CN107739316B - Bromotyrosine alkaloid compound and preparation method and application thereof - Google Patents

Bromotyrosine alkaloid compound and preparation method and application thereof Download PDF

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CN107739316B
CN107739316B CN201711121068.5A CN201711121068A CN107739316B CN 107739316 B CN107739316 B CN 107739316B CN 201711121068 A CN201711121068 A CN 201711121068A CN 107739316 B CN107739316 B CN 107739316B
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dibromo
methoxyphenyl
propionamide
hydroxyphenyl
aminoacetyl
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CN107739316A (en
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孟繁浩
梁经纬
李馨阳
孙琦
王明阳
何鑫
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China Medical University
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
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    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
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Abstract

The invention belongs to the technical field of medicines, and particularly relates to a bromotyrosine alkaloid compound, and a preparation method and application thereof. The invention provides a bromotyrosine alkaloid compound shown in a general formula I and a general formula II, a preparation method thereof and application in preparing antitumor drugs for the first time. The bromotyrosine alkaloid compound has good antitumor activity, simple and feasible preparation method, good yield and wide application prospect.

Description

Bromotyrosine alkaloid compound and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a bromotyrosine alkaloid compound, and a preparation method and application thereof.
Background
Malignant tumors are serious diseases threatening human health, and at present, the malignant tumors exceed cardiovascular diseases and become the first killer to cause human death. The world health organization reports that 1200 million people will die of malignant tumors in the expected 2030 year. The existing antitumor drugs have certain curative effects, but have the defects of poor selectivity, large toxic and side effects and the like, and the drug treatment is expected to be a new breakthrough. Therefore, the search for highly effective, low toxicity, broad spectrum and cheap antitumor drugs has become an important content of current tumor research.
The bromotyrosine alkaloid is a bromine-substituted nitrogen-containing organic compound separated from marine organism sponge, and has complex and various structures and wide biological activity. Although bromotyrosine or bromotyramine is structurally simple as a biological precursor, structurally very abundant metabolites can be produced by different linkages between structural units and structural modifications of side chains and aromatic rings. Itampolins A is bromotyrosine alkaloid separated from sponge of Iotrochota, is obtained by taking bromotyrosine as a synthesis unit and carrying out biosynthesis by similar combinatorial chemistry like other bromotyrosine alkaloids from Verongida, and the itampolinA and enantiomer thereof have activity of inhibiting the growth of tumor cells and the inhibition degree is concentration-dependent. However, the derivatives still can not reach the positive drug level, and meanwhile, the structure-activity relationship of the alkaloids is not reported, so that a series of brominated tyrosine alkaloid derivatives with good anti-tumor activity are synthesized by taking the derivatives as a lead structure.
Disclosure of Invention
The invention aims to provide a bromotyrosine alkaloid compound shown as a general formula I or a general formula II, and the prepared derivative shows good results in an in-vitro antitumor activity test.
The invention also aims to provide a preparation method and application of the bromotyrosine alkaloid compound shown in the general formula I or the general formula II.
In order to achieve the above object, the present invention is realized by: a bromotyrosine alkaloid compound, the chemical formula of the compound is shown as general formula I or general formula II
Figure BDA0001467351370000021
Wherein:
each R is independently H, F, Cl, Br, amino, nitro, cyano, hydroxyl, alkyl with 1-5 carbons, ether group with 1-5 carbons, fatty acylamino with 1-5 carbons, phenylacetyl amino, p-toluenesulfonyl amino, formyl, carboxyl, methoxy, acetoxy and diethylamino.
Preferably, the compound is any one of the following:
(R) -2- (2- (4- (3-acetylaminopropoxy) phenyl) acetylamino) -N- (3, 5-dibromo-4-hydroxyphenylethyl) -3- (3, 5-dibromo-4-methoxyphenyl) propionamide (I1),
(S) -2- (2- (4- (3-acetylaminopropoxy) phenyl) acetylamino) -N- (3, 5-dibromo-4-hydroxyphenylethyl) -3- (3, 5-dibromo-4-methoxyphenyl) propionamide (I2),
(R) -N- (3, 5-dibromo-4-hydroxyphenyl) -3- (3, 5-dibromo-4-methoxyphenyl) -2- [2- (4-methoxyphenyl) aminoacetyl ] propionamide (A1),
(R) -N- (3, 5-dibromo-4-hydroxyphenyl) -3- (3, 5-dibromo-4-methoxyphenyl) -2- [2- (4-ethoxyphenyl) aminoacetyl ] propionamide (A2),
(R) -N- (3, 5-dibromo-4-hydroxyphenyl) -3- (3, 5-dibromo-4-methoxyphenyl) -2- [2- (4-propoxyphenyl) aminoacetyl) ] propionamide (A3),
(R) -N- (3, 5-dibromo-4-hydroxyphenyl) -3- (3, 5-dibromo-4-methoxyphenyl) -2- [2- (4-butoxyphenyl) aminoacetyl ] propionamide (A4),
(R) -N- (3, 5-dibromo-4-hydroxyphenyl) -3- (3, 5-dibromo-4-methoxyphenyl) -2- [2- (4-sec-butoxyphenyl) aminoacetyl ] propionamide (A5),
(R) -N- (3, 5-dibromo-4-hydroxyphenyl) -3- (3, 5-dibromo-4-methoxyphenyl) -2- [2- (4-N-pentylphenyl) aminoacetyl ] propionamide (A6),
(R) -N- (3, 5-dibromo-4-hydroxyphenyl) -3- (3, 5-dibromo-4-methoxyphenyl) -2- [2- (4-N-pentylphenyl) aminoacetyl ] propionamide (A7),
(R) -N- (3, 5-dibromo-4-hydroxyphenyl) -3- (3, 5-dibromo-4-methoxyphenyl) -2- [2- (4-isopropylphenyl) aminoacetyl ] propionamide (A8),
(R) -N- (3, 5-dibromo-4-hydroxyphenyl) -3- (3, 5-dibromo-4-methoxyphenyl) -2- [2- (3-chlorophenyl) aminoacetyl ] propionamide (A9),
(R) -N- (3, 5-dibromo-4-hydroxyphenyl) -3- (3, 5-dibromo-4-methoxyphenyl) -2- [2- (2-chlorophenyl) aminoacetyl ] propionamide (A10),
(R) -N- (3, 5-dibromo-4-hydroxyphenyl) -3- (3, 5-dibromo-4-methoxyphenyl) -2- [2- (4-bromophenyl) aminoacetyl ] propionamide (A11),
(R) -N- (3, 5-dibromo-4-hydroxyphenyl) -3- (3, 5-dibromo-4-methoxyphenyl) -2- [2- (4-fluorophenyl) aminoacetyl ] propionamide (A12),
(R) -N- (3, 5-dibromo-4-hydroxyphenyl) -3- (3, 5-dibromo-4-methoxyphenyl) -2- [2- (2-fluorophenyl) aminoacetyl ] propionamide (A13),
(R) -N- (3, 5-dibromo-4-hydroxyphenyl) -3- (3, 5-dibromo-4-methoxyphenyl) -2- [2- (4-methylphenyl) aminoacetyl ] propionamide (A14),
(R) -N- (3, 5-dibromo-4-hydroxyphenyl) -3- (3, 5-dibromo-4-methoxyphenyl) -2- [2- (4- (2-methylethyl ether)) aminoacetyl ] propionamide (A15).
Preferably, the compound is a pharmaceutically acceptable salt, hydrate or solvate.
A preparation method of a bromotyrosine alkaloid compound comprises the following steps:
l-tyrosine is used as an initial raw material, a key intermediate 2- [ (tert-butoxycarbonyl) amino ] -3- (3, 5-dibromo-4-methoxyphenyl) propionic acid is generated through bromination reaction, Boc protection and methylation, then 4- (2-aminoethyl) -2, 6-dibromophenol hydrobromide obtained through tyramine hydrochloride bromination reaction is condensed with 4- (3-acetamidopropoxy) phenyl) acetic acid and deprotected to obtain (S) -2-amino-N- (3, 5-dibromo-4-hydroxyphenylethyl) -3- (3, 5-dibromo-4-methoxyphenyl) propionamide, and finally, the target compound shown in the general formula I is generated through EDCI/HOBt condensation and system reaction with triethylamine as an acid-binding agent.
The target compound shown in the general formula II is obtained by using D-tyrosine as a starting material according to the same method.
An application of bromotyrosine alkaloid compounds in preparing antineoplastic agent is disclosed.
The compounds of formula i and formula ii of the present invention can be obtained synthetically by scheme 1:
Figure BDA0001467351370000051
compared with the prior art, the invention has the following technical effects:
the invention provides the bromotyrosine alkaloid compounds shown in the general formulas I and II for the first time, and compared with itampoliniA, the bromotyrosine alkaloid compounds have better anti-tumor activity and wide medicine development prospect. In addition, the invention also provides a preparation method of the compound, and the method has the advantages of simple and feasible synthetic route, good yield, simple operation, convenient post-treatment and suitability for industrial production. .
Drawings
FIG. 1 is a synthesis scheme of the present invention.
Detailed Description
The present invention is explained in detail by the following examples, which are merely illustrative and do not limit the scope of the present invention in any way.
Examples 1
Preparation of (R) -2- ((tert-butoxycarbonyl) amino) -3- (3, 5-dibromo-4-methoxyphenyl) propionic acid
Figure BDA0001467351370000061
Liquid bromine (51.8 mmol) was slowly added to a solution of D-tyrosine (25.9 mmol) in acetic acid (30 ml) to react at 70 ℃ for 0.5 hour, the mixture was allowed to cool and stand to precipitate a solid, and after filtration, the product D-3, 5-bromotyrosine bromate was washed from the filter cake with cold ethyl acetate, with a yield of 92%.
Dissolving D-3, 5-bromotyrosine bromate in a mixed solvent of acetonitrile/water (3/1), and adding NaHCO3And Boc2And O, reacting at room temperature overnight, decompressing after the reaction, evaporating the organic solvent, cooling, standing to separate out a solid, and filtering to obtain white flaky crystals.
The white flaky crystal is dissolved in acetonitrile (50m L), and dimethyl sulfate and K are added2CO3(21.1mmol) and reacting at 50 deg.C for half an hour, filtering after the reaction is finished, and evaporating the filtrate under reduced pressureAdding NaOH and 30m L water, reacting at 70 deg.C for 1.5 hr, adjusting pH to 7 with glacial acetic acid, extracting with ethyl acetate, and anhydrous MgSO4After drying and suction filtration, ethyl acetate in the filtrate was evaporated under reduced pressure to give (R) -2- ((tert-butoxycarbonyl) amino) -3- (3, 5-dibromo-4-methoxyphenyl) propionic acid as a pale yellow oily liquid in 83.3% yield.
EXAMPLES example 2
Preparation of (R) -2-amino-N- (3, 5-dibromo-4-hydroxyphenylethyl) -3- (3, 5-dibromo-4-methoxyphenyl) propionamide
Figure BDA0001467351370000071
To a solution of tyramine hydrochloride (25.9 mmol) in glacial acetic acid (30 ml) was slowly added liquid bromine (51.8 mmol) and reacted at 70 ℃ for 0.5 hour, cooled and left to stand to precipitate a solid, after which the product 4- (2-aminoethyl) -2, 6-dibromophenol hydrobromide, which is a filter cake, was washed with cold ethyl acetate, yielding 84%.
(R) -2- ((tert-Butoxycarbonyl) amino) -3- (3, 5-dibromo-4-methoxyphenyl) propionic acid and HOBt were dissolved in dry, anhydrous DMF (3.5m L), EDCI (3.3mmol) was added at 0 ℃ and stirred for half an hour, then 4- (2-aminoethyl) -2, 6-dibromophenol hydrobromide (3.3mmol) and Et were added3N (6.7mmol) at room temperature for 2 hr, pouring into water to separate out a great amount of white solid, filtering to obtain crude product, and purifying with silica gel column (MeOH, H)2O, 0.1% TFA), yield 57%.
EXAMPLE 3
Preparation of 4- (2-aminoethyl) -2, 6-dibromophenol hydrobromide with 4- (3-acetamidopropoxy) phenyl) acetic acid.
Figure BDA0001467351370000081
Dissolving 3-bromopropylamine bromate in a mixed solvent of THF/water-3/1, adding NaHCO3 and Ac2O, reacting at room temperature for 1 hour, evaporating the organic solvent under reduced pressure after the reaction is finished, extracting the water phase with dichloromethane, drying anhydrous MgSO4, evaporating dichloromethane in the filtrate under reduced pressure after suction filtration to obtain light yellow oily liquid N- (3-bromopropyl) acetamide, wherein the yield is 87%.
Adding NaH slowly into a DMF (30m L) solution of methyl p-hydroxyphenylacetate (3.58mmol) at 0 ℃, stirring for half an hour at room temperature, adding the N- (3-bromopropyl) acetamide (3.58mmol) of the product, reacting for 2 hours at room temperature, pouring into water after the reaction is finished, extracting with ethyl acetate, drying with anhydrous MgSO4, filtering, evaporating the ethyl acetate in the filtrate under reduced pressure to obtain a pale yellow oily liquid methyl 2- (4- (3-acetamidopropoxy) phenyl) acetate with the yield of 53%.
Adding the product methyl 2- (4- (3-acetamidopropoxy) phenyl) acetate obtained in the last step into a 3.3M NaOH aqueous solution, reacting for half an hour at 60 ℃, adjusting the solution to be neutral by using 5% diluted hydrochloric acid after the reaction is finished, cooling and standing to separate out a solid, and filtering to obtain white flaky crystal (4- (3-acetamidopropoxy) phenyl) acetic acid with the yield of 64.8%.
EXAMPLE 4
The compounds shown in the general formula I and the general formula II are synthesized by the following technical scheme
The specific scheme is as follows:
(1) preparation of (R) -2- (2- (4- (3-acetylaminopropoxy) phenyl) acetylamino) -N- (3, 5-dibromo-4-hydroxyphenylethyl) -3- (3, 5-dibromo-4-methoxyphenyl) propionamide (I1)
(R) -2- ((tert-Butoxycarbonyl) amino) -3- (3, 5-dibromo-4-methoxyphenyl) propionic acid and HOBt were dissolved in dry, anhydrous DMF (3.5m L), EDCI (3.3mmol) was added at 0 ℃ and stirred for half an hour, then 4- (2-aminoethyl) -2, 6-dibromophenol hydrobromide (3.3mmol) and Et3N (6.7mmol) were added and reacted at room temperature for 2 hours, after completion of the reaction a large amount of white solid was precipitated by pouring into water and the crude product was taken off by suction and purified by silica gel column (MeOH, H2O, 0.1% TFA) in 57% yield.
Dissolving the product (R) - (1- ((3, 5-dibromo-4-hydroxyphenylethyl) amino) -3- (3, 5-dibromo-4-methoxyphenyl) -1-oxopropan-2-yl) carbamate in dichloromethane, adding TFA to react at room temperature for half an hour, pressurizing to evaporate the dichloromethane solvent after the reaction is finished, adjusting the pH of a water phase to be neutral by using sodium bicarbonate, extracting the water phase by using ethyl acetate, slowly dropwise adding concentrated hydrochloric acid after cooling, standing overnight to precipitate crystals, and filtering to obtain white needle-shaped crystals with the yield of 63%.
(4- (3-Acylaminopropoxy) phenyl) acetic acid and HOBt were dissolved in dry, anhydrous DMF (3.5m L), EDCI (3.3mmol) was added at 0 ℃ and stirred for half an hour, then (R) -2-amino-N- (3, 5-dibromo-4-hydroxyphenylethyl) -3- (3, 5-dibromo-4-methoxyphenyl) propionamide and Et were added3And reacting N (6.7mmol) at room temperature for 2 hours, pouring the obtained product into water after the reaction is finished to separate out a large amount of white solid, performing suction filtration to obtain a crude product of (R) -2- (2- (4- (3-acetamidopropoxy) phenyl) acetamido) -N- (3, 5-dibromo-4-hydroxybenzophenone) -3- (3, 5-dibromo-4-methoxyphenyl) propionamide, and recrystallizing ethyl acetate to obtain white solid powder with the yield of 52%.
1H NMR(600MHz,DMSO-d6):8.24(1H,d,J＝8.7Hz),8.09(1H,t,J＝5.6Hz),7.88(1H,t,J＝5.1Hz),7.50(2H,s),7.37(2H,s),6.95-7.02(2H,m),6.74-6.80(2H,m),4.31-4.40(1H,m),3.90(2H,t,J＝6.3Hz),3.74(3H,s),3.20-3.27(3H,m),3.12-3.20(3H,m),2.79(1H,dd,J＝4.0and 13.6Hz),2.53-2.66(3H,m),1.76-1.83(5H,m)；13C NMR(151MHz,DMSO-d6):171.1,170.6,169.5,157.4,152.2,149.4,138.0,134.2,133.8,132.8,130.2,128.5,117.2,114.5,112.2,65.5,60.7,54.1,41.6,37.0,35.9,33.7,29.3,23.0.
(2) Preparation of (S) -2- (2- (4- (3-acetylaminopropoxy) phenyl) acetylamino) -N- (3, 5-dibromo-4-hydroxyphenylethyl) -3- (3, 5-dibromo-4-methoxyphenyl) propionamide (I2).
L-tyrosine is used as a starting material, and (S) -2- (2- (4- (3-acetamidopropoxy) phenyl) acetamido) -N- (3, 5-dibromo-4-hydroxyphenyl) -3- (3, 5-dibromo-4-methoxyphenyl) propionamide is prepared by a method for synthesizing (R) -2- (2- (4- (3-acetamidopropoxy) phenyl) acetamido) -N- (3, 5-dibromo-4-hydroxyphenyl) -3- (3, 5-dibromo-4-methoxyphenyl) propionamide
1H NMR(600MHz,DMSO-d6)8.25(d,J＝8.66Hz,1H),8.10(t,J＝5.65Hz,1H),7.88(t,J＝5.18Hz,1H),7.51(s,2H),7.38(s,2H),6.96-7.02(m,J＝8.66Hz,2H),6.75-6.80(m,J＝8.66Hz,2H),4.34-4.41(m,1H),3.91(t,J＝6.31Hz,2H),3.75(s,3H),3.29-3.42(m,3H),3.13-3.21(m,3H),2.80(dd,J＝3.95,13.55Hz,1H),2.55-2.68(m,3H),1.76-1.84(m,5H)；13C NMR(151MHz,DMSO-d6)171.1,170.6,169.5,157.4,152.2,149.4,138.0,133.8,132.8,130.2,128.5,117.2,114.5,112.2,65.5,60.7,54.1,41.6,37.0,36.2,35.9,33.7,29.3,23.0.
(3) Preparation of (R) -N- (3, 5-dibromo-4-hydroxyphenyl) -3- (3, 5-dibromo-4-methoxyphenyl) -2- [2- (4-methoxyphenyl) aminoacetyl ] propionamide (A1).
Adding methyl p-hydroxyphenylacetate (1eq), an acetone solvent, potassium carbonate (1.5eq) and dimethyl sulfate (1.1eq) into a flask respectively, reacting for about 3 to 4 hours at 60 ℃, determining the reaction end point by a T L C detection method, adding a certain amount of water into the flask after the reaction is finished, extracting by ethyl acetate, adding a certain amount of sodium carbonate into a separating funnel to wash unreacted raw materials in an organic layer for multiple times, determining whether the unreacted raw materials are removed by a T L C detection method, drying the organic layer overnight by sodium sulfate, performing suction filtration, spin drying, and performing hydrolysis reaction for 5 hours in an aqueous solution prepared by NaOH (5eq) at 80 ℃ to obtain the 4-methoxyphenylacetic acid.
The above 4-methoxyphenylacetic acid was condensed with (R) -2-amino-N- (3, 5-dibromo-4-hydroxyphenylethyl) -3- (3, 5-dibromo-4-methoxyphenyl) propionamide to give a white solid in a yield of 43%.
1H NMR(600MHz,DMSO-d6)8.44(s,1H),8.19(br.s.,1H),7.45(s,2H),7.39(s,2H),7.20-7.25(m,J＝8.5Hz,2H),6.71-6.85(m,J＝8.5Hz,2H),6.28(d,J＝8.5Hz,1H),4.32-4.48(m,1H),3.75(s,3H),3.68(s,3H),3.26-3.35(m,1H),3.20(dd,J＝12.1,5.7Hz,1H),2.85(dd,J＝13.5,4.0Hz,1H),2.69-2.78(m,1H),2.60(d,J＝4.9Hz,2H)；13C NMR(151MHz,DMSO-d6)171.6,155.1,154.4,152.2,137.8,133.8,133.6,132.7,119.8,117.3,114.2,112.3,60.7,55.5,54.2,38.0,33.7.
(4) Preparation of (R) -N- (3, 5-dibromo-4-hydroxyphenyl) -3- (3, 5-dibromo-4-methoxyphenyl) -2- [2- (4-ethoxyphenyl) aminoacetyl ] propionamide (A2).
2-bromoethane is taken as a raw material and is hydrocarbonylated with methyl p-hydroxyphenylacetate and then hydrolyzed to prepare 4-ethoxyphenylacetic acid, and the 4-ethoxyphenylacetic acid is condensed with (R) -2-amino-N- (3, 5-dibromo-4-hydroxyphenylethyl) -3- (3, 5-dibromo-4-methoxyphenyl) propionamide to prepare white solid with the yield of 47 percent.
1H NMR(600MHz,DMSO-d6)8.44(s,1H),8.19(br.s.,1H),7.45(s,2H),7.39(s,2H),7.20-7.25(m,J＝8.5Hz,2H),6.71-6.85(m,J＝8.5Hz,2H),6.28(d,J＝8.5Hz,1H),4.32-4.48(m,1H),3.75(s,3H),3.68(s,3H),3.26-3.35(m,1H),3.20(dd,J＝12.1,5.7Hz,1H),2.85(dd,J＝13.5,4.0Hz,1H),2.69-2.78(m,1H),2.60(d,J＝4.9Hz,2H)；13C NMR(151MHz,DMSO-d6)171.6,155.1,154.4,152.2,137.8,133.8,133.6,132.7,119.8,117.3,114.2,112.3,60.7,55.5,54.2,38.0,33.7.
(5) (R) -N- (3, 5-dibromo-4-hydroxyphenyl) -3- (3, 5-dibromo-4-methoxyphenyl) -2- [2- (4-propoxyphenyl) aminoacetyl) ] propionamide (A3)
1-bromopropane is taken as a raw material and is hydrocarbonylated with methyl p-hydroxyphenylacetate and then hydrolyzed to prepare 4-propoxyphenylacetic acid, which is condensed with (R) -2-amino-N- (3, 5-dibromo-4-hydroxyphenylethyl) -3- (3, 5-dibromo-4-methoxyphenyl) propionamide to prepare white solid with the yield of 67 percent.
1H NMR(600MHz,DMSO-d6)8.44(s,1H),8.19(br.s.,1H),7.45(s,2H),7.39(s,2H),7.20-7.25(m,J＝8.5Hz,2H),6.71-6.85(m,J＝8.5Hz,2H),6.28(d,J＝8.5Hz,1H),4.32-4.48(m,1H),3.75(s,3H),3.68(s,3H),3.26-3.35(m,1H),3.20(dd,J＝12.1,5.7Hz,1H),2.85(dd,J＝13.5,4.0Hz,1H),2.69-2.78(m,1H),2.60(d,J＝4.9Hz,2H)；13C NMR(151MHz,DMSO-d6)171.6,155.1,154.4,152.2,137.8,133.8,133.6,132.7,119.8,117.3,114.2,112.3,60.7,55.5,54.2,38.0,33.7.
(6) (R) -N- (3, 5-dibromo-4-hydroxyphenyl) -3- (3, 5-dibromo-4-methoxyphenyl) -2- [2- (4-butoxyphenyl) aminoacetyl ] propionamide (A4).
1-bromobutane is taken as a raw material to be hydrocarbonylated with methyl p-hydroxyphenylacetate and then hydrolyzed to prepare 4-butoxyphenylacetic acid, which is condensed with (R) -2-amino-N- (3, 5-dibromo-4-hydroxyphenylethyl) -3- (3, 5-dibromo-4-methoxyphenyl) propionamide to prepare white solid with the yield of 63 percent.
1H NMR(600MHz,DMSO-d6)8.44(s,1H),8.19(br.s.,1H),7.45(s,2H),7.39(s,2H),7.20-7.25(m,J＝8.5Hz,2H),6.71-6.85(m,J＝8.5Hz,2H),6.28(d,J＝8.5Hz,1H),4.32-4.48(m,1H),3.75(s,3H),3.68(s,3H),3.26-3.35(m,1H),3.20(dd,J＝12.1,5.7Hz,1H),2.85(dd,J＝13.5,4.0Hz,1H),2.69-2.78(m,1H),2.60(d,J＝4.9Hz,2H)；13C NMR(151MHz,DMSO-d6)171.6,155.1,154.4,152.2,137.8,133.8,133.6,132.7,119.8,117.3,114.2,112.3,60.7,55.5,54.2,38.0,33.7.
(7) (R) -N- (3, 5-dibromo-4-hydroxyphenyl) -3- (3, 5-dibromo-4-methoxyphenyl) -2- [2- (4-sec-butoxyphenyl) aminoacetyl ] propionamide (A5)
Bromo-sec-butyl alkane is used as a raw material to be alkylated with methyl p-hydroxyphenylacetate and then hydrolyzed to prepare 4-sec-butoxy phenylacetic acid, and the 4-sec-butoxy phenylacetic acid is condensed with (R) -2-amino-N- (3, 5-dibromo-4-hydroxyphenylethyl) -3- (3, 5-dibromo-4-methoxyphenyl) propionamide to prepare white solid with the yield of 65 percent.
1H NMR(600MHz,DMSO-d6)8.44(s,1H),8.19(br.s.,1H),7.45(s,2H),7.39(s,2H),7.20-7.25(m,J＝8.5Hz,2H),6.71-6.85(m,J＝8.5Hz,2H),6.28(d,J＝8.5Hz,1H),4.32-4.48(m,1H),3.75(s,3H),3.68(s,3H),3.26-3.35(m,1H),3.20(dd,J＝12.1,5.7Hz,1H),2.85(dd,J＝13.5,4.0Hz,1H),2.69-2.78(m,1H),2.60(d,J＝4.9Hz,2H)；13C NMR(151MHz,DMSO-d6)171.6,155.1,154.4,152.2,137.8,133.8,133.6,132.7,119.8,117.3,114.2,112.3,60.7,55.5,54.2,38.0,33.7.
(8) (R) -N- (3, 5-dibromo-4-hydroxyphenyl) -3- (3, 5-dibromo-4-methoxyphenyl) -2- [2- (4-N-pentylphenyl) aminoacetyl ] propionamide (A6).
bromo-N-pentane is used as a raw material and is hydrocarbonylated with methyl p-hydroxyphenylacetate to be hydrolyzed to prepare 4-N-pentoxyphenylacetic acid, and the 4-N-pentoxyphenylacetic acid is condensed with (R) -2-amino-N- (3, 5-dibromo-4-hydroxyphenylethyl) -3- (3, 5-dibromo-4-methoxyphenyl) propionamide to prepare white solid with the yield of 57 percent.
1H NMR(600MHz,DMSO-d6)8.25(d,J＝8.7Hz,1H),8.09(t,J＝5.6Hz,1H),7.51(s,2H),7.35-7.41(m,2H),6.95-7.01(m,J＝8.5Hz,2H),6.72-6.78(m,J＝8.7Hz,2H),4.33-4.42(m,1H),3.89(t,J＝6.5Hz,2H),3.72-3.78(m,3H),3.30-3.38(m,2H),3.15-3.27(m,2H),2.81(dd,J＝13.6,3.9Hz,1H),2.54-2.67(m,3H),1.68(quin,J＝6.8Hz,2H),1.29-1.41(m,4H),0.89(t,J＝7.1Hz,3H)；13C NMR(151MHz,DMSO-d6)171.6,155.1,154.4,152.2,137.8,133.8,133.6,132.7,119.8,117.3,114.2,112.3,60.7,55.5,54.2,38.0,33.7.
(9) (R) -N- (3, 5-dibromo-4-hydroxyphenyl) -3- (3, 5-dibromo-4-methoxyphenyl) -2- [2- (4-N-pentylphenyl) aminoacetyl ] propionamide (A7).
3-chloropropyl morpholine is used as a raw material and is hydrocarbonylated with methyl p-hydroxyphenylacetate to be hydrolyzed to prepare 4- (3-morpholine propoxy) phenylacetic acid, and the latter is condensed with (R) -2-amino-N- (3, 5-dibromo-4-hydroxybenzene ethyl) -3- (3, 5-dibromo-4-methoxyphenyl) propionamide to prepare white solid with the yield of 48 percent.
1H NMR(600MHz,DMSO-d6)8.44(s,1H),8.19(br.s.,1H),7.45(s,2H),7.39(s,2H),7.20-7.25(m,J＝8.5Hz,2H),6.71-6.85(m,J＝8.5Hz,2H),6.28(d,J＝8.5Hz,1H),4.32-4.48(m,1H),3.75(s,3H),3.68(s,3H),3.26-3.35(m,1H),3.20(dd,J＝12.1,5.7Hz,1H),2.85(dd,J＝13.5,4.0Hz,1H),2.69-2.78(m,1H),2.60(d,J＝4.9Hz,2H)；13C NMR(151MHz,DMSO-d6)171.6,155.1,154.4,152.2,137.8,133.8,133.6,132.7,119.8,117.3,114.2,112.3,60.7,55.5,54.2,38.0,33.7.
(10) (R) -N- (3, 5-dibromo-4-hydroxyphenyl) -3- (3, 5-dibromo-4-methoxyphenyl) -2- [2- (4-isopropylphenyl) aminoacetyl ] propionamide (A8).
Bromo-isopropyl is used as a raw material to be alkylated with methyl p-hydroxyphenylacetate and then hydrolyzed to prepare 4-isopropylphenylacetic acid, and the 4-isopropylphenylacetic acid is condensed with (R) -2-amino-N- (3, 5-dibromo-4-hydroxyphenylethyl) -3- (3, 5-dibromo-4-methoxyphenyl) propionamide to prepare a white solid with the yield of 63%.
1H NMR(600MHz,DMSO-d6)8.44(s,1H),8.19(br.s.,1H),7.45(s,2H),7.39(s,2H),7.20-7.25(m,J＝8.5Hz,2H),6.71-6.85(m,J＝8.5Hz,2H),6.28(d,J＝8.5Hz,1H),4.32-4.48(m,1H),3.75(s,3H),3.68(s,3H),3.26-3.35(m,1H),3.20(dd,J＝12.1,5.7Hz,1H),2.85(dd,J＝13.5,4.0Hz,1H),2.69-2.78(m,1H),2.60(d,J＝4.9Hz,2H)；13C NMR(151MHz,DMSO-d6)171.6,155.1,154.4,152.2,137.8,133.8,133.6,132.7,119.8,117.3,114.2,112.3,60.7,55.5,54.2,38.0,33.7.
(11) (R) -N- (3, 5-dibromo-4-hydroxyphenyl) -3- (3, 5-dibromo-4-methoxyphenyl) -2- [2- (3-chlorophenyl) aminoacetyl ] propionamide (A9)
3-Chlorobenzeneacetic acid and (R) -2-amino-N- (3, 5-dibromo-4-hydroxyphenylethyl) -3- (3, 5-dibromo-4-methoxyphenyl) propionamide were condensed to give a white solid with a yield of 74%.
1H NMR(600MHz,DMSO-d6)8.40(d,J＝8.5Hz,1H),8.13(t,J＝5.6Hz,1H),7.46-7.52(m,2H),7.38(s,2H),7.23-7.27(m,2H),7.19(s,1H),6.98-7.09(m,1H),4.37-4.43(m,1H),3.75(s,3H),3.42-3.48(m,1H),3.40(s,1H),3.31-3.37(m,2H),2.81(dd,J＝13.7,4.1Hz,1H),2.55-2.68(m,3H)；13C NMR(151MHz,DMSO-d6)171.6,155.1,154.4,152.2,137.8,133.8,133.6,132.7,119.8,117.3,114.2,112.3,60.7,55.5,54.2,38.0,33.7.
(12) (R) -N- (3, 5-dibromo-4-hydroxyphenyl) -3- (3, 5-dibromo-4-methoxyphenyl) -2- [2- (2-chlorophenyl) aminoacetyl ] propionamide (A10).
2-Chlorobenzeneacetic acid and (R) -2-amino-N- (3, 5-dibromo-4-hydroxyphenylethyl) -3- (3, 5-dibromo-4-methoxyphenyl) propionamide were condensed to give a white solid with a yield of 77%.
1H NMR(600MHz,DMSO-d6)9.68(br.s.,1H),8.35(d,J＝8.7Hz,1H),8.11(t,J＝5.6Hz,1H),7.54(s,2H),7.40(s,2H),7.35(dd,J＝7.7,1.5Hz,1H),7.17-7.24(m,2H),7.11-7.15(m,1H),4.44(ddd,J＝10.5,8.8,4.0Hz,1H),3.72-3.79(m,3H),3.49-3.60(m,2H),3.31-3.41(m,2H),2.63-2.68(m,2H),2.57-2.63(m,2H)；13C NMR(151MHz,DMSO-d6)171.6,155.1,154.4,152.2,137.8,133.8,133.6,132.7,119.8,117.3,114.2,112.3,60.7,55.5,54.2,38.0,33.7.
(13) (R) -N- (3, 5-dibromo-4-hydroxyphenyl) -3- (3, 5-dibromo-4-methoxyphenyl) -2- [2- (4-bromophenyl) aminoacetyl ] propionamide (A11).
4-bromophenylacetic acid and (R) -2-amino-N- (3, 5-dibromo-4-hydroxyphenylethyl) -3- (3, 5-dibromo-4-methoxyphenyl) propionamide are condensed to prepare a white solid, and the yield is 71%.
1H NMR(600MHz,DMSO-d6)9.68(br.s.,1H),8.37(d,J＝8.7Hz,1H),8.12(t,J＝5.6Hz,1H),7.49(s,2H),7.37-7.43(m,4H),7.05(d,J＝8.3Hz,2H),4.33-4.46(m,1H),3.75(s,3H),3.42(d,J＝13.9Hz,1H),3.29-3.38(m,2H),3.19(dq,J＝12.6,6.3Hz,1H),2.81(dd,J＝13.6,4.0Hz,1H),2.55-2.68(m,3H)；13C NMR(151MHz,DMSO-d6)171.6,155.1,154.4,152.2,137.8,133.8,133.6,132.7,119.8,117.3,114.2,112.3,60.7,55.5,54.2,38.0,33.7.
(14) (R) -N- (3, 5-dibromo-4-hydroxyphenyl) -3- (3, 5-dibromo-4-methoxyphenyl) -2- [2- (4-fluorophenyl) aminoacetyl ] propionamide (A12).
4-Fluorophenylacetic acid and (R) -2-amino-N- (3, 5-dibromo-4-hydroxyphenylethyl) -3- (3, 5-dibromo-4-methoxyphenyl) propionamide were condensed to give a white solid with a yield of 75%.
1H NMR(600MHz,DMSO-d6)8.44(s,1H),8.19(br.s.,1H),7.45(s,2H),7.39(s,2H),7.20-7.25(m,J＝8.5Hz,2H),6.71-6.85(m,J＝8.5Hz,2H),6.28(d,J＝8.5Hz,1H),4.32-4.48(m,1H),3.75(s,3H),3.68(s,3H),3.26-3.35(m,1H),3.20(dd,J＝12.1,5.7Hz,1H),2.85(dd,J＝13.5,4.0Hz,1H),2.69-2.78(m,1H),2.60(d,J＝4.9Hz,2H)；13C NMR(151MHz,DMSO-d6)171.0,152.2,137.9,133.8,132.8,131.0,131.0,117.2,115.2,115.1,112.2,60.7,54.0,41.5,33.7.
(15) (R) -N- (3, 5-dibromo-4-hydroxyphenyl) -3- (3, 5-dibromo-4-methoxyphenyl) -2- [2- (2-fluorophenyl) aminoacetyl ] propionamide (A13).
2-Fluorophenylacetic acid and (R) -2-amino-N- (3, 5-dibromo-4-hydroxyphenylethyl) -3- (3, 5-dibromo-4-methoxyphenyl) propionamide were condensed to give a white solid with a yield of 69%.
1H NMR(600MHz,DMSO-d6)(s,1H),8.19(br.s.,1H),7.45(s,2H),7.39(s,2H),7.20-7.25(m,J＝8.5Hz,2H),6.71-6.85(m,J＝8.5Hz,2H),6.28(d,J＝8.5Hz,1H),4.32-4.48(m,1H),3.75(s,3H),3.68(s,3H),3.26-3.35(m,1H),3.20(dd,J＝12.1,5.7Hz,1H),2.85(dd,J＝13.5,4.0Hz,1H),2.69-2.78(m,1H),2.60(d,J＝4.9Hz,2H)；13C NMR(151MHz,DMSO-d6)171.6,155.1,154.4,152.2,137.8,133.8,133.6,132.7,119.8,117.3,114.2,112.3,60.7,55.5,54.2,38.0,33.7.
(16) (R) -N- (3, 5-dibromo-4-hydroxyphenyl) -3- (3, 5-dibromo-4-methoxyphenyl) -2- [2- (4-methylphenyl) aminoacetyl ] propionamide (A14).
4-Methylphenylacetic acid and (R) -2-amino-N- (3, 5-dibromo-4-hydroxyphenylethyl) -3- (3, 5-dibromo-4-methoxyphenyl) propionamide were condensed to give a white solid with a yield of 68%.
1H NMR(600MHz,DMSO-d6)9.64(br.s.,1H),8.27(d,J＝8.7Hz,1H),8.09(t,J＝5.6Hz,1H),7.51(s,2H),7.39(s,2H),7.00-7.04(m,J＝7.9Hz,2H),6.94-6.98(m,J＝7.9Hz,2H),4.32-4.45(m,1H),3.76(s,3H),3.39(d,J＝13.9Hz,1H),3.34(dd,J＝13.5,6.7Hz,1H),3.27(d,J＝13.9Hz,1H),3.13-3.23(m,1H),2.80(dd,J＝13.6,4.0Hz,1H),2.54-2.67(m,3H),2.19-2.25(m,3H)；13C NMR(151MHz,DMSO-d6)171.6,155.1,154.4,152.2,137.8,133.8,133.6,132.7,119.8,117.3,114.2,112.3,60.7,55.5,54.2,38.0,33.7.
(17) (R) -N- (3, 5-dibromo-4-hydroxyphenyl) -3- (3, 5-dibromo-4-methoxyphenyl) -2- [2- (4- (2-methylethyl ether)) aminoacetyl ] propionamide (A15).
1-bromo-2-methylethyl ether is used as a raw material to be alkylated with methyl p-hydroxyphenylacetate and then hydrolyzed to prepare 4- (2-methylethyl ether) oxyphenylacetic acid, which is condensed with (R) -2-amino-N- (3, 5-dibromo-4-hydroxyphenylethyl) -3- (3, 5-dibromo-4-methoxyphenyl) propionamide to prepare a white solid with the yield of 63%.
1H NMR(600MHz,DMSO-d6)8.44(s,1H),8.19(br.s.,1H),7.45(s,2H),7.39(s,2H),7.20-7.25(m,J＝8.5Hz,2H),6.71-6.85(m,J＝8.5Hz,2H),6.28(d,J＝8.5Hz,1H),4.32-4.48(m,1H),3.75(s,3H),3.68(s,3H),3.26-3.35(m,1H),3.20(dd,J＝12.1,5.7Hz,1H),2.85(dd,J＝13.5,4.0Hz,1H),2.69-2.78(m,1H),2.60(d,J＝4.9Hz,2H)；13C NMR(151MHz,DMSO-d6)171.6,155.1,154.4,152.2,137.8,133.8,133.6,132.7,119.8,117.3,114.2,112.3,60.7,55.5,54.2,38.0,33.7.
Example 5 in vitro antitumor activity test.
The screening method comprises the following steps: tetrazolium salt (MTT) reduction.
Cell lines: a549, H460
The test method comprises the steps of after the cells are cultured to a logarithmic growth phase, digesting adherent cells for about 5min by using 0.25% pancreatin digestive juice, adding 10% fetal calf serum RMPI1640 culture medium to stop digestion, blowing and beating the cells into a cell suspension, transferring the cell suspension into a15 m L centrifuge tube, carrying out 1000-transfer centrifugation for 5min (the suspended growing cells are not required to be digested, directly transferring the cell suspension into a15 m L centrifuge tube, carrying out 1000-transfer centrifugation for 5min), abandoning the supernatant, adding 10% fetal calf serum DMEM culture medium, blowing and beating the cells uniformly to prepare a single cell suspension, and adjusting the concentration of the cell suspension to 5.0 × 104Spreading the cell suspension in a 96-well plate, wherein each well is 200u L, each group is provided with 3 wells, the other 3 wells are reserved, 10% fetal bovine serum RMPI1640 culture medium 200u L is added to serve as a blank control well, after the continuous culture is carried out for 24 hours, each group of an experimental group is added with the tested drug 2u L, the control group is added with RMPI 16402 u L, the culture is carried out for 24 hours, the culture plate is taken out 4 hours before the culture is finished, each well is added with 5mg/m L MTT 20u L (keeping out of light), the continuous culture is carried out, after the culture is finished, the culture medium is sucked away, each well is added with DMSO 150u L, the culture plate is shaken evenly, the absorbance value is measured on a microplate reader at the wavelength of 570nm, the steps are repeated for 3 times, and the50The value is obtained. The activity data are shown in Table 1.
TABLE 1 list of antitumor activities
Figure BDA0001467351370000181
Figure BDA0001467351370000191
The experimental result shows that the anti-tumor activity of the brominated tyrosine alkaloid compound is superior to that of Itampolin A.

Claims (4)

1. A bromotyrosine alkaloid compound is characterized in that the compound is any one of the following compounds:
(R) -N- (3, 5-dibromo-4-hydroxyphenyl) -3- (3, 5-dibromo-4-methoxyphenyl) -2- [2- (4-methoxyphenyl) aminoacetoyl ] propionamide (a 1);
(R) -N- (3, 5-dibromo-4-hydroxyphenyl) -3- (3, 5-dibromo-4-methoxyphenyl) -2- [2- (4-ethoxyphenyl) aminoacetoyl ] propionamide (a 2);
(R) -N- (3, 5-dibromo-4-hydroxyphenyl) -3- (3, 5-dibromo-4-methoxyphenyl) -2- [2- (4-propoxyphenyl) aminoacetoyl) ] propionamide (a 3);
(R) -N- (3, 5-dibromo-4-hydroxyphenyl) -3- (3, 5-dibromo-4-methoxyphenyl) -2- [2- (4-butoxyphenyl) aminoacetoyl ] propionamide (a 4);
(R) -N- (3, 5-dibromo-4-hydroxyphenyl) -3- (3, 5-dibromo-4-methoxyphenyl) -2- [2- (4-N-pentylphenyl) aminoacetoyl ] propionamide (a 7);
(R) -N- (3, 5-dibromo-4-hydroxyphenyl) -3- (3, 5-dibromo-4-methoxyphenyl) -2- [2- (2-chlorophenyl) aminoacetyl ] propionamide (a 10);
(R) -N- (3, 5-dibromo-4-hydroxyphenyl) -3- (3, 5-dibromo-4-methoxyphenyl) -2- [2- (4-bromophenyl) aminoacetyl ] propionamide (a 11);
(R) -N- (3, 5-dibromo-4-hydroxyphenyl) -3- (3, 5-dibromo-4-methoxyphenyl) -2- [2- (4-fluorophenyl) aminoacetyl ] propanamide (a 12);
(R) -N- (3, 5-dibromo-4-hydroxyphenyl) -3- (3, 5-dibromo-4-methoxyphenyl) -2- [2- (2-fluorophenyl) aminoacetyl ] propanamide (a 13);
(R) -N- (3, 5-dibromo-4-hydroxyphenyl) -3- (3, 5-dibromo-4-methoxyphenyl) -2- [2- (4- (2-methylethyl ether)) aminoacetyl ] propionamide (A15).
2. A bromotyrosine alkaloid compound according to claim 1, characterized in that it is a pharmaceutically acceptable salt.
3. The process for preparing a bromotyrosine alkaloid compound according to claim 1, wherein the process comprises the steps of: to be provided withDTyrosine as initial material and through bromination reaction,Boc protection and methylation to generate key intermediate 2- [ (tert-butyloxycarbonyl) amino]-3- (3, 5-dibromo-4-methoxyphenyl) propionic acid, condensing 4- (2-aminoethyl) -2, 6-dibromophenol hydrobromide obtained by tyramine hydrochloride bromination reaction with 4- (3-acetamidopropoxy) phenyl) acetic acid, removing protection to obtain (R) -2-amino-N- (3, 5-dibromo-4-hydroxyphenylethyl) -3- (3, 5-dibromo-4-methoxyphenyl) propionamide, and finally carrying out EDCI/HOBt condensation and a system reaction with triethylamine as an acid binding agent to obtain the compound of claim 1.
4. The use of the bromotyrosine alkaloid compound of claim 1 in the preparation of an anti-tumor medicament.
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