CN104876917A - Synthesis method of triadimefon serving as fatty acid synthase inhibitor - Google Patents
Synthesis method of triadimefon serving as fatty acid synthase inhibitor Download PDFInfo
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- 0 C*C(C=C)=CC(C=C)=CC(C(c(cc1)ccc1NC(OC1C=CC([N+]([O-])=O)=CC=C1)=O)=C)=C Chemical compound C*C(C=C)=CC(C=C)=CC(C(c(cc1)ccc1NC(OC1C=CC([N+]([O-])=O)=CC=C1)=O)=C)=C 0.000 description 3
- VXWVFZFZYXOBTA-UHFFFAOYSA-N Brc1ccc2[nH]ccc2c1 Chemical compound Brc1ccc2[nH]ccc2c1 VXWVFZFZYXOBTA-UHFFFAOYSA-N 0.000 description 1
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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Abstract
The invention discloses a synthesis method of triadimefon serving as a fatty acid synthase inhibitor. The method is implemented through the method shown by a formula in the specification, and has the advantages of mild reaction, high efficiency, easiness in operation, environmental friendliness, short line, high yield and suitability for industrial production.
Description
Technical field
The present invention relates to a kind of synthetic method being used as the synthetic method, particularly GSK2194069 of the triazolone of fatty acid sythetase inhibitor, belong to organic synthesis field.
Background introduction
The lipid acid of human body can be taken in as ectogenous fat acid from food, also self can synthesize Endogenous fatty acid by body.Fatty acid synthetase (FAS) is the key enzyme in organism Endogenous fatty acid building-up process, and FAS expresses in each tissue such as liver and fat under normal circumstances, and its function is by carbohydrate synthetic fatty acid, stores with the form of triglyceride level.Research finds, FAS has overexpression in the tumour cell of fat and various tumour patient, as prostate cancer, ovarian cancer, colorectal carcinoma, carcinoma of endometrium, lung cancer, bladder cancer, cancer of the stomach and kidney etc., the research of FAS inhibitor has important meaning for the generation of the disease such as obesity controlling, tumour and development.Patent WO2011103546 reports a series of compound having FAS inhibit activities, and skeleton symbol is wherein important one such as formula 1, GSK2194069.
Patent WO2011103546 discloses the synthetic method of this compounds, for the synthetic method of this compounds of GSK2194069 schema as shown in Figure 1.Have a large amount of jelly in the building-up process of compound 2 to produce, make material be difficult to be uniformly dispersed, require very high to whipping device, and post-processing operation is complicated.The synthesis yield of compound 6 and product purity are all lower, affect the purifying of next step ring closure reaction.The synthesis of compound GSK2194069 needs to use microwave reaction, and condition is harsh, not easily realizes amplifying producing.This route total recovery 35%.
Therefore need exploitation variation route in order to synthesize this compounds, this route reaction mild condition, simple to operate, convenient post-treatment, total recovery are high, be applicable to industrial production.
Summary of the invention
The object of this invention is to provide a kind of synthetic method being used as the triadimefon compound of fatty acid sythetase inhibitor, the method reaction conditions is gentle, simple to operate, convenient post-treatment, total recovery are high, be applicable to industrial production.
Preparation method of the present invention is more specifically described below.However, it should be understood that the present invention is not limited to following given concrete reaction conditions (amount, temperature of reaction, reaction required time etc. as solvent, compound used therefor).
The synthetic method flow process as shown in Figure 2 of triadimefon compound provided by the invention represents:
More specifically, preparation method of the present invention comprises following steps:
A. compound 1 and halide reagent are obtained by reacting compound 2 in alcohol;
Wherein R
3definition with accompanying drawing 2, be preferably methyl;
Described halide reagent is sulfur oxychloride, phosphorus trichloride, phosphorus tribromide, phosphorus oxychloride, is preferably sulfur oxychloride; The molar feed ratio of described halide reagent and compound 1 is 1 ~ 10:1, is preferably 1 ~ 3:1;
Described alcohol is methyl alcohol, ethanol, propyl alcohol, butanols, amylalcohol, hexanol, Virahol, isopropylcarbinol, the trimethyl carbinol, primary isoamyl alcohol, tertiary amyl alcohol, 3-amylalcohol, is preferably methyl alcohol, ethanol; The volume ratio of described alcohol and compound 1 is 5 ~ 20:1, is preferably 5 ~ 10:1;
Till the described reaction times completes with detection reaction, be generally 1 ~ 48 hour, be preferably 3 ~ 5 hours.
Described temperature of reaction is 0 ~ 100 DEG C, is preferably 20 ~ 30 DEG C.
Compound 1 obtains for commercially available purchase.
B. compound 2 obtains compound 5 through three-step reaction synthesis;
Wherein R
1and R
3definition is with accompanying drawing 2, R
1be preferably cyclopropyl.
By the method for the 2-in-1 one-tenth compound 5 of compound with patent WO2011103546.
C. compound 8 obtains compound 9 through Suzuki coupling;
Wherein R
2definition with accompanying drawing 2,6 yuan of described aryl or heteroaryl ring also 5 yuan or 6 rings, be selected from benzoglyoxaline, indoles, cumarone, Dihydrobenzofuranes, indoline, imidazopyridine, quinoline, azaindole, isoquinoline 99.9, isoquinolone, quinazoline, naphthalene, indane, indenes and indazole, wherein be preferably cumarone, described R
2bromo-derivative and the mol ratio of compound 8 be 1 ~ 5:1, be preferably 1 ~ 2:1.
Described Suzuki coupling catalyst is four (triphenyl phosphorus) palladium (Pd (PPh
3)
4), palladium (Pd (OAc)
2), [1,1'-two (diphenylphosphino) ferrocene] palladium chloride (PdCl
2(dppf)), three (dibenzalacetone) two palladium Pd
2(dba)
3, be wherein preferably [two (diphenylphosphino) ferrocene of 1,1'-] palladium chloride, the molar feed ratio of described catalyzer and compound 8 is 0.01 ~ 0.2:1, is preferably 0.05 ~ 0.1:1.
The alkali of described Suzuki linked reaction is sodium carbonate, salt of wormwood, cesium carbonate, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, lithium hydroxide, hydrated barta, potassium acetate, potassium propionate etc., be preferably salt of wormwood, the molar feed ratio of described alkali and compound 8 is 2 ~ 10:1, is preferably 3 ~ 5:1.
Described solvent is DMF, DMSO, NMP, tetrahydrofuran (THF), acetonitrile, dioxane etc., is preferably DMF.
Till the described reaction times completes with detection reaction, be generally 1 ~ 48 hour, be preferably 10 ~ 14 hours.
Described temperature of reaction is 0 ~ 120 DEG C, is preferably 80 ~ 100 DEG C.
Described compound 8 and R
2bromo-derivative be commercially available purchase and obtain.
D. compound 9 and SM3 are obtained by reacting compound 10 in the basic conditions;
Wherein R
2definition with accompanying drawing 2, R
2be preferably 5-benzofuryl.
The molar feed ratio of described compound S M3 and compound 9 is 1 ~ 3:1, is preferably 1 ~ 2:1.
Described alkali is sodium carbonate, salt of wormwood, cesium carbonate, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, lithium hydroxide, the mineral alkalis such as hydrated barta, or pyridine, triethylamine, diisopropyl ethyl amine, triethylene diamine (DABCO), 1, 8-diazabicyclo [5.4.0] 11 carbon-7-alkene (DBU), 1, 5-diazabicyclo [4.3.0]-5-in ninth of the ten Heavenly Stems alkene (DBN), DMAP (DMAP), N-methylmorpholine, Tetramethyl Ethylene Diamine etc., be preferably pyridine, the mol ratio of described alkali and compound 9 is 1 ~ 5:1, be preferably 1 ~ 2:1.
Described solvent is methylene dichloride, acetonitrile, DMF, dioxane, ethyl acetate, methyl tertiary butyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, ether, toluene, or any mixing of above-mentioned solvent, is preferably methylene dichloride.
Till the described reaction times completes with detection reaction, be generally 1 ~ 48 hour, be preferably 10 ~ 14 hours.
Described temperature of reaction is 0 ~ 100 DEG C, is preferably 20 ~ 40 DEG C.
Described compound S M3 is that commercially available purchase obtains.
E. compound 10 and compound 5 are obtained by reacting compound 11;
Wherein R
1and R
2definition with accompanying drawing 2, R
1be preferably cyclopropyl, R
2be preferably 5-benzofuryl.
Described compound 10 is 1 ~ 3:1 with the molar feed ratio of compound 5, is preferably 1 ~ 2:1.
Described alkali is sodium carbonate, salt of wormwood, cesium carbonate, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, lithium hydroxide, the mineral alkalis such as hydrated barta, or pyridine, triethylamine, diisopropyl ethyl amine, triethylene diamine (DABCO), 1, 8-diazabicyclo [5.4.0] 11 carbon-7-alkene (DBU), 1, 5-diazabicyclo [4.3.0]-5-in ninth of the ten Heavenly Stems alkene (DBN), DMAP (DMAP), N-methylmorpholine, Tetramethyl Ethylene Diamine etc., be preferably triethylamine, the mol ratio of described alkali and compound 5 is 1 ~ 5:1, be preferably 1 ~ 2:1.
Described solvent is methylene dichloride, acetonitrile, DMF, dioxane, ethyl acetate, methyl tertiary butyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, ether, toluene, or any mixing of above-mentioned solvent, is preferably methylene dichloride.
Till the described reaction times completes with detection reaction, be generally 1 ~ 12 hour, be preferably 1 ~ 3 hour.
Described temperature of reaction is 0 ~ 100 DEG C, is preferably 20 ~ 40 DEG C.
F. compound 11 in the basic conditions, and Guan Huan obtains compound 12;
Wherein R
1and R
2definition with accompanying drawing 2, R
1be preferably cyclopropyl, R
2be preferably 5-benzofuryl.
Described alkali is sodium carbonate, salt of wormwood, cesium carbonate, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, lithium hydroxide, hydrated barta etc., and the mol ratio of described alkali and compound 11 is 5 ~ 15:1, is preferably 5 ~ 7:1.
Described solvent is water, Virahol, methyl alcohol, ethanol, tetrahydrofuran (THF), DMF, dioxane, 2-methyltetrahydrofuran, ether, or any mixing of above-mentioned solvent, is preferably water and Virahol.
Till the described reaction times completes with detection reaction, be generally 1 ~ 24 hour, be preferably 10 ~ 14 hours.
Described temperature of reaction is 0 ~ 120 DEG C, is preferably 80 ~ 100 DEG C.
The advantage of the inventive method is mainly:
1) the building-up reactions gentleness of compound 2 is quick again, and aftertreatment is simple;
2) by the method for p-nitrophenyl chloroformate ester carbonylate, reaction temperature is with efficient, and aftertreatment is simple;
3) route is short, and yield is high, total recovery 50%;
4) simple to operate, environmental friendliness, is applicable to industrial production;
Present method is a brand-new synthetic route capable of being industrialized, and meanwhile, the synthesis of this route to similar compound has good methodology meaning.
Accompanying drawing explanation
Fig. 1 is the schema of triadimefon compound synthetic method disclosed in patent WO2011103546;
Fig. 2 is the schema of triadimefon compound synthetic method provided by the invention, wherein R
1for substituted or non-substituted C
1-6alkyl, substituted or non-substituted C
3-7cycloalkyl ,-OC
1-6alkyl, C
4-6azacycloalkyl, oxacycloalkyl; R
2be 6 yuan of aryl or heteroaryl ring, or 6 yuan of aryl or heteroaryl ring 5 yuan or 6 rings, it contains 0-3 heteroatoms and 0-2 double bond; R
3for substituted or non-substituted C
1-6alkyl.
Specific embodiment
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, conveniently condition is carried out usually.
Raw material used in embodiment or reagent except special instruction, all commercially.
Room temperature described in embodiment all refers to 20-35 DEG C.Unless otherwise indicated, the not purified direct use of described reagent.The equal available from commercial supplier of all solvents, such as aldrich (Aldrich), and not treatedly just can to use.Reaction is analyzed by TLC and/or is analyzed by LC-MS, is judged the termination of reacting by the consumption of parent material.The thin-layer chromatography (TLC) analyzed carries out on the sheet glass (EMD chemical company (EMD Chemicals)) of pre-coated silica gel 60F2540.25 millimeter plate, with the iodine developing on UV light (254nm) and/or silica gel, and/or heat together with alcohol phospho-molybdic acid, ninidrine solution, potassium permanganate solution or ceric sulfate solution with TLC product dyed thereby.
1H-NMR spectrum is on ten thousand Ruian-Mo Qiuli-VX400 (Varian Mercury-VX400) instrument, records under 400MHz operation.
The abbreviation used in the present invention has this area conventional sense, as: DCM represents methylene dichloride, and DMF represents DMF.
Embodiment 1
Add compd A (15g, 65.4mmol) and methyl alcohol (300mL) in the there-necked flask of 500mL, slowly drip thionyl chloride (4.6mL, 65.4mmol), control rate of addition, make reacting liquid temperature be stabilized in less than 30 DEG C.After thionyl chloride drips, reaction solution continues to stir 3h in room temperature.Reaction solution concentrates, and obtaining compound 2-1 is colorless oil (15.9g, yield: 100%, purity 97.1%), is directly used in the next step.LC-MS(ES+)m/z＝244[M+H]+
Embodiment 2
Add the solution of compound 2-1 (15.9g, 65.4mmol) and 500mL HCl/ methyl tertiary butyl ether in the there-necked flask of 1L, stirred overnight at room temperature, TLC detects raw material and disappears.Reaction solution concentrated by rotary evaporation, concentration residue is dissolved in methylene dichloride (200mL), mixing solutions is joined in the there-necked flask of 500mL, triethylamine (27.8mL is added under stirring at room temperature, 199.5mmol), reaction solution is cooled to 0 DEG C, drips cyclopropyl acyl chlorides (6.8g, 65.4mmol).Dropwise, reaction solution is slowly raised to room temperature, stirs 2 hours.Reaction solution 0.5N HCl (100mL), 1M sodium bicarbonate aqueous solution wash (100mL), saturated aqueous common salt (100mL) is washed, and are separated organic phase, dry, filter, and concentrate to obtain crude product.Concentration residue is dissolved in ethanol (200mL), adds hydrazine hydrate (66.5g, 1.33mol).Reaction solution is heated to backflow, and stirring is spent the night.Reaction solution concentrates to obtain oily matter, adds 200mL ethanol, again concentrated by rotary evaporation, the oily matter dchloromethane obtained, drying, filters, concentrated, obtains white slurry compound 5-1 (13g, yield: 94%, purity: 96.8%), is directly used in the next step.LC-MS(ES+)m/z＝212[M+H]+
Embodiment 3
5-bromobenzofuran (21g is added in 250mL reaction flask, 0.1mol), p-aminophenyl pinacol borate (21.9g, 0.1mol), PdCl2 (dppf) (4g, 0.005mol), salt of wormwood (27.2g, 0.2mol), 100mL DMF, nitrogen replacement three times.Reaction is heated to 100 DEG C, and stirring is spent the night.In reaction solution, add saturated aqueous common salt (300mL), be extracted with ethyl acetate (100mL × 2), merge organic phase, dry, filter, the thick product that filtrate is concentrated.Through column chromatography purification, obtaining compound 9-1 is white solid product (19.8g, yield: 89%, purity 98.2%).
1H NMR(DMSO-d
6,400MHz):7.98(s,1H),7.75(s,1H),7.57(d,1H),7.45(d,1H),7.35(d,2H),6.95(s,1H),6.64(d,2H),5.18(s,2H)ppm，LC-MS(ES+)m/z＝210[M+H]
+
Embodiment 4
Compound 9-1 (12g, 57mmol) is added successively, p-nitrophenyl chloroformate ester (12g in 500mL reaction flask, 57mmol), methylene dichloride (200mL), pyridine (4.8g, 61mmol), reaction solution stirred overnight at room temperature.Saturated aqueous common salt (500mL) is added in reaction system, with 1N HCl adjust pH to 3-4, with dichloromethane extraction (200mL × 2), organic phase merges, drying, concentrated that compound 10-1 is light yellow solid (21g, yield: 97.7%, purity: 97%), solid is directly used in the next step.LC-MS(ES+)m/z＝375[M+H]
+
Embodiment 5
Add compound 10-1 (21g, 56mmol) successively in 500mL reaction flask, compound 5-1 (12g, 56mmol), methylene dichloride (300mL), then drip triethylamine (9.5mL).Reaction solution stirring at room temperature 1 hour, has a large amount of solid to separate out.Filter to obtain yellow solid, by washed with dichloromethane, obtaining compound 11-1 after drying is that (purity: 96.7%), is directly used in the next step to yellow solid product for 24g, yield: 95.8%.LC-MS(ES+)m/z＝447[M+H]
+
Embodiment 6
Compound 11-1 (24g, 54mmol) is added successively, salt of wormwood (39g, 278mmol), water (150mL), Virahol (15mL), reaction solution heated overnight at reflux in 250mL reaction flask.Reaction solution dichloromethane extraction (100mL × 2), organic phase merges, dry, concentrates to obtain crude product.Crude product column chromatography purification, obtaining compound GSK2194069 is white solid (20g, yield: 87%, purity: 98.1%).
1H NMR(CDCl
3,400MHz):9.77-9.87(d,1H),7.83(d,1H),7.77(d,2H),7.71(d,1H),7.56(d,1H),7.54(d,1H),7.41(d,2H),6.87(s,1H),3.94(m,0.5H),3.62-3.74(m,2H),3.42(m,0.5H),3.24(m,0.5H),3.12(m,0.5H),2.57-2.71(m,3H),2.22(m,0.5H),2.1(m,0.5H),1.57-1.75(m,2H),0.98-1.01(m,2H),0.75-0.77(m,2H)ppm,LC-MS(ES+)m/z＝429[M+H]
+
Embodiment 7
5-bromo indole (10g, 51mmol) is added, p-aminophenyl pinacol borate (11g, 51mmol), PdCl in 100mL reaction flask
2(dppf) (1.8g, 2.5mmol), salt of wormwood (13.8g, 0.1mol), 50mL DMF, nitrogen replacement three times.Reaction is heated to 100 DEG C, and stirring is spent the night.In reaction solution, add saturated aqueous common salt (200mL), be extracted with ethyl acetate (100mL × 2), merge organic phase, dry, filter, the thick product that filtrate is concentrated.Through column chromatography purification, obtain compound 9-2 white solid product (9.7g, yield: 91%, purity 97.5%).
1H NMR(DMSO-d
6,400MHz):10.98(s,1H),7.64(s,1H),7.39(d,1H),7.32(d,2H)，7.31(d,1H),7.27(d,1H),6.63(d,2H),6.42(d,1H),5.04(s,2H)ppm,LC-MS(ES+)m/z＝209[M+H]
+
Embodiment 8
Compound 9-2 (9.7g, 47mmol) is added successively, p-nitrophenyl chloroformate ester (9.4g in 500mL reaction flask, 47mmol), methylene dichloride (200mL), pyridine (4g, 51mmol), reaction solution stirred overnight at room temperature.Saturated aqueous common salt (500mL) is added in reaction system, adjust aqueous pH values to 3-4 with the 1N HCl aqueous solution, with dichloromethane extraction (100mL × 2), organic phase merges, drying, concentrated that compound 10-2 is faint yellow solid (17g, yield: 97%, purity: 97.2%), solid is directly used in the next step.LC-MS(ES+)m/z＝374[M+H]
+
Embodiment 9
Add compound 10-2 (17g, 46mmol) successively in 500mL reaction flask, compound 5-1 (9.6g, 46mmol), methylene dichloride (300mL), then drip triethylamine (8mL).Reaction solution stirring at room temperature 1 hour, has a large amount of solid to separate out.Filter to obtain yellow solid, by washed with dichloromethane, obtaining compound 11-2 after drying is that (purity: 96%), is directly used in the next step to yellow solid product for 20g, yield: 93%.LC-MS(ES+)m/z＝446[M+H]
+
Embodiment 10
Compound 11-1 (20g, 45mmol) is added successively, salt of wormwood (39g, 278mmol), water (200mL), Virahol (20mL), reaction solution heated overnight at reflux in 250mL reaction flask.Reaction solution dichloromethane extraction (100mL × 2), organic phase merges, dry, concentrates to obtain crude product.Crude product column chromatography purification, obtaining compound 12-2 is white solid (16.5g, yield: 86%, purity: 97.5%).
1H NMR(DMSO-d
6，400MHz)δ＝11.72(d,1H),11.23(s，1H),7.82(d，2H),7.69(s，1H),7.64(d，1H),7.48(d，2H),7.41(t,1H),7.36(d,1H),6.47(t,1H),3.61-3.86(m,1H),3.47-3.60(m,1H),2.87-3.43(m,2H),2.34-2.66(m,3H),1.91-2.13(m,1H),1.44-1.74(m,2H),0.61-0.73(m,4H)ppm,LC-MS(ES+)m/z＝428[M+H]
+。
Embodiment 11
6-bromoquinoline (10g, 48mmol) is added, p-aminophenyl pinacol borate (10.6g, 48mmol), PdCl in 100mL reaction flask
2(dppf) (1.8g, 2.4mmol), salt of wormwood (13.2g, 0.096mol), 50mLDMF, nitrogen replacement three times.Reaction is heated to 100 DEG C, and stirring is spent the night.In reaction solution, add saturated aqueous common salt (150mL), be extracted with ethyl acetate (100mL × 2), merge organic phase, dry, filter, the thick product that filtrate is concentrated.Through column chromatography purification, obtain the white solid product (9.8g, yield: 92%, purity 97.1%) of compound 9-3.
1H NMR(DMSO-d
6,400MHz):8.83(m,1H),8.34(m,1H),8.12(s,1H),8.02(d,1H),8.00(d,1H),7.54(d,2H),7.50(m,1H),6.71(d,2H),5.35(s,2H)ppm,LC-MS(ES+)m/z＝221[M+H]
+
Embodiment 12
Compound 9-3 (9.8g, 44mmol) is added successively, p-nitrophenyl chloroformate ester (8.9g in 500mL reaction flask, 44mmol), methylene dichloride (200mL), pyridine (3.5g, 44mmol), reaction solution stirred overnight at room temperature.Saturated aqueous common salt (500mL) is added in reaction system, with 1N HCl aqueous solution adjust pH to 3-4, with dichloromethane extraction (100mL × 2), organic phase merges, drying, concentrated that compound 10-3 is faint yellow solid (17g, yield: 94%, purity: 97.8%), solid is directly used in the next step.LC-MS(ES+)m/z＝386[M+H]
+
Embodiment 13
Add compound 10-3 (17g, 44mmol) successively in 500mL reaction flask, compound 5-1 (9.3g, 44mmol), methylene dichloride (300mL), then drip triethylamine (8mL).Reaction solution stirring at room temperature 1 hour, has a large amount of solid to separate out.Filter to obtain yellow solid, by washed with dichloromethane, obtaining compound 11-3 after drying is that (purity: 96.5%), is directly used in the next step to yellow solid product for 18.4g, yield: 91%.LC-MS(ES+)m/z＝458[M+H]
+
Embodiment 14
Compound 11-3 (18.4g, 40mmol) is added successively, salt of wormwood (33g, 240mmol), water (100mL), Virahol (10mL), reaction solution heated overnight at reflux in 250mL reaction flask.Reaction solution dichloromethane extraction (75mL × 2), organic phase merges, dry, concentrates to obtain crude product.Crude product column chromatography purification, obtaining compound 12-3 is white solid (15.5g, yield: 88%, purity: 97.1%).
1H NMR(400MHz，DMSO-d
6)δ＝11.13(s，1H),8.83(d,1H),8.38(d,1H),8.21(d,1H),8.04(d,1H),7.82(d，2H),7.75(s，1H),7.58(t,1H),7.48(d，2H),3.62-3.89(m，1H),3.50-3.62(m,1H),2.95-3.40(m,2H),2.32-2.59(m,3H),1.90-2.11(m,1H),1.45-1.69(m,2H),0.63-0.76(m,4H)ppm,LC-MS(ES+)m/z＝440[M+H]
+。
Embodiment 15
Add the solution of compound 2-1 (10g, 41.1mmol) and 250mL HCl/ methyl tertiary butyl ether in the there-necked flask of 500mL, stirred overnight at room temperature, TLC detects raw material and disappears.Reaction solution concentrated by rotary evaporation, concentration residue is dissolved in methylene dichloride (100mL), mixing solutions is joined in the there-necked flask of 250mL, triethylamine (12.5g is added under stirring at room temperature, 123mmol), reaction solution is cooled to 0 DEG C, drips trimethyl-acetyl chloride (5g, 41.1mmol).Dropwise, reaction solution is slowly raised to room temperature, stirs 2 hours.Reaction solution 0.5N HCl (100mL), 1M sodium bicarbonate aqueous solution wash (100mL), saturated aqueous common salt (100mL) is washed, and are separated organic phase, dry, filter, and concentrate to obtain crude product.Concentration residue is dissolved in ethanol (200mL), adds hydrazine hydrate (41g, 822mmol).Reaction solution is heated to backflow, and stirring is spent the night.Reaction solution concentrates to obtain oily matter, adds 100mL ethanol, again concentrated by rotary evaporation, the oily matter dchloromethane obtained, drying, filters, concentrated, obtains white slurry compound 5-2 (8.7g, yield: 93%, purity: 97.2%), is directly used in the next step.LC-MS(ES+)m/z＝228[M+H]
+
Embodiment 16
Add compound 10-3 (14.7g, 38mmol) successively in 500mL reaction flask, compound 5-2 (26.1g, 114mmol), toluene (300mL), then drip triethylamine (16.6mL).Reaction solution is slowly warming up to 100 DEG C, and stir 0.5h, slow cooling, to room temperature, has a large amount of solid to separate out.Filter to obtain yellow solid, by toluene wash, obtaining compound 11-4 after drying is that (purity: 97.8%), is directly used in the next step to yellow solid product for 16.8g, yield: 93%.LC-MS(ES+)m/z＝474[M+H]
+
Embodiment 17
Compound 9-1 (16.8g, 35.5mmol) is added successively, salt of wormwood (29g, 213mmol), water (150mL), Virahol (15mL), reaction solution heated overnight at reflux in 250mL reaction flask.Reaction solution dichloromethane extraction (100mL × 2), organic phase merges, dry, concentrates to obtain crude product.Crude product column chromatography purification, obtaining compound 12-4 is white solid (14.4g, yield: 89%, purity: 98.4%).
1H NMR(CDCl
3,400MHz):11.09(s,1H),8.81(d,1H),8.40(d,1H),8.19(d,1H),8.03(d,1H),7.81(d，2H),7.76(s，1H),7.60(t,1H),7.49(d，2H),3.59-3.83(m，1H),3.47-3.60(m,1H),2.91-3.32(m,2H),2.30-2.51(m,3H),1.47-1.67(m,2H),1.29(s,9H)ppm,LC-MS(ES+)m/z＝456[M+H]
+。
Claims (10)
1. be used as a synthetic method for the triadimefon compound 12 of fatty acid sythetase inhibitor, it is characterized in that comprising following steps:
C. compound 8 is under catalyst action, obtains compound 9 through Suzuki coupling;
D. compound 9 and SM3 are obtained by reacting compound 10 in the basic conditions;
E. compound 10 and compound 5 are obtained by reacting compound 11;
F. compound 11 in the basic conditions, and Guan Huan obtains compound 12;
Wherein R1 is substituted or non-substituted C
1-6alkyl, substituted or non-substituted C
3-7cycloalkyl ,-OC
1-6alkyl, C
4-6azacycloalkyl, oxacycloalkyl; R
2be 6 yuan of aryl or heteroaryl ring, or 6 yuan of aryl or heteroaryl ring 5 yuan or 6 rings, it contains 0-3 heteroatoms and 0-2 double bond.
2. the synthetic method of compound 12 according to claim 1, is characterized in that, described R
1for cyclopropyl or the tertiary butyl, described R
2be selected from benzoglyoxaline, indoles, cumarone, Dihydrobenzofuranes, indoline, imidazopyridine, quinoline, azaindole, isoquinoline 99.9, isoquinolone, quinazoline, naphthalene, indane, indenes and indazole.
3. the synthetic method of compound 12 according to claim 1, it is characterized in that, in step c, described catalyzer is four (triphenyl phosphorus) palladium, palladium, [1, two (diphenylphosphino) ferrocene of 1'-] palladium chloride, one or more in palladium of three (dibenzalacetone) two, the molar feed ratio of described catalyzer and compound 8 is 0.01 ~ 0.2:1.
4. the synthetic method of compound 12 according to claim 1, it is characterized in that, in steps d, the molar feed ratio of described compound S M3 and compound 9 is 1 ~ 3:1; Described alkali is selected from sodium carbonate, salt of wormwood, cesium carbonate, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, lithium hydroxide, the mineral alkalis such as hydrated barta, or pyridine, triethylamine, diisopropyl ethyl amine, triethylene diamine, 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene, 1,5-diazabicyclo [4.3.0]-5-in ninth of the ten Heavenly Stems alkene DMAP, N-methylmorpholine, Tetramethyl Ethylene Diamine, the mol ratio of described alkali and compound 9 is 1 ~ 5:1; Described solvent is methylene dichloride, acetonitrile, DMF, dioxane, ethyl acetate, methyl tertiary butyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, ether, toluene, or any mixing of above-mentioned solvent; Described temperature of reaction is 0 ~ 100 DEG C.
5. the synthetic method of compound 12 according to claim 4, it is characterized in that, the molar feed ratio of described compound S M3 and compound 9 is 1 ~ 2:1; Described alkali is pyridine, and the mol ratio of itself and compound 9 is 1 ~ 2:1; Described solvent is methylene dichloride; Described temperature of reaction is 20 ~ 40 DEG C.
6. the synthetic method of compound 12 according to claim 1, it is characterized in that, in step e, described alkali is selected from sodium carbonate, salt of wormwood, cesium carbonate, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, lithium hydroxide, the mineral alkalis such as hydrated barta, or pyridine, triethylamine, diisopropyl ethyl amine, triethylene diamine (DABCO), 1, 8-diazabicyclo [5.4.0] 11 carbon-7-alkene (DBU), 1, 5-diazabicyclo [4.3.0]-5-in ninth of the ten Heavenly Stems alkene (DBN), DMAP (DMAP), N-methylmorpholine, Tetramethyl Ethylene Diamine etc., be preferably triethylamine, the mol ratio of described alkali and compound 8 is 1 ~ 5:1, be preferably 1 ~ 2:1, described solvent is methylene dichloride, acetonitrile, DMF, dioxane, ethyl acetate, methyl tertiary butyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, ether, toluene, or any mixing of above-mentioned solvent, is preferably methylene dichloride, till the described reaction times completes with detection reaction, be generally 1 ~ 12 hour, be preferably 1 ~ 3 hour, described temperature of reaction is 0 ~ 100 DEG C, is preferably 20 ~ 40 DEG C.
7. the synthetic method of compound 12 according to claim 1, is characterized in that, in step f, described alkali is sodium carbonate, salt of wormwood, cesium carbonate, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, lithium hydroxide, hydrated barta etc., the mol ratio of described alkali and compound 5 is 5 ~ 15:1, is preferably 5 ~ 7:1; Described solvent is water, Virahol, methyl alcohol, ethanol, tetrahydrofuran (THF), DMF, dioxane, 2-methyltetrahydrofuran, ether, or any mixing of above-mentioned solvent, is preferably water and Virahol; Till the described reaction times completes with detection reaction, be generally 1 ~ 24 hour, be preferably 10 ~ 14 hours; Described temperature of reaction is 0 ~ 120 DEG C, is preferably 80 ~ 100 DEG C.
8. the synthetic method of compound 12 according to claim 1, it is characterized in that, the preparation method of described compound 5 comprises following steps:
A. compound 1 and halide reagent are obtained by reacting compound 2 in alcohol;
B. compound 2 obtains compound 5 through three-step reaction synthesis;
Wherein R
3for substituted or non-substituted C
1-6alkyl.
9. the synthetic method of compound 12 according to claim 8, it is characterized in that, in step a, described halide reagent is selected from sulfur oxychloride, phosphorus trichloride, phosphorus tribromide, phosphorus oxychloride, and the molar feed ratio of itself and compound 1 is 1 ~ 10:1; Described alcohol is selected from methyl alcohol, ethanol, propyl alcohol, butanols, amylalcohol, hexanol, Virahol, isopropylcarbinol, the trimethyl carbinol, primary isoamyl alcohol, tertiary amyl alcohol, 3-amylalcohol, and the volume ratio of described alcohol and compound 1 is 5 ~ 20:1; Described temperature of reaction is 0 ~ 100 DEG C.
10. the synthetic method of compound 12 according to claim 8, is characterized in that, described R
3for methyl, described halide reagent is sulfur oxychloride, and described alcohol is methyl alcohol or ethanol; The volume ratio of itself and compound 1 is 5 ~ 10:1; Described temperature of reaction is 20 ~ 30 DEG C.
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| CN102858175A (en) * | 2010-02-22 | 2013-01-02 | 葛兰素史密斯克莱有限责任公司 | Triazolones as fatty acid synthase inhibitors |
| WO2014108858A1 (en) * | 2013-01-10 | 2014-07-17 | Glaxosmithkline Intellectual Property (No.2) Limited | Fatty acid synthase inhibitors |
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| CN110655482A (en) * | 2019-10-18 | 2020-01-07 | 四川轻化工大学 | Preparation method of gulconine |
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