22-4.26(m,1H),3.39(t,4H),3.29-3.32(m,2H),2.93-2.95(m,2H),2.44-2.46(m,1H),1.76-1.87(m,4H)
Embodiment 19:(R)-N-(1-benzyloxycarbonyl-4-piperidine formyl base)-phenylalanine-(R)-2-benzamide base-3-phenylpropyl alcohol ester (STM-YL-19)
1H-NMR(CDCl
3,δppm):7.08-7.95(m,20H),6.56(s,1H),6.43(s,1H),5.34(S,2H),4.80-4.83(m,1H),4.55-4.57(m,1H),4.48-4.51(m,1H),4.22-4.26(m,1H),3.39(t,4H),3.29-3.32(m,2H),2.93-2.95(m,2H),2.44-2.46(m,1H),1.76-1.87(m,4H)
Embodiment 20:(S)-N-(1-benzyloxycarbonyl-4-piperidine formyl base)-phenylalanine-(R)-2-benzamide base-3-phenylpropyl alcohol ester (STM-YL-20)
1H-NMR(CDCl
3,δppm):7.08-7.95(m,20H),6.56(s,1H),6.43(s,1H),5.34(S,2H),4.80-4.83(m,1H),4.55-4.57(m,1H),4.48-4.51(m,1H),4.22-4.26(m,1H),3.39(t,4H),3.29-3.32(m,2H),2.93-2.95(m,2H),2.44-2.46(m,1H),1.76-1.87(m,4H)
Embodiment 21:(S)-N-benzoyl tyrosine-(S)-2-benzamide base-3-phenylpropyl alcohol ester (STM-YL-21)
Steps A: the preparation of (S)-N-tertiary butyl oxycarbonyl-O-benzyl tyrosine-(S)-2-benzamide base-3-phenylpropyl alcohol ester (1):
With 5.90g N-BOC-O-benzyl-TYR and 3.3g N, N '-dicyclohexylcarbodiimide is dissolved in the chloroform of 50mL, and at room temperature stirs 1 hour.Under this condition, splash into the 3.02g N-benzoyl of 50mL chloroform dilution-L-phenylalaninol.Drip and finish, room temperature continues to stir 4 days.Crude product gets white solid 6.32g, yield: 65%, ESI-MS m/z:609.2[M+1 through column chromatography purifying (the oil mystery: ethyl acetate, volume ratio are 10: 1)]
+
Step B:(S)-1-((S)-2-benzamide base-benzene propoxy-)-3-(4-benzyloxy phenyl)-1-oxygen-2 the third ammonia fluoroform sulphonate (2)
0.3g (1) and 1.5mL trifluoroacetic acid are at room temperature stirred 4h jointly, and solvent is divided exactly in decompression, obtains white solid 0.25g, yield: 80%, ESI-MS m/z:623.2[M+1]
+
The preparation of step C:(S)-N-benzoyl-O-benzyl tyrosine-(S)-2-benzamide base-3-phenylpropyl alcohol ester (3):
Gained 0.25g (2) are dissolved in the 200mL pyridine, dropwise splash into 60 μ L Benzoyl chlorides under room temperature, drip and finish, continue reaction and spend the night.Under decompression, steam the pyridine except 2/3 volume, surplus solution pours in frozen water, separates out white precipitate, and suction filtration obtains white solid 0.23g.Yield: 92%, ESI-MS m/z:613.2[M+1]
+
The preparation of step D:(S)-N-benzoyl tyrosine-(S)-2-benzamide base-3-phenylpropyl alcohol ester (1):
0.5g (3) are dissolved in 50mL methyl alcohol, add the palladium carbon of 0.2g 10%, in 30 ℃ of reactions 1 hour, filtering palladium carbon obtained (1) 0.36g.Productive rate: 85%.
1H-NMR(CDCl
3,δppm):6.68-7.95(m,19H),6.56(s,1H),6.43(s,1H),5.61(s,1H),4.80-4.83(m,1H),4.55-4.57(m,1H),4.48-4.51(m,1H),4.22-4.26(m,1H),3.30-3.35(m,2H),2.93-2.95(m,2H)。
Embodiment 22:(R)-N-benzoyl tyrosine-(S)-2-benzamide base-3-phenylpropyl alcohol ester (STM-YL-22)
Steps A: the preparation of (R)-N-tertiary butyl oxycarbonyl-O-benzyl tyrosine-(S)-2-benzamide base-3-phenylpropyl alcohol ester (1):
With 5.90g N-BOC-O-benzyl-D-Tyrosine and 3.3g N, N '-dicyclohexylcarbodiimide is dissolved in the chloroform of 50mL, and at room temperature stirs 1 hour.Under this condition, splash into the 3.02g N-benzoyl of 50mL chloroform dilution-L-phenylalaninol.Drip and finish, room temperature continues to stir 4 days.Crude product gets white solid 6.32g, yield: 65%, ESI-MS m/z:609.2[M+1 through column chromatography purifying (the oil mystery: ethyl acetate, volume ratio are 10: 1)]
+
Step B:(R)-1-((S)-2-benzamide base-benzene propoxy-)-3-(4-benzyloxy phenyl)-1-oxygen-2 the third ammonia fluoroform sulphonate (2)
0.3g (1) and 1.5mL trifluoroacetic acid are at room temperature stirred 4h jointly, and solvent is divided exactly in decompression, obtains white solid 0.25g, yield: 80%, ESI-MS m/z:623.2[M+1]
+
The preparation of step C:(R)-N-benzoyl-O-benzyl tyrosine-(S)-2-benzamide base-3-phenylpropyl alcohol ester (3):
Gained 0.25g (2) are dissolved in the 200mL pyridine, dropwise splash into 60 μ L Benzoyl chlorides under room temperature, drip and finish, continue reaction and spend the night.Under decompression, steam the pyridine except 2/3 volume, surplus solution pours in frozen water, separates out white precipitate, and suction filtration obtains white solid 0.23g.Yield: 92%, ESI-MS m/z:613.2[M+1]
+
The preparation of step D:(R)-N-benzoyl tyrosine-(S)-2-benzamide base-3-phenylpropyl alcohol ester (1):
0.5g (3) are dissolved in 50mL methyl alcohol, add the palladium carbon of 0.2g 10%, in 30 ℃ of reactions 1 hour, filtering palladium carbon obtained (1) 0.36g.Productive rate: 85%.
1H-NMR(CDCl
3,δppm):6.68-7.95(m,19H),6.56(s,1H),6.43(s,1H),5.61(s,1H),4.80-4.83(m,1H),4.55-4.57(m,1H),4.48-4.51(m,1H),4.22-4.26(m,1H),3.30-3.35(m,2H),2.93-2.95(m,2H)。
Embodiment 23:(R)-N-benzoyl tyrosine-(R)-2-benzamide base-3-phenylpropyl alcohol ester (STM-YL-23)
Steps A: the preparation of (R)-N-tertiary butyl oxycarbonyl-O-benzyl tyrosine-(R)-2-benzamide base-3-phenylpropyl alcohol ester (1):
With 5.90g N-BOC-O-benzyl-D-Tyrosine and 3.3g N, N '-dicyclohexylcarbodiimide is dissolved in the chloroform of 50mL, and at room temperature stirs 1 hour.Under this condition, splash into the 3.02g N-benzoyl of 50mL chloroform dilution-D-phenylalaninol.Drip and finish, room temperature continues to stir 4 days.Crude product gets white solid 6.32g, yield: 65%, ESI-MS m/z:609.2[M+1 through column chromatography purifying (the oil mystery: ethyl acetate, volume ratio are 10: 1)]
+
Step B:(R)-1-((R)-2-benzamide base-benzene propoxy-)-3-(4-benzyloxy phenyl)-1-oxygen-2 the third ammonia fluoroform sulphonate (2)
0.3g (1) and 1.5mL trifluoroacetic acid are at room temperature stirred 4h jointly, and solvent is divided exactly in decompression, obtains white solid 0.25g, yield: 80%, ESI-MS m/z:623.2[M+1]
+
The preparation of step C:(R)-N-benzoyl-O-benzyl tyrosine-(R)-2-benzamide base-3-phenylpropyl alcohol ester (3):
Gained 0.25g (2) are dissolved in the 200mL pyridine, dropwise splash into 60 μ L Benzoyl chlorides under room temperature, drip and finish, continue reaction and spend the night.Under decompression, steam the pyridine except 2/3 volume, surplus solution pours in frozen water, separates out white precipitate, and suction filtration obtains white solid 0.23g.Yield: 92%, ESI-MS m/z:613.2[M+1]
+
The preparation of step D:(R)-N-benzoyl tyrosine-(R)-2-benzamide base-3-phenylpropyl alcohol ester (1):
0.5g (3) are dissolved in 50mL methyl alcohol, add the palladium carbon of 0.2g 10%, in 30 ℃ of reactions 1 hour, filtering palladium carbon obtained (1) 0.36g.Productive rate: 85%.
1H-NMR(CDCl
3,δppm):6.68-7.95(m,19H),6.56(s,1H),6.43(s,1H),5.61(s,1H),4.80-4.83(m,1H),4.55-4.57(m,1H),4.48-4.51(m,1H),4.22-4.26(m,1H),3.30-3.35(m,2H),2.93-2.95(m,2H)。
Embodiment 24:(S)-N-benzoyl tyrosine-(R)-2-benzamide base-3-phenylpropyl alcohol ester (STM-YL-24)
Steps A: the preparation of (S)-N-tertiary butyl oxycarbonyl-O-benzyl tyrosine-(R)-2-benzamide base-3-phenylpropyl alcohol ester (1):
With 5.90g N-BOC-O-benzyl-TYR and 3.3g N, N '-dicyclohexylcarbodiimide is dissolved in the chloroform of 50mL, and at room temperature stirs 1 hour.Under this condition, splash into the 3.02g N-benzoyl of 50mL chloroform dilution-D-phenylalaninol.Drip and finish, room temperature continues to stir 4 days.Crude product gets white solid 6.32g, yield: 65%, ESI-MS m/z:609.2[M+1 through column chromatography purifying (the oil mystery: ethyl acetate, volume ratio are 10: 1)]
+
Step B:(S)-1-((R)-2-benzamide base-benzene propoxy-)-3-(4-benzyloxy phenyl)-1-oxygen-2 the third ammonia fluoroform sulphonate (2)
0.3g (1) and 1.5mL trifluoroacetic acid are at room temperature stirred 4h jointly, remove solvent under reduced pressure, obtain white solid 0.25g, yield: 80%, ESI-MS m/z:623.2[M+1]
+
The preparation of step C:(S)-N-benzoyl-O-benzyl tyrosine-(R)-2-benzamide base-3-phenylpropyl alcohol ester (3):
Gained 0.25g (2) are dissolved in the 200mL pyridine, dropwise splash into 60 μ L Benzoyl chlorides under room temperature, drip and finish, continue reaction and spend the night.Under decompression, steam the pyridine except 2/3 volume, surplus solution pours in frozen water, separates out white precipitate, and suction filtration obtains white solid 0.23g.Yield: 92%, ESI-MS m/z:613.2[M+1]
+
The preparation of step D:(S)-N-benzoyl tyrosine-(R)-2-benzamide base-3-phenylpropyl alcohol ester (1):
0.5g (3) are dissolved in 50mL methyl alcohol, add the palladium carbon of 0.2g 10%, in 30 ℃ of reactions 1 hour, filtering palladium carbon obtained (1) 0.36g.Productive rate: 85%.
1H-NMR(CDCl
3,δppm):6.68-7.95(m,19H),6.56(s,1H),6.43(s,1H),5.61(s,1H),4.80-4.83(m,1H),4.55-4.57(m,1H),4.48-4.51(m,1H),4.22-4.26(m,1H),3.30-3.35(m,2H),2.93-2.95(m,2H)。
Embodiment 25:(S)-((S)-2-(4-(2-hydroxybenzoyl) amido)-3-hydrocinnamyl)-2-(4-(2-hydroxybenzoyl) amido)-3-phenylpropyl alcohol ester (STM-YL-25)
Steps A: (S)-((S)-2-(4-benzyloxy benzoylamino)-3-hydrocinnamyl)-2-tertbutyloxycarbonyl-3-phenylpropyl alcohol ester (1)
With 4.24g N-BOC-L-phenylalanine and 3.3g N, N '-dicyclohexylcarbodiimide is dissolved in the chloroform of 50mL, and at room temperature stirs 1 hour.Under this condition, splash into the 5.78g N-(4-benzyloxy benzoyl) of 50mL chloroform dilution-L-phenylalaninol.Drip and finish, room temperature continues to stir 4 days.Crude product through the column chromatography purifying (sherwood oil: ethyl acetate, volume ratio are 10: 1) white solid 6.62g, yield: 68%, ESI-MS m/z:6 09.2[M+1]
+
Step B:
(S)-1-((S)-2-(4-benzyloxy benzoylamino)-3-benzene propoxy-)-1-oxygen-3-phenyl-2 the third ammonia fluoroform sulphonate (2)
0.3g (1) and 1.5mL trifluoroacetic acid are at room temperature stirred 4h jointly, and solvent is divided exactly in decompression, obtains white solid 0.25g, yield: 80%, ESI-MS m/z:623.6[M+1]
+
Step C:(S)-((S)-2-(4-benzyloxy benzoylamino)-3-hydrocinnamyl)-2-(4-benzyloxy benzoylamino)-3-phenylpropyl alcohol ester (3)
Gained 0.25g (2) are dissolved in the 200mL pyridine, dropwise splash into 60 μ L 4-benzyloxy Benzoyl chlorides under room temperature, drip and finish, continue reaction and spend the night.Under decompression, steam the pyridine except 2/3 volume, surplus solution pours in frozen water, separates out white precipitate, and suction filtration obtains the 0.26g white solid.Yield: 90%, ESI-MS m/z:719.3[M+1]
+
Step D:(S)-((S)-2-(4-(2-hydroxybenzoyl) amido)-3-hydrocinnamyl)-2-(4-(2-hydroxybenzoyl) amido)-3-phenylpropyl alcohol ester
0.5g (3) are dissolved in 50mL methyl alcohol, add the palladium carbon of 0.2g 10%, in 30 ℃ of reactions 1 hour, filtering palladium carbon obtained (1) 0.32g.Productive rate: 85%.
1H-NMR(CDCl
3,δppm):6.91-7.78(m,18H),6.56(s,1H),6.43(s,1H),5.61(s,2H),
4.80-4.83(m,1H),4.55-4.57(m,1H),4.48-4.51(m,1H),4.22-4.26(m,1H),3.30-3.35(m,2H),2.93-2.95(m,2H)。
Embodiment 26:(R)-((S)-2-(4-(2-hydroxybenzoyl) amido)-3-hydrocinnamyl)-2-(4-(2-hydroxybenzoyl) amido)-3-phenylpropyl alcohol ester (STM-YL-26)
Steps A: (R)-((S)-2-(4-benzyloxy benzoylamino)-3-hydrocinnamyl)-2-tertbutyloxycarbonyl-3-phenylpropyl alcohol ester (1)
With 4.24g N-BOC-D-phenylalanine and 3.3g N, N '-dicyclohexylcarbodiimide is dissolved in the chloroform of 50mL, and at room temperature stirs 1 hour.Under this condition, splash into the 5.78g N-(4-benzyloxy benzoyl) of 50mL chloroform dilution-L-phenylalaninol.Drip and finish, room temperature continues to stir 4 days.Crude product through the column chromatography purifying (sherwood oil: ethyl acetate, volume ratio are 10: 1) white solid 6.62g, yield: 68%, ESI-MS m/z:609.2[M+1]
+
Step B:(R)-1-((S)-2-(4-benzyloxy benzoylamino)-3-benzene propoxy-)-1-oxygen-3-phenyl-2 the third ammonia fluoroform sulphonate (2)
0.3g (1) and 1.5mL trifluoroacetic acid are at room temperature stirred 4h jointly, remove solvent under reduced pressure, obtain white solid 0.25g, yield: 80%, ESI-MS m/z:623.6[M+1]
+
Step C:(R)-((S)-2-(4-benzyloxy benzoylamino)-3-hydrocinnamyl)-2-(4-benzyloxy benzoylamino)-3-phenylpropyl alcohol ester (3)
Gained 0.25g (2) are dissolved in the 200mL pyridine, dropwise splash into 60 μ L 4-benzyloxy Benzoyl chlorides under room temperature, drip and finish, continue reaction and spend the night.Under decompression, steam the pyridine except 2/3 volume, surplus solution pours in frozen water, separates out white precipitate, and suction filtration obtains the 0.26g white solid.Yield: 90%, ESI-MS m/z:719.3[M+1]
+
Step D:(R)-((S)-2-(4-(2-hydroxybenzoyl) amido)-3-hydrocinnamyl)-2-(4-(2-hydroxybenzoyl) amido)-3-phenylpropyl alcohol ester
0.5g (3) are dissolved in 50mL methyl alcohol, add the palladium carbon of 0.2g 10%, in 30 ℃ of reactions 1 hour, filtering palladium carbon obtained (1) 0.32g.Productive rate: 85%.
1H-NMR(CDCl
3,δppm):6.91-7.78(m,18H),6.56(s,1H),6.43(s,1H),5.61(s,2H),4.80-4.83(m,1H),4.55-4.57(m,1H),4.48-4.51(m,1H),4.22-4.26(m,1 H),3.30-3.35(m,2H),2.93-2.95(m,2H)。
Embodiment 27:(R)-((R)-2-(4-(2-hydroxybenzoyl) amido)-3-hydrocinnamyl)-2-(4-(2-hydroxybenzoyl) amido)-3-phenylpropyl alcohol ester (STM-YL-27)
Steps A: (R)-((R)-2-(4-benzyloxy benzoylamino)-3-hydrocinnamyl)-2-tertbutyloxycarbonyl-3-phenylpropyl alcohol ester (1)
With 4.24g N-BOC-D-phenylalanine and 3.3g N, N '-dicyclohexylcarbodiimide is dissolved in the chloroform of 50mL, and at room temperature stirs 1 hour.Under this condition, splash into the 5.78g N-(4-benzyloxy benzoyl) of 50mL chloroform dilution-D-phenylalaninol.Drip and finish, room temperature continues to stir 4 days.Crude product gets white solid 6.62g, yield: 68%, ESI-MS m/z:609.2[M+1 through column chromatography purifying (sherwood oil: ethyl acetate, volume ratio are 10: 1)]
+
Step B:(R)-1-((R)-2-(4-benzyloxy benzoylamino)-3-benzene propoxy-)-1-oxygen-3-phenyl-2 the third ammonia fluoroform sulphonate (2)
0.3g (1) and 1.5mL trifluoroacetic acid are at room temperature stirred 4h jointly, remove solvent under reduced pressure, obtain white solid 0.25g, yield: 80%, ESI-MS m/z:623.6[M+1]
+
Step C:(R)-((R)-2-(4-benzyloxy benzoylamino)-3-hydrocinnamyl)-2-(4-benzyloxy benzoylamino)-3-phenylpropyl alcohol ester (3)
Gained 0.25g (2) are dissolved in the 200mL pyridine, dropwise splash into 60 μ L 4-benzyloxy Benzoyl chlorides under room temperature, drip and finish, continue reaction and spend the night.Under decompression, steam the pyridine except 2/3 volume, surplus solution pours in frozen water, separates out white precipitate, and suction filtration obtains the 0.26g white solid.Yield: 90%, ESI-MS m/z:719.3[M+1]
+
Step D:(R)-((R)-2-(4-(2-hydroxybenzoyl) amido)-3-hydrocinnamyl)-2-(4-(2-hydroxybenzoyl) amido)-3-phenylpropyl alcohol ester
0.5g (3) are dissolved in 50mL methyl alcohol, add the palladium carbon of 0.2g 10%, in 30 ℃ of reactions 1 hour, filtering palladium carbon obtained (1) 0.32g.Productive rate: 85%.
1H-NMR(CDCl
3,δppm):6.91-7.78(m,18H),6.56(s,1H),6.43(s,1H),5.61(s,2H),4.80-4.83(m,1H),4.55-4.57(m,1H),4.48-4.51(m,1H),4.22-4.26(m,1H),3.30-3.35(m,2H),2.93-2.95(m,2H)。
Embodiment 28:(S)-((R)-2-(4-(2-hydroxybenzoyl) amido)-3-hydrocinnamyl)-2-(4-(2-hydroxybenzoyl) amido)-3-phenylpropyl alcohol ester (STM-YL-28)
Steps A: (S)-((R)-2-(4-benzyloxy benzoylamino)-3-hydrocinnamyl)-2-tertbutyloxycarbonyl-3-phenylpropyl alcohol ester (1)
With 4.24g N-BOC-L-phenylalanine and 3.3g N, N '-dicyclohexylcarbodiimide is dissolved in the chloroform of 50mL, and at room temperature stirs 1 hour.Under this condition, splash into the 5.78g N-(4-benzyloxy benzoyl) of 50mL chloroform dilution-D-phenylalaninol.Drip and finish, room temperature continues to stir 4 days.Crude product gets white solid 6.62g, yield: 68%, ESI-MS m/z:609.2[M+1 through column chromatography purifying (sherwood oil: ethyl acetate, volume ratio are 10: 1)]
+
Step B:(S)-1-((R)-2-(4-benzyloxy benzoylamino)-3-benzene propoxy-)-1-oxygen-3-phenyl-2 the third ammonia fluoroform sulphonate (2)
0.3g (1) and 1.5mL trifluoroacetic acid are at room temperature stirred 4h jointly, remove solvent under reduced pressure, obtain white solid 0.25g, yield: 80%, ESI-MS m/z:623.6[M+1]
+
Step C:(S)-((R)-2-(4-benzyloxy benzoylamino)-3-hydrocinnamyl)-2-(4-benzyloxy benzoylamino)-3-phenylpropyl alcohol ester (3)
Gained 0.25g (2) are dissolved in the 200mL pyridine, dropwise splash into 60 μ L 4-benzyloxy Benzoyl chlorides under room temperature, drip and finish, continue reaction and spend the night.Under decompression, steam the pyridine except 2/3 volume, surplus solution pours in frozen water, separates out white precipitate, and suction filtration obtains the 0.26g white solid.Yield: 90%, ESI-MS m/z:719.3[M+1]
+
Step D:(S)-((R)-2-(4-(2-hydroxybenzoyl) amido)-3-hydrocinnamyl)-2-(4-(2-hydroxybenzoyl) amido)-3-phenylpropyl alcohol ester
0.5g (3) are dissolved in 50mL methyl alcohol, add the palladium carbon of 0.2g 10%, in 30 ℃ of reactions 1 hour, filtering palladium carbon obtained (1) 0.32g.Productive rate: 85%.
1H-NMR(CDCl
3,δppm):6.91-7.78(m,18H),6.56(s,1H),6.43(s,1H),5.61(s,2H),4.80-4.83(m,1H),4.55-4.57(m,1H),4.48-4.51(m,1H),4.22-4.26(m,1H),3.30-3.35(m,2H),2.93-2.95(m,2H)。
The compounds process for production thereof of 29-36 is with embodiment 25-28.
Embodiment 29:(S)-((S)-2-(3-(2-hydroxybenzoyl) amido)-3-hydrocinnamyl)-2-(4-(2-hydroxybenzoyl) amido)-3-phenylpropyl alcohol ester (STM-YL-29)
1H-NMR(CDCl
3,δ ppm):6.91-7.78(m,18H),6.56(s,1H),6.43(s,1H),5.61(s,2H),4.80-4.83(m,1H),4.55-4.57(m,1H),4.48-4.51(m,1H),4.22-4.26(m,1H),3.30-3.35(m,2H),2.93-2.95(m,2H)。
Embodiment 30:(R)-((S)-2-(3-(2-hydroxybenzoyl) amido)-3-hydrocinnamyl)-2-(4-(2-hydroxybenzoyl) amido)-3-phenylpropyl alcohol ester (STM-YL-30)
1H-NMR(CDCl
3,δ ppm):6.91-7.78(m,18H),6.56(s,1H),6.43(s,1H),5.61(s,2H),4.80-4.83(m,1H),4.55-4.57(m,1H),4.48-4.51(m,1H),4.22-4.26(m,1H),3.30-3.35(m,2H),2.93-2.95(m,2H)。
Embodiment 31:(R)-((R)-2-(3-(2-hydroxybenzoyl) amido)-3-hydrocinnamyl)-2-(4-(2-hydroxybenzoyl) amido)-3-phenylpropyl alcohol ester (STM-YL-31)
1H-NMR(CDCl
3,δ ppm):6.91-7.78(m,18H),6.56(s,1H),6.43(s,1H),5.61(s,2H),4.80-4.83(m,1H),4.55-4.57(m,1H),4.48-4.51(m,1H),4.22-4.26(m,1H),3.30-3.35(m,2H),2.93-2.95(m,2H)。
Embodiment 32:(S)-((R)-2-(3-(2-hydroxybenzoyl) amido)-3-hydrocinnamyl)-2-(4-(2-hydroxybenzoyl) amido)-3-phenylpropyl alcohol ester (STM-YL-32)
1H-NMR(CDCl
3,δ ppm):6.91-7.78(m,18H),6.56(s,1H),6.43(s,1H),5.61(s,2H),4.80-4.83(m,1H),4.55-4.57(m,1H),4.48-4.51(m,1H),4.22-4.26(m,1H),3.30-3.35(m,2H),2.93-2.95(m,2H)。
Embodiment 33:(S)-((S)-2-(2-Hydroxylbenzamide base)-3-hydrocinnamyl)-2-(4-(2-hydroxybenzoyl) amido)-3-phenylpropyl alcohol ester (STM-YL-33)
1H-NMR(CDCl
3,δ ppm):6.91-7.78(m,18H),6.56(s,1H),6.43(s,1H),5.61(s,2H),4.80-4.83(m,1H),4.55-4.57(m,1H),4.48-4.51(m,1H),4.22-4.26(m,1H),3.30-3.35(m,2H),2.93-2.95(m,2H)。
Embodiment 34:(R)-((S)-2-(2-Hydroxylbenzamide base)-3-hydrocinnamyl)-2-(4-(2-hydroxybenzoyl) amido)-3-phenylpropyl alcohol ester (STM-YL-34)
1H-NMR(CDCl
3,δppm):6.91-7.78(m,18H),6.56(s,1H),6.43(s,1H),5.61(s,2H),4.80-4.83(m,1H),4.55-4.57(m,1H),4.48-4.51(m,1H),4.22-4.26(m,1H),3.30-3.35(m,2H),2.93-2.95(m,2H)。
Embodiment 35:(R)-((R)-2-(2-Hydroxylbenzamide base)-3-hydrocinnamyl)-2-(4-(2-hydroxybenzoyl) amido)-3-phenylpropyl alcohol ester (STM-YL-35)
1H-NMR(CDCl
3,δ ppm):6.91-7.78(m,18H),6.56(s,1H),6.43(s,1H),5.61(s,2H),4.80-4.83(m,1H),4.55-4.57(m,1H),4.48-4.51(m,1H),4.22-4.26(m,1H),3.30-3.35(m,2H),2.93-2.95(m,2H)。
Embodiment 36:(S)-((R)-2-(2-Hydroxylbenzamide base)-3-hydrocinnamyl)-2-(4-(2-hydroxybenzoyl) amido)-3-phenylpropyl alcohol ester (STM-YL-36)
1H-NMR(CDCl
3,δppm):6.91-7.78(m,18H),6.56(s,1H),6.43(s,1H),5.61(s,2H),4.80-4.83(m,1H),4.55-4.57(m,1H),4.48-4.51(m,1H),
4.22-4.26(m,1H),3.30-3.35(m,2H),2.93-2.95(m,2H)。
Embodiment 37:(S)-((S)-2-(4-methylpiperazine-1-yl)-3-hydrocinnamyl)-2-(4-methylpiperazine-1-yl)-3-phenylpropyl alcohol ester (STM-YL-37)
Steps A: the preparation of (S)-N-tertiary butyl oxycarbonyl phenylalanine-(S)-2-tertiary butyl oxygen base amide group-3-phenylpropyl alcohol ester (1):
With 4.24g N-BOC-L-phenylalanine and 3.3g N, N '-dicyclohexylcarbodiimide is dissolved in the chloroform of 50mL, and at room temperature stirs 1 hour.Under this condition, splash into the 4.02g N-BOC-L-phenylalaninol of 50mL chloroform dilution.Drip and finish, room temperature continues to stir 4 days.Crude product gets white solid 5.50g, yield: 69%, ESI-MS m/z:499.2[M+1 through column chromatography purifying (the oil mystery: ethyl acetate, volume ratio are 10: 1)]
+
The preparation of step B:(S)-((S)-2-amino-3-hydrocinnamyl)-2-amino-3-phenylpropyl alcohol ester fluoroform sulphonate (2):
0.3g (1) and 1.5mL trifluoroacetic acid are at room temperature stirred 4h jointly, and solvent is divided exactly in decompression, obtains white solid 0.25g, yield: 80%, ESI-MS m/z:527.1[M+1]
+
The preparation of step C:(S)-((S) 2-(4-methylpiperazine-1-yl)-3-hydrocinnamyl)-2-(4-methylpiperazine-1-yl)-3-phenylpropyl alcohol ester
1g (2) and 0.6g mustargen are dissolved in the 20mL dioxane, are adding wherein 1g sodium hydroxide and 2mL water, reacted 5 hours, steaming desolventizes, and obtains product 0.72g, productive rate: 82%.
1H-NMR(CDCl
3,δppm):7.08-7.21(m,10H),4.80-4.83(m,1H),4.55-4.57(m,1H),3.84-3.86(m,1H),3.60-3.63(m,1H),3.12-3.16(m,2H),2.73-2.77(m,2H),2.46(t,16H),2.27(s,6H)。
Embodiment 38:(R)-((S)-2-(4-methylpiperazine-1-yl)-3-hydrocinnamyl)-2-(4-methylpiperazine-1-yl)-3-phenylpropyl alcohol ester (STM-YL-38)
Steps A: the preparation of (R)-N-tertiary butyl oxycarbonyl phenylalanine-(S)-2-tertiary butyl oxygen base amide group-3-phenylpropyl alcohol ester (1):
With 4.24g N-BOC-D-phenylalanine and 3.3g N, N '-dicyclohexylcarbodiimide is dissolved in the chloroform of 50mL, and at room temperature stirs 1 hour.Under this condition, splash into the 4.02g N-BOC-L-phenylalaninol of 50mL chloroform dilution.Drip and finish, room temperature continues to stir 4 days.Crude product gets white solid 5.50g, yield: 69%, ESI-MS m/z:499.2[M+1 through column chromatography purifying (the oil mystery: ethyl acetate, volume ratio are 10: 1)]
+
The preparation of step B:(R)-((S)-2-amino-3-hydrocinnamyl)-2-amino-3-phenylpropyl alcohol ester fluoroform sulphonate (2):
0.3g (1) and 1.5mL trifluoroacetic acid are at room temperature stirred 4h jointly, and solvent is divided exactly in decompression, obtains white solid 0.25g, yield: 80%, ESI-MS m/z:527.1[M+1]
+
The preparation of step C:(R)-((S)-2-(4-methylpiperazine-1-yl)-3-hydrocinnamyl)-2-(4-methylpiperazine-1-yl)-3-phenylpropyl alcohol ester
1g (2) and 0.6g mustargen are dissolved in the 20mL dioxane, are adding wherein 1g sodium hydroxide and 2mL water, reacted 5 hours, steaming desolventizes, and obtains product 0.72g, productive rate: 82%.
1H-NMR(CDCl
3,δppm):7.08-7.21(m,10H),4.80-4.83(m,1H),4.55-4.57(m,1H),3.84-3.86(m,1H),3.60-3.63(m,1H),3.12-3.16(m,2H),2.73-2.77(m,2H),2.46(t,16H),2.27(s,6H)。
Embodiment 39:(R)-((R)-2-(4-methylpiperazine-1-yl)-3-hydrocinnamyl)-2-(4-methylpiperazine-1-yl)-3-phenylpropyl alcohol ester (STM-YL-39)
Steps A: the preparation of (R)-N-tertiary butyl oxycarbonyl phenylalanine-(R)-2-tertiary butyl oxygen base amide group-3-phenylpropyl alcohol ester (1):
With 4.24g N-BOC-D-phenylalanine and 3.3g N, N '-dicyclohexylcarbodiimide is dissolved in the chloroform of 50mL, and at room temperature stirs 1 hour.Under this condition, splash into the 4.02g N-BOC-D-phenylalaninol of 50mL chloroform dilution.Drip and finish, room temperature continues to stir 4 days.Crude product gets white solid 5.50g, yield: 69%, ESI-MS m/z:499.2[M+1 through column chromatography purifying (the oil mystery: ethyl acetate, volume ratio are 10: 1)]
+
The preparation of step B:(R)-((R)-2-amino-3-hydrocinnamyl)-2-amino-3-phenylpropyl alcohol ester fluoroform sulphonate (2):
0.3g (1) and 1.5mL trifluoroacetic acid are at room temperature stirred 4h jointly, and solvent is divided exactly in decompression, obtains white solid 0.25g, yield: 80%, ESI-MS m/z:527.1[M+1]
+
The preparation of step C:(R)-((R)-2-(4-methylpiperazine-1-yl)-3-hydrocinnamyl)-2-(4-methylpiperazine-1-yl)-3-phenylpropyl alcohol ester
1g (2) and 0.6g mustargen are dissolved in the 20mL dioxane, are adding wherein 1g sodium hydroxide and 2mL water, reacted 5 hours, steaming desolventizes, and obtains product 0.72g, productive rate: 82%.
1H-NMR(CDCl
3,δppm):7.08-7.21(m,10H),4.80-4.83(m,1H),4.55-4.57(m,1H),3.84-3.86(m,1H),3.60-3.63(m,1H),3.12-3.16(m,2H),2.73-2.77(m,2H),2.46(t,16H),2.27(s,6H)。
Embodiment 40:(S)-((R)-2-(4-methylpiperazine-1-yl)-3-hydrocinnamyl)-2-(4-methylpiperazine-1-yl)-3-phenylpropyl alcohol ester (STM-YL-40)
Steps A: the preparation of (S)-N-tertiary butyl oxycarbonyl phenylalanine-(R)-2-tertiary butyl oxygen base amide group-3-phenylpropyl alcohol ester (1):
With 4.24g N-BOC-L-phenylalanine and 3.3g N, N '-dicyclohexylcarbodiimide is dissolved in the chloroform of 50mL, and at room temperature stirs 1 hour.Under this condition, splash into the 4.02g N-BOC-D-phenylalaninol of 50mL chloroform dilution.Drip and finish, room temperature continues to stir 4 days.Crude product gets white solid 5.50g, yield: 69%, ESI-MS m/z:499.2[M+1 through column chromatography purifying (the oil mystery: ethyl acetate, volume ratio are 10: 1)]
+
The preparation of step B:(S)-((R)-2-amino-3-hydrocinnamyl)-2-amino-3-phenylpropyl alcohol ester fluoroform sulphonate (2):
0.3g (1) and 1.5mL trifluoroacetic acid are at room temperature stirred 4h jointly, and solvent is divided exactly in decompression, obtains white solid 0.25g, yield: 80%, ESI-MS m/z:527.1[M+1]
+
The preparation of step C:(S)-((R)-2-(4-methylpiperazine-1-yl)-3-hydrocinnamyl)-2-(4-methylpiperazine-1-yl)-3-phenylpropyl alcohol ester
1g (2) and 0.6g mustargen are dissolved in the 20mL dioxane, are adding wherein 1g sodium hydroxide and 2mL water, reacted 5 hours, steaming desolventizes, and obtains product 0.72g, productive rate: 82%.
1H-NMR(CDCl
3,δppm):7.08-7.21(m,10H),4.80-4.83(m,1H),4.55-4.57(m,1H),3.84-3.86(m,1H),3.60-3.63(m,1H),3.12-3.16(m,2H),2.73-2.77(m,2H),2.46(t,16H),2.27(s,6H)。
The pharmacological research of embodiment 41 products of the present invention
The anti-tumor activity test:
The cell of taking the logarithm vegetative period is inoculated in 96 orifice plates with the cell density of every 2000/mL in hole, and every hole 100 μ L are placed in 37 ℃, 5%CO2 saturated humidity incubator and hatched 24 hours, make it adherent.Then variant concentration test-compound is added in 96 orifice plates, continue to cultivate after 4 days, every hole adds MTT solution (2mg/mL) 50 μ L, hatched 4 hours for 37 ℃, sucking-off supernatant liquor, every hole add DMSO 200 μ L, and the room temperature micro oscillation is after 10 minutes, absorbance A (OD) in the every hole of measurement, MR700 type microplate reader 570nm place calculates inhibition tumor cell growth rate.
Table 1 N, the restraining effect (μ g/mL) of N '-substituted amino acid aminoalcohol ester analog derivative to T47D and MDA-MB231 tumour cell
Compound | T47D(IC 50) | MDA-MB231(IC 50) | Compound | T47D(IC 50) | MDA-MB231(IC 50) |
STM-YL-1 STM-YL-2 STM-YL-3 STM-YL-4 STM-YL-13 STM-YL-14 STM-YL-15 STM-YL-16 STM-YL-17 STM-YL-18 | >100 10.66 29.36 9.58 >100 6.39 36.67 10.25 >100 10.67 | >100 16.32 32.39 13.21 >100 9.69 40.96 12.74 >100 13.88 | STM-YL-19 STM-YL-20 STM-YL-21 STM-YL-22 STM-YL-23 STM-YL-24 STM-YL-37 STM-YL-38 STM-YL-39 STM-YL-40 | 22.67 9.36 >100 3.37 21.36 5.69 >100 0.57 13.57 3.21 | 25.79 11.79 >100 5.69 25.96 7.89 >100 1.22 15.99 5.26 |
Claims (5)
1.N N '-substituted phenylpropylamino acid phenylpropylaminoalcesters esters derivatives is characterized in that: with derivative, its raceme or optically active isomer or its pharmacy acceptable salt of following general formula (I) expression:
Wherein, R
1, R
2Be phenyl or hydroxyl-substituted base; R
3Be selected from 4-pyridine formyl radical, 3-pyridine formyl radical, 2-furancarbonyl, 3-furancarbonyl, 2-Thenoyl, 3-Thenoyl; R
4Be selected from benzoyl or hydroxyl-substituted formyl radical; R
5, R
6Be hydrogen; n
1, n
2, n
3Be 1; X is O, and Y is O.
2.N N '-substituted phenylpropylamino acid phenylpropylaminoalcesters esters derivatives is characterized in that: this derivative is selected from:
(R)-N-(2-furancarbonyl)-phenylalanine-(S)-2-benzamide base-3-phenylpropyl alcohol ester;
(R)-N-(2-furancarbonyl)-phenylalanine-(R)-2-benzamide base-3-phenylpropyl alcohol ester;
(S)-N-(2-furancarbonyl)-phenylalanine-(R)-2-benzamide base-3-phenylpropyl alcohol ester;
(R)-N-(2-Thenoyl)-phenylalanine-(S)-2-benzamide base-3-phenylpropyl alcohol ester;
(R)-N-(2-Thenoyl)-phenylalanine-(R)-2-benzamide base-3-phenylpropyl alcohol ester;
(S)-N-(2-Thenoyl)-phenylalanine-(R)-2-benzamide base-3-phenylpropyl alcohol ester;
(R)-N-(1-benzyloxycarbonyl-4-piperidine formyl base)-phenylalanine-(S)-2-benzamide base-3-phenylpropyl alcohol ester;
(R)-N-(1-benzyloxycarbonyl-4-piperidine formyl base)-phenylalanine-(R)-2-benzamide base-3-phenylpropyl alcohol ester;
(S)-N-(1-benzyloxycarbonyl-4-piperidine formyl base)-phenylalanine-(R)-2-benzamide base-3-phenylpropyl alcohol ester;
(R)-((S)-2-(4-methylpiperazine-1-yl)-3-hydrocinnamyl)-2-(4-methylpiperazine-1-yl)-3-phenylpropyl alcohol ester;
(R)-((R)-2-(4-methylpiperazine-1-yl)-3-hydrocinnamyl)-2-(4-methylpiperazine-1-yl)-2-phenylpropyl alcohol ester;
(S)-((R)-2-(4-methylpiperazine-1-yl)-3-hydrocinnamyl)-2-(4-methylpiperazine-1-yl)-3-phenylpropyl alcohol ester.
3. N according to claim 1, N '-substituted phenylpropylamino acid phenylpropylaminoalcesters esters derivatives, it is the represented (S of general formula (III), R) represented (R of configurational isomer or general formula (IV), R) represented (R, S) configurational isomer of configurational isomer or logical formula V
。
4. medicinal compositions, it comprises the described N of claim 1-3 any one, N '-substituted phenylpropylamino acid phenylpropylaminoalcesters esters derivatives, its raceme or optically active isomer, or its pharmacy acceptable salt is as effective constituent, and the tablet of making in conjunction with one or more pharmaceutically acceptable carriers or vehicle, capsule, infusion are with solution or suppository, patch, the powder formulation that can suck, suspensoid, emulsifiable paste or ointment.
5. the described N of claim 1-3 any one, N '-substituted phenylpropylamino acid phenylpropylaminoalcesters esters derivatives, its raceme or optically active isomer, or the application of its pharmacy acceptable salt in preparation treatment cancer drug.
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N.J.McCorkindale et al..Synthesis and Chemistry of N-Benzoyl-O-[N’-Benzoyl-L-Phenylalanyl]-Phenylalaninol, the Major Mycelial Metabolite of Penicillium Canadense.《Tetrahedron》.1978,第34卷2791-2795. * |
N.J.McCorkindaleetal..SynthesisandChemistryofN-Benzoyl-O-[N’-Benzoyl-L-Phenylalanyl]-Phenylalaninol the Major Mycelial Metabolite of Penicillium Canadense.《Tetrahedron》.1978 |
Pei-Lin Wu et al..Cytotoxic and Anti-HIV Principles from the Rhizomes of Begonia nantoensis.《Chem.Pharm.Bull.》.2004,第52卷(第3期),345-349. * |
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