CN109180775A - C-28 imines substituted white birch lipidol isomers derivative and its preparation method and application - Google Patents

C-28 imines substituted white birch lipidol isomers derivative and its preparation method and application Download PDF

Info

Publication number
CN109180775A
CN109180775A CN201811029947.XA CN201811029947A CN109180775A CN 109180775 A CN109180775 A CN 109180775A CN 201811029947 A CN201811029947 A CN 201811029947A CN 109180775 A CN109180775 A CN 109180775A
Authority
CN
China
Prior art keywords
white birch
lipidol
isomers
preparation
imines substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201811029947.XA
Other languages
Chinese (zh)
Other versions
CN109180775B (en
Inventor
石玮
汤凝
程勇
阎卫东
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Huaide College of Changzhou University
Original Assignee
Huaide College of Changzhou University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Huaide College of Changzhou University filed Critical Huaide College of Changzhou University
Priority to CN201811029947.XA priority Critical patent/CN109180775B/en
Publication of CN109180775A publication Critical patent/CN109180775A/en
Application granted granted Critical
Publication of CN109180775B publication Critical patent/CN109180775B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0005—Oxygen-containing hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention relates to Natural Medicine Chemistry technical fields, especially a kind of C-28 imines substituted white birch lipidol isomers derivative and its preparation method and application, shown in structure such as formula (I), R is aryl, benzyl, heterocyclic substituent or alkyl in formula (I).Preparation method includes: that raw material C-28 white birch amide derivatives and catalyst are added in organic solvent, is heated to 40-80 DEG C, stirring to fully reacting, post-processing obtains C-28 imines substituted white birch lipidol isomers derivative.The C-28 imines substituted white birch lipidol isomers derivative is a kind of important natural products reactive intermediate, and preparation methods steps are simple, and post-processing is simple, and reaction yield is high.

Description

C-28 imines substituted white birch lipidol isomers derivative and its preparation method and application
Technical field
The present invention relates to field of natural medicinal chemistry, specific field is that a kind of C-28 imines substituted white birch lipidol isomers spreads out Biologic artifact.
Background technique
Betulin isomers (Allobetulin) derivative belongs to oleanane type compound, is widely present in natural In product, such compound is important reactive compound and important medicinal intermediate.In recent decades, due in pharmaceutical chemistry In application and its unique bioactivity, the synthetic method of such compound cause the interest of a large amount of study on the synthesis person. Recent studies indicate that betulin and betulic acid derivative are under the conditions of acid (inorganic acid, organic acid, lewis acid) It can reset and generate betulin isomers (Allobetulin) and 28- oxo betulin isomers (28- Oxoallobetulin), however the structure of C-28 imines substituted white birch lipidol isomers is not reported, synthetic method There is no document report.
Summary of the invention
The purpose of the present invention is to provide a kind of important natural active compound C-28 imines substituted white birch lipidol isomeries Syntaxy object and its preparation method and application, this method step is simple, easily operated, the high income of product, and post-processing is simple, real It is stronger with property.
To achieve the above object, the invention provides the following technical scheme:
A kind of C-28 imines substituted white birch lipidol isomers derivative, shown in structure such as formula (I):
R is aryl, benzyl, heterocyclic substituent or alkyl in formula (I).
C-28 imines substituted white birch lipidol isomers derivative of the present invention, wherein change shown in the formula (I) Closing object is one of following compounds:
The preparation method of C-28 imines substituted white birch lipidol isomers derivative of the present invention, comprising the following steps: Raw material C-28 white birch amide derivatives and catalyst are added in organic solvent, are heated to 40-80 DEG C, stirring is to having reacted Entirely, post-processing obtains C-28 imines substituted white birch lipidol isomers series derivates；
Shown in the C-28 white birch amide derivatives structure such as formula (II):
Wherein, R is aryl, benzyl, heterocyclic substituent or alkyl.
Reaction equation is as follows:
Referring to above-mentioned reaction equation, starting material betulic acid (1) obtains 3- acetyl group white birch rouge through acetylization reaction Sour (2), synthetic method are shown in document (Molecules 2012,17,12003)；3- acetyl group betulic acid is reacted with amine To 3- acetyl group white birch amide derivatives, synthetic method is shown in document (PCT Int.Appl., 2007002411)；It obtains 3- acetyl group white birch amide derivatives are for synthesizing C-28 imines substituted white birch lipidol isomers derivative.
The preparation method of C-28 imines substituted white birch lipidol isomers derivative of the present invention, wherein the raw material Molar ratio be C-28 white birch amide derivatives: catalyst=1:0.05~1.
The preparation method of C-28 imines substituted white birch lipidol isomers derivative of the present invention, wherein described is anti- It is 2-8 hours between seasonable.
The preparation method of C-28 imines substituted white birch lipidol isomers derivative of the present invention, wherein described has Solvent is selected from chloroform, methylene chloride or dichloroethanes.
The preparation method of C-28 imines substituted white birch lipidol isomers derivative of the present invention, wherein described urges Agent includes iron chloride, p-methyl benzenesulfonic acid or trifluoroacetic acid.
The preparation method of C-28 imines substituted white birch lipidol isomers derivative of the present invention, wherein after described Processing is to after the reaction was completed, with saturated sodium bicarbonate aqueous solution quenching reaction, then is extracted with ethyl acetate to obtain corresponding C- 28 imines substituted white birch lipidol isomers derivatives.
C-28 imines substituted white birch lipidol isomers derivative application in preparation of anti-tumor drugs of the present invention.
The beneficial effects of the present invention are:
(1) the present invention provides a kind of important natural activity intermediate C-28 imines substituted white birch lipidol isomery syntaxies Object is conducive to push with the synthesis for the new drug and intermediate that such compound is synthesis basis；
(2) invention also provides the preparation methods of above-mentioned C-28 imines substituted white birch lipidol isomers derivative, should Method and step is simple, and post-processing is simple, and reaction yield is high.
Specific embodiment
The technical scheme in the embodiments of the invention will be clearly and completely described below, it is clear that described implementation Example is only a part of the embodiment of the present invention, instead of all the embodiments.Based on the embodiments of the present invention, this field is common Technical staff's every other embodiment obtained without making creative work belongs to the model that the present invention protects It encloses.
Examples 1 to 10
C-28 white birch amide derivatives, catalyst is added in the tool plug test tube of 10ml according to the raw material proportioning of table 1 and has Solvent 2ml, heating stirring, according to table 1 reaction condition after the reaction was completed, be added 5ml saturated aqueous solution of sodium bicarbonate be quenched Reaction, three times with the extraction of 2ml ethyl acetate, organic phase is dry with anhydrous sodium sulfate, is evaporated, and obtains corresponding C-28 imines and replaces Betulin isomers derivative (I), reaction process is shown below:
Table 1
Wherein, T is reaction temperature, and t is the reaction time.
Structure confirmation data
By the structure detection data for the C-28 imines substituted white birch lipidol isomers derivative that Examples 1 to 10 is prepared It is respectively as follows:
(1) fusing point, the core for the C-28 imines substituted white birch lipidol isomers derivative (I-1) being prepared by embodiment 1 Magnetic resonance (1H NMR) and (13C NMR), the detection data of high resolution mass spec are as follows:
Fusing point: 360-362 DEG C (not correcting)；1H NMR(400MHz,CDCl3) δ 8.81 (dd, J=4.1,1.6Hz, 1H), 8.09 (dd, J=8.3,1.6Hz, 1H), 7.54-7.44 (m, 2H), 7.34 (dd, J=8.3,4.1Hz, 1H), 7.19 (dd, J= 6.7,1.7Hz, 1H), 4.49 (dd, J=9.9,6.4Hz, 1H), 3.75 (s, 1H), 2.19 (dd, J=31.4,8.9Hz, 2H), 2.05(s,3H),2.02(s,1H),1.86–1.78(m,2H),1.74–1.62(m,4H),1.58–1.50(m,5H),1.48– 1.38 (m, 4H), 1.33 (dd, J=26.0,7.3Hz, 2H), 1.21 (d, J=3.4Hz, 1H), 1.17 (s, 3H), 1.04-1.00 (m, 1H), 0.98 (d, J=8.9Hz, 1H), 0.96 (s, 3H), 0.91 (s, 3H), 0.89 (s, 3H), 0.87 (s, 3H), 0.86 (s, 3H), 0.82 (d, J=7.0Hz, 1H), 0.80 (s, 3H)13C NMR(101MHz,CDCl3)δ171.07,165.83, 149.10,146.82,141.73,135.80,128.97,126.60,122.42,120.94,119.56,87.48,80.94, 55.64,51.20,47.24,45.80,40.78,40.35,38.62,37.84,37.23,35.44,34.19,34.10, 33.81,32.38,28.74,27.95,27.42,26.59,26.39,24.24,23.69,21.36,20.98,18.18, 16.62,16.53,15.69,13.86.HRMS(EI-TOF):m/z[M+] calculated value C41H56N2O3[M]+624.4291 actual measurement: 624.4281。
(2) fusing point, the core for the C-28 imines substituted white birch lipidol isomers derivative (I-2) being prepared by embodiment 2 Magnetic resonance (1H NMR) and (13C NMR), the detection data of high resolution mass spec are as follows:
Fusing point: 271-272 DEG C (not correcting)；1H NMR(400MHz,CDCl3) δ 8.52 (d, J=4.1Hz, 1H), 7.62 (td, J=7.7,1.8Hz, 1H), 7.43 (d, J=7.8Hz, 1H), 7.11 (dd, J=6.8,5.3Hz, 1H), 4.85 (d, J= 15.9Hz, 1H), 4.59 (d, J=15.9Hz, 1H), 4.48 (dd, J=10.6,5.8Hz, 1H), 3.86 (s, 1H), 2.05 (s, 3H), 1.97 (d, J=13.0Hz, 1H), 1.76-1.68 (m, 2H), 1.67-1.62 (m, 2H), 1.61-1.57 (m, 1H), 1.51 (dd, J=8.9,3.9Hz, 4H), 1.47 (d, J=2.9Hz, 1H), 1.42 (dd, J=10.2,8.1Hz, 2H), 1.38-1.30 (m, 5H), 1.29-1.18 (m, 2H), 1.15 (d, J=12.5Hz, 1H), 1.08-1.01 (m, 1H), 1.00-0.96 (m, 1H), 0.94(s,3H),0.91(s,3H),0.90(s,3H),0.89(s,3H),0.86(s,3H),0.85(s,3H),0.84(s,3H), 0.80 (d, J=9.7Hz, 1H)13C NMR(101MHz,CDCl3)δ171.04,166.74,161.19,148.91,136.34, 121.49,121.32,86.80,80.87,55.58,52.62,51.12,47.02,45.42,40.64,40.15,38.60, 37.80,37.17,35.58,34.34,34.05,33.68,32.50,28.78,27.91,27.41,26.38,26.22, 24.13,23.66,21.34,20.93,18.07,16.59,16.49,15.48,13.78.HRMS(EI-TOF):m/z[M+] meter Calculation value C38H56N2O3[M]+588.4291 actual measurement: 588.4281.
(3) fusing point, the core for the C-28 imines substituted white birch lipidol isomers derivative (I-3) being prepared by embodiment 3 Magnetic resonance (1H NMR) and (13C NMR), the detection data of high resolution mass spec are as follows:
Fusing point: 294-295 DEG C (not correcting)；1H NMR(400MHz,CDCl3) δ 7.35 (d, J=7.0Hz, 2H), 7.28 (dd, J=9.9,4.4Hz, 2H), 7.19 (t, J=7.2Hz, 1H), 4.71 (d, J=14.3Hz, 1H), 4.47 (dd, J= 10.6,5.8Hz, 1H), 4.41 (d, J=14.3Hz, 1H), 3.84 (s, 1H), 2.04 (s, 3H), 1.93 (d, J=13.1Hz, 1H), 1.71 (dd, J=12.0,5.0Hz, 2H), 1.68-1.62 (m, 2H), 1.60 (d, J=2.4Hz, 1H), 1.56-1.46 (m,5H),1.44–1.38(m,2H),1.38–1.23(m,7H),1.20–1.02(m,2H),1.01–0.97(m,1H),0.95 (s,3H),0.90(s,3H),0.89(s,3H),0.87(s,3H),0.86(s,3H),0.85(s,3H),0.84(s,3H),0.79 (d, J=9.7Hz, 1H)13C NMR(101MHz,CDCl3)δ171.05,166.03,141.17,128.14,127.79, 126.20,80.90,55.60,51.13,50.57,46.99,45.31,40.63,40.15,38.62,37.81,37.18, 35.62,34.28,34.06,33.65,32.47,28.81,27.92,27.35,26.39,26.20,24.15,23.68, 21.34,20.96,18.08,16.60,16.49,15.41,13.81.HRMS(EI-TOF):m/z[M]+Calculated value C39H57NO3 [M]+587.4338, actual measurement: 587.4335.
(4) fusing point, the core for the C-28 imines substituted white birch lipidol isomers derivative (I-4) being prepared by embodiment 1 Magnetic resonance (1H NMR) and (13C NMR), the detection data of high resolution mass spec are as follows:
Fusing point: 201-203 DEG C (not correcting)；1H NMR(400MHz,CDCl3) δ 7.40 (d, J=7.4Hz, 2H), 7.33- 7.26 (m, 2H), 7.17 (t, J=7.3Hz, 1H), 4.95 (q, J=6.6Hz, 1H), 4.48 (dd, J=10.5,5.8Hz, 1H), 3.78 (s, 1H), 2.04 (s, 3H), 1.93 (d, J=13.3Hz, 1H), 1.74-1.61 (m, 5H), 1.52 (d, J=12.7Hz, 2H),1.48–1.39(m,7H),1.38–1.18(m,6H),1.15–0.98(m,5H),0.93(s,3H),0.89(s,3H), 0.85 (t, J=5.5Hz, 12H), 0.81 (s, 3H), 0.80-0.77 (m, 1H)13C NMR(101MHz,CDCl3)δ171.04, 163.25,146.97,128.03,126.63,126.08,86.31,80.90,55.60,54.65,51.13,46.88,44.84, 40.64,40.11,38.61,37.82,37.19,35.60,34.17,33.94,33.66,32.25,28.66,27.93, 27.14,26.32,26.24,24.40,24.11,23.69,21.35,21.01,18.11,16.56,16.51,15.38, 13.85.HRMS(EI-TOF):m/z[M+] calculated value C40H59NO3[M]+601.4495 actual measurement: 601.4487.
(5) fusing point, the core for the C-28 imines substituted white birch lipidol isomers derivative (I-5) being prepared by embodiment 5 Magnetic resonance (1H NMR) and (13C NMR), the detection data of high resolution mass spec are as follows:
Fusing point: 294-295 DEG C (not correcting)；1H NMR(400MHz,CDCl3) δ 7.30 (t, J=7.8Hz, 2H), 7.04 (dd, J=14.7,7.4Hz, 3H), 4.48 (dd, J=10.4,5.9Hz, 1H), 3.87 (s, 1H), 2.05 (s, 3H), 1.99 (d, J=13.7Hz, 1H), 1.75 (d, J=11.1Hz, 1H), 1.70 (dd, J=9.9,3.5Hz, 2H), 1.60 (ddd, J=17.7, 9.5,6.3Hz, 6H), 1.53-1.47 (m, 3H), 1.44 (d, J=5.0Hz, 1H), 1.41-1.32 (m, 4H), 1.26 (t, J= 7.2Hz, 1H), 1.19 (ddd, J=12.6,9.1,3.7Hz, 2H), 1.02 (dd, J=11.6,5.5Hz, 2H), 0.96 (s, 3H), 0.95 (s, 3H), 0.93 (s, 3H), 0.92 (s, 3H), 0.85 (s, 6H), 0.84 (s, 3H), 0.80 (d, J=9.5Hz, 1H).13C NMR(101MHz,CDCl3)δ171.07,165.10,147.85,128.66,123.28,122.17,87.41, 80.88,55.60,51.12,46.67,45.67,40.68,40.09,38.61,37.82,37.18,35.51,34.08, 33.99,33.72,32.66,28.98,27.93,27.27,26.29,24.11,23.67,21.36,20.92,18.11, 16.56,16.51,15.50,14.22,13.81.m/z[M+] calculated value C38H55NO3[M]+573.4182 actual measurement: 573.4173.
(6) fusing point, the core for the C-28 imines substituted white birch lipidol isomers derivative (I-6) being prepared by embodiment 6 Magnetic resonance (1H NMR) and (13C NMR), the detection data of high resolution mass spec are as follows:
Fusing point: 306-308 DEG C (not correcting)；1H NMR(400MHz,CDCl3) δ 7.10 (d, J=8.0Hz, 2H), 6.93 (d, J=8.1Hz, 2H), 4.47 (dd, J=10.3,6.0Hz, 1H), 3.86 (s, 1H), 3.73 (s, 1H), 2.30 (s, 3H), 2.04 (s, 3H), 1.99 (d, J=13.4Hz, 1H), 1.74 (d, J=11.2Hz, 1H), 1.64 (dd, J=14.7,6.0Hz, 4H),1.58–1.54(m,2H),1.47(s,2H),1.39–1.32(m,4H),1.32–1.23(m,4H),1.21–1.14(m, 2H),1.03–0.98(m,2H),0.97(s,3H),0.94–0.90(m,9H),0.86–0.83(m,9H),0.81–0.78(m, 1H).13C NMR(101MHz,CDCl3)δ171.07,164.99,145.10,132.62,129.27,122.08,87.28, 80.89,55.60,51.12,46.65,45.63,43.46,40.68,40.08,38.61,37.81,37.17,35.47, 34.09,33.99,33.72,32.68,29.72,29.01,27.93,27.26,26.28,24.10,23.67,21.35, 20.96,20.92,18.10,16.55,16.50,15.49,13.81.HRMS(EI-TOF):m/z[M+] calculated value C39H57NO3 [M]+587.4338 actual measurement: 587.4329.
(7) fusing point, the core for the C-28 imines substituted white birch lipidol isomers derivative (I-7) being prepared by embodiment 7 Magnetic resonance (1H NMR) and (13C NMR), the detection data of high resolution mass spec are as follows:
Fusing point: 312-315 DEG C (not correcting)；1H NMR(400MHz,CDCl3) δ 7.31-7.26 (m, 2H), 6.98 (d, J= 8.6Hz, 2H), 4.54-4.45 (m, 1H), 3.90 (s, 1H), 2.07 (s, 3H), 2.03-1.95 (m, 1H), 1.78 (d, J= 11.1Hz, 1H), 1.70 (dd, J=13.5,10.1Hz, 2H), 1.66-1.61 (m, 4H), 1.59-1.54 (m, 2H), 1.53- 1.41(m,5H),1.40–1.28(m,4H),1.25–1.16(m,2H),1.06–0.99(m,2H),0.98(s,3H),0.96(s, 3H), 0.95 (s, 3H), 0.94 (s, 3H), 0.87 (s, 6H), 0.86 (s, 3H), 0.82 (d, J=9.5Hz, 1H)13C NMR (101MHz,CDCl3)δ170.54,165.32,145.86,128.21,127.98,123.14,87.29,80.35,55.10, 50.60,46.17,45.35,40.17,39.58,39.57,38.11,37.31,36.68,35.08,33.52,33.42, 33.20,32.15,28.45,27.42,26.76,25.77,25.71,23.57,23.16,20.84,20.40,17.60, 16.06,16.00,14.99,13.30. calculated value C38H54ClNO3[M]+607.3792 actual measurement: 607.3784.
(8) fusing point, the core for the C-28 imines substituted white birch lipidol isomers derivative (I-8) being prepared by embodiment 8 Magnetic resonance (1H NMR) and (13C NMR), the detection data of high resolution mass spec are as follows:
Fusing point: 286-289 DEG C (not correcting)；1H NMR(400MHz,CDCl3) δ 7.14 (dd, J=17.0,7.6Hz, 2H), 6.96 (td, J=7.4,0.9Hz, 1H), 6.88 (d, J=7.7Hz, 1H), 4.48 (dd, J=10.4,5.9Hz, 1H), 3.85 (s, 1H), 2.24 (s, 3H), 2.06 (s, 1H), 2.05 (s, 3H), 1.77 (d, J=11.2Hz, 1H), 1.70 (d, J= 16.2Hz,2H),1.67–1.61(m,4H),1.61–1.48(m,5H),1.48–1.42(m,2H),1.41–1.33(m,4H), 1.22 (ddd, J=21.6,8.7,5.4Hz, 2H), 1.08-0.98 (m, 2H), 0.96 (s, 3H), 0.94 (s, 3H), 0.92 (s, 6H), 0.85 (s, 6H), 0.84 (s, 3H), 0.81 (d, J=9.2Hz, 1H)13C NMR(101MHz,CDCl3)δ171.07, 164.49,146.57,130.11,129.45,126.05,123.23,121.29,87.27,80.87,55.61,51.15, 46.81,45.67,40.68,40.18,38.65,37.82,37.17,35.64,34.23,34.11,33.72,32.69, 28.96,27.92,27.45,26.39,24.20,23.67,21.35,20.94,18.43,18.08,16.62,16.51, 15.58,13.77. calculated value C39H57NO3[M]+587.4338 actual measurement: 587.4331.
(9) fusing point, the core for the C-28 imines substituted white birch lipidol isomers derivative (I-9) being prepared by embodiment 9 Magnetic resonance (1H NMR) and (13C NMR), the detection data of high resolution mass spec are as follows:
Fusing point: 295-297 DEG C (not correcting)；1H NMR(400MHz,CDCl3)δ7.07–7.00(m,2H),6.88–6.83 (m, 2H), 4.47 (dd, J=10.5,5.8Hz, 1H), 3.87 (s, 1H), 3.78 (s, 3H), 2.04 (s, 3H), 1.98 (d, J= 13.3Hz, 1H), 1.74 (d, J=11.1Hz, 1H), 1.70 (dd, J=9.4,3.6Hz, 1H), 1.62 (ddd, J=21.2, 9.6,5.7Hz, 6H), 1.56-1.46 (m, 4H), 1.45-1.39 (m, 2H), 1.33 (ddd, J=15.8,10.9,3.2Hz, 4H), 1.23-1.14 (m, 2H), 1.01 (d, J=8.8Hz, 1H), 0.99 (s, 3H), 0.96 (d, J=3.2Hz, 1H), 0.93 (s, 3H), 0.92 (s, 3H), 0.91 (s, 3H), 0.85 (s, 3H), 0.84 (s, 3H), 0.84 (s, 3H), 0.80 (d, J= 9.6Hz,1H).13C NMR(101MHz,CDCl3)δ171.06,164.76,155.76,140.71,123.46,113.92, 87.32,80.88,55.60,55.40,51.11,46.59,45.67,40.66,40.08,38.60,37.81,37.17, 35.49,34.09,34.05,33.71,32.68,29.04,27.92,27.26,26.29,24.10,23.67,21.34, 20.91,18.10,16.55,16.50,15.50,13.81. calculated value C39H57NO4[M]+603.4288 actual measurement: 603.4274.
(10) fusing point for the C-28 imines substituted white birch lipidol isomers derivative (I-10) being prepared by embodiment 10, Nuclear magnetic resonance (1H NMR) and (13C NMR), the detection data of high resolution mass spec are as follows:
Fusing point: 225-226 DEG C (not correcting)；1H NMR(400MHz,CDCl3) δ 4.47 (dd, J=10.5,5.8Hz, 1H), 3.80 (s, 1H), 3.41 (dt, J=12.0,7.3Hz, 1H), 3.25 (dt, J=12.0,7.0Hz, 1H), 2.05 (s, 3H), 1.84 (d, J=12.9Hz, 1H), 1.75-1.62 (m, 4H), 1.58 (dd, J=13.0,5.2Hz, 2H), 1.53 (d, J= 7.0Hz, 2H), 1.50-1.46 (m, 2H), 1.46-1.42 (m, 2H), 1.41 (d, J=3.5Hz, 1H), 1.40-1.28 (m, 12H), 1.24 (dd, J=11.9,3.0Hz, 2H), 1.11 (s, 1H), 1.05 (dd, J=13.9,8.3Hz, 1H), 1.00 (d, J =11.7Hz, 3H), 0.96 (d, J=4.2Hz, 1H), 0.92 (s, 1H), 0.90 (s, 3H), 0.89 (s, 3H), 0.88 (s, 1H), 0.88 (s, 3H), 0.86 (s, 3H), 0.84 (s, 3H), 0.83 (s, 3H), 0.79 (d, J=10.7Hz, 1H)13C NMR (101MHz,CDCl3)δ171.03,164.41,86.20,80.89,55.59,51.12,46.85,46.77,44.94,40.60, 40.11,38.60,37.80,37.17,35.55,34.25,34.12,33.67,32.51,31.78,30.81,28.87, 27.91,27.37,27.23,26.34,26.25,24.13,23.67,22.69,22.51,21.33,20.98,18.09, 16.57,16.49,15.40,14.13,13.79.HRMS(EI-TOF):m/z[M+] calculated value C38H63NO3[M]+581.4808, Actual measurement 581.4801.
It is thin that selection example 2,3,7,10 synthesizes obtained C-28 imines substituted white birch lipidol isomers progress human leukemia The anti tumor activity in vitro test of born of the same parents' strain HL60 tumour cell, with mtt assay detection candidate compound to human leukemia HL60 cell The inhibiting effect of in-vitro multiplication ability.
Antitumor result is as shown in table 2 below.It can be seen that from result, C-28 imines substituted white birch lipidol isomers is shown Better than the anti-tumor activity of raw material betulic acid (12.3 μM), wherein I-7 ability is best, IC50Value is 3.7 μM, and therefore, C-28 is sub- Amine substituted white birch lipidol isomers is worth further research, to filter out more biologically active lead compounds.
The cytotoxicity of 2 C-28 imines substituted white birch lipidol isomers anti-leukocythemia HL-60 of table
aIC in table50Value is that experiment is averaged three times.
It although an embodiment of the present invention has been shown and described, for the ordinary skill in the art, can be with A variety of variations, modification, replacement can be carried out to these embodiments without departing from the principles and spirit of the present invention by understanding And modification, the scope of the present invention is defined by the appended.

Claims (9)

1. a kind of C-28 imines substituted white birch lipidol isomers derivative, it is characterised in that: shown in structure such as formula (I):
R is aryl, benzyl, heterocyclic substituent or alkyl in formula (I).
2. C-28 imines substituted white birch lipidol isomers derivative according to claim 1, it is characterised in that: the formula (I) compound represented is one of following compounds:
3. the preparation method of C-28 imines substituted white birch lipidol isomers derivative according to claim 1 or 2, feature It is, comprising the following steps: raw material C-28 white birch amide derivatives and catalyst are added in organic solvent, are heated to 40- 80 DEG C, stirring to fully reacting, post-processing obtains C-28 imines substituted white birch lipidol isomers series derivates；
Shown in the C-28 white birch amide derivatives structure such as formula (II):
Wherein, R is aryl, benzyl, heterocyclic substituent or alkyl.
4. the preparation method of C-28 imines substituted white birch lipidol isomers derivative according to claim 3, feature exist In: the molar ratio of the raw material is C-28 white birch amide derivatives: catalyst=1:0.05~1.
5. the preparation method of C-28 imines substituted white birch lipidol isomers derivative according to claim 3, feature exist In: the reaction time is 2-8 hours.
6. the preparation method of C-28 imines substituted white birch lipidol isomers derivative according to claim 3, feature exist In: the organic solvent is selected from chloroform, methylene chloride or dichloroethanes.
7. the preparation method of C-28 imines substituted white birch lipidol isomers derivative according to claim 3, feature exist In: the catalyst includes iron chloride, p-methyl benzenesulfonic acid or trifluoroacetic acid.
8. the preparation method of C-28 imines substituted white birch lipidol isomers derivative according to claim 3, feature exist It is with saturated sodium bicarbonate aqueous solution quenching reaction, then to be extracted with ethyl acetate to after the reaction was completed in: the post-processing To corresponding C-28 imines substituted white birch lipidol isomers derivative.
9. C-28 imines substituted white birch lipidol isomers derivative of any of claims 1 or 2 is in the preparation of antitumor drugs Using.
CN201811029947.XA 2018-09-05 2018-09-05 C-28 imine substituted betulin isomer derivative and preparation method and application thereof Active CN109180775B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201811029947.XA CN109180775B (en) 2018-09-05 2018-09-05 C-28 imine substituted betulin isomer derivative and preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201811029947.XA CN109180775B (en) 2018-09-05 2018-09-05 C-28 imine substituted betulin isomer derivative and preparation method and application thereof

Publications (2)

Publication Number Publication Date
CN109180775A true CN109180775A (en) 2019-01-11
CN109180775B CN109180775B (en) 2021-03-23

Family

ID=64914508

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201811029947.XA Active CN109180775B (en) 2018-09-05 2018-09-05 C-28 imine substituted betulin isomer derivative and preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN109180775B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114392262A (en) * 2022-01-28 2022-04-26 河南省生殖健康科学技术研究院(河南省出生缺陷干预工程技术研究中心) Betulinic acid derivatives for inhibiting nervous system degenerative diseases

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1045475A (en) * 1962-08-24 1966-10-12 Shionogi & Co Steroid 8ª‰,11ª‰-carboimidic lactones and their preparation
WO2001090096A2 (en) * 2000-05-23 2001-11-29 Univerzita Palackeho V Olomouci Triterpenoid derivatives and their use as antiproliferative agents
US20080167254A1 (en) * 2006-10-27 2008-07-10 Andre Pichette Triterpenes derivatives and uses thereof as antitumor agents or anti-inflammatory agents

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1045475A (en) * 1962-08-24 1966-10-12 Shionogi & Co Steroid 8ª‰,11ª‰-carboimidic lactones and their preparation
WO2001090096A2 (en) * 2000-05-23 2001-11-29 Univerzita Palackeho V Olomouci Triterpenoid derivatives and their use as antiproliferative agents
US20080167254A1 (en) * 2006-10-27 2008-07-10 Andre Pichette Triterpenes derivatives and uses thereof as antitumor agents or anti-inflammatory agents

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CSUK, RENE: "《Synthesis and biological evaluation of antitumour-active betulin》", 《BIOORGANIC & MEDICINAL CHEMISTRY》 *
KONYSHEVA, ANASTASIA V: "《Synthesis of cytotoxically active derivatives based on alkylated》", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114392262A (en) * 2022-01-28 2022-04-26 河南省生殖健康科学技术研究院(河南省出生缺陷干预工程技术研究中心) Betulinic acid derivatives for inhibiting nervous system degenerative diseases
CN114392262B (en) * 2022-01-28 2024-03-01 威海赛宝工业信息技术研究院有限公司 Betulinic acid derivative for inhibiting nervous system degenerative diseases

Also Published As

Publication number Publication date
CN109180775B (en) 2021-03-23

Similar Documents

Publication Publication Date Title
CN110300753A (en) Cap dependence endonuclease enzyme inhibitor
CN107266348B (en) Preparation, structure and the purposes of 4-acetylbiphenyl hydrazone -3- indolecarboxaldehyde Schiff base
CN108147995A (en) A kind of low 1,8- Naphthalamide derivatives of toxicity and its synthetic method and application
CA3107566A1 (en) A cocrystal of 2-[(1r,6r)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol
CN113666824A (en) Cannabidiol-2-propionate and application thereof
CN109180775A (en) C-28 imines substituted white birch lipidol isomers derivative and its preparation method and application
CN111205311A (en) Novel high-antitumor-activity white leaf vine zinc (II) complex and synthesis method and application thereof
CN108947949A (en) Antianxiety deuterated compound and its medical usage
Zhang et al. Three pharmaceuticals cocrystals of adefovir: Syntheses, structures and dissolution study
CN112409183B (en) Zanthoxylum bungeanum ketene and derivative thereof, and preparation method and application thereof
Da Silva et al. New chiral imidazolium ionic liquids from isomannide
CN102503860A (en) Synthetic method of 1, 3-two substituted ureas and carbamate
CN107698648B (en) Naphthylimide derivative containing cholesterol and synthesis and application thereof
Zhou et al. The synthesis and biological evaluation of some caffeic acid amide derivatives: E-2-Cyano-(3-substituted phenyl) acrylamides
EP2851363B1 (en) Agomelatine acid radical composite, and preparation method and application thereof
Vu et al. Simple two-step procedure for the synthesis of memantine hydrochloride from 1, 3-dimethyl-adamantane
CN103764620A (en) Novel ceramide analogues, processes for preparing same and uses thereof
CN110526955A (en) 18 β-enoxolone class the compound of the segment containing hydroxamic acid structure and its application
CN107118147B (en) Preparation, structure and the purposes of 4-acetylbiphenyl hydrazone -3- acetylindole Schiff base
CN111039844A (en) Polysubstituted arylpyrrole compounds
CN104892372B (en) A kind of synthetic method of little molecule Polyethylene Glycol
CN105693660B (en) Jaspine B, 3 epi Jaspine B oxo analogs, its preparation method and application
CN110305160A (en) A kind of phosphoric acid of copper catalysis mixes the synthetic method of ester type compound
CN116444528A (en) Oxo-triazine piperazine heterocyclic compound and preparation method and application thereof
CN104341360A (en) A rufinamide preparing method

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant