CN103880653B - The preparation method of sub-tribute diterpenoid acid compound and method gained compound thereof - Google Patents

The preparation method of sub-tribute diterpenoid acid compound and method gained compound thereof Download PDF

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CN103880653B
CN103880653B CN201410148590.2A CN201410148590A CN103880653B CN 103880653 B CN103880653 B CN 103880653B CN 201410148590 A CN201410148590 A CN 201410148590A CN 103880653 B CN103880653 B CN 103880653B
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陈玉琦
董锋
曾峥
吴靓
武广龙
于宝辉
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Zhen Ao Group Co ltd
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Abstract

The invention discloses preparation method and the method gained compound thereof of sub-tribute diterpenoid acid compound, sub-tribute diterpenoid acid is by compound

Description

The preparation method of sub-tribute diterpenoid acid compound and method gained compound thereof
Technical field
The present invention relates to chemosynthesis technical field, particularly the chemical preparation of Yacon diterpene acid compounds (and pharmacologically acceptable salts) and method gained compound thereof.
Background technology
Ya Gong (Smallanthus sonchifolitus (Proepp. & Endl.) H.Robinson, former name Polymnia sonchifolia), composite family (Asteraceae), tubiform floret subfamily (Heliantheae) plant, primary in the Andes of height above sea level 880-3500 rice, from Venezuela's expression in the eyes to Argentinian northeast.Ya Gong plantation has now spread all over other each continent, originally planted among a small circle in several states of the U.S., after sell in supermarket as a kind of special vegetables in New Zealand, the eighties in 20th century, sub-tribute introduced a fine variety to the Japan in Asia from New Zealand, and then introduce a fine variety the states such as Italy, Germany, France, Czech, Korea S, Brazil, Russia, introduced a fine variety to China in the recent period, in Taiwan, Yunnan, Hainan, Hunan, the ground successful introduction such as Liaoning.
Sub-tribute fruit is fragrant and sweet crisp and refreshing, and can be used as fruit and eat, its Subterranean fruits part contains a large amount of polyphenol, Nutriflora P and cellulose family composition, discovery among the people its have anti-oxidant, anti-aging, promote gastrointestinal peristalsis, prevent the functions such as constipation.Research in recent years finds, the carbohydrate in sub-tribute fruit is not absorption of human body, belongs to low calorific food, is therefore well suited for slimmer and eats.Ya Gong (Smallanthus sochifolius) leaf can be processed into tea-drinking use, reduces blood pressure, antidiabetic effect.
Although since the seventies in last century, the chemical composition of people to Smallanthus platymiscium has carried out a series of research, up to the present, has therefrom obtained the different chemical composition of 100 various structures, comprise various types of new monoterpene, sesquiterpene, diterpene, and acetophenone derivs.But up to now, rarely have the definite report about anti-diabetic activity composition in sub-tribute.CN101225042 patent once reported four diterpene acids extracted from sub-tribute, and extracting method and structural identification data.But there is no the report of the synthetic method about these four compounds.
Summary of the invention
The object of the present invention is to provide the chemical preparation process of sub-tribute diterpenoid acid, and method gained compound.
A preparation method for sub-tribute diterpenoid acid compound, obtains as follows:
1. preparation formula (XII) compound is reacted by formula (XIII) compound and acylating reagent;
2. by formula (XII) compound and oxidant reaction preparation formula (XI) compound;
3. by formula (XI) compound and oxidant reaction preparation formula (X) compound;
4. under alkali existence condition, preparation formula (VIII) compound is reacted with formula (X) compound by formula (IX) compound;
5. preparation formula (VII) compound is reacted by formula (VIII) compound and reductive agent;
6. under alkali existence condition, preparation formula (VI) compound is reacted with acylating reagent by formula (VII) compound;
7. (V) compound is prepared by formula (VI) compound and oxidant reaction;
8. by formula (V) compound and oxidant reaction preparation formula (III) compound;
9. under the effect of alkali, preparation formula (II) compound is reacted by formula (III) compound and formula (IV) compound;
10. under the effect of alkali, formula (I) compound is hydrolyzed to by formula (II) compound;
Described step 1.-10. in:
R 1for (Z)-4-hydroxyl-2-butylene-2-base or (R)-2-hydroxyl-3-butene-2-Ji, structure is:
R 2for 2-methyl-propen-1-base or 3-methyl-butene-2-base,
Structure is:
R 1' structure is:
R 3, R 4, R 5and R 6independently represent by the C1-5 straight or branched alkyl of 0-1 substituting group W replacement, by the C3-6 cycloalkyl of 0-1 substituting group W replacement, by the C3-6 thiazolinyl of 0-1 substituting group W replacement or by the C3-6 alkynyl of 0-1 substituting group W replacement;
Described W is independently selected from hydroxyl, amino, carboxyl, sulfydryl, alkoxyl group or first sulfydryl;
R 7for ethyl;
R 8it is 2,2,2-trifluoroethyl.
Further, step 1. in:
Described acylating reagent is selected from aceticanhydride or Acetyl Chloride 98Min.;
Alkali used is mineral alkali and/or organic bases;
Wherein mineral alkali is selected from one or more in sodium bicarbonate, saleratus, salt of wormwood, cesium carbonate or sodium carbonate;
Organic bases be selected from pyridine, triethylamine, lupetidine, DMAP one or more;
Reaction solvent be selected from pyridine, tetrahydrofuran (THF), methylene dichloride, ether, acetonitrile, aceticanhydride, methyltetrahydrofuran one or more;
Temperature of reaction is 0 DEG C-180 DEG C; Reaction times is 1-48 hour;
The molar ratio of described formula (XIII) compound and acylating reagent is 1:1 ~ 1:10;
Step 2. in:
Described oxygenant be selected from Periodic acid, metachloroperbenzoic acid, hydrogen peroxide, Peracetic Acid, potassium hydrogen persulfate one or more;
Reaction solvent be selected from tetrahydrofuran (THF), methylene dichloride or chloroform one or more;
Temperature of reaction is 0 DEG C ~ 50 DEG C; Reaction times is 1-48 hour;
The molar ratio of described formula (XII) compound and oxygenant is 1:1 ~ 1:10;
Step 3. in:
Described oxygenant be selected from Periodic acid, metachloroperbenzoic acid, hydrogen peroxide, Peracetic Acid or potassium hydrogen persulfate one or more;
The solvent of reaction is organic solvent and/or water, described organic solvent be selected from tetrahydrofuran (THF), methylene dichloride, chloroform one or more;
Temperature of reaction is 0 DEG C ~ 50 DEG C; Reaction times is 1-48 hour;
The molar ratio of described formula (XI) compound and oxygenant is 1:1 ~ 1:10;
Further, step 10. in:
Described alkali is mineral alkali, described mineral alkali be selected from lithium hydroxide, sodium hydroxide, potassium hydroxide one or more.
Solvent for use is organic solvent and/or water, described organic solvent be selected from methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF) one or more.
Temperature used is 0 degree to 100 degrees Celsius.
The ratio of formula (II) compound and alkali is 1:1 ~ 1:10.
The general formula that the present invention also provides aforesaid method to prepare is the sub-tribute diterpenoid acid of (I).
The present invention also provide be made up of described sub-tribute diterpenoid acid, pharmaceutically acceptable salt.
Further, described sub-tribute diterpene hydrochlorate is inorganic base salts.
Further, described inorganic base salts is sodium salt.
The present invention also provides with the above-mentioned sub-tribute diterpenoid acid of 0.1%-99.5% or its pharmacy acceptable salt for activeconstituents (weight ratio), and the solid preparation made, as tablet, pulvis, granula, capsule; Liquid preparation, if water or oil-suspending agent or other liquid preparation are as syrup; Injection, as injection liquid, powder pin, the transfusion of Large Copacity sodium-chlor.
The present invention also provides and comprises above-mentioned sub-tribute diterpenoid acid compound, its pharmacy acceptable salt, and solvate or its isomer, or the prodrug of its prodrug or its salt, with one or more pharmaceutical carriers and/or thinner, make and be applicable to clinical pharmaceutical preparation.
Further, step 9. in:
Described alkali is mineral alkali and/or organic bases;
Wherein mineral alkali is selected from potassium hydroxide, sodium hydroxide, salt of wormwood or sodium carbonate;
Organic bases is selected from sodium hydride, n-Butyl Lithium, 2-butyllithium, tert-butyl lithium, potassium tert.-butoxide, sodium tert-butoxide, the two silicon amine lithium of hexamethyl, the two silicon amine sodium of hexamethyl or the two silicon amine potassium of hexamethyl;
The solvent of reaction be selected from tetrahydrofuran (THF), ether, methyl tertiary butyl ether or methyltetrahydrofuran one or more;
Temperature of reaction is-78 DEG C of extremely backflows; According to the difference of alkali, temperature of reaction is different, and if sodium hydride is highly basic, temperature of reaction is lower; In some cases, when using mineral alkali, reaction needed is carried out at high temperature, likely reaches backflow.
The molar ratio of formula (III) and formula (IV) compound is at 1:1 ~ 1:3;
Formula (II) compound that the present invention also provides aforesaid method to prepare.
Further, step 8. in:
Oxygenant be selected from Periodic acid, metachloroperbenzoic acid, hydrogen peroxide, Peracetic Acid, potassium hydrogen persulfate one or more;
The solvent of reaction is organic solvent and/or water, described organic solvent be selected from tetrahydrofuran (THF), methylene dichloride, chloroform one or more;
The temperature of reaction is 0 DEG C ~ 50 DEG C;
The molar ratio of described formula (V) compound and oxygenant is 1:1 ~ 1:10;
Formula (III) compound that the present invention also provides aforesaid method to prepare.
Formula (IV) compound that the present invention also provides aforesaid method to prepare.
Further, step 7. in:
Described oxygenant be selected from Periodic acid, metachloroperbenzoic acid, hydrogen peroxide, Peracetic Acid, potassium hydrogen persulfate one or more;
The solvent of reaction is one or more in tetrahydrofuran (THF), methylene dichloride, chloroform;
The temperature of reaction is 0 DEG C ~ 50 DEG C.
The molar ratio of described formula (VI) compound and oxygenant is 1:1 ~ 1:10;
Formula (V) compound that the present invention also provides aforesaid method to prepare.
Further, step 6. in:
Described acylating reagent is aceticanhydride or Acetyl Chloride 98Min.;
Alkali used is mineral alkali and/or organic bases;
Wherein mineral alkali is selected from one or more in sodium bicarbonate, saleratus, salt of wormwood, cesium carbonate, sodium carbonate;
Organic bases be selected from pyridine, triethylamine, lupetidine, DMAP one or more;
The solvent of reaction be selected from pyridine, tetrahydrofuran (THF), methylene dichloride, ether, acetonitrile, aceticanhydride, methyltetrahydrofuran one or more;
Temperature of reaction is 0 DEG C ~ 50 DEG C; Reaction times is 1-48 hour;
Described formula (VII) is 1:1 ~ 1:10 with the molar ratio of acylating reagent;
Formula (VI) compound that the present invention also provides aforesaid method to prepare.
Further, step 5. in:
Described reductive agent be selected from lithium aluminum hydride, sodium borohydride, diisobutyl aluminum hydrogen one or more;
The solvent of reaction is tetrahydrofuran (THF) and/or ether;
Temperature of reaction be subzero 78 degree to room temperature; Reaction times is 1-48 hour; According to the difference of reductive agent, temperature of reaction is different, as used diisobutyl aluminum hydrogen, may need-78 degrees Celsius of reactions, but when using sodium borohydride, temperature of reaction is room temperature.
The molar ratio of described formula (VIII) compound and reductive agent is 1:1 ~ 1:10;
(VII) compound that the present invention also provides aforesaid method to prepare.
Further, step 4. in:
Alkali is mineral alkali and/or organic bases,
Wherein mineral alkali is selected from one or more in potassium hydroxide, sodium hydroxide, salt of wormwood, sodium carbonate;
Organic bases is selected from sodium hydride, n-Butyl Lithium, 2-butyllithium, tert-butyl lithium, potassium tert.-butoxide, sodium tert-butoxide, the two silicon amine lithium of hexamethyl, one or more in the two silicon amine sodium of hexamethyl, the two silicon amine potassium of hexamethyl;
Reaction solvent be selected from tetrahydrofuran (THF), ether, methyl tertiary butyl ether, methyltetrahydrofuran one or more;
Temperature of reaction is in subzero 78 degrees Celsius of extremely backflows; According to the difference of alkali, temperature of reaction is different, and the sodium hydride used in embodiment is highly basic, and temperature of reaction is lower; In some cases, when using mineral alkali, reaction needed is carried out at high temperature, likely reaches backflow.Reaction times is 1-48 hour;
The molar ratio of described formula (X) compound and formula (IX) compound is at 1:1 ~ 1:3;
Formula (VIII) compound that the present invention also provides aforesaid method to prepare.
Formula (I) compound preferred structure is as table 1:
Table 1 compd A, B, C, D structure and data thereof
Method provided by the invention prepares sub-tribute diterpenoid acid compound and midbody compound thereof, wherein compd A find in testing in vitro Dui α ?-glucuroide has good inhibit activities, its activity intensity and Remedies for diabetes glucobay (acarbose) are suitable, can apply preparing in antidiabetic medicine.
Embodiment
The following examples can make the present invention of those skilled in the art comprehend, but limit invention never in any form.
embodiment 1:(2Z, 6Z, 10Z)-12-hydroxyl-6-(methylol)-10-methyl-2-(4-methylpent-3-thiazolinyl) 12 the preparation of-2,6,10-tri-olefinic carboxylic acid (compd A)
The synthetic route of compd A is as follows:
Compound I X-a synthesizes
Be added to by methylpyridinium iodide magnesium (166mL, 500mmol) in 400mL anhydrous diethyl ether, cryosel bath is cooled to 0 DEG C.Anhydrous diethyl ether (100mL) solution of Cyclopropyl Methyl Ketone (42g, 500mmol) is slowly dripped in this solution.In dropping process, control temperature is not higher than 5 DEG C.After dropwising, room temperature continues stirring 2 hours.This reaction solution is slowly poured in dilute sulphuric acid (the 200mL vitriol oil, the 500mL water) solution being cooled to 0 DEG C in advance.Room temperature stirs 1 hour again.The aqueous phase extracted with diethyl ether (2x500mL) that separatory obtains, merges ether phase, with the water washing of 1L saturated common salt.Anhydrous sodium sulfate drying.Pressure reducing and steaming solvent, with column chromatography purification (200-300 order normal phase column chromatography silica gel, moving phase sherwood oil: ethyl acetate=1000:1), obtains the iodo-2-methylpent of 5--2-alkene, 63g, light yellow liquid, productive rate 60%. 1H NMR(400MHz,CDCl 3)δ5.12(t,1H),3.13(t,2H),2.60(dt,2H),1.72(s,3H),1.64(s,3H)。
By 90mL2-(diethoxy phosphoryl)-ethyl acetate (100g; 440mmol) be added to containing 24g(60%) in the 1.5L dry DMF suspension of sodium hydride (600mmol); stirring at room temperature is after 2 hours; the 200mL anhydrous DMF solution of 5-iodo-2-methylpent-2-alkene (61.5g, 300mmol) is dripped in this reaction solution.In nitrogen atmosphere, heat this mixture to 60 DEG C, and maintain this temperature stir spend the night.Add 2L water, extraction into ethyl acetate (2x1.5L), combining extraction liquid after reaction solution cooling, use the 0.1NHCl solution of 1L successively, the water washing of 1L saturated common salt, anhydrous sodium sulfate drying.Pressure reducing and steaming solvent, with column chromatography purification (200-300 order normal phase column chromatography silica gel, moving phase sherwood oil: ethyl acetate=3:1), obtains IX-a, 61g light yellow oil, productive rate 40%. 1H NMR(400MHz,CDCl 3)δ5.11-5.02(m,1H),4.30-4.10(m,6H),3.02-2.90(m,1H),2.12-1.82(m,4H),1.70(s,3H),1.59(s,3H)1.38-1.27(m,9H)。
The synthesis of compound IV-a
By 2-(two trifluoro ethoxy phosphoryls)-ethyl acetate (10g; 30mmol) be added to containing 1.6g(60%) in the 100mL dry DMF suspension of sodium hydride (40mmol); stirring at room temperature is after 2 hours; the 20mL anhydrous DMF solution of 5-iodo-2-methylpent-2-alkene (4.2g, 20mmol) is dripped in this reaction solution.Stirred overnight at room temperature in nitrogen atmosphere.Add 200mL water, extraction into ethyl acetate (2x200mL), combining extraction liquid after reaction solution cooling, use the 0.1N HCl solution of 200mL successively, the water washing of 200mL saturated common salt, anhydrous sodium sulfate drying.Pressure reducing and steaming solvent, with column chromatography purification (200-300 order normal phase column chromatography silica gel, moving phase sherwood oil: ethyl acetate=3:1), obtains IV-a, 7.5g light yellow oil, productive rate 60%. 1H NMR(400MHz,CDCl 3)δ5.10-5.03(m,1H),4.50-4.30(m,4H),4.29-4.22(m,2H),3.18-3.08(m,1H),2.18-1.84(m,4H),1.72(s,3H),1.61(s,3H)1.32(t,3H)。
The synthesis of compounds X II-a
Salt of wormwood (8.22g, 59.5mmol) is added in the 40mL aceticanhydride solution of vernol (40g, 259mmol).Reaction solution is heated to 135 DEG C, and stirring is spent the night.Add 1L diluted ethyl acetate after reaction solution cooling, use 500mL water successively, the water washing of 500mL saturated common salt, anhydrous sodium sulfate drying.Pressure reducing and steaming solvent, with column chromatography purification (200-300 order normal phase column chromatography silica gel, moving phase sherwood oil: ethyl acetate=100:1 ~ 10:1), obtains XII-a, 45.6g, colorless oil, productive rate 90%.
The synthesis of compounds X I-a
By compounds X II-a(45.6g, 233mmol) be dissolved in 300mL anhydrous methylene chloride, ice bath is cooled to 0 DEG C, adds m-CPBA(metachloroperbenzoic acid) (62.9g, 256mmol).Reaction solution at room temperature stirs 2 hours.Add 200mL aqueous sodium hydroxide solution (2M) cancellation reaction, dichloromethane extraction (2x150mL), combining extraction liquid, with the water washing of 200mL saturated common salt, anhydrous sodium sulfate drying.Pressure reducing and steaming solvent, obtains XI-a, 44.8g, light yellow oil, productive rate 90%.
The synthesis of compounds X-a
At 0 DEG C, by H 5iO 6the aqueous solution (100mL) of (27.8g, 130.7mmol) is added drop-wise to compounds X I-a(25.2g, 118.8mmol) tetrahydrofuran solution (100mL) in.After reaction solution stirs 3 hours, add 200mL saturated aqueous common salt, extraction into ethyl acetate (2x200mL), combining extraction liquid, anhydrous sodium sulfate drying.Pressure reducing and steaming solvent, with column chromatography purification (200-300 order normal phase column chromatography silica gel, moving phase sherwood oil: ethyl acetate=10:1 ~ 5:1), obtains X-a, 15.3g, light yellow oil, productive rate 75%. 1H NMR(300MHz,CDCl 3)δ9.77(s,1H),5.39(t,1H,J=7.5Hz),4.57(d,2H,J=9.0Hz),2.55-2.52(m,2H),2.46-2.40(m,2H),2.05(s,3H),1.75(s,1H)。
Compound VI II-a synthesizes
At 0 DEG C, by 3.96g(60%) sodium hydride (99mmol) joins Compound I X-a(27.5g, in dry tetrahydrofuran solution (100mL) 90mmol), stir after 2 hours, be cooled to-20 DEG C, in mixed solution, drip compounds X-a(15.3g, 90mmol) tetrahydrofuran solution (100mL).Reaction solution continues stirring 2 hours.Add 50mL saturated aqueous ammonium chloride cancellation reaction, extraction into ethyl acetate (2x200mL), combining extraction liquid, with the water washing of 200mL saturated common salt, anhydrous sodium sulfate drying.Pressure reducing and steaming solvent, with column chromatography purification (200-300 order normal phase column chromatography silica gel, moving phase sherwood oil: ethyl acetate=20:1 ~ 15:1), obtains VIII-a, 3.68g, light yellow oil, productive rate 13% and isomer VIII-a1,9.2g, productive rate 32%. 1H NMR(300MHz,CDCl 3)δ5.80(t,1H,J=7.5Hz),5.08-5.06(m,1H),4.58-4.55(m,1H),4.56(d,2H,J=9Hz),4.20(dd,2H,J=13.5,7.5Hz),2.56-2.48(m,2H),2.25-2.18(m,4H),2.15-2.08(m,1H),2.05(s,3H),1.75(s,3H),1.68(s,3H),1.55(s,3H),1.25(t,3H,J=7.5Hz)。
Compound VI I-a synthesizes
At 0 DEG C, by compound VI II-a(3.68g, 11.4mmol) anhydrous ether solution (10mL) be added drop-wise in the 40mL anhydrous diethyl ether suspension containing 2.17g lithium aluminium hydride (57.1mmol).Reaction stirring added Na after 1 hour 2sO 410H 2o, the solid that filtering is separated out, filter cake ethyl acetate washing (2x50mL), merges organic phase, with the water washing of 100mL saturated common salt, anhydrous sodium sulfate drying.Pressure reducing and steaming solvent, obtains VII-a, 2.1g, light yellow oil, productive rate 77%. 1H NMR(300MHz,CDCl 3)δ5.47(t,1H,7.5Hz),5.31(t,1H,6.0Hz),5.12-5.10(m,1H),4.09-4.02(m,4H),2.22-2.14(m,8H),1.76(s,3H),1.74-1.70(m,2H),1.69(s,3H),1.61(s,3H)。
Compound VI-a synthesizes
Aceticanhydride (4.48g, 44mmol) is joined compound VI I-a(2.1g, 8.8mmol) pyridine solution (10mL) in.React after 4 hours under room temperature, add 100mL diluted ethyl acetate, use 1M hydrochloric acid soln (2x50mL) successively, saturated aqueous common salt (50mL) washs, anhydrous sodium sulfate drying.Pressure reducing and steaming solvent, with column chromatography purification (200-300 order normal phase column chromatography silica gel, moving phase sherwood oil: ethyl acetate=10:1), obtains VI-a, 2.7g, light yellow oil, productive rate 95%. 1H NMR(300MHz,CDCl 3)δ5.39-5.35(m,2H),5.08(bs,1H),4.58-4.54(m,4H),2.21-2.14(m,4H),2.09-2.07(m,4H),2.06(s,3H),2.05(s,3H),1.77(s,3H),1.69(s,3H),1.61(s,3H)。
The synthesis of compound V-a
By compound VI-a(2.7g, 8.38mmol) molten in 30mL anhydrous methylene chloride, ice bath is cooled to 0 DEG C, adds m-CPBA(2.26g, 9.22mmol).Reaction solution at room temperature stirs 2 hours.Add 20mL aqueous sodium hydroxide solution (2M) cancellation reaction, dichloromethane extraction (2x20mL), combining extraction liquid, with the water washing of 20mL saturated common salt, anhydrous sodium sulfate drying.Pressure reducing and steaming solvent, obtains V-a, 2.4g, light yellow oil, productive rate 85%.
The synthesis of compound III-a
At 0 DEG C, by H 5iO 6the aqueous solution (20mL) of (1.66g, 7.87mmol) is added drop-wise to compound V-a(2.4g, 7.1mmol) tetrahydrofuran solution (20mL) in.After reaction solution stirs 3 hours, add 20mL saturated aqueous common salt, extraction into ethyl acetate (2x20mL), combining extraction liquid, anhydrous sodium sulfate drying.Pressure reducing and steaming solvent, with column chromatography purification (200-300 order normal phase column chromatography silica gel, moving phase sherwood oil: ethyl acetate=10:1 ~ 5:1), obtains III-a, 1.8g, light yellow oil, productive rate 85%. 1H NMR(400MHz,CDCl 3)δ9.79(s,1H),5.43-5.39(m,2H),4.61(s,2H),4.55(d,2H,J=3.0Hz),2.59-2.53(m,2H),2.45-2.41(m,2H),2.25-2.10(m,4H),2.06(s,3H),2.05(s,3H),1.77(s,1H)。
The synthesis of Compound II per-a
At 0 DEG C, by 132mg(60%) sodium hydride (3.3mmol) joins compound IV-a(1.25g, in dry tetrahydrofuran solution (5mL) 3.0mmol), stir after 2 hours, be cooled to-20 DEG C, in mixed solution, drip compound III-a(0.9g, 3.0mmol) tetrahydrofuran solution (5mL).Reaction solution continues stirring 2 hours.Add 10mL saturated aqueous ammonium chloride cancellation reaction, extraction into ethyl acetate (2x20mL), combining extraction liquid, with the water washing of 20mL saturated common salt, anhydrous sodium sulfate drying.Pressure reducing and steaming solvent, purifies (Waters Auto-purification system, Gemini-C18150x21.2mm, 5um by preparation liquid phase, moving phase: ACN-H2O, 40% ~ 60%, 0.1%TFA, flow velocity 20mL/Min), obtain II-a, 200mg, light yellow oil, productive rate 15%. 1H NMR(300MHz,CDCl 3)δ5.81(t,1H,J=7.5Hz),5.41-5.34(m,2H),5.08(t,1H,J=7.5Hz),4.59-4.54(m,4H),4.24-4.12(m,2H),2.57-2.50(m,2H),2.25-2.10(m,10H),2.06(s,3H),2.05(s,3H),1.76(s,3H),1.68(s,3H),1.58(s,3H),1.30(t,3H,J=7.5Hz)。
The synthesis of compd A
Sodium hydroxide (178mg, 4.4mmol) is joined Compound II per-a(200mg, 0.44mmol) ethanol/water (1:1,6mL) solution in.Reaction solution is heated to 60 DEG C, stirs 2 hours, adds 1M salt acid for adjusting pH to 3 after cooling, extraction into ethyl acetate (2x20mL), combining extraction liquid, anhydrous sodium sulfate drying.Pressure reducing and steaming solvent, purifies (Waters Auto-purification system, Gemini-C18150x21.2mm, 5um by preparation liquid phase, moving phase: ACN-H2O, 40% ~ 60%, 0.1%TFA, flow velocity 20mL/Min), obtain A, 74mg, light yellow oil, productive rate 50%. 1H NMR(300MHz,CDCl 3)δ5.99(t,1H,J=7.5Hz),5.45(t,1H,J=7.5Hz),5.29(t,1H,J=7.5Hz)，5.08(t,1H,J=7.5Hz)，4.19(bs,4H),4.12-4.08(m,4H),2.61-2.56(m,2H),2.24-2.10(m,10H),1.74(s,3H),1.67(s,3H),1.58(s,3H)。
Embodiment 2:(2Z, 6Z, 10Z) synthesis of-12-hydroxyl-6-(methylol)-10-methyl-2-(4-methyl-3-methylene radical pentenyl) ten two-2,6,10-tri-olefinic carboxylic acids (Compound C)
The synthetic route of Compound C is as follows:
The synthesis of compound IV-b
Be added in 170mL anhydrous methylene chloride by 2,3-dimethyl-1-butylene (8.3g, 98.16mmol) and paraformaldehyde (2.46g, 81.8mmol) successively, ice bath is cooled to 0 DEG C.Slowly Me is dripped in this solution 2the hexane solution (100mL, 90mmol, 0.9M) of AlCl.After dropwising, room temperature continues stirring and spends the night.In this reaction solution, 5mL NaH is poured under ice bath 2pO 4solution, separates out precipitation, drips 10% hydrochloric acid until precipitation is dissolved completely.Isolate organic phase, aqueous phase, with dichloromethane extraction (2x200mL), merges organic phase, anhydrous sodium sulfate drying.Pressure reducing and steaming solvent, with column chromatography purification (200-300 order normal phase column chromatography silica gel, moving phase sherwood oil 100% ~ methylene dichloride 100%), obtains 4-methyl-3-methyne-1-amylalcohol, 8g, colorless oil, productive rate 71%. 1H NMR(300MHz,CDCl 3)δ4.88(s,1H),4.76(s,1H),3.72(t,2H,J=7.5Hz),2.34-2.30(m,2H),2.29-2.22(m,1H),1.05(s,3H),1.03(s,3H)。
Successively by triphenylphosphine (17.7g, 67.4mmol) with imidazoles (9.6g, 67.4mmol) add 4-methyl-3-methyne-1-amylalcohol (7g, in 150mL anhydrous tetrahydrofuran solution 61.3mmol), in this reaction solution, the 150mL anhydrous tetrahydrofuran solution of iodine (17g, 67.4mmol) is dripped under ice bath.Reaction solution room temperature for overnight.250mL saturated sodium thiosulfate solution is added, dichloromethane extraction (2x250mL), combining extraction liquid in reaction solution, with the water washing of 250mL saturated common salt, anhydrous sodium sulfate drying.Pressure reducing and steaming solvent, with column chromatography purification (200-300 order normal phase column chromatography silica gel, moving phase 100% sherwood oil), obtains this methylpentane of the iodo-4-methyl of 1--3-, 8g, colorless oil, productive rate 58%. 1H NMR(300MHz,CDCl 3)δ4.87(s,1H),4.73(s,1H),3.24(t,2H,J=9.0Hz),2.64-2.57(m,2H),2.26-2.21(m,1H),1.04(s,3H),0.95(s,3H)。
By 2-(two trifluoro ethoxy phosphoryls)-ethyl acetate (9.2g; 27.67mmol) be added in the 70mL dry DMF suspension containing 4.66g potassium tert.-butoxide (41.5mmol); stirring at room temperature is after 2 hours; the 30mL anhydrous DMF solution of this methylpentane (6.2g, 27.67mmol) of the iodo-4-methyl of 1--3-is dripped in this reaction solution.Stirred overnight at room temperature in nitrogen atmosphere.In reaction solution, add 300mL water, extraction into ethyl acetate (3x150mL), combining extraction liquid, use the 0.1N HCl solution of 200mL successively, the water washing of 200mL saturated common salt, anhydrous sodium sulfate drying.Pressure reducing and steaming solvent, with column chromatography purification (200-300 order normal phase column chromatography silica gel, moving phase sherwood oil: ethyl acetate=2:1), obtains IV-b, 2g, colorless oil, productive rate 17%. 1H NMR(300MHz,CDCl 3)δ4.84(s,1H),4.70(s,1H),4.44-4.37(m,4H),4.24(q,2H,J=7.5Hz),3.20-3.10(m,1H),2.19-2.05(m,5H),1.24(t,3H,J=7.5Hz),1.04(d,3H,J=3.0Hz),1.02(d,3H,J=3.0Hz)。
The synthesis of Compound II per-c
At 0 DEG C, by 89mg(60%) sodium hydride (2.22mmol) joins compound IV-b(839mg, in dry tetrahydrofuran solution (5mL) 2.02mmol), stir after 2 hours, be cooled to-20 DEG C, in mixed solution, drip compound III-a(0.6g, 2.02mmol) tetrahydrofuran solution (5mL).Reaction solution continues stirring 2 hours.Add 10mL saturated aqueous ammonium chloride cancellation reaction, extraction into ethyl acetate (2x20mL), combining extraction liquid, with the water washing of 20mL saturated common salt, anhydrous sodium sulfate drying.Pressure reducing and steaming solvent, with column chromatography purification (200-300 order normal phase column chromatography silica gel, moving phase sherwood oil: ethyl acetate=5:1), obtains II-c, 500mg, light yellow oil, productive rate 53%. 1H NMR(300MHz,CDCl 3)δ5.84(t,1H,J=4.5Hz),5.40-5.29(m,2H),4.75(s,1H),4.67(s,1H),4.58-4.53(m,4H),4.18(q,2H,J=7.5Hz),2.55(q,2H,J=6.0Hz),2.40-2.27(m,2H),2.21-2.07(m,9H),2.06(s,3H),2.04(s,3H),1.76(s,3H),1.28(t,3H,J=7.5Hz),1.04(d,3H,J=3.0Hz),1.02(d,3H,J=3.0Hz)。
The synthesis of Compound C
Sodium hydroxide (432mg, 10.8mmol) is joined Compound II per-c(500mg, 1.08mmol) ethanol/water (1:1,16mL) solution in.Reaction solution is heated to 60 DEG C, stirs 2 hours, adds 1M salt acid for adjusting pH to 3 after cooling, extraction into ethyl acetate (2x20mL), combining extraction liquid, anhydrous sodium sulfate drying.Pressure reducing and steaming solvent, purifies (Waters Auto-purification system, Gemini-C18150x21.2mm, 5um by preparation liquid phase, moving phase: ACN-H2O, 40% ~ 60%, 0.1%TFA, flow velocity 20mL/Min), obtain Compound C, 120mg, light yellow oil, productive rate 32%. 1H NMR(400MHz,CDCl 3)δ6.04(t,1H,J=6.0Hz),5.47-5.46(m,1H),5.35-5.32(m,1H),4.79(s,1H),4.70(s,1H),4.14-4.10(m,4H),2.66-2.61(m,2H),2.39-2.27(m,2H),2.25-2.10(m,9H),1.76(s,3H),1.05(s,3H),1.04(s,3H)。
Embodiment 3:(R, 2Z, 6Z) synthesis of-10-hydroxyl-6-(methylol)-10-methyl-2-(4-methylpent-3-thiazolinyl) ten two-2,6,11-tri-olefinic carboxylic acids (compd B)
The synthetic route of compd B is as follows:
The synthesis of compounds X II-b
Successively DMAP (50g, 410mmol) and acetic anhydride (80mL) are added in the 800mL acetonitrile solution of (-)-phantol (46g, 300mmol).Reaction solution is heated to backflow, continues return stirring and spends the night.Question response liquid cooling but adds 1.5L diluted ethyl acetate afterwards, uses 0.1N HCl solution (1L) and saturated aqueous common salt (1L) washing successively, anhydrous sodium sulfate drying.Pressure reducing and steaming solvent, with column chromatography purification (200-300 order normal phase column chromatography silica gel, moving phase sherwood oil: ethyl acetate=10:1), obtains XII-b, 44g, colorless oil, productive rate 75%. 1H NMR(400MHz,CDCl 3)δ5.99(dd,1H),5.20-5.07(m,3H),2.02(s,3H),2.01-1.95(m,2H),1.93-1.73(m,2H),1.69(s,3H),1.61(s,3H),1.56(s,3H)。
The synthesis of compounds X I-b
By compounds X II-b(44g, 225mmol) molten in 500mL anhydrous methylene chloride, ice bath is cooled to 0 DEG C, adds m-CPBA(56g, 250mmol).Reaction solution at room temperature stirs 2 hours.Add 200mL aqueous sodium hydroxide solution (2M) cancellation reaction, dichloromethane extraction (2x150mL), combining extraction liquid, with the water washing of 500mL saturated common salt, anhydrous sodium sulfate drying.Pressure reducing and steaming solvent, obtains XI-b, 45.3g, light yellow oil, and crude product is not purified, is directly used in next step, productive rate 95%. 1H NMR(400MHz,CDCl 3)δ6.05-5.90(m,1H),5.22-5.13(m,2H),2.72(t,1H),2.07-1.97(m,5H),1.68-1.45(m,5H),1.32(s,3H),1.28(s,3H)。
The synthesis of compounds X-b
At 0 DEG C, by H 5iO 6the aqueous solution (250mL) of (53g, 250mmol) is added drop-wise to compounds X I-b(45.3g, 213mmol) tetrahydrofuran solution (300mL) in.After reaction solution stirs 3 hours, add 500mL saturated aqueous common salt, extraction into ethyl acetate (2x500mL), combining extraction liquid, anhydrous sodium sulfate drying.Pressure reducing and steaming solvent, with column chromatography purification (200-300 order normal phase column chromatography silica gel, moving phase sherwood oil: ethyl acetate=10:1), obtains X-b, 29g, colorless oil, productive rate 80%. 1H NMR(400MHz,CDCl 3)δ9.66(s,1H),5.95(dd,1H),5.17-5.09(m,2H),2.52-2.42(m,2H),2.12-1.97(m,2H),1.96(s,3H),1.48(s,3H)。
The synthesis of compound VI II-b and VIII-b1
At 0 DEG C, by 8g(60%) sodium hydride (200mmol) joins Compound I X-a(55g, in dry tetrahydrofuran solution (600mL) 180mmol), stir after 2 hours, at 0 DEG C, in mixed solution, drip compounds X-b(29g, 170mmol) tetrahydrofuran solution (100mL).Reaction solution is slowly returned to room temperature, and room temperature continues stirring and spends the night.Add 500mL saturated aqueous ammonium chloride cancellation reaction, extraction into ethyl acetate (2x500mL), combining extraction liquid, with the water washing of 800mL saturated common salt, anhydrous sodium sulfate drying.Pressure reducing and steaming solvent, with column chromatography purification (200-300 order normal phase column chromatography silica gel, moving phase sherwood oil: ethyl acetate=13:1), obtain VIII-b and VIII-b1 mixture, 31g, colorless oil, judge according to nuclear-magnetism, the relative proportion of required compound VIII-b and isomer VIII-b1 is 1:3. 1H NMR(400MHz,CDCl 3)δ6.74(t,0.75H),6.04-5.93(m,1H),5.84(t,0.25H),5.22-5.08(m,3H),4.24-4.17(m,2H),2.50-2.05(m,6H),2.03(s,3H),2.02-1.81(m,2H),1.70(s,3H),1.62-1.56(m,6H),1.35-1.28(m,3H)。
The synthesis of compound VI I-b
At 0 DEG C, the anhydrous ether solution (50mL) of mixture (VIII-b and VIII-b1) (31g, 97mmol) is added drop-wise in the 500mL anhydrous diethyl ether suspension containing 19g lithium aluminium hydride (500mmol).Reaction stirring added Na after 1 hour 2sO 410H 2o(250g), the solid that filtering is separated out, filter cake ethyl acetate washing (2x500mL), merges organic phase, with the water washing of 1.5L saturated common salt, anhydrous sodium sulfate drying.Pressure reducing and steaming solvent, with column chromatography purification (200-300 order normal phase column chromatography silica gel, moving phase sherwood oil: ethyl acetate=5:1), purifies (the preset post of purification on normal-phase silica gel, DCM:MeOH=200:1) with Combi Flash further, obtains VII-b, 3.0 g, light yellow oil, productive rate 13%. 1H NMR(400MHz,CDCl 3)δ5.98-5.89(m,1H),5.35(t,1H),5.27-5.20(m,1H),5.16-5.05(m,2H),4.15(s,2H),2.25-2.00(m,4H),1.71(s,3H),1.65-1.50(m,5H),1.42-1.26(m,5H)。
The synthesis of compound VI-b
Successively DMAP (2g, 17mmol) and acetic anhydride (10mL) are added to compound VI I-b(3g, 12.8mmol) 60mL acetonitrile solution in.Reaction solution is heated to backflow, continues return stirring and spends the night.After question response liquid cooling but, add 200mL diluted ethyl acetate, use 0.1N hydrochloric acid soln (150mL) successively, saturated aqueous common salt (150mL) washs, anhydrous sodium sulfate drying.Pressure reducing and steaming solvent, with column chromatography purification (200-300 order normal phase column chromatography silica gel, moving phase sherwood oil: ethyl acetate=13:1), obtains VI-b, 3.8g, light yellow oil, productive rate 92%. 1H NMR(400MHz,CDCl 3)δ6.02-5.94(m,1H),5.41(t,1H),5.21-5.08(m,3H),4.60(s,2H),2.15-2.05(m,9H),2.04(s,3H),1.98-1.76(m,2H),1.71(s,3H),1.62(s,3H),1.57(s,3H)。
The synthesis of compound V-b
By compound VI-b(3.8g, 11.7mmol) molten in 50mL anhydrous methylene chloride, ice bath is cooled to 0 DEG C, adds m-CPBA(2.9g, 13mmol).Reaction solution at room temperature stirs 2 hours.Add 20mL aqueous sodium hydroxide solution (2M) cancellation reaction, dichloromethane extraction (2x20mL), combining extraction liquid, with the water washing of 50mL saturated common salt, anhydrous sodium sulfate drying.Pressure reducing and steaming solvent, obtains V-b, 3.4g, light yellow oil, and crude product is not purified, is directly used in next step, productive rate 86%. 1H NMR(400MHz,CDCl 3)δ6.02-5.94(m,1H),5.46(t,1H),5.21-5.12(m,2H),4.62(s,2H),2.73(t,1H),2.33-2.10(m,2H),2.09(s,3H),1.98-1.58(m,6H),1.56(s,3H),1.33(s,3H),1.29(s,3H)。
The synthesis of compound III-b
At 0 DEG C, by H 5iO 6the aqueous solution (20mL) of (2.8g, 13mmol) is added drop-wise to compound V-b(3.4g, 10mmol) tetrahydrofuran solution (30mL) in.After reaction solution stirs 3 hours, add 50mL saturated aqueous common salt, extraction into ethyl acetate (2x50mL), combining extraction liquid, anhydrous sodium sulfate drying.Pressure reducing and steaming solvent, with column chromatography purification (200-300 order normal phase column chromatography silica gel, moving phase sherwood oil: ethyl acetate=4:1), obtains III-b, 2.4g, light yellow oil, productive rate 80%. 1H NMR(400MHz,CDCl 3)δ9.79(s,1H),6.02-5.94(m,1H),5.44(t,1H),5.22-5.12(m,2H),4.61(s,2H),2.63-2.56(m,2H),2.46-2.38(m,2H),2.15-2.07(m,4H),2.04(s,3H),1.97-1.64(m,3H),1.56(s,3H)。
The synthesis of Compound II per-b
At 0 DEG C, by 120mg(60%) sodium hydride (3mmol) joins compound IV-a(1.2g, in dry tetrahydrofuran solution (15mL) 2.9mmol), stir after 2 hours, be cooled to-20 DEG C, in mixed solution, drip compound III-b(828mg, 2.8mmol) tetrahydrofuran solution (5mL).Reaction solution continues stirring 2 hours.Add 20mL saturated aqueous ammonium chloride cancellation reaction, extraction into ethyl acetate (2x20mL), combining extraction liquid, with the water washing of 20mL saturated common salt, anhydrous sodium sulfate drying.Pressure reducing and steaming solvent, purifies (Waters Auto-purification system, Gemini-C18150x21.2mm, 5um by preparation liquid phase, moving phase: ACN-H2O, 40% ~ 60%, 0.1%TFA, flow velocity 20mL/Min), obtain II-b, 300mg, light yellow oil, productive rate 24%. 1H NMR(400MHz,CDCl 3)δ5.97(dd,1H),5.83(t,1H),5.43(t,1H),5.20-5.08(m,3H),4.60(s,2H),4.22(q,2H),2.58-2.52(m,2H),2.30-2.24(m,2H),2.23-2.08(m,6H),2.09(s,3H),2.04(s,3H),1.95-1.75(m,2H),1.70(s,3H),1.61(s,3H),1.56(s,3H),1.33(t,3H)。
The synthesis of compd B
Sodium hydroxide (264mg, 6.6mmol) is joined Compound II per-b(300mg, 0.66mmol) ethanol/water (1:1,6mL) solution in.Reaction solution is heated to 60 DEG C, stirs 2 hours, adds 1M salt acid for adjusting pH to 5 after cooling, extraction into ethyl acetate (2x13mL), combining extraction liquid, anhydrous sodium sulfate drying.Pressure reducing and steaming solvent, purifies (Waters Auto-purification system, Gemini-C18150x21.2mm, 5um by preparation liquid phase, moving phase: ACN-H2O, 40% ~ 60%, 0.1%TFA, flow velocity 20mL/Min), obtain compd B, 66mg, colorless oil, productive rate 30%. 1H NMR(400MHz,CDCl 3)δ6.01(t,1H),5.93(dd,1H),5.33(t,1H),5.22(d,1H),5.15-5.05(m,2H),4.22-4.14(m,2H),2.67-2.59(m,2H),2.33-2.21(m,4H),2.21-2.10(m,4H),1.70(s,3H),1.64-1.56(m,5H),1.31(s,3H)。
Embodiment 4:(R, 2Z, 6Z) synthesis of-10-hydroxyl-6-(methylol)-10-methyl-2-(4-methyl-3-methylene radical pentenyl) ten two-2,6,11-tri-olefinic carboxylic acids (Compound D)
The synthetic route of Compound D is as follows:
The synthesis of Compound II per-d
At 0 DEG C, by 120mg(60%) sodium hydride (3mmol) joins compound IV-b(1.25g, in dry tetrahydrofuran solution (15mL) 2.9mmol), stir after 2 hours, be cooled to-20 DEG C, in mixed solution, drip compound III-b(828mg, 2.8mmol) tetrahydrofuran solution (5mL).Reaction solution continues stirring 2 hours.Add 20mL saturated aqueous ammonium chloride cancellation reaction, extraction into ethyl acetate (2x20mL), combining extraction liquid, with the water washing of 20mL saturated common salt, anhydrous sodium sulfate drying.Pressure reducing and steaming solvent, purifies (Waters Auto-purification system, Gemini-C18150x21.2mm, 5um by preparation liquid phase, moving phase: ACN-H2O, 40% ~ 60%, 0.1%TFA, flow velocity 20mL/Min), obtain II-d, 300mg, light yellow oil, productive rate 23%. 1H NMR(400MHz,CDCl 3)δ6.02-5.93(m,1H),5.86(t,1H),5.42(t,1H),5.22-5.11(m,2H),4.78-4.58(m,4H),4.26-4.20(m,2H),2.60-2.10(m,11H),2.08(s,3H),2.03(s,3H),1.95-1.73(m,2H),1.56(s,3H),1.32(t,3H),1.05(s,3H),1.03(t,3H)。
The synthesis of Compound D
Sodium hydroxide (264mg, 6.6mmol) is joined Compound II per-d(300mg, 0.65mmol) ethanol/water (1:1,6mL) solution in.Reaction solution is heated to 60 DEG C, stirs 2 hours, adds 1M salt acid for adjusting pH to 5 after cooling, extraction into ethyl acetate (2x13mL), combining extraction liquid, anhydrous sodium sulfate drying.Pressure reducing and steaming solvent, purifies (Waters Auto-purification system, Gemini-C18150x21.2mm, 5um by preparation liquid phase, moving phase: ACN-H2O, 40% ~ 60%, 0.1%TFA, flow velocity 20mL/Min), obtain Compound D, 100mg, colorless oil, productive rate 45%. 1H NMR(400MHz,CDCl 3)δ6.04(t,1H),5.91(dd,1H),5.35(t,1H),5.23(d,1H),5.08(d,1H),4.80-4.68(m,2H),4.22-4.13(m,2H),2.68-2.60(m,2H),2.45-2.37(m,2H),2.30-2.12(m,7H),1.66-1.58(m,2H),1.30(s,3H),1.06(s,3H),1.04(s,3H)。
Embodiment 5: the preparation of compd A sodium salt
Embodiment 1 gained compd A (20mg, 0.06mmol) is dissolved in 10mL ethanol, adds the NaHCO of 0.1mol/L 3the aqueous solution (0.6mL, 0.06mmol), stirring at room temperature 2 hours.With Rotary Evaporators decompression (bath temperature 50 degrees Celsius) concentration of reaction solution.When being 2mL to residue volume, stop concentrated.By residue lyophilize, obtain 21.5mg white solid, quantitative yield.
Embodiment 6: the preparation of compd A tablet
Prescription forms
Table 2
Activeconstituents (compd A) 10mg
Lactose 187mg
W-Gum 50mg
Magnesium Stearate 3mg
Preparation method: by activeconstituents (embodiment 1 products obtained therefrom), the mixing of newborn sugar and starch, evenly moistening with water, sieves the mixture after moistening drying, after sieve, add stearic acid and do not have, then by mixture compressing tablet, the heavy 250mg of every sheet, active component content is 10mg.
Embodiment 7: the preparation of compd B capsule
Prescription forms
Table 3
Activeconstituents (compd B) 20mg
Lactose 178mg
Magnesium Stearate 2mg
Preparation method: activeconstituents (compd B) is mixed with auxiliary agent, sieves.Mix in suitable container, the mixture obtained is loaded hard gelatin capsule, the heavy 200mg of each capsule, active component content is 20mg.
Test example 1:
The anti-diabetic activity of compd A, compd B, Compound C, Compound D:
Material: embodiment 1,2,3,4 compd As prepared, Compound C, compd B, Compound D; Acarbose (Acarbose, trade(brand)name: glucobay (acarbose), article No.: A8980-1G), Sigma; α ?-glucuroide (article No.: G0660), Sigma; L-reduced glutathion (article No.: G4251), Sigma; 4-nitrophenyl-α-D-glucopyranoside (PNPG, article No.: N1377), Sigma; Potassium primary phosphate (article No.: P-5379), Sigma; Other chemical reagent is domestic analytical pure.
Instrument: METTLER XS205DU type electronic balance, plum Teller-Tuo benefit Instrument Ltd. of Switzerland; The long microplate reader of EnSpire2300 all-wave, perkin elmer (Perkin Elmer) Instrument Ltd..
The determination of optimal reaction system: the reaction system after optimization is add compound 16 l successively in 67mmol/L potassiumphosphate (pH6.8) 144 l, 0.16mg/ml reduced glutathione 5 l, 0.8U/ml-glucuroide 7 l, 37 DEG C of constant-temperature incubations 10 minutes, add 4mM PNPG28 l again, 37 DEG C are reacted 20 minutes, and sucking-off 33.3 l reaction solution, adds the sodium carbonate solution 166.7 l stopped reaction of 100mM. read 400nm absorbance.
Enzyme activity unit defines: 37 DEG C, under pH6.8 condition, the enzyme amount of per minute hydrolysis substrate 1 mol p-NP, is defined as an enzyme activity unit (U).Inhibition percentage=(suppressing vigor/enzyme activity) × 100%.
Result is as shown in the table, the half-inhibition concentration (IC50) of the p-glucosidase activity of positive control medicine glucobay (acarbose) is 0.399mg/ml, inhibition and the glucobay (acarbose) of the p-glucosidase activity of compd A are very close, and half-inhibition concentration is 0.394mg/ml.Compd B, Compound C, the Compound D activity to enzyme then has no significant effect.
The inhibit activities of the p-glucuroide of table 4 compd A, compd B, Compound C, Compound D

Claims (10)

1. a preparation method for sub-tribute diterpenoid acid compound, is characterized in that, obtain as follows:
1. preparation formula (XII) compound is reacted by formula (XIII) compound and acylating reagent;
2. by formula (XII) compound and oxidant reaction preparation formula (XI) compound;
3. by formula (XI) compound and oxidant reaction preparation formula (X) compound;
4. under alkali existence condition, preparation formula (VIII) compound is reacted with formula (X) compound by formula (IX) compound;
5. preparation formula (VII) compound is reacted by formula (VIII) compound and reductive agent;
6. under alkali existence condition, preparation formula (VI) compound is reacted with acylating reagent by formula (VII) compound;
7. (V) compound is prepared by formula (VI) compound and oxidant reaction;
8. by formula (V) compound and oxidant reaction preparation formula (III) compound;
9. under the effect of alkali, preparation formula (II) compound is reacted by formula (III) compound and formula (IV) compound;
10. under the effect of alkali, formula (I) compound is hydrolyzed to by formula (II) compound;
Described step 1.-10. in:
R 1for (Z)-4-hydroxyl-2-butylene-2-base or (R)-2-hydroxyl-3-butene-2-Ji, structure is:
R 2for 2-methyl-propen-1-base or 3-methyl-butene-2-base, structure is:
R 1' structure is:
R 3, R 4, R 5and R 6independently represent the C replaced by 0-1 substituting group W 1-5straight or branched alkyl, the C replaced by 0-1 substituting group W 3-6cycloalkyl, the C replaced by 0-1 substituting group W 3-6thiazolinyl or the C replaced by 0-1 substituting group W 3-6alkynyl;
Described W is independently selected from hydroxyl, amino, carboxyl, sulfydryl, alkoxyl group or first sulfydryl;
R 7for ethyl;
R 8it is 2,2,2-trifluoroethyl.
2. preparation method according to claim 1, is characterized in that, step 1. in:
Described acylating reagent is selected from aceticanhydride or Acetyl Chloride 98Min.;
Alkali used is mineral alkali and/or organic bases;
Wherein mineral alkali is selected from one or more in sodium bicarbonate, saleratus, salt of wormwood, cesium carbonate, sodium carbonate;
Organic bases be selected from pyridine, triethylamine, lupetidine, DMAP one or more;
Reaction solvent be selected from pyridine, tetrahydrofuran (THF), methylene dichloride, ether, acetonitrile, aceticanhydride, methyltetrahydrofuran one or more;
Temperature of reaction is 0 DEG C-180 DEG C; Reaction times is 1-48 hour;
The molar ratio of described formula (XIII) compound and acylating reagent is 1:1 ~ 1:10;
Step 2. in:
Described oxygenant be selected from Periodic acid, metachloroperbenzoic acid, hydrogen peroxide, Peracetic Acid, potassium hydrogen persulfate one or more;
Reaction solvent be selected from tetrahydrofuran (THF), methylene dichloride, chloroform one or more;
Temperature of reaction is 0 DEG C ~ 50 DEG C; Reaction times is 1-48 hour;
The molar ratio of described formula (XII) compound and oxygenant is 1:1 ~ 1:10;
Step 3. in:
Described oxygenant be selected from Periodic acid, metachloroperbenzoic acid, hydrogen peroxide, Peracetic Acid, potassium hydrogen persulfate one or more;
The solvent of reaction is organic solvent and/or water, described organic solvent be selected from tetrahydrofuran (THF), methylene dichloride, chloroform one or more;
Temperature of reaction is 0 DEG C ~ 50 DEG C; Reaction times is 1-48 hour;
The molar ratio of described formula (XI) compound and oxygenant is 1:1 ~ 1:10.
3. preparation method according to claim 1 and 2, is characterized in that, step 10. in:
Described alkali is mineral alkali, described mineral alkali be selected from lithium hydroxide, sodium hydroxide, potassium hydroxide one or more;
Solvent for use is organic solvent and/or water, described organic solvent be selected from methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF) one or more;
Temperature used is 0 degree to 100 degrees Celsius;
The ratio of formula (II) compound and alkali is 1:1 ~ 1:10.
4. preparation method according to claim 1, is characterized in that, step 9. in:
Described alkali is mineral alkali and/or organic bases;
Wherein mineral alkali is selected from one or more in potassium hydroxide, sodium hydroxide, salt of wormwood, sodium carbonate;
Organic bases is selected from sodium hydride, n-Butyl Lithium, 2-butyllithium, tert-butyl lithium, potassium tert.-butoxide, sodium tert-butoxide, the two silicon amine lithium of hexamethyl, one or more in the two silicon amine sodium of hexamethyl, the two silicon amine potassium of hexamethyl;
The solvent of reaction be selected from tetrahydrofuran (THF), ether, methyl tertiary butyl ether, methyltetrahydrofuran one or more;
Temperature of reaction is-78 DEG C of extremely backflows;
The molar ratio of formula (III) and formula (IV) compound is at 1:1 ~ 1:3.
5. formula (II) compound for preparing of method described in claim 1 or 4.
6. preparation method according to claim 1, is characterized in that, step 8. in:
Oxygenant be selected from Periodic acid, metachloroperbenzoic acid, hydrogen peroxide, Peracetic Acid, potassium hydrogen persulfate one or more;
The solvent of reaction is organic solvent and/or water, described organic solvent be selected from tetrahydrofuran (THF), methylene dichloride, chloroform one or more;
The temperature of reaction is 0 DEG C ~ 50 DEG C;
The molar ratio of described formula (V) compound and oxygenant is 1:1 ~ 1:10.
7. preparation method according to claim 1, is characterized in that, step 7. in:
Described oxygenant be selected from Periodic acid, metachloroperbenzoic acid, hydrogen peroxide, Peracetic Acid, potassium hydrogen persulfate one or more;
The solvent of reaction be selected from tetrahydrofuran (THF), methylene dichloride, chloroform one or more;
The temperature of reaction is 0 DEG C ~ 50 DEG C;
The molar ratio of described formula (VI) compound and oxygenant is 1:1 ~ 1:10.
8. preparation method according to claim 1, is characterized in that, step 6. in:
Described acylating reagent is aceticanhydride or Acetyl Chloride 98Min.;
Alkali used is mineral alkali and/or organic bases;
Wherein mineral alkali is selected from one or more in sodium bicarbonate, saleratus, salt of wormwood, cesium carbonate, sodium carbonate;
Organic bases be selected from pyridine, triethylamine, lupetidine, DMAP one or more;
The solvent of reaction be selected from pyridine, tetrahydrofuran (THF), methylene dichloride, ether, acetonitrile, aceticanhydride, methyltetrahydrofuran one or more;
Temperature of reaction is 0 DEG C ~ 50 DEG C; Reaction times is 1-48 hour;
Described formula (VII) is 1:1 ~ 1:10 with the molar ratio of acylating reagent.
9. preparation method according to claim 1, is characterized in that, step 5. in:
Described reductive agent be selected from lithium aluminum hydride, sodium borohydride, diisobutyl aluminum hydrogen one or more;
The solvent of reaction is tetrahydrofuran (THF) and/or ether;
Temperature of reaction be subzero 78 degree to room temperature; Reaction times is 1-48 hour;
The molar ratio of described formula (VIII) compound and reductive agent is 1:1 ~ 1:10.
10. preparation method according to claim 1, is characterized in that, step 4. in:
Alkali is mineral alkali and/or organic bases;
Wherein mineral alkali is selected from one or more in potassium hydroxide, sodium hydroxide, salt of wormwood, sodium carbonate;
Organic bases is selected from sodium hydride, n-Butyl Lithium, 2-butyllithium, tert-butyl lithium, potassium tert.-butoxide, sodium tert-butoxide, the two silicon amine lithium of hexamethyl, one or more in the two silicon amine sodium of hexamethyl, the two silicon amine potassium of hexamethyl;
Reaction solvent be selected from tetrahydrofuran (THF), ether, methyl tertiary butyl ether, methyltetrahydrofuran one or more;
Temperature of reaction is in subzero 78 degrees Celsius of extremely backflows; Reaction times is 1-48 hour;
The molar ratio of described formula (X) compound and formula (IX) compound is at 1:1 ~ 1:3.
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