CN103214486A - Beta-carboline derivative or medicinal salt as well as preparation method and anti-tumour application thereof - Google Patents
Beta-carboline derivative or medicinal salt as well as preparation method and anti-tumour application thereof Download PDFInfo
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Abstract
The invention discloses a beta-carboline derivative or medicinal salt of a general formula (I) structure with anti-tumour activity, wherein R, R1 and R2 are defined in the specification.
Description
Technical field:
The invention belongs to technical field of pharmaceuticals, more specifically say so beta-carboline derivatives or pharmacologically acceptable salt, its preparation method and antineoplastic application thereof.
Background technology:
Tumour is the cell of human organ tissue, is that produced under external and interior long term at adverse factor a kind of is the true tumor of principal feature with the cell hyperproliferation.This true tumor is irrelevant with the physiological requirements of the organ of getting involved, and not according to the rule growth of normal organ, loses Normocellular function, has destroyed original organ structure, and what have can transfer to other position, threat to life.Tumour can be divided into innocent tumour and malignant tumour two big classes, and innocent tumour is less to the HUMAN HEALTH influence, and cancer then belongs to malignant tumour.According to incompletely statistics, the whole world has 2,000 ten thousand malignant tumour new cases every year approximately.Tumor treatment mainly contains operative treatment, radiotherapy and pharmacological agent.The sixties in last century, more new drug is put to clinical application, and to change single drug be drug combination, not only improve curative effect, reduced toxic side effect, and enlarged therapeutic domain, make such as acute lymphoblastic leukemia the existing possibility of curing of tumours such as choriocarcinoma.Chemotherapeutic major advantage is both can treat solid tumor, and non-solid tumor also is expected to treat metastatic tumor.Traditional antitumor drug mainly contains following a few class: directly act on the medicine (as: alkylating agent, metal platinum compound, topoisomerase enzyme inhibitor) that DNA destroys its 26S Proteasome Structure and Function 1.; 2. disturb DNA and nucleic acid synthetic medicine (as: purine, pyrimidine, antifol); 3. antimitotic influences the medicine (paclitaxel analogs) of protein synthesis; 4. other (as: hormone medicine).But because tumour cell increases soon, easily variation, thereby generation multidrug resistance, cause the chemotherapy of tumors failure, the therapeutic index of most of antitumour drugs is less simultaneously, and selectivity is low, in killing tumor cell, also damages healthy tissues, especially breed histocyte rapidly, when therapeutic dose, can cause more untoward reaction.Therefore, carry out the research of antitumor drug, have great importance.
Summary of the invention:
The object of the present invention is to provide beta-carboline derivatives or pharmacologically acceptable salt, its preparation method and antineoplastic application thereof are so that provide more medicament selection for human treatment's tumor disease.
Beta-carboline derivatives of the present invention has the structure of logical formula I:
Wherein, the group of R representative is selected from: hydrogen, COOR
3Or C (R
4)
2OR
5, R wherein
3Be C
1-4Alkyl; R
4Be hydrogen, C
1-4Alkyl or phenyl; R
5Be hydrogen, C
1-4Alkyl, benzyl, C
2-4Alkanoyl or benzoyl;
R
1The group of representative is selected from: anthryl, phenanthryl, 1-naphthyl, 2-naphthyl, randomly replaced separately by one or more identical or different groups, and substituting group is selected from halogen, hydroxyl, cyano group, nitro, ester group, straight or branched C
1-6Alkyl, straight or branched C
1-6Alkoxyl group;
R
2The group of representative is selected from: hydrogen, C
1-4Alkyl, benzyl.
Described beta-carboline derivatives can be following any one compound and pharmacologically acceptable salt thereof:
Wherein:
R
1For: anthryl, phenanthryl, 1-naphthyl, 2-naphthyl, randomly replaced separately by one or more identical or different groups, substituting group is selected from halogen, hydroxyl, cyano group, nitro, ester group, straight or branched (C
1-C
6) alkyl, straight or branched (C
1-C
6) alkoxyl group;
R
2For: hydrogen, methyl, ethyl, propyl group, butyl, benzyl;
R
3Be methyl, ethyl, propyl group, sec.-propyl, butyl.
Preferably, R
5Be hydrogen, ethanoyl; R
1The group of representative is selected from: anthryl, phenanthryl, 1-naphthyl, 2-naphthyl, methoxyl group naphthyl;
More preferably, beta-carboline derivatives is selected from following compound:
9-anthryl 2-click ripple quinoline methyl esters (2a);
6-methoxyl group-2-naphthyl click ripple ethyl morpholine (2k);
(1-(9-anthryl)-9H-pyridine [3,4-b]-3-indyl) methyl alcohol (4a);
The 2-(1-(1-naphthyl)-9H-pyridine [3,4-b] 3-indyl)-2-propyl alcohol (5b);
The 2-(1-(2-naphthyl)-9H-pyridine [3,4-b] 3-indyl)-2-propyl alcohol (5c);
(1-(6-methoxyl group 2-naphthyl)-9H-pyridine [3,4-b]-3 bases) methyl alcohol (4d);
2-(1-(6-methoxyl group-2-naphthyl)-9H-pyridine [3,4-b] 3-indyl)-2-propyl alcohol (5d);
(1-(9-phenanthryl)-9H-pyridine [3,4-b]-3 bases) methyl alcohol (4e);
The 2-(1-(9-phenanthryl)-9H-pyridine [3,4-b] 3-indyl)-2-propyl alcohol (5e);
(9-methyl isophthalic acid-(2-naphthyl)-9H-pyridine [3,4-b]-3 bases) methyl alcohol (4j);
2-(9-methyl 1-(2-naphthyl)-9H-pyridine [3,4-b] 3-indyl)-2-propyl alcohol (5j);
(1-(6-methoxyl group 2-naphthyl)-9-methyl-9H-pyridine [3,4-b]-3 bases) methyl alcohol (4l);
2-(1-(6-methoxyl group 2-naphthyl)-9 methyl-9H-pyridine [3,4-b] 3-indyl)-2-propyl alcohol (5l);
(1-(6-methoxyl group 2-naphthyl)-9-ethyl-9H-pyridine [3,4-b]-3 bases) methyl alcohol (4m);
(1-(9-phenanthryl)-9-methyl-9H-pyridine [3,4-b]-3 bases) methyl alcohol (4n);
(1-(9-phenanthryl)-9-ethyl-9H-pyridine [3,4-b]-3 bases) methyl alcohol (4o);
(1-(2-naphthyl)-9H-pyridine [3,4 ,-b] 3-indyl) methyl acetate (6g);
(1-(9-phenanthryl)-9H-pyridine [3,4 ,-b] 3-indyl) methyl acetate (6m).
Above-mentioned all compounds or pharmacologically acceptable salt and isomer thereof, raceme, diastereomer, solvate constitute a part of the present invention.
Drug regimen of the present invention contains the carrier of permitting on above-claimed cpd or pharmacologically acceptable salt, the pharmacopedics or with mix the combination with pharmaceutical excipient or thinner of this compounds as activeconstituents.
Compound of the present invention or pharmacologically acceptable salt are used in the medicine of preparation treatment and prophylaxis of tumours disease.
The acceptable carrier is meant the pharmaceutical carrier of pharmaceutical field routine on the described drug regimen Chinese materia medica that is used for the treatment of tumour of the present invention, for example: thinner such as water etc.; Vehicle agent such as starch, sucrose etc., tackiness agent such as derivatived cellulose, alginate, gelatin etc.; Wetting agent such as glycerine; Disintegrating agent such as agar, lime carbonate, Calcium hydrogen carbonate etc.; Absorption agent such as quaternary ammonium compound; Tensio-active agent such as cetyl alcohol; Absorption carrier such as kaolin etc.; Lubricant such as talcum powder, calcium stearate, magnesium etc.Can also in composition, add other assistant agent such as flavouring agent, sweeting agent etc. in addition.
The compounds of this invention may composition form by oral, snuffing is gone into, the mode of rectum or administered parenterally is applied to the patient who needs this treatment.Be used for when oral, can be made into conventional solid preparation such as tablet, pulvis, granula, capsule etc., make liquid preparation such as water or oil-suspending agent or other liquid preparations such as syrup, tincture etc.; When being used for administered parenterally, can be made into solution, water or the oiliness suspension agent etc. of injection, preferred form is tablet, capsule and injection.
The various formulations of drug regimen of the present invention can be according to the conventional production method preparation of pharmaceutical field.Activeconstituents is mixed with one or more carriers, be made into required formulation then.
Pharmaceutical composition of the present invention preferably contains the activeconstituents that weight ratio is 0.1%-99.5%, most preferably contains the activeconstituents that proportion is 0.5%-95%.
By test, compound provided by the present invention has than the better anti-tumor activity of positive control cis-platinum.
Among the preparation method of formula I compound of the present invention, when R is COOR
3The time, the preparation method may further comprise the steps:
A) use the synthetic formula III compound of alcohol and thionyl chloride and formula II compound effects:
Wherein used alcohol is a kind of in methyl alcohol, ethanol, propyl alcohol, Virahol, the butanols.
B) utilize the Pictet-Spengler reaction, make formula III compound and R
1The CHO effect obtains Tetrahydrocarboline, and Tetrahydrocarboline obtains formula (I A) compound under the aromatic yl reagent-ing effect:
C) utilize haloalkane under the alkali effect, to obtain formula (I B) compound with the reaction of formula (I A) compound:
Wherein, R
1, R
2, R
3With aforementioned definition.
Among the preparation method of formula I compound of the present invention, when R is CH
2During OH, may further comprise the steps:
Utilize reductive agent reduction-type (I B) compound, reaction obtains formula (I C) compound under the effect of acid again:
Wherein, R
1, R
2, R
3With aforementioned definition.
Among the preparation method of formula I compound of the present invention, when R is C
3H
6During OH, may further comprise the steps:
Utilize the reaction of Grignard reagent or lithium alkylide and formula (I B) compound to obtain formula (I D) compound:
Wherein, R
1, R
2, R
3With aforementioned definition.
Among the preparation method of formula I compound of the present invention, when R is CH
2During OAc, may further comprise the steps:
Utilize acyl chlorides under the alkali effect, to obtain formula (I E) compound with the reaction of formula (I C) compound:
Embodiment:
The following examples only are used for that the present invention will be described, but do not limit the present invention in any way.
The raw materials used commercial goods that is in the embodiment of the invention, the spectral data of made compound is that testing method records routinely.
Embodiment 1
Synthesizing of compound 1
Get absolute alcohol R
3OH300mL is cooled to-15 ℃ in flask, drip the 20mL thionyl chloride, finishes to stir 30min, adds tryptophan methyl ester 40g, 60 ℃ of backflow 24h, and steaming desolventizes, and the resistates water dissolution is used Na
2CO
3Transfer to alkalescence, ethyl acetate extraction merges organic phase, drying, and steaming desolventizes and obtains white solid compound 1.As shown in table 1, in the present embodiment, with R
3Be selected from the difference of methyl, ethyl and sec.-propyl, make compound 1a, compound 1b and compound 1c respectively.Compound 1a, 1b and 1c spectral data separately is as shown in table 1.
Table 1
Embodiment 2
Synthesizing of compound 2
Get embodiment 1 made compound 1(5mmol) be dissolved in anhydrous CH
2Cl
2(80mL), add aldehyde R
1CHO(5mmol), add the 4A molecular sieve behind the 1h, normal-temperature reaction 2 days is chilled to 0 ℃, and (570mg 5mmol), finishes and rises to room temperature reaction 24h, adds the saturated Na of 10mL to add trifluoroacetic acid
2CO
3Solution, suction filtration, filtrate is washed 3 times with saturated NaCl, anhydrous Na
2SO
4Dry.DDQ(2.28g 10mmol) adds exsiccant filtrate in batches, normal-temperature reaction 30min, and water washing is colourless to water layer, organic layer anhydrous Na SO
4Drying, evaporate to dryness obtain light yellow solid shape compound 2.In the present embodiment, with R in the compound 1
3Substituting group and aldehyde R
1R among the CHO
1Substituent difference makes compound 2a-2o as shown in table 2 respectively.Compound 2a is a 9-anthryl 2-click ripple quinoline methyl esters in the table 2, and compound 2k is 6-methoxyl group-2-naphthyl click ripple ethyl morpholine, the extracorporeal anti-tumor IC of compound 2a and compound 2k
50Value sees Table 7.
Table 2
Embodiment 3
Synthesizing of compound 3
With embodiment 2 made compound 2a(0.25mmol) be dissolved in DMF(3mL) in, add anhydrous K successively
2CO
3Powder (69mg, 0.5mmol), methyl iodide (106mg, 0.75mmol), normal-temperature reaction 12h.In the reaction solution impouring frozen water, be positioned in the refrigerator and extremely precipitate fully, suction filtration, drying gets white solid compound 3a.
Further, replace compound 2a with a certain compound that is selected among the series compound 2a-2o, with iodo-alkyl R
2I replaces methyl iodide, reacts with corresponding mol ratio by above-mentioned reaction conditions, according to substituent R in the selected raw material
3, R
1And R
2Difference, can make the 3a-3ae series compound shown in the table 3.
Table 3
Embodiment 4
Synthesizing of compound 4
LiAlH
4(20mg 0.5mmol) is suspended in (10mL) among the anhydrous THF, drips the THF solution (0.25mmol is dissolved among the anhydrous THF of 2mL) of compound 2 or 3, and normal-temperature reaction 1h adds 0.13mL H successively under the ice bath
2O, 0.13mL15%NaOH solution, 0.13mL H
2O, reactant diatomite filtration, evaporate to dryness obtain light yellow solid shape compound 4.
In the present embodiment, R in compound of selecting for use according to raw material 2 or the compound 3
1R
2Substituent difference, obtained compound 4 is the compound 4a-4o shown in the table 4.Wherein, compound 4a is (1-(9-anthryl)-9H-pyridine [3,4-b]-3-indyl) methyl alcohol; Compound 4d is (1-(6-methoxyl group 2-naphthyl)-9H-pyridine [3,4-b]-3 bases) methyl alcohol; Compound 4e is (1-(9-phenanthryl)-9H-pyridine [3,4-b]-3 bases) methyl alcohol; Compound 4j is (9-methyl isophthalic acid-(2-naphthyl)-9H-pyridine [3,4-b]-3 bases) methyl alcohol; Compound 4l is (1-(6-methoxyl group 2-naphthyl)-9-methyl-9H-pyridine [3,4-b]-3 bases) methyl alcohol; Compound 4m is (1-(6-methoxyl group 2-naphthyl)-9-ethyl-9H-pyridine [3,4-b]-3 bases) methyl alcohol; Compound 4n is (1-(9-phenanthryl)-9-methyl-9H-pyridine [3,4-b]-3 bases) methyl alcohol; Compound 4o is (1-(9-phenanthryl)-9-ethyl-9H-pyridine [3,4-b]-3 bases) methyl alcohol; The extracorporeal anti-tumor IC of described compound 4a, 4d, 4e, 4j, 4l, 4m, 4n and 4o
50Value sees Table 7.
Table 4
Embodiment 5
Synthesizing of compound 5
Compound 2 or compound 3(0.25mmol) be dissolved in (10mL) among the anhydrous THF, Ar
2Protection drips methyl-magnesium-bromide down, and (3mmol, 0.5mL), normal-temperature reaction 8h, ice bath add saturated ammonium chloride cancellation reaction, ethyl acetate dilution, saturated NaCl solution washing, anhydrous Na down
2SO
4Drying, evaporate to dryness obtains buff powder, last silicagel column, sherwood oil: the ethyl ester wash-out obtains white solid compound 5.
In the present embodiment, be R in compound 2 or the compound 3 according to selected raw material
2, R
3Substituent difference can make compound 5a-5o as shown in table 5 respectively.In the table 5, compound 5b is the 2-(1-(1-naphthyl)-9H-pyridine [3,4-b] 3-indyl)-the 2-propyl alcohol; Compound 5c
Be the 2-(1-(2-naphthyl)-9H-pyridine [3,4-b] 3-indyl)-the 2-propyl alcohol; Compound 5d is 2-(1-(6-methoxyl group-2-naphthyl)-9H-pyridine [3,4-b] 3-indyl)-the 2-propyl alcohol; Compound 5e is the 2-(1-(9-phenanthryl)-9H-pyridine [3,4-b] 3-indyl)-the 2-propyl alcohol; Compound 5j is
2-(9-methyl 1-(2-naphthyl)-9H-pyridine [3,4-b] 3-indyl)-the 2-propyl alcohol; Compound 5l is a 2-(1-(6-methoxyl group 2-naphthyl)-9 methyl-9H-pyridine [3,4-b] 3-indyl)-the 2-propyl alcohol.The extracorporeal anti-tumor IC of compound 5b, 5c, 5d, 5e, 5j and 5l
50Value sees Table 7.
Table 5
Embodiment 6
Synthesizing of compound 6
Compound 4(0.12mmol) is dissolved in anhydrous CH
2Cl
2In in (8mL), add successively triethylamine (13mg, 0.13mmol), aceticanhydride (13mg, 0.13mmol) and catalytic amount DMAP.Normal-temperature reaction 12h, reaction solution water washing 3 times, anhydrous Na
2SO
4Drying, last silicagel column, Shi You Mi ︰ Yi Zhi ︰ methylene dichloride=10 ︰, 1 ︰, 2.5 wash-outs gets white solid compound 6.
In the present embodiment, be R in the compound 4 according to selected raw material
1, R
2Substituent difference can make series compound 6a-6o as shown in table 6 respectively.Compound 6g in the table 6 is (1-(2-naphthyl)-9H-pyridine [3,4 ,-b] 3-indyl) methyl acetate; Compound 6m is (1-(9-phenanthryl)-9H-pyridine [3,4 ,-b] 3-indyl) methyl acetate.The extracorporeal anti-tumor IC of described compound 6g, 6m
50Value sees Table 7.
Table 6
Embodiment 7
The extracorporeal anti-tumor screening is the leukemia strain with HL-60 respectively, and SMMC-772 is a hepatoma cell strain, the A-549 lung cancer cell line, and the MCF-7 breast carcinoma cell strain, the SW480 colon cancer cell line is tested; Detection method is a mtt assay.
Mtt assay: be made into the individual cells suspension with the nutrient solution (DMEM or RMPI1640) that contains 10% foetal calf serum, with every hole 10000-20000 cell inoculation to 96 orifice plates, every pore volume 100 μ L, attached cell shifts to an earlier date the 12h inoculation culture.Add testing compound solution (fixed concentration 40 μ M primary dcreening operations are suppressed near 50% compound in this concentration to growth of tumour cell and establish 5 concentration and enter gradient and sieve again), every hole final volume 200 μ L, every kind of processing is all established 3 and is answered holes.Behind 37 ℃ of cultivation 48h, every hole adds MTT solution 20 μ L.Continue to hatch 4h, stop to cultivate, the careful suction abandons that culture supernatant 100 μ L are to avoid cell loss in the hole, and every hole adds 20% SDS100 μ L, and night incubation (37 ℃ of temperature) is fully melted crystallisate.Select the 595nm wavelength, enzyme-linked immunosorbent assay instrument (Bio-Rad680) reads each hole absorbance value, and the record result is an X-coordinate with concentration, cell survival rate is that ordinate zou is drawn cell growth curve, uses the IC of two-point method (Reed and Muench method) computerized compound
50Be worth as shown in table 7.
The part of compounds extracorporeal anti-tumor IC that table 7. is involved in the present invention
50Value
Claims (12)
1. compound or the pharmacologically acceptable salt represented of formula I:
Wherein, the group of R representative is selected from: hydrogen, COOR
3Or C (R
4)
2OR
5, R wherein
3Be C
1-4Alkyl; R
4Be hydrogen, C
1-4Alkyl or phenyl; R
5Be hydrogen, C
1-4Alkyl, benzyl, C
2-4Alkanoyl or benzoyl;
R
1The group of representative is selected from: anthryl, phenanthryl, 1-naphthyl, 2-naphthyl, randomly replaced separately by one or more identical or different groups, and substituting group is selected from halogen, hydroxyl, cyano group, nitro, ester group, straight or branched C
1-6Alkyl, straight or branched C
1-6Alkoxyl group;
R
2The group of representative is selected from: hydrogen, C
1-4Alkyl, benzyl.
2. compound according to claim 1 or pharmacologically acceptable salt is characterized in that being following any one compound and pharmacologically acceptable salt thereof:
Wherein:
R
1For: anthryl, phenanthryl, 1-naphthyl, 2-naphthyl, randomly replaced separately by one or more identical or different groups, substituting group is selected from halogen, hydroxyl, cyano group, nitro, ester group, straight or branched (C
1-C
6) alkyl, straight or branched (C
1-C
6) alkoxyl group;
R
2For: hydrogen, methyl, ethyl, propyl group, butyl, benzyl;
R
3Be methyl, ethyl, propyl group, sec.-propyl, butyl.
3. compound according to claim 1 and 2 and pharmacologically acceptable salt thereof is characterized in that,
R
5Be hydrogen, ethanoyl;
R
1The group of representative is selected from: anthryl, phenanthryl, 1-naphthyl, 2-naphthyl, methoxyl group naphthyl.
4. compound according to claim 1 or pharmacologically acceptable salt is characterized in that being selected from following compound and pharmacologically acceptable salt thereof:
9-anthryl 2-click ripple quinoline methyl esters;
6-methoxyl group-2-naphthyl click ripple ethyl morpholine;
(1-(9-anthryl)-9H-pyridine [3,4-b]-3-indyl)) methyl alcohol;
The 2-(1-(1-naphthyl)-9H-pyridine [3,4-b] 3-indyl)-the 2-propyl alcohol;
The 2-(1-(2-naphthyl)-9H-pyridine [3,4-b] 3-indyl)-the 2-propyl alcohol;
(1-(6-methoxyl group 2-naphthyl)-9H-pyridine [3,4-b]-3 bases) methyl alcohol;
2-(1-(6-methoxyl group-2-naphthyl)-9H-pyridine [3,4-b] 3-indyl)-the 2-propyl alcohol;
(1-(9-phenanthryl)-9H-pyridine [3,4-b]-3 bases) methyl alcohol;
The 2-(1-(9-phenanthryl)-9H-pyridine [3,4-b] 3-indyl)-the 2-propyl alcohol;
(9-methyl isophthalic acid-(2-naphthyl)-9H-pyridine [3,4-b]-3 bases) methyl alcohol;
2-(9-methyl 1-(2-naphthyl)-9H-pyridine [3,4-b] 3-indyl)-the 2-propyl alcohol;
(1-(6-methoxyl group 2-naphthyl)-9-methyl-9H-pyridine [3,4-b]-3 bases) methyl alcohol;
2-(1-(6-methoxyl group 2-naphthyl)-9 methyl-9H-pyridine [3,4-b] 3-indyl)-the 2-propyl alcohol;
(1-(6-methoxyl group 2-naphthyl)-9-ethyl-9H-pyridine [3,4-b]-3 bases) methyl alcohol;
(1-(9-phenanthryl)-9-methyl-9H-pyridine [3,4-b]-3 bases) methyl alcohol;
(1-(9-phenanthryl)-9-ethyl-9H-pyridine [3,4-b]-3 bases) methyl alcohol;
(1-(2-naphthyl)-9H-pyridine [3,4 ,-b] 3-indoleacetic acid methyl esters;
(1-(9-phenanthryl)-9H-pyridine [3,4 ,-b] 3-indoleacetic acid methyl esters.
5. the isomer of compound described in the claim 1~4 or pharmacologically acceptable salt, solvate.
6. drug regimen contains the carrier of permitting on compound described in the claim 1~4 or pharmacologically acceptable salt, the pharmacopedics or with mix the combination with pharmaceutical excipient or thinner of this compounds as activeconstituents.
7. compound described in the claim 1~4 or the pharmacologically acceptable salt application in the medicine of preparation treatment and prophylaxis of tumours disease.
8. the application of the drug regimen described in the claim 6 in the medicine of preparation treatment and prophylaxis of tumours disease.
9. the preparation method of formula I compound in the claim 1 is characterized in that, when R is COOR
3The time, the preparation method may further comprise the steps:
A) use the synthetic formula III compound of alcohol and thionyl chloride and formula II compound effects:
Wherein used alcohol is a kind of in methyl alcohol, ethanol, propyl alcohol, Virahol, the butanols;
B) utilize the Pictet-Spengler reaction, make formula III compound and R
1The CHO effect obtains Tetrahydrocarboline, and Tetrahydrocarboline obtains formula (I A) compound under the aromatic yl reagent-ing effect,
C) utilize haloalkane under the alkali effect, to obtain formula (I B) compound with the reaction of formula (I A) compound,
Wherein, R
1, R
2, R
3With definition in the claim 1.
10. the preparation method of formula I compound in the claim 1 is characterized in that, when R is CH
2During OH, may further comprise the steps:
Utilize reductive agent reduction-type (I B) compound, reaction obtains formula (I C) compound under the effect of acid again,
Wherein, R
1, R
2, R
3With definition in the claim 1.
11. the preparation method of formula I compound is characterized in that in the claim 1, when R is C
3H
6During OH, may further comprise the steps:
Utilize the reaction of Grignard reagent or lithium alkylide and formula (I B) compound to obtain formula (I D) compound
Wherein, R
1, R
2, R
3With definition in the claim 1.
12. the preparation method of formula I compound is characterized in that in the claim 1, when R is CH
2During OAc, may further comprise the steps:
Utilize acyl chlorides under the alkali effect, to obtain formula (I E) compound with the reaction of formula (I C) compound,
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