CN105968163B - The Preparation Method And Their Intermediate of enoxolone octadecyl ester - Google Patents
The Preparation Method And Their Intermediate of enoxolone octadecyl ester Download PDFInfo
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- CN105968163B CN105968163B CN201610349268.5A CN201610349268A CN105968163B CN 105968163 B CN105968163 B CN 105968163B CN 201610349268 A CN201610349268 A CN 201610349268A CN 105968163 B CN105968163 B CN 105968163B
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- enoxolone
- preparation
- organic solvent
- octadecyl ester
- white solid
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- 229960003720 enoxolone Drugs 0.000 title claims abstract description 37
- MPDGHEJMBKOTSU-UHFFFAOYSA-N Glycyrrhetinsaeure Natural products C12C(=O)C=C3C4CC(C)(C(O)=O)CCC4(C)CCC3(C)C1(C)CCC1C2(C)CCC(O)C1(C)C MPDGHEJMBKOTSU-UHFFFAOYSA-N 0.000 title claims abstract description 36
- WNIFXKPDILJURQ-UHFFFAOYSA-N stearyl glycyrrhizinate Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C)CCC(C(=O)OCCCCCCCCCCCCCCCCCC)(C)CC5C4=CC(=O)C3C21C WNIFXKPDILJURQ-UHFFFAOYSA-N 0.000 title claims abstract description 36
- -1 enoxolone octadecyl ester Chemical class 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 239000007787 solid Substances 0.000 claims abstract description 19
- 239000003960 organic solvent Substances 0.000 claims abstract description 18
- MPDGHEJMBKOTSU-YKLVYJNSSA-N 18beta-glycyrrhetic acid Chemical compound C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C(O)=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-YKLVYJNSSA-N 0.000 claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 14
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims abstract description 11
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 9
- 239000003513 alkali Substances 0.000 claims abstract description 6
- 150000007530 organic bases Chemical class 0.000 claims abstract description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 2
- 235000009508 confectionery Nutrition 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 1
- 150000004985 diamines Chemical class 0.000 claims 1
- 125000003698 tetramethyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 6
- 239000012535 impurity Substances 0.000 abstract description 5
- 239000000543 intermediate Substances 0.000 abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- VTAJIXDZFCRWBR-UHFFFAOYSA-N Licoricesaponin B2 Natural products C1C(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2)C(O)=O)C)(C)CC2)(C)C2C(C)(C)CC1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O VTAJIXDZFCRWBR-UHFFFAOYSA-N 0.000 description 4
- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 description 4
- 229960004949 glycyrrhizic acid Drugs 0.000 description 4
- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 description 4
- 239000001685 glycyrrhizic acid Substances 0.000 description 4
- 235000019410 glycyrrhizin Nutrition 0.000 description 4
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000003810 ethyl acetate extraction Methods 0.000 description 3
- 150000002342 glycyrrhetinic acids Chemical class 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 244000303040 Glycyrrhiza glabra Species 0.000 description 2
- 235000006200 Glycyrrhiza glabra Nutrition 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000004134 energy conservation Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- HDECRAPHCDXMIJ-UHFFFAOYSA-N 2-methylbenzenesulfonyl chloride Chemical compound CC1=CC=CC=C1S(Cl)(=O)=O HDECRAPHCDXMIJ-UHFFFAOYSA-N 0.000 description 1
- 102000053187 Glucuronidase Human genes 0.000 description 1
- 108010060309 Glucuronidase Proteins 0.000 description 1
- 241000202807 Glycyrrhiza Species 0.000 description 1
- 240000008917 Glycyrrhiza uralensis Species 0.000 description 1
- 235000000554 Glycyrrhiza uralensis Nutrition 0.000 description 1
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- LTINPJMVDKPJJI-UHFFFAOYSA-N iodinated glycerol Chemical compound CC(I)C1OCC(CO)O1 LTINPJMVDKPJJI-UHFFFAOYSA-N 0.000 description 1
- 235000021374 legumes Nutrition 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- DKVBOUDTNWVDEP-NJCHZNEYSA-N teicoplanin aglycone Chemical compound N([C@H](C(N[C@@H](C1=CC(O)=CC(O)=C1C=1C(O)=CC=C2C=1)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)OC=1C=C3C=C(C=1O)OC1=CC=C(C=C1Cl)C[C@H](C(=O)N1)NC([C@H](N)C=4C=C(O5)C(O)=CC=4)=O)C(=O)[C@@H]2NC(=O)[C@@H]3NC(=O)[C@@H]1C1=CC5=CC(O)=C1 DKVBOUDTNWVDEP-NJCHZNEYSA-N 0.000 description 1
- 230000002087 whitening effect Effects 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of Preparation Method And Their Intermediates of enoxolone octadecyl ester.The preparation method includes：(1) in organic solvent, in the presence of organic base, enoxolone is reacted with p-methyl benzene sulfonic chloride, filters to obtain white solid after reaction；(2) in organic solvent, in the presence of alkali, the white solid is reacted with octadecyl alcolol, and reaction terminates, and the enoxolone octadecyl ester is detached to obtain from system.The present invention also provides the intermediates of the enoxolone octadecyl ester of preparation.The invention discloses a kind of high income, the methods for producing enoxolone octadecyl ester that impurity is few, at low cost.
Description
Technical field
Preparation method more particularly to a kind of high income, impurity the present invention relates to enoxolone octadecyl ester is few, at low cost
Produce the method and its intermediate of enoxolone octadecyl ester.
Background technology
Radix Glycyrrhizae is glycyrrhizic legume (Glycyrrhiza uralensis Fisch), swollen fruit Radix (Glycyrrhiza
In flata Bat) or glycyrrhiza glabra (Glycyrrhiza glabra L) root and rhizome, main product is in Inner Mongol, Xinjiang, sweet
The ground such as respectful.Radix Glycyrrhizae be used as medicine it is with a long history,《Sheng Nong's herbal classic》The superior of medicine is just classified as, ancient medicine person's honor is called
" state is old ".Due to its resource preciousness, national second class protection natural crude drugs are included in by country.
Glycyrrhizic acid is the principle active component of Radix Glycyrrhizae, and the aglycon of glycyrrhizic acid is enoxolone, and in human body, glycyrrhizic acid passes through
Hydrochloric acid in gastric juice hydrolyzes or resolves into enoxolone by the GRD beta-glucuronidase in liver, and the pharmacological action of glycyrrhizic acid is substantially Radix Glycyrrhizae
The effect of hypo acid.
Enoxolone octadecyl ester is also known as stearyl alcohol glycyrrhetin acid esters, enoxolone stearyl etc., theoretically by Radix Glycyrrhizae time
Acid reacts generation under alkaline condition with tristearin, not soluble in water, has the effects that whitening, anti-oxidant, in the row such as medicine, cosmetics
Industry is all widely used, and market demand is larger.At present, due to limitations such as preparation method, working conditions, there are no maturations
The technique of mass production enoxolone octadecyl ester, causes its yield that far can not meet the market demand, and the market price is excessively high.
The present invention provides a kind of method of new chemical preparation enoxolone octadecyl ester, this preparation method high income, works
Skill is novel, easy to operate, energy conservation and environmental protection, has good practicability, at present, does not have related patents report to pass through chemical synthesis
The preparation method of enoxolone octadecyl ester is obtained in high yield.
Invention content
Goal of the invention：The present invention provides a kind of high income, the sides for producing enoxolone octadecyl ester that impurity is few, at low cost
Method.
The present invention reacts the special physico-chemical property of the compound of generation according to enoxolone with p-methyl benzene sulfonic chloride, with this
Compound is intermediate product, therefore compound, insoluble in mother liquor, impurity will not be precipitated in mother liquor, and filtering can obtain high-purity
Intermediate compound, this compound react the enoxolone octadecyl ester that can produce that content is high, impurity is few with octadecyl alcolol again.
Technical solution：A kind of preparation method of enoxolone octadecyl ester, including：
(1) in organic solvent, in the presence of organic base, enoxolone is reacted with p-methyl benzene sulfonic chloride, after reaction mistake
Filter to obtain white solid；
(2) in organic solvent, in the presence of alkali, the white solid is reacted with octadecyl alcolol, and reaction terminates, and is divided from system
From enoxolone octadecyl ester that must be described.
The chemical equation of preparation method of the present invention：
In above-mentioned steps (1), the molar ratio of the p-methyl benzene sulfonic chloride and enoxolone is 1~1.6：1, preferably
1：1, the molar ratio of p-methyl benzene sulfonic chloride and enoxolone is 1:When 1, it can fully ensure that enoxolone reacts completely, but if
Toluene sulfonyl chloride crosses at most residue and too much, causes to waste.
The volume of the organic solvent is 50~150 times of enoxolone mole, preferably 100~150 times, more preferably
It it is 100 times, the volume unit of the organic solvent is milliliter.Addition is small, can lead to enoxolone and p-methyl benzene sulfonic chloride
It cannot be completely dissolved, influence the progress of reaction, addition, which is more than, can lead to wastage of material.Organic solvent includes ethyl acetate, two
Chloromethanes, chloroform, tetrahydrofuran etc..
The volume of the triethylamine is 20~80 times of enoxolone mole, preferably 50 times, the volume of the triethylamine
Unit is milliliter.Applicant has found that addition is more than 50 times and the alkalinity of reaction system is caused to become strong, there is side reaction hair in research
It is raw, when addition is less than 50 times, reactant can be caused not react completely.
Organic base is the acid-base value in order to adjust solution, and the organic base is triethylamine, triethanolamine, triethylene two
Amine, tetramethylethylenediamine, pyridine etc..
In step (1), the reaction time is 1~3h, and reaction temperature is 20~40 DEG C, it is preferred that reaction time 2h, reaction
Temperature is 25 DEG C.
In step (2), 150~300 times for the mole of the white solid of the volume of organic solvent, preferably 200
~250 times, more preferably 200 times, the volume unit of the organic solvent is milliliter.Addition can lead to raw material more than 200 times
Waste, addition are less than 200 milliliters, can cause reactant that can not be completely dissolved, and influence the progress of reaction so that whole yield drop
It is low.The organic solvent is DMF, tetrahydrofuran, acetone, chloroform etc..
The octadecyl alcolol and the molar ratio of white solid are 0.8~1.3：1, preferably 1：1, octadecyl alcolol addition is small,
The step of causing to participate in reaction (1), the white solid of generation had residue, and similarly addition conference leads to the waste of octadecyl alcolol.
Conjugate of the white solid for hydroxyl and the tolysulfonyl acyl chlorides of enoxolone, this compound structure and
Characterize data is as follows：
m p:186-187℃.1H NMR (DMSO, 300MHz), 12.18 (s, 1H, OH), 7.95-7.92 (d, J=
6.06Hz, 1H, ArH), 7.76-7.74 (d, J=1.23Hz, 1H, ArH), 7.45-7.43 (m, 2H, ArH), 5.75 (s, 1H,
CH),3.39(m,1H,CH),2.36(s,3H,CH3), 2.03 (m, 3H, CH), 1.85-1.92 (m, 8H, CH2),1.55-1.67
(m,8H,CH2), 1.29 (s, 3H, CH3), 1.10 (s, 3H, CH3), 1.05 (s, 3H, CH3), 0.93 (m, 2H, CH2),0.88(s,
3H,CH3), 0.85 (s, 3H, CH3), 0.66 (s, 3H, CH3), 0.67 (s, 3H*, CH3), MS (ESI):624.8(C37H53O6S,[M
+H]+).Anal.Calcd for C37H52O6S:C,71.22；H,8.39；O,15.36Found:C,71.25；H,8.42；O,
15.38
In step (2), alkali can adjust the alkalinity of solution, and alkali can be sodium carbonate, saleratus, sodium bicarbonate etc., institute
The molar ratio for stating potassium carbonate and white solid is 1.5~3：1, preferably 1.5~2：1, potassium carbonate addition is less than 1.5:1 can lead
Cause reaction that can not carry out.
In step (2), the reaction time is 4~8h, and reaction temperature is 60~90 DEG C, it is preferred that reaction time 5h, reaction
Temperature is 70 DEG C.
Compared with prior art, beneficial effects of the present invention include：
The present invention provides a kind of side of preparation in high yield of new acquisition enoxolone octadecyl ester with chemical synthesising technology
Method, has filled up the blank in enoxolone octadecyl ester production technology, this preparation method has the energy conservation and environmental protection, production cost low etc. excellent
Point, preparation process of the invention are verified by more batches of productions, it was demonstrated that its repeatability, stability are all preferable, are suitble to industrialization
Production, it is easy to spread, there is very strong practicability.
Specific embodiment
With reference to embodiment, the present invention is further illustrated.
DMF：Dimethylformamide
Embodiment 1
1mol enoxolones and 100 milliliters of ethyl acetate of addition in 1mol p-methyl benzene sulfonic chlorides, 50 milliliters of triethylamines, often
(25 DEG C) of temperature stirs 2 hours, there is white solid precipitation, filters.The above-mentioned white solids of 1mol, 1mol ten are added in 200 milliliters of DMF
Eight alcohol, 70 DEG C of the potassium carbonate of 1.5mol react 5 hours, add water, ethyl acetate extraction, and organic phase drying obtains product 685.9g, receives
Rate 95%.
Detection method：Using Shimadzu LC-20AT liquid chromatographs, with InertSustain C18 columns (4.6 × 150mm × 5
μm) it is chromatographic column, with acetonitrile:1mol/L phosphate aqueous solutions (85：15) it is mobile phase, Detection wavelength 254nm, flow velocity 1.0ml/
Min is measured.HPLC purity 98.3%.
Embodiment 2
1mol enoxolones and 150 milliliters of ethyl acetate of addition in 1mol p-methyl benzene sulfonic chlorides, 50 milliliters of triethylamines, often
Temperature stirring 2 hours, there is white solid precipitation, filters.1mol white solids, 1mol octadecyl alcolols, 2mol are added in 200 milliliters of DMF
70 DEG C of potassium carbonate react 5 hours, add water, ethyl acetate extraction, organic phase drying obtains product 649.8g, yield 90%.
Detection method：Using Shimadzu LC-20AT liquid chromatographs, with InertSustain C18 columns (4.6 × 150mm × 5
μm) it is chromatographic column, with acetonitrile:1mol/L phosphate aqueous solutions (85：15) it is mobile phase, Detection wavelength 254nm, flow velocity 1.0ml/
Min is measured, HPLC purity 92.9%.
Embodiment 3
1mol enoxolones and 100 milliliters of ethyl acetate of addition in 1.5mol p-methyl benzene sulfonic chlorides, 50 milliliters of triethylamines,
Stirring at normal temperature 2 hours has white solid precipitation, filtering.The above-mentioned white solids of 1mol, 1mol 18 are added in 250 milliliters of DMF
Alcohol, 70 DEG C of the potassium carbonate of 1.5mol react 5 hours, add water, ethyl acetate extraction is dry, obtains product 664.24g, yield 92%.
Detection method：Using Shimadzu LC-20AT liquid chromatographs, with InertSustain C18 columns (4.6 × 150mm × 5
μm) it is chromatographic column, with acetonitrile:1mol/L phosphate aqueous solutions (85：15) it is mobile phase, Detection wavelength 254nm, flow velocity 1.0ml/
Min is measured, HPLC purity 93.5%.
Claims (7)
1. a kind of preparation method of enoxolone octadecyl ester, which is characterized in that including：
(1) in organic solvent, in the presence of organic base, enoxolone reacts 1~3h with p-methyl benzene sulfonic chloride in 20~40 DEG C, instead
White solid is filtered to obtain after answering；Wherein, the organic base is triethylamine, triethanolamine, triethylene diamine, tetramethyl second
Diamines or pyridine；
(2) in organic solvent, in the presence of alkali, the white solid reacts 4~8h, reaction knot in 60~90 DEG C with octadecyl alcolol
Beam detaches to obtain the enoxolone octadecyl ester from system；Wherein, the alkali is sodium carbonate, saleratus or bicarbonate
Sodium.
2. preparation method according to claim 1, which is characterized in that the p-methyl benzene sulfonic chloride and enoxolone
Molar ratio is 1~1.6：1.
3. preparation method according to claim 1, which is characterized in that in step (1), the volume of the organic solvent is sweet
50~150 times of careless hypo acid mole, the volume unit of the organic solvent is milliliter；The organic solvent is acetic acid second
Ester, dichloromethane, chloroform or tetrahydrofuran.
4. preparation method according to claim 1, which is characterized in that in step (1), the volume of the triethylamine is Radix Glycyrrhizae
20~80 times of hypo acid mole, the volume unit of the triethylamine is milliliter.
5. preparation method according to claim 1, which is characterized in that in step (2), the volume of organic solvent is described white
150~300 times of the mole of color solid, the volume unit of the organic solvent is milliliter；The organic solvent for DMF,
Tetrahydrofuran, acetone or chloroform.
6. preparation method according to claim 1, which is characterized in that in step (2), the octadecyl alcolol and white solid
Molar ratio be 0.8~1.3：1.
7. a kind of intermediate for preparing enoxolone octadecyl ester, which is characterized in that structure is：
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