CN110407848A - L-amino acid -14- (7- ether-soft stem Amethystoidin A) ester trifluoroacetic acid salt compound and preparation method thereof - Google Patents

L-amino acid -14- (7- ether-soft stem Amethystoidin A) ester trifluoroacetic acid salt compound and preparation method thereof Download PDF

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CN110407848A
CN110407848A CN201910863834.8A CN201910863834A CN110407848A CN 110407848 A CN110407848 A CN 110407848A CN 201910863834 A CN201910863834 A CN 201910863834A CN 110407848 A CN110407848 A CN 110407848A
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amethystoidin
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CN110407848B (en
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刘宏民
胡天星
可钰
王淙
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Zhengzhou University
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Abstract

The present invention relates to natural products and field of medicinal chemistry, disclose l-amino acid -14- (7- ether-soft stem Amethystoidin A) ester trifluoroacetic acid salt compound, preparation method and applications.Preparation method: using soft stem Amethystoidin A as starting material; under the premise of not destroying its activated centre; it is reacted by 7 etherification of hydroxyl groups; obtained product and N-BOC-L- amino acid occur that 14- is bit esterified to react; obtain the soft stem amethystoidin A-ester of N-BOC-L- amino acid; BOC protecting group is removed in excessive trifluoroacetic acid, obtains l-amino acid -14 (7- ether-soft stem Amethystoidin A) ester trifluoroacetate at salt.Such compound has anticancer activity and good water solubility, can be used for preparing anti-tumor drug, is applied to clinical treatment cancer of the esophagus, gastric cancer, primary carcinoma of liver, cancer of pancreas, breast cancer and acute myeloid leukemia etc..It is with following general formula:

Description

L-amino acid -14- (7- ether-soft stem Amethystoidin A) ester trifluoroacetic acid salt chemical combination Object and preparation method thereof
Technical field
The present invention relates to natural products and field of medicinal chemistry, and in particular to novel soft stem Amethystoidin A class compound: L-amino acid -14- (7- ether-soft stem Amethystoidin A) ester trifluoroacetic acid salt compound and preparation method thereof and its application.
Background technique
Rabdosia rubescens is Labiatae Rabdosia plant, most excavated and goes out from Linxian, henan Province traditional herbal medicine earlier than 1972. The plant medicinal part is stem and leaf, contains single note, sequiterpene, diterpene, triterpene, volatile oil, alkaloid, amino acid, polysaccharide, Huang The chemical components such as ketone and steroidal.Ent-kaurenoids class compound is to the cancer of the esophagus, cardia cancer lung cancer, cream in Rabdosia rubescens Gland cancer, prostate cancer, primary carcinoma of liver etc. have good therapeutic effect.
Inventor is extracted from the Rabdosia rubescens of Jiyuan pure on the basis of literature survey and summary previous work by serial of methods Change and obtains the lead compound of the present invention that skeleton is Ent-kaurenoids: soft stem Amethystoidin A (Flexicaulin A, FA).External activity is studies have shown that guide's chemical combination has good bioactivity and wider Antitumor test.
α-subunit cyclopentanone structure has been confirmed as such diterpene compound anti-tumor activity center, such chemical combination Object has superior pharmacological activity, but its poor water solubility and stability constrain its application and development clinically. In addition, derivative synthesis and structure activity study in relation to soft stem Amethystoidin A are also comparatively weak.Therefore, the research winter is soft The derivative synthesis of stem Amethystoidin A and modifying for chemical structure simultaneously study its structure-activity relationship, to further therefrom find chemistry Property is more superior, and the higher new chemical entities of anti-tumor activity have important theoretical significance and practical application value.
Summary of the invention
It is an object of that present invention to provide a series of soft stem Amethystoidin A derivatives and its pharmaceutically acceptable salt, and improve Its antitumor action, dissolubility and stability provide possibility for its application clinically.
Another object of the present invention is to provide preparation method and its in the application for preparing anti-tumor drug.
Soft stem Amethystoidin A and N-Boc-L- amino-acid ester are melted into salt system by purpose to realize the present invention, the present invention Column derivative improves its dissolubility and stability, while retaining or enhancing its anti-tumor activity.
The structure of l-amino acid -14- (7- ether-soft stem Amethystoidin A) ester trifluoroacetic acid salt compound provided by the invention is logical Formula is as follows:
Wherein R1For C1-C5 alkyl, 4- cyanogen-benzyl；
Wherein R is the alkyl-substituted amino of C1-C10, and alkyl chain is connected with the carbonyl in general formula I；5-10 circle heterocyclic ring virtue containing N Base, the 5-10 membered heterocycloalkyl containing N or R areWherein R ' is hydrogen, C1-C3 alkyl, R2For the C1- of linear chain or branched chain C10 alkyl；The sulfenyl replaced by C1-C10 linear or branched alkyl group, and alkyl chain is connected with amino；The C1-C10 that amino replaces The C1-C3 alkyl that alkyl, phenyl or phenyl replace.
It is preferred that: R1For propargyl, methyl, 4- cyanogen-benzyl；R is the alkyl-substituted amino of C1-C5, and in alkyl chain and general formula Carbonyl is connected；5,6 membered heterocycloalkyls or R containing N areWherein R ' is hydrogen, methyl；R2For the C1-C5 of linear chain or branched chain Alkyl；The sulfenyl replaced by C1-C5 straight chained alkyl, and alkyl chain is connected with amino；Amino replace C1-C5 alkyl, phenyl or The C1-C3 alkyl that phenyl replaces.
It is more preferable: R1For methyl, 4- cyanogen-benzyl, propargyl；R is the alkyl-substituted amino of C1-C5, and in alkyl chain and general formula Carbonyl be connected；5,6 membered heterocycloalkyls or R containing N areWherein R ' is hydrogen, methyl；R2For one of following group:
For preparation needs, the present invention also needs further to protect the pharmaceutical salt of above compound, and acceptable salt is Acylate, inorganic acid salt, organic alkali salt or inorganic base salts, wherein organic acid include acetic acid, methanesulfonic acid, citric acid, fumaric acid, Maleic acid, glycolic, lactic acid, salicylic acid, succinic acid, p-methyl benzenesulfonic acid, tartaric acid, methanesulfonic acid, malonic acid, lipoic acid；It is inorganic Acid includes hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid；Organic base includes meglumine, Glucosamine；Inorganic base includes alkali gold Belong to the alkali compounds of sodium, potassium, barium, calcium, magnesium, zinc.
L-amino acid -14- (7- ether-soft stem Amethystoidin A) ester trifluoroacetic acid salt compound of the present invention passes through Following synthetic route obtains:
A, soft stem Amethystoidin A (1) is raw material, and DMF (n,N-Dimethylformamide) is solvent, is made under agitation It is all dissolved, and iodomethane or iodoethane, propargyl bromide, to itrile group cylite are added under conditions of sodium hydride is as catalyst Deng column chromatography purifies to obtain intermediate 2；
B, intermediate 2 obtained by a is dissolved in methylene chloride, with DCC (dicyclohexylcarbodiimide and DMAP (4- diformazan Aminopyridine) as catalyst and N-BOC-L amino acid generation esterification, column chromatography purifies to obtain intermediate product 3；
C, intermediate product 3 obtained by b is dissolved in methylene chloride, excessive trifluoroacetic acid, which is added, makes it take off BOC protection Base and at salt, makes its precipitation obtain product 4 (general formula I) for isopropyl ether is added after system concentrated by rotary evaporation.
Wherein R1For C1-C5 alkyl, 4- cyanogen-benzyl；
Wherein R is the alkyl-substituted amino of C1-C10, and alkyl chain is connected with the carbonyl in general formula I；5-10 circle heterocyclic ring virtue containing N Base, the 5-10 membered heterocycloalkyl containing N or R areWherein R ' is hydrogen, C1-C3 alkyl, R2For the C1- of linear chain or branched chain C10 alkyl；The sulfenyl replaced by C1-C10 linear or branched alkyl group, and alkyl chain is connected with amino；The C1-C10 that amino replaces The C1-C3 alkyl that alkyl, phenyl or phenyl replace.
It is preferred that: R1For propargyl, methyl, 4- cyanogen-benzyl；R is the alkyl-substituted amino of C1-C5, and in alkyl chain and general formula Carbonyl is connected；5,6 membered heterocycloalkyls or R containing N areWherein R ' is hydrogen, methyl；R2For the C1-C5 of linear chain or branched chain Alkyl；The sulfenyl replaced by C1-C5 straight chained alkyl, and alkyl chain is connected with amino；Amino replace C1-C5 alkyl, phenyl or The C1-C3 alkyl that phenyl replaces.
It is more preferable: R1For methyl, 4- cyanogen-benzyl, propargyl；R is the alkyl-substituted amino of C1-C5, and in alkyl chain and general formula Carbonyl be connected；5,6 membered heterocycloalkyls or R containing N areWherein R ' is hydrogen, methyl；R2For one of following group:
Innovative point of the present invention and advantage: using soft stem Amethystoidin A as starting material, before not destroying its activated centre It puts, is reacted by 7 etherification of hydroxyl groups, occur that 14- is bit esterified to react with N-BOC-L- amino acid, obtain N-BOC-L- amino acid Soft stem amethystoidin A-ester removes BOC protecting group, obtains object at salt.Such compound has anticancer activity and good Water solubility can be used for preparing anti-tumor drug, be applied to clinical treatment cancer of the esophagus, gastric cancer, primary carcinoma of liver, cancer of pancreas, mammary gland Cancer and acute myeloid leukemia etc. have good development prospect.
Specific embodiment
The present invention is further illustrated by example in detail below, but should be noted that the scope of the present invention does not receive these Any restrictions of embodiment.
Embodiment 1:
(1)R1When for methyl, the preparation of midbody compound 2
Work as R1When for methyl, under condition of ice bath, 2g (5.1mmol) soft stem Rabdosia amethystoides is added in 122mg (5.1mmol) sodium hydride In the DMF solution of A prime, after stirring 10min, 476 μ L (7.7mmol) iodomethane are slowly added dropwise, ice bath is kept to react 4h, are added The dilution of 30mL ethyl acetate, is respectively washed three times with saturated sodium bicarbonate and saturated salt solution, and twice by combining water layer back extraction, is merged Ester layer, anhydrous sodium sulfate is dry, and concentration rear pillar chromatogram purification obtains white solid 1.1g, yield 53%.1H NMR(400MHz, DMSO-d6) δ 5.73 (s, 1H), 5.25 (s, 1H), 5.06 (s, 1H), 4.67 (d, J=12.5Hz, 1H), 4.48 (s, 1H), 4.26 (d, J=1.9Hz, 1H), 4.09 (d, J=12.5Hz, 1H), 3.97-3.94 (m, 1H), 3.87 (dd, J=12.1, 4.4Hz, 1H), 3.30 (s, 3H), 2.83 (d, J=3.6Hz, 1H), 2.29 (dt, J=14.0,4.0Hz, 1H), 2.13-2.07 (m, 1H), 2.05 (s, 3H), 1.99-1.93 (m, 1H), 1.80 (dd, J=14.1,3.7Hz, 1H), 1.49 (d, J=12.6Hz, 1H), 1.46-1.38 (m, 4H), 1.20-1.17 (m, 1H), 1.05 (d, J=12.6Hz, 1H), 0.97 (s, 3H), 0.87 (s, 4H).13C NMR(101MHz,DMSO-d6)δ205.78,170.72,149.60,114.15,84.74,75.75,65.19, 63.26,62.68,59.14,58.35,52.82,45.09,41.37,41.15,38.01,34.02,33.92,33.21, 23.59,22.57,21.26,18.22.HR-MS(ESI):Calculated for C23H35O7[M+H]+:407.2434,found 407.2441。
(2) preparation of compound I-1
100mg (0.25mmol) intermediate 2 is dissolved in methylene chloride (DCM), 65mg (0.37mmol) N-BOC-L- is added Glycine, catalyst DCC 52mg (0.25mmol), DMAP 3mg (0.025mmol), TLC plate detection reaction to raw material disappear, Methylene chloride 30mL diluting reaction system is added, and three times with saturated ammonium chloride solution washing reaction system, combining water layer is simultaneously anti- Extraction is primary, merges organic phase, and anhydrous sodium sulfate is dry, and concentration, column chromatography purifies to obtain white solid, this white solid is dissolved in In methylene chloride, excessive trifluoroacetic acid is added under condition of ice bath, ice bath is kept to react 30min, the detection reaction of TLC plate is completed Afterwards, concentrated by rotary evaporation removes methylene chloride and trifluoroacetic acid, is then stirred for lower addition isopropyl ether, and white solid is precipitated, and filters simultaneously Filter cake, which is rinsed, with isopropyl ether obtains white solid product I-1.1H NMR(400MHz,DMSO-d6)δ8.29(s,3H),5.95(s, 1H), 5.41 (s, 1H), 5.28 (d, J=4.7Hz, 1H), 5.11 (s, 1H), 4.78 (d, J=12.6Hz, 1H), 4.58-4.55 (m, 1H), 4.14-4.08 (m, 1H), 3.90 (dd, J=12.1,4.4Hz, 1H), 3.44 (d, J=3.7Hz, 2H), 3.31 (s, 3H), 2.96 (s, 1H), 2.09 (s, 3H), 1.96 (d, J=13.0Hz, 2H), 1.87-1.80 (m, 1H), 1.49 (d, J= 8.0Hz, 3H), 1.45 (d, J=3.2Hz, 2H), 1.30-1.25 (m, 1H), 1.14-1.07 (m, 2H), 1.03 (d, J= 6.1Hz,1H),0.96(s,3H),0.89(s,3H).13C NMR(101MHz,DMSO-d6)δ205.95,170.52,166.25, 148.62,116.81,84.20,74.93,69.49,62.26,60.72,59.14,58.41,52.26,44.25,41.94, 40.94,35.45,33.96,33.79,33.71,33.26,23.39,22.60,21.21,18.06.HR-MS(ESI): Calculated for C25H38NO7[M+H]+:464.2648,found 464.2647.Yield 82%.
Embodiment 2:
With 70mg (0.37mmol) N-BOC-L- sarcosine, instead of N-BOC-L- glycine, other are operated with embodiment 1, Obtain white solid product I-2.1H NMR(400MHz,DMSO-d6)δ8.94(s,2H),5.95(s,1H),5.42(s,1H),5.30 (d, J=4.9Hz, 1H), 4.77 (d, J=12.7Hz, 1H), 4.56 (s, 1H), 4.11 (d, J=12.5Hz, 1H), 3.90 (dd, J=12.2,4.5Hz, 1H), 3.62 (s, 2H), 3.31 (s, 3H), 2.97 (t, J=3.8Hz, 1H), 2.56 (s, 4H), 2.11 (s, 1H), 2.09 (s, 3H), 1.99-1.93 (m, 1H), 1.84 (dd, J=15.1,4.2Hz, 1H), 1.74-1.57 (m, 1H), 1.49 (t, J=6.5Hz, 3H), 1.45-1.36 (m, 3H), 1.17 (dd, J=14.2,5.1Hz, 1H), 1.09 (d, J= 11.9Hz,1H),0.96(s,3H),0.88(s,3H).13C NMR(101MHz,DMSO-d6)δ205.93,170.54,165.48, 148.54,116.98,84.18,74.91,69.62,62.25,60.67,59.11,58.41,52.28,48.65,44.21, 41.95,40.93,35.45,33.97,33.73,33.26,32.97,23.36,22.60,21.23,18.05.HR-MS(ESI): Calculated for C26H40NO7[M+H]+:478.2805,found 478.2805.Yield 85%.
Embodiment 3:
With 70mg (0.37mmol) N-BOC-L- alanine, instead of N-BOC-L- glycine, other are operated with embodiment 1, Obtain white solid product I-3.1H NMR(400MHz,DMSO-d6)δ8.35(s,3H),5.94(s,1H),5.43(s,1H),5.28 (d, J=4.7Hz, 1H), 5.11 (s, 1H), 4.79 (d, J=12.7Hz, 1H), 4.59 (s, 1H), 4.11 (d, J=12.6Hz, 1H), 3.90 (dd, J=12.0,4.5Hz, 1H), 3.75 (d, J=7.3Hz, 1H), 3.30 (s, 3H), 2.98 (d, J=4.2Hz, 1H), 2.59-2.52 (m, 1H), 2.08 (s, 4H), 1.82 (dd, J=15.6,3.7Hz, 1H), 1.74-1.57 (m, 1H), 1.49-1.43 (m, 2H), 1.38 (s, 2H), 1.23 (d, J=7.1Hz, 4H), 1.12 (d, J=12.5Hz, 2H), 0.97 (s, 3H),0.89(s,4H).13C NMR(101MHz,DMSO-d6)δ206.00,170.54,168.55,148.67,116.79, 84.14,74.92,69.58,62.27,61.34,59.22,58.39,52.18,48.35,44.25,42.10,40.88, 35.36,34.03,33.92,33.30,23.35,22.68,21.21,18.10,14.77.HR-MS(ESI):Calculated for C26H40NO7[M+H]+:478.2805,found 478.2802.Yield 77%.
Embodiment 4:
With 75mg (0.37mmol) N-BOC- methyl-L-alanine, instead of N-BOC-L- glycine, other operations are the same as implementation Example 1 obtains white solid product I-4.1H NMR(400MHz,DMSO-d6)δ9.07(s,2H),5.95(s,1H),5.44(s,1H), 5.30 (d, J=4.7Hz, 1H), 5.11 (s, 1H), 4.79 (d, J=12.7Hz, 1H), 4.59 (s, 1H), 4.12 (d, J= 12.6Hz, 1H), 3.90 (dd, J=12.0,4.3Hz, 1H), 3.78 (d, J=7.4Hz, 1H), 3.30 (s, 3H), 2.99 (s, 1H), 2.54 (s, 3H), 2.09 (s, 3H), 1.85 (dd, J=15.4,3.6Hz, 1H), 1.76-1.67 (m, 1H), 1.61 (dt, J =12.9,3.9Hz, 1H), 1.49-1.44 (m, 2H), 1.39 (s, 3H), 1.26 (d, J=7.1Hz, 4H), 1.18-1.12 (m, 2H), 1.03 (d, J=6.1Hz, 1H), 0.97 (s, 3H), 0.89 (s, 3H)13C NMR(101MHz,DMSO-d6)δ206.10, 170.55,168.01,148.65,116.90,84.11,74.91,69.92,62.26,61.24,59.23,58.39,55.52, 52.07,44.24,42.13,40.86,35.31,33.92,33.80,33.31,31.02,23.34,22.70,21.24, 18.10,13.07.HR-MS(ESI):Calculated for C27H42NO7[M+H]+:492.2961,found 492.2961。
Yield 78%.
Embodiment 5:
With 75mg (0.37mmol) N-BOC-L- aminobutyric acid, instead of N-BOC-L- glycine, other operate same embodiment 1, obtain white solid product I-5.1H NMR(400MHz,DMSO-d6)δ8.40(s,3H),5.95(s,1H),5.43(s,1H), 5.30 (d, J=4.6Hz, 1H), 5.12 (s, 1H), 4.79 (d, J=12.7Hz, 1H), 4.59 (s, 1H), 4.12 (d, J= 12.6Hz, 1H), 3.90 (dd, J=12.1,4.4Hz, 1H), 3.65 (d, J=5.7Hz, 1H), 3.31 (s, 3H), 2.98 (s, 1H), 2.50 (t, J=1.9Hz, 2H), 2.11 (d, J=3.3Hz, 1H), 2.08 (s, 3H), 1.87-1.80 (m, 1H), 1.75- 1.68 (m, 2H), 1.46 (d, J=10.6Hz, 2H), 1.39 (d, J=19.3Hz, 3H), 1.11 (d, J=12.8Hz, 1H), 1.03 (d, J=6.1Hz, 1H), 0.97 (s, 3H), 0.89 (s, 3H), 0.85 (d, J=7.5Hz, 4H)13C NMR(101MHz, DMSO-d6)δ205.90,170.50,168.14,148.56,116.92,84.10,74.92,69.58,62.26,61.24, 59.19,58.37,53.47,52.25,44.19,42.07,40.86,35.51,34.25,33.88,33.79,33.30, 23.34,22.72,21.20,18.10,9.45.HR-MS(ESI):Calculated for C27H42NO7[M+H]+: 492.2961,found492.2962.Yield 89%.
Embodiment 6:
With 80mg (0.37mmol) (S) -2- (tert-butoxycarbonyl-amino) -3 Methylbutanoic acid, instead of the sweet ammonia of N-BOC-L- Acid, other operations obtain white solid product I-6 with embodiment 1.1H NMR(400MHz,DMSO-d6)δ8.35(s,3H),5.95 (d, J=13.1Hz, 1H), 5.43 (d, J=8.3Hz, 1H), 5.34 (d, J=4.9Hz, 1H), 5.11 (d, J=14.6Hz, 1H), 4.80 (d, J=12.7Hz, 1H), 4.57 (d, J=7.8Hz, 1H), 4.12 (d, J=12.5Hz, 1H), 3.91 (dd, J= 12.2,4.5Hz, 1H), 3.51 (d, J=4.0Hz, 1H), 3.31 (s, 3H), 2.97 (s, 1H), 2.09 (d, J=5.9Hz, 4H), 2.06-2.00 (m, 2H), 1.84 (dd, J=15.1,4.1Hz, 1H), 1.50 (d, J=16.1Hz, 2H), 1.47-1.38 (m, 3H), 1.23-1.14 (m, 1H), 1.10 (dd, J=12.8,5.9Hz, 1H), 1.03 (d, J=6.0Hz, 2H), 0.97 (s, 3H), 0.89 (s, 4H), 0.86 (d, J=6.9Hz, 3H), 0.83 (d, J=7.0Hz, 1H), 0.74 (dd, J=13.1,4.0Hz, 1H) .13C NMR(101MHz,DMSO-d6)δ205.66,170.46,167.73,148.42,117.14,84.10,74.94,69.57, 67.77,62.28,60.85,59.14,58.39,57.95,52.28,44.14,42.05,40.85,35.67,34.33, 33.88,33.31,29.19,23.26,22.76,21.20,18.36,18.21.HR-MS(ESI):Calculated for C28H44NO7[M+H]+:506.3118,found 506.3117.Yield 86%.
Embodiment 7:
With 85mg (0.37mmol) N-BOC- methyl-L-Valine, instead of N-BOC-L- glycine, other operations are the same as implementation Example 1 obtains white solid product I-7.1H NMR(400MHz,DMSO-d6)δ9.13(s,2H),5.97(s,1H),5.44(s,1H), 5.34 (d, J=4.8Hz, 1H), 4.80 (d, J=12.7Hz, 1H), 4.59-4.57 (m, 1H), 4.12 (d, J=12.6Hz, 1H), 3.92 (dd, J=12.1,4.3Hz, 1H), 3.61 (dd, J=12.5,6.4Hz, 1H), 3.53-3.50 (m, 1H), 3.31 (s, 3H), 2.97 (d, J=3.5Hz, 1H), 2.59 (s, 1H), 2.54 (s, 1H), 2.09 (d, J=4.0Hz, 5H), 2.05- 2.00 (m, 1H), 1.91 (dd, J=15.1,3.7Hz, 1H), 1.52-1.44 (m, 3H), 1.40 (s, 3H), 1.03 (d, J= 6.0Hz,3H),0.97(s,4H),0.91(s,2H),0.89(s,5H),0.86(s,2H).13C NMR(101MHz,DMSO-d6)δ 205.57,170.48,166.92,148.43,117.25,84.06,74.94,70.20,66.10,62.23,60.65,59.12, 58.37,52.24,44.08,42.05,40.82,35.64,34.27,33.86,33.30,32.58,28.63,23.24, 22.77,21.21,19.23,18.11,17.60.HR-MS(ESI):Calculated for C29H46NO7[M+H]+: 520.3274,found 520.3278.Yield 80%.
Embodiment 8:
With 80mg (0.37mmol) N-BOC-L- norvaline, instead of N-BOC-L- glycine, other operate same embodiment 1, obtain white solid product I-8.1H NMR(400MHz,DMSO-d6)δ8.40(s,3H),5.94(s,1H),5.43(s,1H), 5.29 (d, J=4.7Hz, 1H), 5.13 (s, 1H), 4.79 (d, J=12.7Hz, 1H), 4.59 (s, 1H), 4.12 (d, J= 12.6Hz, 1H), 3.89 (dd, J=12.1,4.3Hz, 1H), 3.69-3.64 (m, 1H), 3.31 (s, 3H), 2.98 (s, 1H), 2.11 (s, 1H), 2.08 (s, 3H), 1.84 (d, J=15.2Hz, 1H), 1.52-1.40 (m, 5H), 1.35 (s, 3H), 1.25- 1.15 (m, 3H), 1.09 (d, J=12.4Hz, 1H), 1.03 (d, J=6.1Hz, 1H), 0.97 (s, 3H), 0.93 (d, J= 7.3Hz,3H),0.89(s,4H).13C NMR(101MHz,DMSO-d6)δ205.84,170.51,168.38,148.57, 116.85,84.12,74.94,69.65,62.26,61.23,59.17,58.38,52.33,52.15,44.19,42.10, 40.91,35.47,34.25,33.92,33.30,31.26,23.34,23.24,22.71,21.20,18.00,13.74.HR-MS (ESI):Calculated for C28H44NO7[M+H]+:506.3118,found 506.3120.Yield 88%.
Embodiment 9:
With 92mg (0.37mmol) N-BOC-L- methionine, instead of N-BOC-L- glycine, other are operated with embodiment 1, Obtain yellow oil product I-9.1H NMR(400MHz,DMSO-d6)δ8.43(s,3H),5.95(s,1H),5.45(s,1H),5.33 (d, J=4.8Hz, 1H), 4.79 (d, J=12.7Hz, 1H), 4.58 (s, 1H), 4.12 (d, J=12.6Hz, 1H), 3.90 (dd, J=12.1,4.4Hz, 1H), 3.80 (t, J=6.1Hz, 1H), 3.30 (s, 3H), 2.98 (s, 1H), 2.57 (s, 1H), 2.14 (s, 3H), 2.08 (s, 3H), 2.02 (d, J=13.4Hz, 1H), 1.93 (t, J=6.8Hz, 1H), 1.88-1.79 (m, 2H), 1.74-1.58 (m, 1H), 1.51 (s, 1H), 1.48-1.35 (m, 5H), 1.24-1.17 (m, 1H), 1.11 (d, J=12.9Hz, 2H), 1.03 (d, J=6.1Hz, 1H), 0.97 (s, 3H), 0.89 (s, 4H)13C NMR(101MHz,DMSO-d6)δ206.14, 170.50,168.10,148.61,117.06,84.13,74.92,69.81,62.27,60.98,59.19,58.39,52.21, 51.31,44.20,42.11,40.91,35.47,34.05,33.93,33.30,28.87,28.58,23.34,22.68, 21.21,18.10,14.65.HR-MS(ESI):Calculated for C28H44NO7S[M+H]+:538.2838,found 538.2842.Yield 79%.
Embodiment 10:
With 85mg (0.37mmol) N-BOC-L- nor-leucine, instead of N-BOC-L- glycine, other operate same embodiment 1, obtain white solid product I-10.1H NMR(400MHz,DMSO-d6)δ8.32(s,3H),5.94(s,1H),5.44(s,1H), 5.31 (d, J=4.7Hz, 1H), 5.12 (s, 1H), 4.79 (d, J=12.9Hz, 1H), 4.58 (s, 1H), 4.12 (d, J= 12.5Hz, 1H), 3.88 (dd, J=12.3,4.5Hz, 1H), 3.66 (dd, J=7.2,4.9Hz, 1H), 3.31 (s, 3H), 2.99 (s, 1H), 2.59-2.52 (m, 1H), 2.09 (s, 3H), 1.86-1.79 (m, 1H), 1.54 (d, J=12.9Hz, 1H), 1.50- 1.40 (m, 4H), 1.34 (d, J=5.8Hz, 2H), 1.32-1.25 (m, 4H), 1.16-1.10 (m, 2H), 1.04 (d, J= 6.0Hz, 4H), 0.97 (s, 3H), 0.93 (d, J=6.9Hz, 2H), 0.89 (s, 3H)13C NMR(101MHz,DMSO-d6)δ 205.89,170.54,168.40,148.53,116.97,84.16,74.93,69.56,62.22,61.39,59.13,58.40, 52.57,52.33,44.18,42.06,40.99,35.47,34.35,33.97,33.30,28.96,26.68,23.34, 22.64,22.01,21.21,18.09,14.15.HR-MS(ESI):Calculated for C29H46NO7[M+H]+: 520.3274,found 520.3275.Yield 77%.
Embodiment 11:
With 80mg (0.37mmol) N-BOC-L-5- aminovaleric acid, instead of N-BOC-L- glycine, other operations are the same as implementation Example 1 obtains white solid product I-11.1H NMR(400MHz,DMSO-d6)δ7.80(s,3H),5.91(s,1H),5.40(s, 1H), 5.16 (d, J=4.7Hz, 1H), 5.10 (s, 1H), 4.77 (d, J=12.5Hz, 1H), 4.56 (s, 1H), 4.11 (d, J= 12.6Hz, 1H), 3.90 (dd, J=12.1,4.4Hz, 1H), 3.30 (s, 4H), 2.94 (s, 1H), 2.50 (s, 3H), 2.07 (s, 5H), 1.96 (d, J=13.5Hz, 1H), 1.77 (d, J=15.5Hz, 2H), 1.46-1.39 (m, 7H), 1.20 (dd, J= 14.1,5.0Hz, 2H), 1.12 (d, J=12.5Hz, 2H), 0.96 (s, 3H), 0.88 (s, 3H)13C NMR(101MHz,DMSO- d6)δ205.92,170.93,170.56,149.00,116.15,84.23,75.07,67.22,62.33,61.19,59.27, 58.37,52.16,44.44,41.89,40.85,38.91,35.66,33.91,33.83,33.80,33.25,26.82, 23.40,22.68,21.27,21.22,18.08.HR-MS(ESI):Calculated for C28H44NO7[M+H]+: 506.3118,found 506.3121.Yield 88%.
Embodiment 12:
With 85mg (0.37mmol) N-BOC-L-6- aminocaproic acid, instead of N-BOC-L- glycine, other operations are the same as implementation Example 1 obtains white solid product I-12.1H NMR(400MHz,DMSO-d6)δ7.90(s,3H),5.90(s,1H),5.39(s, 1H), 5.16 (d, J=4.7Hz, 1H), 4.77 (d, J=12.6Hz, 1H), 4.56 (s, 1H), 4.11 (d, J=12.6Hz, 1H), 3.90 (dd, J=12.1,4.4Hz, 1H), 3.30 (s, 3H), 2.93 (s, 1H), 2.48 (d, J=16.8Hz, 2H), 2.07 (s, 3H), 2.02 (t, J=7.4Hz, 3H), 1.76 (dd, J=15.2,3.6Hz, 2H), 1.55-1.46 (m, 5H), 1.39 (d, J= 7.3Hz, 4H), 1.25-1.17 (m, 4H), 1.12 (d, J=12.7Hz, 2H), 1.03 (d, J=6.0Hz, 1H), 0.96 (s, 3H),0.88(s,3H).13C NMR(101MHz,DMSO-d6)δ205.80,171.03,170.53,149.00,116.02, 84.24,75.09,67.09,62.33,61.25,59.25,58.34,52.14,44.46,41.88,40.84,35.68, 34.33,33.88,33.78,33.23,27.09,25.70,24.40,23.76,23.41,22.65,21.18,18.07.HR-MS (ESI):Calculated for C29H46NO7[M+H]+:520.3274,found 520.3278.Yield 83%.
Embodiment 13:
With 123mg (0.37mmol) N-BOC-L-2,5- diaminovaleric acid, instead of N-BOC-L- glycine, other operations are same Embodiment 1 obtains white solid product I-13.1H NMR(400MHz,DMSO-d6)δ8.49(s,3H),8.01(s,3H),5.98 (s, 1H), 5.44 (s, 1H), 5.29 (d, J=4.9Hz, 1H), 4.79 (d, J=12.7Hz, 1H), 4.58 (s, 1H), 4.10 (d, J=12.7Hz, 1H), 3.30 (s, 3H), 2.97 (d, J=4.0Hz, 1H), 2.87 (d, J=13.8Hz, 2H), 2.17-2.08 (m, 2H), 2.07 (s, 3H), 2.01 (d, J=13.5Hz, 1H), 1.85 (dd, J=14.8,4.1Hz, 1H), 1.75-1.70 (m, 1H), 1.69-1.59 (m, 3H), 1.54-1.44 (m, 4H), 1.39 (s, 4H), 1.22-1.16 (m, 1H), 1.11 (d, J= 12.3Hz,1H),0.96(s,3H),0.88(s,4H).13C NMR(101MHz,DMSO-d6)δ206.42,170.54,167.83, 148.55,117.27,84.00,74.92,69.91,62.28,61.00,59.28,58.29,52.13,51.91,44.17, 42.12,40.83,38.73,35.38,34.07,33.87,33.26,26.57,23.31,23.16,22.67,21.13, 18.07.HR-MS(ESI):Calculated for C28H45N2O7[M+H]+:521.3227,found 521.3228.Yield 84%.
Embodiment 14:
With 91mg (0.37mmol) N-BOC-L-2,6- diaminocaproic acid, instead of N-BOC-L- glycine, other operations are same Embodiment 1 obtains white solid product I-14.1H NMR(400MHz,DMSO-d6)δ8.46–8.35(m,3H),7.95(s,3H), 5.97 (s, 1H), 5.45 (s, 1H), 5.30 (d, J=4.7Hz, 1H), 4.80 (d, J=12.7Hz, 1H), 4.59 (s, 1H), 4.12 (d, J=12.6Hz, 1H), 3.89 (dd, J=12.1,4.3Hz, 1H), 3.67 (s, 1H), 3.31 (s, 3H), 2.99 (s, 1H),2.89–2.80(m,2H),2.59–2.52(m,1H),2.12–2.01(m,5H),1.87–1.80(m,1H),1.60(t,J =7.9Hz, 4H), 1.52-1.41 (m, 4H), 1.37 (s, 2H), 1.21 (dt, J=19.2,7.0Hz, 3H), 1.11-1.02 (m, 2H),0.97(s,3H),0.89(s,3H).13C NMR(101MHz,DMSO-d6)δ206.12,170.46,168.15,159.11, 148.65,117.03,84.14,74.92,69.82,62.28,61.25,59.25,58.35,52.35,52.15,44.23, 42.17,40.90,38.93,35.45,34.20,33.91,33.30,28.67,26.78,22.69,21.82,21.17, 18.11.HR-MS(ESI):Calculated for C29H47N2O7[M+H]+:535.3383,found 535.3380。
Yield 88%.
Embodiment 15:
With 93mg (0.37mmol) N-BOC-L-2- phenylglycine, instead of N-BOC-L- glycine, other operations are the same as real Example 1 is applied, white solid product I-15 is obtained.1H NMR(400MHz,DMSO-d6)δ8.89(s,3H),7.49–7.42(m,3H), 7.31 (dd, J=6.8,2.9Hz, 2H), 5.32 (d, J=5.1Hz, 1H), 5.29 (s, 1H), 4.80 (d, J=16.8Hz, 2H), 4.74 (d, J=5.6Hz, 1H), 4.46 (s, 1H), 4.08 (d, J=12.5Hz, 1H), 3.89 (dd, J=12.1,4.6Hz, 1H), 3.28 (s, 3H), 2.74 (d, J=4.0Hz, 1H), 2.48-2.42 (m, 1H), 2.15-2.09 (m, 1H), 2.07 (s, 3H), 1.96 (d, J=13.3Hz, 1H), 1.52-1.45 (m, 3H), 1.41 (dd, J=15.3,4.6Hz, 3H), 1.18 (dd, J =13.8,4.6Hz, 1H), 1.14-1.01 (m, 2H), 0.97 (s, 3H), 0.88 (s, 5H)13C NMR(101MHz,DMSO-d6) δ205.38,170.51,167.07,147.00,132.08,129.85,129.40(×2),128.58(×2),117.19, 84.17,74.82,69.60,62.26,60.48,58.85,58.41,56.21,52.29,43.86,41.88,40.94, 35.53,33.93,33.72,33.24,23.38,22.57,21.18,18.04.HR-MS(ESI):Calculated for C31H42NO7[M+H]+:540.2961,found 540.2960.Yield 89%.
Embodiment 16:
With 98mg (0.37mmol) N-BOC-L- phenylalanine, instead of N-BOC-L- glycine, other operate same embodiment 1, obtain white solid product I-16.1H NMR(400MHz,DMSO-d6) δ 8.54 (s, 3H), 7.37 (dd, J=8.1,6.4Hz, 2H), 7.34-7.30 (m, 1H), 7.20 (d, J=7.0Hz, 2H), 6.01 (s, 1H), 5.44 (s, 1H), 5.19 (d, J= 4.7Hz, 1H), 4.74 (d, J=12.8Hz, 1H), 4.53 (s, 1H), 4.07 (d, J=12.7Hz, 1H), 3.93 (d, J= 6.7Hz, 1H), 3.89-3.85 (m, 1H), 3.32 (d, J=3.6Hz, 3H), 3.01-2.94 (m, 3H), 2.09 (s, 1H), 2.07 (s, 3H), 1.87-1.79 (m, 2H), 1.49-1.40 (m, 3H), 1.38-1.31 (m, 2H), 1.08 (s, 1H), 1.04 (d, J= 6.0Hz,3H),0.99(s,4H),0.87(s,3H).13C NMR(101MHz,DMSO-d6)δ205.73,170.45,167.44, 148.50,134.86,129.86(×2),129.24(×2),127.72,116.91,84.07,74.89,69.40,67.77, 62.17,60.42,59.02,58.42,53.37,52.01,44.22,41.78,40.88,35.75,33.95,33.62, 33.23,23.25,22.57,21.18,18.03.HR-MS(ESI):Calculated for C32H44NO7[M+H]+: 554.3118,found 554.3116.Yield 79%.
Embodiment 17:
With 103mg (0.37mmol) N-BOC- methyl L-phenylalanine, instead of N-BOC-L- glycine, other operations are same Embodiment 1 obtains white solid product I-17.1H NMR(400MHz,DMSO-d6) δ 9.47 (s, 2H), 7.36 (d, J=7.4Hz, 2H), 7.33-7.30 (m, 1H), 7.20-7.17 (m, 2H), 6.02 (s, 1H), 5.44 (s, 1H), 5.11 (d, J=4.8Hz, 2H), 4.69 (d, J=12.6Hz, 1H), 4.49 (d, J=1.6Hz, 1H), 4.02-3.94 (m, 2H), 3.83 (dd, J=12.1, 4.4Hz, 1H), 3.32 (s, 3H), 2.97 (d, J=8.4Hz, 1H), 2.94 (s, 1H), 2.52 (s, 4H), 2.06 (s, 3H), 1.88-1.81 (m, 1H), 1.71 (d, J=13.1Hz, 1H), 1.43 (d, J=13.1Hz, 3H), 1.32 (d, J=3.7Hz, 1H), 1.14 (dd, J=13.1,4.1Hz, 1H), 1.03 (d, J=6.1Hz, 1H), 0.99 (s, 3H), 0.85 (s, 6H), 0.83- 0.81(m,1H).13C NMR(101MHz,DMSO-d6)δ205.48,170.46,166.84,148.49,134.47,129.81 (×2),129.24(×2),127.77,117.01,84.01,74.83,69.71,62.08,61.11,60.06,58.88, 58.41,52.01,44.15,41.59,40.83,35.46,34.98,33.98,33.35,33.18,32.15,23.34, 22.51,21.20,17.94.HR-MS(ESI):Calculated for C33H46NO7[M+H]+:568.3274,found 568.3273.Yield 78%.
Embodiment 18:
With 103mg (0.37mmol) N-BOC-L- homophenylalanin, instead of N-BOC-L- glycine, other operations are the same as implementation Example 1 obtains white solid product I-18.1H NMR(400MHz,DMSO-d6) δ 8.46 (s, 3H), 7.37 (t, J=7.4Hz, 2H), 7.30 (d, J=7.4Hz, 2H), 7.25 (t, J=7.3Hz, 1H), 5.90 (s, 1H), 5.41 (s, 1H), 5.34 (d, J= 4.8Hz, 1H), 5.12 (s, 1H), 4.79 (d, J=12.7Hz, 1H), 4.59 (s, 1H), 4.12 (d, J=12.6Hz, 1H), 3.90 (dd, J=12.1,4.4Hz, 1H), 3.69 (dd, J=7.5,4.5Hz, 1H), 3.31 (s, 3H), 2.98 (s, 1H), 2.70–2.61(m,1H),2.60–2.53(m,2H),2.09(s,6H),1.89–1.80(m,2H),1.51–1.44(m,2H), 1.40 (s, 3H), 1.10 (t, J=13.4Hz, 2H), 1.04 (d, J=6.1Hz, 1H), 0.96 (s, 3H), 0.89 (s, 3H)13C NMR(101MHz,DMSO-d6)δ206.02,170.49,168.22,148.58,140.47,128.95(×2),128.81(× 2),126.75,117.03,84.15,74.91,69.82,62.27,61.27,59.21,58.39,52.30,52.17,44.21, 42.13,40.91,35.49,34.23,33.92,33.30,30.93,30.66,23.32,22.68,21.22,18.11.HR-MS (ESI):Calculated for C33H46NO7[M+H]+:568.3274,found 568.3278.Yield 84%.
Embodiment 19:
With 80mg (0.37mmol) N-BOC-L- proline, instead of N-BOC-L- glycine, other are operated with embodiment 1, Obtain white solid product I-19.1H NMR(400MHz,DMSO-d6)δ9.86(s,1H),8.89(s,1H),5.95(s,1H), 5.44 (s, 1H), 5.27 (d, J=4.6Hz, 1H), 4.79 (d, J=12.7Hz, 1H), 4.59 (s, 1H), 4.15-4.08 (m, 2H), 3.90 (dd, J=12.2,4.4Hz, 1H), 3.30 (s, 3H), 3.19 (t, J=7.1Hz, 2H), 2.98 (d, J=4.1Hz, 1H), 2.59-2.52 (m, 1H), 2.08 (s, 4H), 1.89-1.84 (m, 3H), 1.75-1.57 (m, 2H), 1.48 (d, J= 5.8Hz, 2H), 1.46-1.37 (m, 3H), 1.26-1.19 (m, 1H), 1.17-1.11 (m, 2H), 1.03 (d, J=6.1Hz, 2H),0.97(s,3H),0.89(s,3H).13C NMR(101MHz,DMSO-d6)δ206.02,170.52,167.26,148.69, 116.80,84.15,74.93,70.08,62.28,60.82,59.24,59.12,58.38,52.10,45.74,44.28, 42.16,40.88,35.29,33.93,33.77,33.27,27.17,23.56,23.39,22.66,21.19,18.08.HR-MS (ESI):Calculated for C28H42NO7[M+H]+:504.2961,found 504.2960.Yield 88%.
Embodiment 20:
With 85mg (0.37mmol) N-BOC-L-3- piperidinecarboxylic acid, instead of N-BOC-L- glycine, other operations are the same as implementation Example 1 obtains white solid product I-20.1H NMR(400MHz,DMSO-d6)δ8.75(s,1H),8.50(s,1H),5.94(s, 1H), 5.41 (s, 1H), 5.20 (d, J=4.7Hz, 1H), 4.78 (d, J=12.6Hz, 1H), 4.57 (s, 1H), 4.11 (d, J= 12.7Hz, 1H), 3.89 (dd, J=12.1,4.3Hz, 1H), 3.30 (s, 3H), 3.20-3.12 (m, 3H), 2.93 (d, J= 17.9Hz, 4H), 2.09 (d, J=9.0Hz, 4H), 1.97 (d, J=13.2Hz, 2H), 1.83 (d, J=16.1Hz, 4H), 1.44-1.37 (m, 4H), 1.24-1.16 (m, 2H), 1.12 (d, J=12.7Hz, 2H), 0.96 (s, 3H), 0.88 (s, 4H)13C NMR(101MHz,DMSO-d6)δ206.09,171.37,170.56,148.85,116.60,84.24,75.00,67.83, 62.30,61.32,59.29,58.40,52.18,44.39,42.59,41.97,40.84,37.99,35.65,33.91, 33.79,33.26,24.92,24.29,24.15,23.40,22.69,21.22,18.07.HR-MS(ESI):Calculated for C29H44NO7[M+H]+:518.3118,found 518.3113.Yield 89%.
Embodiment 21:
With 85mg (0.37mmol) N-BOC-L-2- piperidinecarboxylic acid, instead of N-BOC-L- glycine, other operations are the same as implementation Example 1 obtains white solid product I-21.1H NMR(400MHz,DMSO-d6)δ9.34(s,1H),9.01(s,1H),5.94(s, 1H), 5.43 (s, 1H), 5.31 (d, J=4.7Hz, 1H), 4.79 (d, J=12.6Hz, 1H), 4.58 (d, J=1.5Hz, 1H), 4.11 (d, J=12.6Hz, 1H), 3.90 (dd, J=12.1,4.4Hz, 1H), 3.78 (s, 1H), 3.30 (s, 3H), 3.22 (d, J =12.3Hz, 1H), 2.99 (d, J=3.4Hz, 1H), 2.91 (s, 1H), 2.60-2.53 (m, 1H), 2.09 (s, 4H), 1.84 (t, J=6.4Hz, 2H), 1.68 (d, J=11.7Hz, 3H), 1.53-1.48 (m, 4H), 1.38 (s, 2H), 1.17 (d, J= 3.9Hz, 1H), 1.15-1.10 (m, 2H), 1.03 (d, J=6.1Hz, 1H), 0.96 (s, 4H), 0.89 (s, 4H)13C NMR (101MHz,DMSO-d6)δ205.97,170.52,167.49,148.62,116.85,84.12,74.90,69.69,62.25, 61.34,59.19,58.38,55.72,52.11,44.24,43.60,42.08,40.83,35.39,33.97,33.89, 33.28,24.70,23.36,22.66,21.70,21.52,21.20,18.09.HR-MS(ESI):Calculated for C29H44NO7[M+H]+:518.3118,found 518.3117.Yield 78%.
Embodiment 22:
(1) work as R1When for propargyl, the preparation of intermediate 2
Work as R1When for propargyl, under condition of ice bath, 2g (5.1mmol) soft stem scented tea is added in 122mg (5.1mmol) sodium hydride In the DMF solution of dish A prime, after stirring 10min, 663 μ L (7.7mmol) propargyl bromides are slowly added dropwise, keeps ice bath to react 4h, adds Enter the dilution of 50mL ethyl acetate, respectively washed three times with saturated sodium bicarbonate and saturated salt solution, and twice by combining water layer back extraction, closes And ester layer, anhydrous sodium sulfate is dry, and concentration rear pillar chromatogram purification obtains white solid 1.2g, yield 54%.1H NMR(400MHz, DMSO-d6) δ 5.71 (s, 1H), 5.27 (s, 1H), 4.78 (d, J=12.7Hz, 1H), 4.64 (s, 1H), 4.32-4.29 (m, 1H), 4.27 (d, J=3.6Hz, 3H), 4.15 (d, J=12.8Hz, 1H), 3.54 (t, J=2.4Hz, 1H), 3.25 (d, J= 3.4Hz, 1H), 2.37 (dt, J=14.1,4.2Hz, 1H), 2.07 (s, 3H), 1.95-1.86 (m, 2H), 1.85-1.76 (m, 2H), 1.62-1.48 (m, 3H), 1.42 (dd, J=11.8,8.0Hz, 3H), 1.07 (d, J=10.5Hz, 1H), 0.93 (s, 4H),0.86(s,4H).13C NMR(101MHz,DMSO-d6)δ203.81,170.08,148.06,113.48,83.97, 79.58,77.84,73.76,65.95,62.87,62.16,58.45,55.45,53.08,40.94,40.61,40.21, 38.35,33.68,33.45,32.47,29.11,22.16,20.79,17.75.HR-MS(ESI):Calculated for C25H35O6[M+H]+:431.2434,found 431.2433。
(2) when R1 is propargyl, the preparation of I-22
By 2 (R of 108mg (0.25mmol) intermediate1For propargyl) it is dissolved in methylene chloride (DCM), 98mg is added (0.37mmol) N-BOC-L- phenylalanine, catalyst DCC 52mg (0.25mmol), DMAP 3mg (0.025mmol), TLC plate Detection reaction to raw material disappears, and methylene chloride 30mL diluting reaction system is added, and with saturated ammonium chloride solution washing reaction body Three times, combining water layer is simultaneously stripped once for system, merges organic phase, anhydrous sodium sulfate is dry, and concentration, column chromatography purifies white solid This white solid is dissolved in methylene chloride by body, and excessive trifluoroacetic acid is added under condition of ice bath, keeps ice bath reaction 30min, TLC plate detect after the reaction was completed, and concentrated by rotary evaporation removes methylene chloride and trifluoroacetic acid, are then stirred for lower addition isopropyl White solid is precipitated in ether, filters and obtains white solid product I-22 with isopropyl ether flushing filter cake.1H NMR(400MHz,DMSO- d6) δ 9.34 (s, 2H), 7.37 (dd, J=8.2,6.3Hz, 2H), 7.34-7.30 (m, 1H), 7.23-7.17 (m, 2H), 6.00 (s, 1H), 5.46 (s, 1H), 5.10 (d, J=4.8Hz, 1H), 4.79 (d, J=12.7Hz, 1H), 4.61 (s, 1H), 4.40- 4.25 (m, 3H), 4.09 (d, J=12.7Hz, 1H), 4.00 (t, J=7.0Hz, 1H), 3.87 (dd, J=12.1,4.3Hz, 1H), 3.38-3.34 (m, 1H), 3.16 (dd, J=14.3,5.8Hz, 1H), 2.96 (dd, J=14.4,8.1Hz, 1H), 2.53 (s, 3H), 2.08 (s, 3H), 1.91 (d, J=13.2Hz, 1H), 1.83-1.65 (m, 3H), 1.51 (t, J=12.5Hz, 1H), 1.43 (d, J=13.2Hz, 2H), 1.36-1.18 (m, 3H), 1.06-1.01 (m, 1H), 0.95 (s, 4H), 0.84 (s, 4H)13C NMR(101MHz,DMSO-d6)δ203.77,169.83,166.30,146.88,133.84,129.36,128.75,127.32, 116.53,82.82,79.52,78.03,73.11,69.21,61.56,60.84,60.55,58.26,55.77,52.29, 41.15,40.29,35.94,34.40,33.64,33.30,32.93,32.45,31.71,28.75,22.10,20.72, 17.48.HR-MS(ESI):Calculated for C35H46NO7[M+H]+:592.3269,found592.3269.Yield 78%.
Embodiment 23:
(1) work as R1When for 4- itrile group phenethyl, the preparation of intermediate 2
Work as R1When for 4- itrile group phenethyl, under condition of ice bath, it is soft that 2g (5.1mmol) is added in 122mg (5.1mmol) sodium hydride In the DMF solution of stem Amethystoidin A, after stirring 10min, 2g (10.2mmol) is added to cyano cylite, keeps ice bath reaction 4h is added the dilution of 50mL ethyl acetate, is respectively washed three times with saturated sodium bicarbonate and saturated salt solution, and combining water layer is stripped two It is secondary, merge ester layer, anhydrous sodium sulfate is dry, and concentration rear pillar chromatogram purification obtains white solid 1.2g, yield 54%.1H NMR (400MHz,DMSO-d6) δ 7.84-7.79 (m, 2H), 7.44 (d, J=8.4Hz, 2H), 5.77 (s, 1H), 5.27 (s, 1H), 4.95 (s, 1H), 4.79 (d, J=12.7Hz, 1H), 4.68 (d, J=12.5Hz, 1H), 4.56-4.51 (m, 2H), 4.27 (d, J =2.1Hz, 1H), 4.18-4.09 (m, 2H), 2.87 (d, J=4.0Hz, 1H), 2.33 (dt, J=14.2,4.1Hz, 1H), 2.06 (s, 4H), 1.96 (d, J=14.2Hz, 1H), 1.83 (dd, J=14.2,4.1Hz, 1H), 1.60 (q, J=12.6Hz, 1H), 1.51-1.33 (m, 5H), 1.05 (d, J=11.0Hz, 1H), 0.91 (s, 4H), 0.86 (s, 4H)13C NMR(101MHz, DMSO-d6)δ205.36,170.21,149.00,143.55,132.24(×2),128.02(×2),118.70,113.78, 110.33,83.10,75.12,71.28,64.86,62.80,62.17,59.04,52.46,44.63,40.88,40.62, 37.62,33.49,33.41,32.68,24.00,22.06,20.77,17.71.HR-MS(ESI):Calculated for C30H38NO6[M+H]+:508.2699,found 508.2722。
(2) work as R1When for 4- itrile group phenethyl, the preparation of I-23
By 2 (R of 127mg (0.25mmol) intermediate1For 4- itrile group phenethyl) it is dissolved in methylene chloride (DCM), 103mg is added (0.37mmol) N-BOC-L- phenylalanine, catalyst DCC 52mg (0.25mmol), DMAP 3mg (0.025mmol), TLC plate Detection reaction to raw material disappears, and methylene chloride 30mL diluting reaction system is added, and with saturated ammonium chloride solution washing reaction body Three times, combining water layer is simultaneously stripped once for system, merges organic phase, anhydrous sodium sulfate is dry, and concentration, column chromatography purifies white solid This white solid is dissolved in methylene chloride by body, and excessive trifluoroacetic acid is added under condition of ice bath, keeps ice bath reaction 30min, TLC plate detect after the reaction was completed, and concentrated by rotary evaporation removes methylene chloride and trifluoroacetic acid, are then stirred for lower addition isopropyl White solid is precipitated in ether, filters and obtains white solid product I-23 with isopropyl ether flushing filter cake.1H NMR(400MHz,DMSO- d6) δ 9.32 (s, 2H), 7.86-7.82 (m, 2H), 7.47 (d, J=8.3Hz, 2H), 7.35 (dd, J=8.1,6.5Hz, 2H), 7.32-7.26 (m, 1H), 7.19 (dd, J=6.8,1.7Hz, 2H), 6.05 (s, 1H), 5.45 (s, 1H), 5.13 (d, J= 4.3Hz, 1H), 4.81 (d, J=12.6Hz, 1H), 4.69 (d, J=12.7Hz, 1H), 4.59-4.52 (m, 2H), 3.16 (dd, J =14.4,5.9Hz, 1H), 2.95 (q, J=8.1Hz, 2H), 2.53 (s, 3H), 2.06 (s, 3H), 2.03 (s, 1H), 1.86 (d, J=12.0Hz, 1H), 1.77-1.68 (m, 2H), 1.65-1.51 (m, 2H), 1.46-1.36 (m, 2H), 1.36-1.18 (m, 4H), 1.15-1.05 (m, 2H), 1.03 (d, J=6.0Hz, 1H), 0.93 (s, 3H), 0.84 (s, 4H)13C NMR(101MHz, DMSO-d6)δ205.00,169.94,166.30,147.91,143.37,133.91,132.24(×2),129.32(×2), 128.76(×2),128.17(×2),127.26,118.68,116.58,110.42,82.05,74.17,71.13,69.31, 61.61,60.58,59.76,58.82,51.65,47.49,43.69,41.14,34.48,33.45,33.30,32.65, 31.71,25.29,24.42,22.01,20.70,17.46.HR-MS(ESI):Calculated for C40H49N2O7[M+H]+: 669.3534,found 669.3538.Yield 75%.
Embodiment 24: the soft stem Amethystoidin A derivative that the present invention synthesizes is to human lung cancer cell A549, stomach cancer cell MGC-803, esophageal cancer cell TE-1, the anti-tumor activity of breast cancer cell MCF-7
Experimental method
Above four kinds of cancer cells are selected to survey synthesized 72 hours antiproliferative activities of compound；By logarithmic growth phase cell pancreatin It is 1-10 × 10 that concentration is configured to after digestion4The cell suspension of a/ml is inoculated in 96 orifice plates by 1000-10000 cells/well, Every hole adds 100 μ L.Plate is set into 37 DEG C, 5%CO2In humidified incubator after 24 hours, it is added dense containing different test-compounds The 100 μ L of culture solution of degree, each compound are set three parallel holes by a certain concentration gradient, and control group adds the culture solution of blank 100 μ L, place into 37 DEG C, 5%CO2It is incubated for 72 hours in humidified incubator.Culture solution is outwelled with quick turnover panel method, every hole is added The 20 μ L of MTT solution that 5mg/mL Fresh is pressed with PBS buffer solution, sets 37 DEG C, 5%CO2Humidified incubator incubates 4 hours, makes MTT is reduced to Formazan, outwells supernatant again, and every hole adds 150 μ L of DMSO (dimethyl sub-maple), shaken with plate shaker 15min after shaking up, measures OD value (OD) (Detection wavelength 570nm) using microplate reader, is pair with solvent control processing cell According to group, the inhibiting rate of compound on intracellular according to the following formula, and press middle efficacious prescriptions journey calculation of half inhibitory concentration IC50:
Inhibiting rate (%)=(control group OD mean value-administration group OD mean value)/control group OD mean value * 100%
Soft stem Amethystoidin A derivative anti-tumor activity
Oridonin is Oridonin
FA is the soft stem Amethystoidin A of lead compound (Flexicaulin A)
It is above-mentioned the experimental results showed that compound of the present invention have preferable anti tumor activity in vitro, can be used for preparing antitumor Drug is applied to clinical treatment cancer of the esophagus, gastric cancer, primary carcinoma of liver, cancer of pancreas, breast cancer and acute myeloid leukemia etc.. Such compound has good water solubility, and new anticancer drug is used to prepare using the compounds of this invention as active constituent, has There is potential application value.

Claims (5)

1.L- amino acid -14- (7- ether-soft stem Amethystoidin A) ester trifluoroacetic acid salt compound, which is characterized in that have logical Structure shown in formula I:
Wherein R1For C1-C5 alkyl, 4- cyanogen-benzyl；
Wherein R is the alkyl-substituted amino of C1-C10, and alkyl chain is connected with the carbonyl in general formula I；5-10 circle heterocyclic ring virtue containing N Base, the 5-10 membered heterocycloalkyl containing N or R areWherein R ' is hydrogen, C1-C3 alkyl, R2For the C1- of linear chain or branched chain C10 alkyl；The sulfenyl replaced by C1-C10 linear or branched alkyl group, and alkyl chain is connected with amino；The C1-C10 that amino replaces The C1-C3 alkyl that alkyl, phenyl or phenyl replace.
2. l-amino acid -14- (7- ether-soft stem Amethystoidin A) ester trifluoroacetic acid salt compound as described in claim 1, It is characterized in that, R1For propargyl, methyl, 4- cyanogen-benzyl；R is the alkyl-substituted amino of C1-C5, and in alkyl chain and general formula Carbonyl be connected；5,6 membered heterocycloalkyls or R containing N areWherein R ' is hydrogen, methyl；R2For the C1- of linear chain or branched chain C5 alkyl；The sulfenyl replaced by C1-C5 straight chained alkyl, and alkyl chain is connected with amino；The C1-C5 alkyl that amino replaces, phenyl Or the C1-C3 alkyl that phenyl replaces.
3. l-amino acid -14- (7- ether-soft stem Amethystoidin A) ester trifluoroacetic acid salt compound as described in claim 1, It is characterized in that, R1For methyl, 4- cyanogen-benzyl, propargyl；R is the alkyl-substituted amino of C1-C5, and in alkyl chain and general formula Carbonyl be connected；5,6 membered heterocycloalkyls or R containing N areWherein R ' is hydrogen, methyl；R2For methyl or following group One of
4. l-amino acid -14- (7- ether-soft stem Amethystoidin A) ester trifluoroacetic acid salt compound as described in claim 1, It is characterized in that, selecting following compound:
5. l-amino acid -14- (7- ether-soft stem Amethystoidin A) ester trifluoroacetic acid as described in one of claim 1-4 The application of salt compounds in medicine preparation, which is characterized in that using it as active ingredient, preparation treatment cancer of the esophagus, gastric cancer, original Diagnosis, cancer of pancreas, breast cancer or acute myeloid leukemia drug.
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