CN110669097B - Synthesis method of oleanoline derivative - Google Patents
Synthesis method of oleanoline derivative Download PDFInfo
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- CN110669097B CN110669097B CN201810707528.0A CN201810707528A CN110669097B CN 110669097 B CN110669097 B CN 110669097B CN 201810707528 A CN201810707528 A CN 201810707528A CN 110669097 B CN110669097 B CN 110669097B
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- synthesis
- acid derivative
- oleanolic acid
- phthalic anhydride
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
- C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
Abstract
The invention discloses a synthesis method of an oleanolic acid derivative, which belongs to the field of chemical synthesis and is synthesized by a one-pot two-step method by taking betulinic acid and phthalic anhydride as raw materials and taking benzene trifluoromethanesulfonate as a catalytic reagent, wherein the synthesis method is shown as a formula I.
Description
Technical Field
The disclosure relates to a compound synthesis process, in particular to a synthesis method of an oleanolic acid alkene derivative.
Background
Pentacyclic triterpene structures are often found in biologically active natural products and drug molecules. Wherein, oleanolic acid is a pentacyclic triterpenoid compound separated and extracted from swertia mileensis grass or ligustrum lucidum fruit of swertia of Gentianaceae, and researches show that the substances and derivatives thereof have good anticancer activity, and the compound (I)
Is one of the derivatives.
At present, the registration of the substance can only be inquired in a natural product website (ZINC72332803), but no relevant information can be found, including product sources, relevant documents, patents and the like, and no synthesis process is reported.
Disclosure of Invention
In order to obtain the compound (I) and develop a way for synthesizing the compound, the invention designs and implements the synthesis of the compound (I) by using betulinic acid and phthalic anhydride as raw materials and benzene trifluoromethanesulfonate as a catalytic reagent and using a one-pot two-step method, wherein the synthetic route of the N-substituted five-membered and six-membered nitrogen heterocyclic compounds is as follows:
a synthetic method of the oleanolic acid alkene derivative shown in the formula I is characterized in that: the method is characterized in that betulinic acid and phthalic anhydride are used as raw materials, benzene trifluoromethanesulfonate is used as a catalytic reagent, and the raw materials are synthesized by a one-pot two-step method.
Wherein: cat. (catalyst) is bismuth triflate tetrahydrate, scandium triflate or copper triflate.
Preferably, the method comprises the following steps:
step 1, adding dichloromethane, betulinic acid and a catalyst into a flask; heating and refluxing, and stirring for 2-30 h;
step 2, adding phthalic anhydride, and continuing to react for 2-10 h;
step 3, cooling the reaction system to room temperature, washing and drying an organic phase;
step 4, filtering and distilling the organic phase under reduced pressure, separating to obtain the oleanolic acid derivative,
the oleanolic acid derivative has a structural formula as follows:
preferably, the washing in step 3 is performed by adding a saturated sodium bicarbonate solution.
Preferably, anhydrous sodium sulfate is used for the dried organic phase in step 3.
Preferably, the separation in step 4 is a mixture of petroleum ether at 40-60 ℃ in a volume ratio of 1: 9: the oleanolic acid derivative is obtained by separating with silica gel column chromatography using dichloromethane mixed solution as developing agent.
Preferably, in any of the above methods
Step 1, adding 10ml of dichloromethane, 0.10mmol of betulinic acid and 0.005mmol of three catalysts into a flask; heating and refluxing, and stirring for 24 h;
step 2, 0.15mmol phthalic anhydride is added and the reaction is continued for 4 h.
The catalyst is bismuth triflate tetrahydrate, scandium triflate or copper triflate.
If it is desired to obtain a salt of compound (I), the synthesis steps and parameters are:
sodium salt of compound (I): a50 ml round-bottomed flask was charged with Compound (I) (0.1g) and 1M aqueous NaOH solution, and reacted at 40 ℃ for 5 hours. After the reaction is finished, cooling to about 5 ℃ in an ice bath, filtering to obtain a precipitate, and washing with water at a low temperature to obtain the sodium salt of the compound (I).
Other salts such as potassium salts, the synthetic procedure is similar.
The synthetic method has simple steps, high product purity and ideal yield.
Detailed Description
The synthesis of the present invention is illustrated by the following specific embodiments.
Experimental materials:
betulinic acid: CAS #472-15-1, purchased from: aladdin
Phthalic anhydride: CAS #85-44-9, purchased from: aladdin
Scandium trifluoromethanesulfonate: CAS #144026-79-9, purchased from: bailingwei-medicine
The method comprises the following steps:
example 1 synthesis of compounds of formula 1:
step 1. addition of methylene Chloride (CH) to a 50ml flask2Cl210ml) followed by betulinic acid (45.6mg, 0.10mmol) and scandium triflate (2.46mg, 0.005 mmol). Heating and refluxing, and stirring for 24 h.
Step 2, adding 0.15mmol of phthalic anhydride and continuing the reaction for 4 hours.
And 3, cooling the reaction system to room temperature, adding 20ml of saturated sodium bicarbonate solution for washing, and drying the organic phase by using anhydrous sodium sulfate.
Step 4. filtration and distillation under reduced pressure, with petroleum ether (40-60 ℃): the product is obtained by silica gel column chromatography with dichloromethane of 1: 9 (volume ratio) as developing agent.
The product detection method comprises the following steps:
the instrument comprises the following steps: the name model of the instrument adopted in nuclear magnetic detection is Bruker 400Hz, and the name model of the instrument used in mass spectrometry is Agilent 6520;
detection result data:
m/z＝604.9(M+H)+。1H NMR(CDCl3，ppm)：0.76(3H,s),0.84(3H,s),0.87(3H,s),0.91(3H,s),0.95(3H,s),0.97(3H,s),1.03(3H,s),3.20(1H,dd),3.93(1H,s)，7.49–7.61(2H,m),7.65–7.74(1H,m),7.83–7.93(1H,m)
the detection result shows that the obtained chemical formula is C38H52O6A compound of formula I.
The yield is 51%, and the process is simple.
Example 2 synthesis of compounds of formula 1:
step 1. addition of methylene Chloride (CH) to a 50ml flask2Cl210ml) followed by betulinic acid (45.6mg, 0.10mmol) and bismuth triflate (3.28mg, 0.005 mmol). Heating and refluxing, and stirring for 2 h.
Step 2, adding 0.15mmol of phthalic anhydride and continuing the reaction for 2 h.
And 3, cooling the reaction system to room temperature, adding 20ml of saturated sodium bicarbonate solution for washing, and drying the organic phase by using anhydrous sodium sulfate.
Step 4. filtration and distillation under reduced pressure, with petroleum ether (40-60 ℃): the product is obtained by silica gel column chromatography with dichloromethane of 1: 9 (volume ratio) as developing agent.
Example 3 synthesis of compounds of formula 1:
step 1. addition of methylene Chloride (CH) to a 50ml flask2Cl210ml), followed by addition of betulinic acid (45.6mg, 0.10mmol) and copper trifluoromethanesulfonate (1.81mg, 0.005mmol), heating under reflux, and stirring for 30 h.
Step 2, adding 0.15mmol of phthalic anhydride and continuing the reaction for 10 h.
And 3, cooling the reaction system to room temperature, adding 20ml of saturated sodium bicarbonate solution for washing, and drying the organic phase by using anhydrous sodium sulfate.
Step 4. filtration and distillation under reduced pressure, with petroleum ether (40-60 ℃): the product is obtained by silica gel column chromatography with dichloromethane of 1: 9 (volume ratio) as developing agent.
The detection method and the results are the same as those of example 1.
The dosages of the starting materials indicated in the above methods are to be understood as ratios, and in practical examples, the synthetic processes are carried out with each starting material being added in equal multiples, according to the different scales of the preparation process.
Claims (6)
1. The synthesis method of the oleanolic acid derivative shown in the formula 1 is characterized in that betulinic acid and phthalic anhydride are used as raw materials, benzene trifluoromethanesulfonate is used as a catalytic reagent, and the oleanolic acid derivative is synthesized by a one-pot two-step method;
the two-step method comprises the following steps:
step 1, adding dichloromethane, betulinic acid and a catalyst into a flask; heating and refluxing, and stirring for 2-30 h;
step 2, adding phthalic anhydride, and continuing to react for 2-10 h;
the catalyst is scandium trifluoromethanesulfonate or copper trifluoromethanesulfonate;
the oleanolic acid derivative has a structural formula as follows:
2. the method of synthesis of claim 1, further comprising the steps of:
step 3, cooling the reaction system to room temperature, washing and drying an organic phase;
and 4, filtering and distilling the organic phase under reduced pressure, and separating to obtain the oleanolic acid derivative.
3. The synthesis of claim 2, wherein the washing in step 3 is performed by adding saturated sodium bicarbonate solution.
4. The method of claim 2, wherein the dried organic phase in step 3 is anhydrous sodium sulfate.
5. The method of synthesis according to claim 2, the separation in step 4 being a separation of petroleum ether at 40-60 ℃ in a volume ratio of 1: 9: the oleanolic acid derivative is obtained by separating with silica gel column chromatography using dichloromethane mixed solution as developing agent.
6. The method of synthesis according to claim 1,
the step 1 is that 10ml of dichloromethane, 0.10mmol of betulinic acid and 0.005mmol of catalyst are added into a flask; heating and refluxing, and stirring for 24 h;
step 2 is to add 0.15mmol phthalic anhydride and continue the reaction for 4 h.
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