CN101921305B - Method for preparing ginsenoside metabolite M1 fatty acid monoester compound - Google Patents
Method for preparing ginsenoside metabolite M1 fatty acid monoester compound Download PDFInfo
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- CN101921305B CN101921305B CN2010102097304A CN201010209730A CN101921305B CN 101921305 B CN101921305 B CN 101921305B CN 2010102097304 A CN2010102097304 A CN 2010102097304A CN 201010209730 A CN201010209730 A CN 201010209730A CN 101921305 B CN101921305 B CN 101921305B
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- solvent
- catalyzer
- fatty acid
- mol ratio
- dewatering agent
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 18
- 235000014113 dietary fatty acids Nutrition 0.000 title claims abstract description 13
- 239000000194 fatty acid Substances 0.000 title claims abstract description 13
- 229930195729 fatty acid Natural products 0.000 title claims abstract description 13
- -1 ginsenoside metabolite M1 fatty acid Chemical class 0.000 title claims abstract description 11
- 238000000034 method Methods 0.000 title abstract description 5
- 239000002904 solvent Substances 0.000 claims abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 9
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 claims abstract description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims abstract description 7
- 150000002466 imines Chemical class 0.000 claims abstract description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 3
- 150000001348 alkyl chlorides Chemical class 0.000 claims abstract description 3
- 238000002425 crystallisation Methods 0.000 claims abstract description 3
- 230000008025 crystallization Effects 0.000 claims abstract description 3
- 239000000741 silica gel Substances 0.000 claims abstract description 3
- 229910002027 silica gel Inorganic materials 0.000 claims abstract description 3
- 229960001866 silicon dioxide Drugs 0.000 claims abstract description 3
- 229930182494 ginsenoside Natural products 0.000 claims description 16
- 229940089161 ginsenoside Drugs 0.000 claims description 16
- 239000003795 chemical substances by application Substances 0.000 claims description 13
- 238000005886 esterification reaction Methods 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 7
- 150000002632 lipids Chemical class 0.000 claims description 7
- NUKYPUAOHBNCPY-UHFFFAOYSA-N 4-aminopyridine Chemical class NC1=CC=NC=C1 NUKYPUAOHBNCPY-UHFFFAOYSA-N 0.000 claims description 5
- 125000004185 ester group Chemical group 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- 239000008103 glucose Substances 0.000 claims description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 2
- 238000010521 absorption reaction Methods 0.000 claims description 2
- 239000012141 concentrate Substances 0.000 claims description 2
- 238000010025 steaming Methods 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims 1
- 239000003480 eluent Substances 0.000 abstract description 6
- 150000004665 fatty acids Chemical class 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 239000003054 catalyst Substances 0.000 abstract 2
- 239000012024 dehydrating agents Substances 0.000 abstract 2
- GXGJIOMUZAGVEH-UHFFFAOYSA-N Chamazulene Chemical group CCC1=CC=C(C)C2=CC=C(C)C2=C1 GXGJIOMUZAGVEH-UHFFFAOYSA-N 0.000 abstract 1
- 150000003927 aminopyridines Chemical class 0.000 abstract 1
- 238000010828 elution Methods 0.000 abstract 1
- 150000002148 esters Chemical class 0.000 abstract 1
- 238000001179 sorption measurement Methods 0.000 abstract 1
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 239000005639 Lauric acid Substances 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- 241000208343 Panax Species 0.000 description 3
- 230000032050 esterification Effects 0.000 description 3
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 3
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- 235000002791 Panax Nutrition 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229960001701 chloroform Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 150000002194 fatty esters Chemical class 0.000 description 2
- 229960001031 glucose Drugs 0.000 description 2
- CMESPBFFDMPSIY-UHFFFAOYSA-N n,n'-diphenylmethanediimine Chemical compound C1=CC=CC=C1N=C=NC1=CC=CC=C1 CMESPBFFDMPSIY-UHFFFAOYSA-N 0.000 description 2
- KIALCSMRIHRFPL-UHFFFAOYSA-N n-(2,5-diphenylpyrazol-3-yl)-4-nitrobenzamide Chemical compound C1=CC([N+](=O)[O-])=CC=C1C(=O)NC1=CC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 KIALCSMRIHRFPL-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 2
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- SFOOCBDACJVZCY-UHFFFAOYSA-N C1(=CC=CC=C1)P(C1=CC=CC=C1)(C1=CC=CC=C1)C(C)N(C(C)C)C(C)C Chemical compound C1(=CC=CC=C1)P(C1=CC=CC=C1)(C1=CC=CC=C1)C(C)N(C(C)C)C(C)C SFOOCBDACJVZCY-UHFFFAOYSA-N 0.000 description 1
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 229960002246 beta-d-glucopyranose Drugs 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 239000000039 congener Substances 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- GZYPWOGIYAIIPV-JBDTYSNRSA-N ginsenoside Rb1 Chemical compound C([C@H]1O[C@H]([C@@H]([C@@H](O)[C@@H]1O)O)O[C@@](C)(CCC=C(C)C)[C@@H]1[C@@H]2[C@@]([C@@]3(CC[C@H]4C(C)(C)[C@@H](O[C@H]5[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O5)O[C@H]5[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O5)O)CC[C@]4(C)[C@H]3C[C@H]2O)C)(C)CC1)O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O GZYPWOGIYAIIPV-JBDTYSNRSA-N 0.000 description 1
- 230000010224 hepatic metabolism Effects 0.000 description 1
- 230000031891 intestinal absorption Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000001397 quillaja saponaria molina bark Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229930182490 saponin Natural products 0.000 description 1
- 150000007949 saponins Chemical class 0.000 description 1
- 229930000044 secondary metabolite Natural products 0.000 description 1
- 201000000498 stomach carcinoma Diseases 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
The invention discloses a method for preparing a ginsenoside metabolite M1 fatty acid monoester compound. Fatty acid is used as an acylating reagent, dimethylene disubstituted imine is used as a dehydrating agent, 4-N,N-disubstitutent aminopyridine is used as a catalyst. The method comprises the following steps of: reacting the fatty acid and M1 for 1 to 10 hours at the temperature of between 15 and 30 DEG C in a chloroalkane solvent; terminating the reaction by using hydrochloric acid after the reaction is finished; and extracting the residue by using chloroform after the solvent is evaporated, combing the solvent, collecting eluent by concentration, silica-gel column adsorption and elution respectively, and performing concentration and crystallization to obtain three ester products introduced to 3, 4 and 6-O sites of a glucose unit in the M1 structure respectively, wherein the molar ratio of the M1 to the acylating reagent is 1.0: 1.0-1.5, the molar ratio of the M1 to the dehydrating agent is 1.0: 1.0-1.2, the molar ratio of the M1 to the catalyst is 1: 0.060-0.070, and 25 to 32ml of solvent is used in 1mmol of M1. The method has the characteristic of mild conditions, and is suitable for industrialized production.
Description
Technical field
The invention belongs to the plant is the pharmaceutical product technical field that contains organic effective constituent in source; Relate to ginsenoside metabolin M 1 fatty acid ester compound, particularly the preparation method of glucose unit 3,4,6-position hydroxyl mono-esterification product in the M1 structure.Also relate to simultaneously antineoplastic active medicine.
Background technology
Ginsenoside is a main effective constituent in Araliaceae Panax (Panax) the per nnial herb genseng (Panax ginsengC.A.Meyer), has multiple biological activitys such as antitumor.Pharmacokinetic shows that bacterium metabolite and fatty ester possibly be the real effectively one-tenth compositions of ginsenoside performance effect in the ginsenoside intestines.In the intravital metabolic mechanism of research ginsenoside animal, find that the intravital colon bacterium of animal can be with ginsenoside Rb
1, Rb
2, diol type ginsenoside metabolism such as Rc are a kind of new ginsenoside 20-O-(β-D-Glucopyranose)-20 (S)-protopanoxadiol saponin(es (being M1 or C-K).M1 by intestinal absorption after, through liver metabolism, in liver, further react with lipid acid, form the fatty ester EM1 (fatty acid esterof M1) of M1.The esterification products of glucose unit 6-OH among the patent report M1 and synthetic was once arranged, and this compounds shows tangible anti-tumor activity to rat liver cancer, cancer of the stomach etc.But the esterification products of glucose unit 3-OH, 4-OH does not appear in the newspapers as yet among the M1.
Reference
1.CN?100484951C?2009.5.6.
2.United?States?Patent?Application?20060234956.2006.10.19.
3.Jun?Lei，et?al.Isolation，Synthesis?and?Structures?of?Cytotoxic?GinsenosideDerivatives.Molecules，2007，12，2140-2150.
4. the study on the synthesis of ginsenoside secondary metabolite. Li Na etc. modernization of Chinese medicine .2008,28 (7): 523-525
Summary of the invention
Deficiency to prior art exists the object of the present invention is to provide a kind of ginsenoside metabolin
The mono-esterification product of glucose 3,4-position hydroxyl in the M1 structure, and the preparation method of the mono-esterification product of glucose 3,4,6-position hydroxyl in the M1 structure.
The ginsenoside metabolin M 1 structural formula is:
Technical scheme of the present invention is: employing lipid acid is acylating reagent, and adopting the two substituted imine compounds of the two forks of first is dewatering agent, with DMAP (4-dimethylaminopyridine, the abbreviation of 4-Dimethylamino pyridine, down with) or congener be catalyzer, at CH
2Cl
2, CHCl
3, Et
3React in N or the pyridine.
The compounds of this invention general structure (1) is:
R wherein
1, R
2With R
3In one when being acyl group, all the other two is H.
The structure of glucose unit 3-OH position introducing ester group (2) is in the M1 structure:
The structure (3) of glucose unit 4-OH position introducing ester group is in the M1 structure:
The structure (4) of glucose unit 6-OH position introducing ester group is in the M1 structure:
Wherein R is straight chained alkyl, unsaturated fatty acids base, alicyclic radical, has the aromatic base of alkyl, or has the fatty group of alicyclic radical, aromatic base.Wherein the structural formula of straight chained alkyl, unsaturated fatty acids base can be used C
nH
2n+1-x(n=2,4,6,8 ..., 20, X=0,2,4,6) expression; Aromatic base has C
nH
2n+1C
6H
4(or (C
nH
2n+1)
2C
6H
3) (n=0,1,2,3 ..., 12) structure; The preferred compound of the present invention wherein R is straight chained alkyl, unsaturated fatty acids base, alicyclic radical and the aromatic base that has alkyl.
The preparation method of product of the present invention adopts following condition: adopting M1 and lipid acid is acylating reagent; Adopting the two substituted imine compounds of the two forks of first is dewatering agent; With 4-N, the disubstituted EL-970 of N is a catalyzer, in the alkyl chloride solvent, reacts; Temperature of reaction is 15～30 ℃, and the reaction times is 1～10h; Temperature of reaction is usually at room temperature for well, solvent with methylene dichloride or trichloromethane for well.
Reaction finishes and uses the hydrochloric acid termination reaction; Steaming desolventizes the back and uses the chloroform extraction residue; Extract merges; And use anhydrous sodium sulfate drying, dry thing is through concentrating, silicagel column absorption, drip washing, collecting elutriant respectively, again through concentrate, crystallization obtains glucose unit 3,4 in three kinds of M1 structures respectively, the ester group product is introduced in the 6-OH position.
When carrying out single-esterification, the mol ratio of M1 and acylating reagent is 1.0: 1.0～1.5, and the mol ratio of M1 and dewatering agent is 1.0: 1.0～1.2, and the mol ratio of M1 and catalyzer is 1: 0.060～0.070, solvent load for 1mmol M1 with solvent 25～32ml; R in the dewatering agent structure
4=CH (CH
3)
2, or c-C
6H
11(being cyclohexyl, down together);
Reactions step is: in reaction vessel, add lipid acid successively, catalyzer and solvent, after adding M1 5～9h behind the stirring at room 1h with 1N HCl solution stopped reaction.
The used two substituted imine compounds of the two forks of dewatering agent first of the present invention have following structure:
R
4-N＝C＝N-R
4
R wherein
4=CH (CH
3)
2, c-C
6H
11, C
6H
5, p-NO
2-C
6H
4, or be PPh
3-DEAD (abbreviation of triphenylphosphino-diethyl azodicarboxylate triphenylphosphine-ethyl azodicaboxylate, down together), PPh
3-DIPEA (triphenylphosphino-diisopropylethylamine, the abbreviation of triphenylphosphine-diisopropylethylamine, down together).The preferred dewatering agent of the present invention is DIC (diisopropylcarbodiimide, N, the abbreviation of N '-DIC; DCC (dicyclohexylcarbodiimide, N, the abbreviation of N '-NSC 57182 down together); Together following) and DPC (diphenylcarbodiimide; N, the abbreviation of N '-phenylbenzene carbodiimide, down together).R wherein
4=CH (CH
3)
2, c-C
6H
11And phenyl.
Catalyzer 4-N according to the invention, the disubstituted EL-970 of N has following structure:
R wherein
5, R
6Independently be selected from C separately
nH
2n+1And C
mH
2mCOOH, n are 1～18 integer, and m is 1～18 integer.The preferred catalyzer of the present invention is DMAP (4-dimethylaminopyridine, 4-Dimethylamino pyridine) or DPAP (4-{N-decyl, N-propionyl}aminopyridine, R
5=C
10H
21, R
6=CH
2CH
2COOH, 4-{N-decyl, N-propionyloxy } abbreviation of EL-970, down with).The advantage that the present invention gives prominence to has been to provide a kind of method of synthetic above-mentioned esterification products, has the characteristics of mild condition, is suitable for suitability for industrialized production.
Embodiment
Embodiment 1
In the 50mL round-bottomed flask, add successively LAURIC ACID 99 MIN (32.03mg, 0.16mmol), DIC (20.3mg, 0.16mmol), DMAP (2.6mg, 0.008mmol), 5mL CH
2Cl
2As solvent.Add behind the stirring at room 1h M1 (100mg, 0.16mmol).Behind the 5h with 1N HCl solution stopped reaction.Through conventional aftertreatment, use anhydrous Na at last
2SO
4Drying, silica gel column chromatography (eluent is an ethyl acetate/petroleum ether 20%, 50%, 70%) obtains compound 2,3,4 (R=C
11H
23), productive rate is respectively 25%, 25%, 10% (by M1).The analytical data of 3 kinds of compounds is following: compound 2 (R=C
11H
23): white solid is soluble in CH
2Cl
2, CHCl
3, m.p.92～93 ℃; [α]
D 25+ 25 ° of (c 1mg/mL CH
2Cl
2);
IR(cm
-1)：3361.94，2965.67，2932.09，2851.49，1729.85，1629.10，1454.48，1387.31。
1H?NMR(CDCl
3，500MHz)δ：5.098(1H，t，J＝6.6Hz，H-24)，4.912(1H，t，J＝9.3Hz，glc-H-3)，4.623(1H，t，J＝7.75Hz，glc-H-1)，3.86(1H，dd，J＝3.25Hz，gla-Ha-6)，3.767(1H，dd，J＝3.25Hz，glc-Hb-6)，3.649(1H，t，J＝9.1Hz，glc-H-4)，3.579(1H，dt，J＝5.3Hz，10.3Hz，H-12)，3.463(1H，t，J＝8.9Hz，glc-H-2)，3.348(1H，dt/ddd，J＝4.25Hz，glc-H-5)，3.193(1H，dd，J＝4.6Hz，H-3)，2.4(2H，t，J＝7.5Hz，H-2″)，2.18(1H，m，H-17)，2.09(1H，H-23a)，2.01(1H，H-23b)，1.88(1H，H-16a)，1.28(1H，H-16b)，1.88(3H，H-19)，1.72(1H，H-11a)，1.25(1H，H-11b)，1.76(1H，H-13)，1.73(1H，H-1a)，0.97(1H，H-1b)，1.70(2H，H-22)，1.64(2H，H-10″)，1.62(1H，H-26a)，1.57(1H，H-26b)，1.62(1H，H-2a)，1.57(1H，H-2b)，1.63(2H，H-3″)，1.61(3H，H-27)，1.53(2H，H-15)，1.48(2H，H-6)，1.36(1H，H-9)，1.34(3H，H-21)，1.29(2H，H-11″)，1.28(2H，H-7)，1.26(6H，H-4″-9″)，0.98(3H，s，H-28)，0.89(3H，s，H-30)，0.88(3H，t，J＝7.35Hz，H-12″)，0.87(3H，s，H-18)，0.78(3H，s，H-29)，0.71(1H，t，J＝11.0Hz，H-5)。
13C?NMR(CDCl
3，125MHz)175.56，131.83，124.34，97.26，84.57，78.87，78.29，75.6，71.96，70.59，69.64，62.43，55.87，51.69，51.53，49.82，48.14，39.8，39.8，38.95，37.11，35.43，34.77，34.39，31.93，30.62，30.37，29.71，29.62，29.47，29.35，29.27，29.11，28.05，27.42，27.42，26.63，25.68，24.94，22.7，22.44，21.92，18.29，17.76，16.13，15.77，15.39，14.12ppm。
Compound 3 (R=C
11H
23): white solid is soluble in CH
2Cl
2, CHCl
3, m.p. ℃; [α]
D 25+ 17 ° of (c 2mg/mL CH
2Cl
2).
IR(cm
-1)：3388.81，2965.67，2918.66，2851.49，1743.28，1662.69，1622.39，1461.19，1387.31。
1H?NMR(CDCl
3，500MHz)5.101(1H，t，J＝6.4Hz，H-24)，4.869(1H，t，J＝9.6Hz，glc-H-4)，4.561(1H，d，J＝7.7Hz，glc-H-1)，3.694(1H，t，J＝9.4Hz，glc-H-3)，3.663-3.638(1H，m，H-12)，3.663-3.638(1H，m，glc-Ha-6)，3.573-3.548(1H，m，glc-Hb-6)，3.412(1H，t，glc-H-2)，3.395-3.377(1H，m，glc-H-5)，3.196(1H，dd，J＝4.6Hz，11.2Hz，H-3)，2.356(2H，H-2″)，2.19(1H，H-17)，2.13(2H，H-23)，1.89(2H，H-16)，1.83(2H，H-11)，1.777(1H，H-13)，1.73(1H，H-1a)，0.96(1H，H-1b)，1.688(2H，H-22)，1.68(3H，H-26)，1.63(2H，H-3″)，1.63(2H，H-2)，1.61(3H，H-27)，1.58?(2H，H-6)，1.53(2H，H-15)，1.47(2H，H-7)，1.365(1H，H-9)，1.342(3H，H-21)，1.26(1H，H-11″a)，0.86(1H，H-11″b)，1.257(2H，H-10″)，1.25(6H，H-4″-9″)，1.01(3H，H-18)，0.976(3H，H-28)，0.9(3H，H-19)，0.9(3H，H-30)，0.897(3H，H-12″)，0.803(3H，H-29)，0.716(1H，H-5)。
13C?NMR(CDCl
3，125MHz)173.99，131.87，124.31，96.84，84.43，78.9，74.6874.27，74.07，70.67，70.48，61.74，55.91，51.74，51.46，49.86，49.46，48.07，39.82，38.99，38.95，37.12，35.47，34.29，31.92，30.66，30.46，29.71，29.61，29.45，29.34，29.25，29.1，28.06，27.43，26.66，25.69，24.93，22.69，22.36，21.86，18.29，17.76，16.98，16.15，15.77，15.38，14.11ppm。
Compound 4 (R=C
11H
23) structured data and document
[1,3]Data consistent.
Embodiment 2
In the 50mL round-bottomed flask, add successively LAURIC ACID 99 MIN (32.03mg, 0.161mmol), DIC (20.32mg, 0.161mmol), DPAP (3.0mg, 0.008mmol), 5mL CHCl
3As solvent.Add behind the stirring at room 1h M1 (100mg, 0.16mmol).Behind the 8h with 1N HCl solution stopped reaction.Through conventional aftertreatment, use anhydrous Na at last
2SO
4Drying after concentrating, obtains compound 2,3,4 (R=C through silica gel column chromatography (eluent is an ethyl acetate/petroleum ether 20%, 50%, 70%)
11H
23), productive rate is respectively 10%, 15%, 30% (by M1).The analytical data of three kinds of compounds is shown in embodiment 1.
Embodiment 3
In the 50mL round-bottomed flask, add successively LAURIC ACID 99 MIN (32.03mg, 0.16mmol), DCC (33.0mg, 0.16mmol), DMAP (2.6mg, 0.008mmol), 5mL CH
2Cl
2As solvent.Add behind the stirring at room 1h M1 (100mg, 0.16mmol).Behind the 5h with 1N HCl solution stopped reaction.Through conventional aftertreatment, use anhydrous Na at last
2SO
4Drying after concentrating, obtains compound 2,3,4 (R=C through silica gel column chromatography (eluent is an ethyl acetate/petroleum ether 20%, 50%, 70%)
11H
23), productive rate is respectively 15%, 15%, 20% (by M1).The analytical data of three kinds of compounds is shown in embodiment 1.
Embodiment 4
In the 50mL round-bottomed flask, add successively LAURIC ACID 99 MIN (32.03mg, 0.16mmol), DPC (diphenylcarbodiimide, N, N '-phenylbenzene carbodiimide) (31.08mg, 0.16mmol), DMAP (1.4mg, 0.011mmol), 5mL CH
2Cl
2As solvent.Add behind the stirring at room 1h M1 (100mg, 0.16mmol).Behind the 5h with 1N HCl solution stopped reaction.Through conventional aftertreatment, use anhydrous Na at last
2SO
4Drying after concentrating, obtains compound 2,3,4 (R=C through silica gel column chromatography (eluent is an ethyl acetate/petroleum ether 20%, 50%, 70%)
11H
23), productive rate is respectively 10%, 15%, 10% (by M1).The analytical data of three kinds of compounds is shown in embodiment 1.
Embodiment 5
In the 50mL round-bottomed flask, add successively capric acid (41.32mg, 0.24mmol), DIC (30.29mg, 0.24mmol), DMAP (6.47mg, 0.053mmol), 5mL CH
2Cl
2As solvent.Add behind the stirring at room 1h M1 (150mg, 0.24mmol).Behind the 5h with 1N HCl solution stopped reaction.Through conventional aftertreatment, use anhydrous Na at last
2SO
4Drying, silica gel column chromatography (eluent is an ethyl acetate/petroleum ether 30%, 50%, 70%) obtains compound 2,3,4 (R=C
9H
19), productive rate is respectively 10%, 20%, 30% (by M1).
Compound 2 (R=C
9H
19): white solid is soluble in CH
2Cl
2, CHCl
3, IR (cm
-1): 3381.98,2958.96,2919.01,2851.49,2360.20,1736.57,1622.40,1461.19,1407.45;
Compound 3 (R=C
9H
19): white solid is soluble in CH
2Cl
2, CHCl
3, IR (cm
-1): 3382.09,2958.96,2918.66,2852.06,2361.19,1736.57,1622.30,1460.53,1406.62;
Compound 4 (R=C
9H
19): water white transparency oily thing is soluble in CH
2Cl
2, CHCl
3, IR (cm
-1): 3382.09,2958.96,2918.66,2851.49,2361.19,1736.57,1622.39,1461.19,1407.46.
Claims (6)
1. the preparation method of ginsenoside metabolin M 1 fatty acid ester compound is that glucose 3,4,6-position hydroxyl carry out single-esterification and form in the M1 of following structure compound;
It is characterized in that: be acylating reagent with lipid acid, the two substituted imines of the two forks of first are dewatering agent, 4-N, and the disubstituted EL-970 of N is a catalyzer, in the solvent alkyl chloride, reacts 1～10h with M1 down at 15～30 ℃; Reaction finishes and uses the hydrochloric acid termination reaction; Steaming desolventizes the back and uses the chloroform extraction residue; Extraction liquid merges; And use anhydrous sodium sulfate drying, dry thing is through concentrating, silicagel column absorption, drip washing, collecting elutriant respectively, again through concentrate, crystallization obtains glucose unit 3,4 in three kinds of M1 structures respectively, the ester group product is introduced in the 6-OH position;
Wherein: the mol ratio of M1 and acylating reagent is 1.0: 1.0～1.5, and the mol ratio of M1 and dewatering agent is 1.0: 1.0～1.2, and the mol ratio of M1 and catalyzer is 1: 0.060～0.070, solvent load for 1mmol M1 with solvent 25～32ml;
Said catalyzer 4-N, the disubstituted EL-970 of N has following structure:
R wherein
5, R
6Independently be selected from C separately
nH
2n+1And C
mH
2mCOOH, n are 1～18 integer, and m is 1～18 integer;
The structure of the two substituted imines of the two forks of said dewatering agent first is:
R
4-N＝C＝N-R
4
R wherein
4=CH (CH
3)
2, c-C
6H
11, C
6H
5, or p-NO
2-C
6H
4
2. according to the preparation method of the said ginsenoside metabolin M 1 fatty acid ester compound of claim 1; It is characterized in that when carrying out single-esterification; The mol ratio of M1 and acylating reagent is 1.0: 1.0; The mol ratio of M1 and dewatering agent is 1.0: 1.0, and the mol ratio of M1 and catalyzer is 1: 0.060～0.070, solvent load for 1mmol M1 with solvent 25～32ml; R in the dewatering agent structure
4=CH (CH
3)
2, or c-C
6H
11
3. according to the preparation method of the said ginsenoside metabolin M 1 fatty acid ester compound of claim 1, it is characterized in that when carrying out single-esterification, in the structure of described catalyzer, R
5Be C
10H
21, R
6Be CH
2CH
2COOH.
4. according to the preparation method of the said ginsenoside metabolin M 1 fatty acid ester compound of claim 1, it is characterized in that when carrying out single-esterification, in the structure of described catalyzer, R
5=R
6=CH
3
5. according to the preparation method of the said ginsenoside metabolin M 1 fatty acid ester compound of claim 1; It is characterized in that reactions step is: in reaction vessel, add lipid acid successively; Catalyzer and solvent, after adding M15～9h behind the stirring at room 1h with 1N HCl solution stopped reaction.
6. according to the preparation method of the said ginsenoside metabolin M 1 fatty acid ester compound of claim 1; When it is characterized in that carrying out single-esterification; The mol ratio of M1 and acylating reagent is 1.0: 1.0; The mol ratio of M1 and dewatering agent is 1.0: 1.0, and the mol ratio of M1 and catalyzer is 1: 0.060～0.070, solvent load for 1mmol M1 with solvent 25～32ml; R in the dewatering agent structure
4=CH (CH
3)
2, or c-C
6H
11In the structure of catalyzer, R
5=R
6=CH
3Or R
5Be C
10H
21, R
6Be CH
2CH
2COOH; Reactions step is: in reaction vessel, add lipid acid successively, catalyzer and solvent, after adding M15～9h behind the stirring at room 1h with 1NHCl solution stopped reaction.
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