CN104876917B - The synthetic method of triazolone as fatty acid sythetase inhibitor - Google Patents
The synthetic method of triazolone as fatty acid sythetase inhibitor Download PDFInfo
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- QSSDLTPSEKRLNU-UHFFFAOYSA-N NC(C(C1)C1(CC1)CN1C(C1CC1)=O)=O Chemical compound NC(C(C1)C1(CC1)CN1C(C1CC1)=O)=O QSSDLTPSEKRLNU-UHFFFAOYSA-N 0.000 description 1
- XRBCZQDWXXBNNI-INIZCTEOSA-N O=C(C[C@H](CC1)CN1C(C1CC1)=O)NNC(Nc(cc1)ccc1-c1ccc2[o]ccc2c1)=O Chemical compound O=C(C[C@H](CC1)CN1C(C1CC1)=O)NNC(Nc(cc1)ccc1-c1ccc2[o]ccc2c1)=O XRBCZQDWXXBNNI-INIZCTEOSA-N 0.000 description 1
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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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Abstract
The invention discloses a kind of synthetic method of the triazolone as fatty acid sythetase inhibitor, implemented by such as following formula method, this method reaction is gentle efficient, is simple to operate and friendly to environment, route is short, high income, is adapted to industrial production.
Description
Technical field
The present invention relates to a kind of synthetic method of the triazolone as fatty acid sythetase inhibitor, particularly
GSK2194069 synthetic method, belongs to organic synthesis field.
Background introduction
It is ectogenous fat acid that the aliphatic acid of human body can be taken in from food, also itself can synthesize endogenous by vivo
Aliphatic acid.Fatty acid synthetase (FAS) is the key enzyme in organism Endogenous fatty acid building-up process, under normal circumstances FAS
Expressed in liver and fat etc. respectively tissue, its function is, by carbohydrate synthetic fatty acid, to be stored up in the form of triglycerides
Deposit.Research finds that FAS has overexpression in the tumour cell of fat and various tumor patients, such as：Prostate cancer, oophoroma,
Colon cancer, carcinoma of endometrium, lung cancer, carcinoma of urinary bladder, stomach cancer and kidney etc., the research of FAS inhibitor is for obesity controlling, tumour etc.
The occurrence and development of disease have important meaning.Patent WO2011103546 reports a series of chemical combination for having a FAS inhibitory activity
Thing, skeleton symbol such as formula 1, GSK2194069 is wherein important one kind.
Patent WO2011103546 discloses the synthetic method of this kind of compound, such compound by taking GSK2194069 as an example
Synthetic method flow chart as shown in Figure 1.A large amount of jellies are had in the building-up process of compound 2 to produce, and make material difficult
To be uniformly dispersed, very high is required to mixing plant, and post-processing operation is complicated.The synthesis yield and product purity of compound 6
It is all relatively low, influence the purifying of next step ring closure reaction.Compound GSK2194069 synthesis needs to use microwave reaction, and condition is severe
Carve, be difficult to realize amplification production.The route total recovery 35%.
Therefore one variation route of exploitation is needed to synthesize such compound, the route reaction condition is gentle, simple to operate,
Convenient post-treatment, total recovery are high, be adapted to industrial production.
The content of the invention
It is an object of the invention to provide a kind of synthesis side of the triadimefon compound as fatty acid sythetase inhibitor
Method, this method reaction condition is gentle, simple to operate, convenient post-treatment, total recovery high, be adapted to industrial production.
The preparation method of the present invention is described more particularly below.However, it should be understood that the invention is not limited in given below
The specific reaction condition gone out (such as the time required to the amount of solvent, compound used therefor, reaction temperature, reaction).
The flow of the synthetic method for the triadimefon compound that the present invention is provided as shown in Figure 2 is represented：
More specifically, preparation method of the invention is comprised the following steps：
A. compound 1 is reacted with halide reagent in alcohol obtains compound 2；
Wherein R3Definition with accompanying drawing 2, preferably methyl；
Described halide reagent is thionyl chloride, phosphorus trichloride, phosphorus tribromide, POCl3, preferably thionyl chloride；Institute
The halide reagent and the molar feed ratio of compound 1 stated are 1~10:1, preferably 1~3:1；
Described alcohol be methanol, ethanol, propyl alcohol, butanol, amylalcohol, hexanol, isopropanol, isobutanol, the tert-butyl alcohol, isoamyl alcohol,
Tert-pentyl alcohol, 3- amylalcohols, preferably methanol, ethanol；The volume ratio of the alcohol and compound 1 is 5~20:1, preferably 5~10:1；
The described reaction time with detect reaction complete untill, usually 1~48 hour, preferably 3~5 hours.
Described reaction temperature is 0~100 DEG C, preferably 20~30 DEG C.
Compound 1 is commercially available to be commercially available.
B. compound 2 obtains compound 5 through three-step reaction synthesis；
Wherein R1And R3Definition is with accompanying drawing 2, R1Preferably cyclopropyl.
By the 2-in-1 method into compound 5 of compound with patent WO2011103546.
C. compound 8 obtains compound 9 through Suzuki couplings；
Wherein R2Definition with accompanying drawing 2, it is preferred that R2Selected from benzimidazole, indoles, benzofuran, Dihydrobenzofuranes,
Indoline, imidazopyridine, quinoline, azaindole, isoquinolin, isoquinolone, quinazoline, naphthalene, indane, indenes and indazole,
More preferably benzofuran, the R2The mol ratio of bromo-derivative and compound 8 be 1~5:1, preferably 1~2:1.
The Suzuki coupling catalysts are four (triphenyl phosphorus) palladium (Pd (PPh3)4), palladium (Pd (OAc)2)、[1,
Double (diphenylphosphino) ferrocene of 1'-] palladium chloride (PdCl2(dppf)), three (dibenzalacetone) two palladium Pd2(dba)3, its
In be preferably [1,1'- double (diphenylphosphino) ferrocene] palladium chloride, the catalyst and the molar feed ratio of compound 8 are
0.01~0.2:1, preferably 0.05~0.1:1.
The alkali of the Suzuki coupling reactions is sodium carbonate, potassium carbonate, cesium carbonate, sodium acid carbonate, saleratus, hydroxide
Sodium, potassium hydroxide, lithium hydroxide, preferably barium hydroxide, potassium acetate, potassium propionate etc., potassium carbonate, the alkali and compound 8
Molar feed ratio is 2~10:1, preferably 3~5:1.
Described solvent is DMF, DMSO, NMP, tetrahydrofuran, acetonitrile, dioxane etc., preferably DMF.
The described reaction time with detect reaction complete untill, usually 1~48 hour, preferably 10~14 hours.
Described reaction temperature is 0~120 DEG C, preferably 80~100 DEG C.
Described compound 8 and R2Bromo-derivative be commercially available be commercially available.
D. compound 9 and SM3 reacts in the basic conditions obtains compound 10；
Wherein R2Definition with accompanying drawing 2, R2Preferably 5- benzofuranyls.
The compound SM3 and the molar feed ratio of compound 9 are 1~3:1, preferably 1~2:1.
Described alkali is sodium carbonate, potassium carbonate, cesium carbonate, sodium acid carbonate, saleratus, sodium hydroxide, potassium hydroxide, hydrogen
Lithia, the inorganic base such as barium hydroxide, or pyridine, triethylamine, diisopropyl ethyl amine, triethylene diamine (DABCO), 1,8- bis-
Carbon -7- the alkene (DBU) of azabicyclo [5.4.0] 11,1,5- diazabicyclo [4.3.0] nonyl- 5- alkene (DBN), 4- dimethylaminos
Pyridine (DMAP), N-methylmorpholine, tetramethylethylenediamine etc., preferably pyridine, the mol ratio of the alkali and compound 9 for 1~
5:1, preferably 1~2:1.
Described solvent is dichloromethane, acetonitrile, DMF, dioxane, ethyl acetate, methyl tertiary butyl ether(MTBE), tetrahydrochysene furan
Mutter, 2- methyltetrahydrofurans, ether, toluene, or above-mentioned solvent any mixing, preferably dichloromethane.
The described reaction time with detect reaction complete untill, usually 1~48 hour, preferably 10~14 hours.
Described reaction temperature is 0~100 DEG C, preferably 20~40 DEG C.
Described compound SM3 is commercially available to be commercially available.
E. compound 10 obtains compound 11 with the reaction of compound 5；
Wherein R1And R2Definition with accompanying drawing 2, R1Preferably cyclopropyl, R2Preferably 5- benzofuranyls.
The molar feed ratio of the compound 10 and compound 5 is 1~3:1, preferably 1~2:1.
Described alkali is sodium carbonate, potassium carbonate, cesium carbonate, sodium acid carbonate, saleratus, sodium hydroxide, potassium hydroxide, hydrogen
Lithia, the inorganic base such as barium hydroxide, or pyridine, triethylamine, diisopropyl ethyl amine, triethylene diamine (DABCO), 1,8- bis-
Carbon -7- the alkene (DBU) of azabicyclo [5.4.0] 11,1,5- diazabicyclo [4.3.0] nonyl- 5- alkene (DBN), 4- dimethylaminos
The mol ratio of pyridine (DMAP), N-methylmorpholine, preferably tetramethylethylenediamine etc., triethylamine, the alkali and compound 5 is 1
~5:1, preferably 1~2:1.
Described solvent is dichloromethane, acetonitrile, DMF, dioxane, ethyl acetate, methyl tertiary butyl ether(MTBE), tetrahydrochysene furan
Mutter, 2- methyltetrahydrofurans, ether, toluene, or above-mentioned solvent any mixing, preferably dichloromethane.
The described reaction time with detect reaction complete untill, usually 1~12 hour, preferably 1~3 hour.
Described reaction temperature is 0~100 DEG C, preferably 20~40 DEG C.
F. in the basic conditions, cyclization obtains compound 12 to compound 11；
Wherein R1And R2Definition with accompanying drawing 2, R1Preferably cyclopropyl, R2Preferably 5- benzofuranyls.
Described alkali is sodium carbonate, potassium carbonate, cesium carbonate, sodium acid carbonate, saleratus, sodium hydroxide, potassium hydroxide, hydrogen
Lithia, barium hydroxide etc., the mol ratio of the alkali and compound 11 is 5~15:1, preferably 5~7:1.
Described solvent be water, isopropanol, methanol, ethanol, tetrahydrofuran, DMF, dioxane, 2- methyltetrahydrofurans,
Ether, or above-mentioned solvent any mixing, preferably water and isopropanol.
The described reaction time with detect reaction complete untill, usually 1~24 hour, preferably 10~14 hours.
Described reaction temperature is 0~120 DEG C, preferably 80~100 DEG C.
The advantage of the inventive method is essentially consisted in：
1) synthetic reaction of compound 2 is gentle and quick, and post processing is simple；
2) method that carbonyl is introduced with p-nitrophenyl chloroformate ester, reaction is gentle efficient, and post processing is simple；
3) route is short, high income, total recovery 50%；
4) it is simple to operate and friendly to environment, is adapted to industrial production；
This method is a brand-new synthetic route capable of being industrialized, meanwhile, synthesis of the route to similar compound has
There is good methodology meaning.
Brief description of the drawings
Fig. 1 is the flow chart of triadimefon compound synthetic method disclosed in patent WO2011103546；
Fig. 2 is the flow chart for the triadimefon compound synthetic method that the present invention is provided, wherein R1To be substituted or non-substituted
C1-6Alkyl, substituted or non-substituted C3-7Cycloalkyl ,-OC1-6Alkyl, C4-6Azacycloalkyl, oxacycloalkyl；R2For 6 yuan
Aryl or heteroaryl ring, or 6 yuan of aryl or heteroaryl ring and 5 yuan or 6 yuan of rings, it contains 0-3 hetero atom and 0-2 double
Key；R3For substituted or non-substituted C1-6Alkyl.
Specific embodiment
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate the present invention
Rather than limitation the scope of the present invention.The experimental method of unreceipted actual conditions in the following example, generally according to conventional strip
Part is carried out.
Raw material used or reagent are commercially available in addition to special instruction in embodiment.
Room temperature described in embodiment refers both to 20-35 DEG C.Unless otherwise indicated, described reagent is not purified directly makes
With.All solvents are purchased from commercialization supplier, such as aldrich (Aldrich), and just can be used without processing.Reaction
Analyzed and/or analyzed by LC-MS by TLC, the termination of reaction is judged by the consumption of parent material.The thin layer of analysis
Chromatography (TLC) is the glass plate (EMD chemical companies (EMD in 0.25 millimeter of plate of pre-coated silica gel 60F254
Chemicals carried out on)), with the iodine developing on UV light (254nm) and/or silica gel, and/or with TLC product dyed therebies such as alcohol phosphorus
Molybdic acid, ninhydrin solution, liquor potassic permanganate or ceric sulfate solution are heated together.
1H-NMR spectrums are on ten thousand Ruian-Mo Qiuli-VX400 (Varian Mercury-VX400) instrument, in 400MHz behaviour
Make lower record.
The abbreviation used in the present invention has this area conventional sense, such as：DCM represents dichloromethane, and DMF represents N, N- bis-
NMF.
Embodiment 1
Compound A (15g, 65.4mmol) and methanol (300mL) are added in 500mL there-necked flask, dichloro is slowly added dropwise sub-
Sulfone (4.6mL, 65.4mmol), controls rate of addition, makes reacting liquid temperature stable below 30 DEG C.After thionyl chloride is dripped,
Reaction solution continues to stir 3h in room temperature.Reaction solution is concentrated, and obtains compound 2-1 for colorless oil (15.9g, yield：100%,
Purity 97.1%), it is directly used in the next step.LC-MS (ES+) m/z=244 [M+H]+
Embodiment 2
In 1L there-necked flask add compound 2-1 (15.9g, 65.4mmol) and 500mL HCl/ methyl tertiary butyl ether(MTBE)s it is molten
Liquid, is stirred overnight at room temperature, and TLC detection raw materials disappear.Reaction solution concentrated by rotary evaporation, dichloromethane is dissolved in by concentration residue
(200mL), mixed solution is added in 500mL there-necked flask, be stirred at room temperature it is lower addition triethylamine (27.8mL,
199.5mmol), reaction solution is cooled to 0 DEG C, and cyclopropyl acyl chlorides (6.8g, 65.4mmol) is added dropwise.Completion of dropping, reaction solution is slowly
Room temperature is raised to, is stirred 2 hours.Reaction solution washes (100mL), saturated common salt with 0.5N HCl (100mL), 1M sodium bicarbonate aqueous solutions
Water (100mL) is washed, and separates organic phase, is dried, and filtering is concentrated to give crude product.Concentration residue is dissolved in ethanol (200mL), added
Hydrazine hydrate (66.5g, 1.33mol).Reaction solution is heated to backflow, and is stirred overnight.Reaction solution is concentrated to give grease, adds
200mL ethanol, concentrated by rotary evaporation, obtained grease dchloromethane, are dried again, are filtered, and concentration obtains white slurry
Compound 5-1 (13g, yield：94%, purity：96.8%), it is directly used in the next step.LC-MS (ES+) m/z=212 [M+H]
+
Embodiment 3
Addition 5- bromobenzofurans (21g, 0.1mol) in 250mL reaction bulbs, p-aminophenyl pinacol borate (21.9g,
0.1mol), PdCl2 (dppf) (4g, 0.005mol), potassium carbonate (27.2g, 0.2mol), 100mL DMF, nitrogen displacement three times.
Reaction is heated to 100 DEG C, and is stirred overnight.Saturated aqueous common salt (300mL) is added into reaction solution, is extracted with ethyl acetate
(100mL × 2), merge organic phase, dry, filtering, the crude product of filtrate concentration.Purified through column chromatography, it is white to obtain compound 9-1
Color solid product (19.8g, yield：89%, purity 98.2%).
1H NMR(DMSO-d6,400MHz):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
Sequentially add compound 9-1 (12g, 57mmol) in 500mL reaction bulbs, p-nitrophenyl chloroformate ester (12g,
57mmol), dichloromethane (200mL), pyridine (4.8g, 61mmol), reaction solution is stirred overnight at room temperature.Added into reaction system
Saturated aqueous common salt (500mL), adjusts pH value to 3-4, is extracted with dichloromethane (200mL × 2), organic phase merges, do with 1N HCl
It is dry, compound 10-1 is concentrated to give for light yellow solid (21g, yield：97.7%, purity：97%), to be directly used in lower step anti-for solid
Should.LC-MS (ES+) m/z=375 [M+H]+
Embodiment 5
Compound 10-1 (21g, 56mmol), compound 5-1 (12g, 56mmol), two are sequentially added in 500mL reaction bulbs
Chloromethanes (300mL), is then added dropwise triethylamine (9.5mL).1 hour is stirred at room temperature in reaction solution, has a large amount of solids to separate out.Filtering
Yellow solid is obtained, is washed with dichloromethane, it is yellow solid product (24g, yield that compound 11-1 is obtained after drying：95.8%, it is pure
Degree：96.7%), it is directly used in the next step.LC-MS (ES+) m/z=447 [M+H]+
Embodiment 6
Compound 11-1 (24g, 54mmol), potassium carbonate (39g, 278mmol), water are sequentially added in 250mL reaction bulbs
(150mL), isopropanol (15mL), reaction solution heated overnight at reflux.Reaction solution extracts (100mL × 2), organic phase with dichloromethane
Merge, dry, be concentrated to give crude product.Crude product is purified with column chromatography, obtains compound GSK2194069 for white solid (20g, yield：
87%, purity：98.1%).
1H NMR(CDCl3,400MHz):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
Addition 5- bromo indoles (10g, 51mmol) in 100mL reaction bulbs, p-aminophenyl pinacol borate (11g,
51mmol), PdCl2(dppf) (1.8g, 2.5mmol), potassium carbonate (13.8g, 0.1mol), 50mL DMF, nitrogen displacement three times.
Reaction is heated to 100 DEG C, and is stirred overnight.Saturated aqueous common salt (200mL) is added into reaction solution, is extracted with ethyl acetate
(100mL × 2), merge organic phase, dry, filtering, the crude product of filtrate concentration.Purified through column chromatography, obtain compound 9-2 whites
Solid product (9.7g, yield：91%, purity 97.5%).
1H NMR(DMSO-d6,400MHz):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
Sequentially add compound 9-2 (9.7g, 47mmol) in 500mL reaction bulbs, p-nitrophenyl chloroformate ester (9.4g,
47mmol), dichloromethane (200mL), pyridine (4g, 51mmol), reaction solution is stirred overnight at room temperature.Added into reaction system full
With saline solution (500mL), adjust aqueous pH values to 3-4 with 1N HCl/waters solution, (100mL × 2), organic phase are extracted with dichloromethane
Merge, dry, be concentrated to give compound 10-2 for 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
Compound 10-2 (17g, 46mmol), compound 5-1 (9.6g, 46mmol), two are sequentially added in 500mL reaction bulbs
Chloromethanes (300mL), is then added dropwise triethylamine (8mL).1 hour is stirred at room temperature in reaction solution, has a large amount of solids to separate out.Filter
Yellow solid, is washed with dichloromethane, and it is yellow solid product (20g, yield that compound 11-2 is obtained after drying：93%, purity：
96%), it is directly used in the next step.LC-MS (ES+) m/z=446 [M+H]+
Embodiment 10
Compound 11-1 (20g, 45mmol), potassium carbonate (39g, 278mmol), water are sequentially added in 250mL reaction bulbs
(200mL), isopropanol (20mL), reaction solution heated overnight at reflux.Reaction solution extracts (100mL × 2), organic phase with dichloromethane
Merge, dry, be concentrated to give crude product.Crude product is purified with column chromatography, obtains compound 12-2 for white solid (16.5g, yield：86%,
Purity：97.5%).
1H NMR(DMSO-d6, 400MHz) and 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
Addition 6- bromoquinolines (10g, 48mmol) in 100mL reaction bulbs, p-aminophenyl pinacol borate (10.6g,
48mmol), PdCl2(dppf) (1.8g, 2.4mmol), potassium carbonate (13.2g, 0.096mol), 50mL DMF, nitrogen displacement three
It is secondary.Reaction is heated to 100 DEG C, and is stirred overnight.Saturated aqueous common salt (150mL) is added into reaction solution, is extracted with ethyl acetate
(100mL × 2), merge organic phase, dry, filtering, the crude product of filtrate concentration.Purified through column chromatography, obtain the white of compound 9-3
Color solid product (9.8g, yield：92%, purity 97.1%).
1H NMR(DMSO-d6,400MHz):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
Sequentially add compound 9-3 (9.8g, 44mmol) in 500mL reaction bulbs, p-nitrophenyl chloroformate ester (8.9g,
44mmol), dichloromethane (200mL), pyridine (3.5g, 44mmol), reaction solution is stirred overnight at room temperature.Added into reaction system
Saturated aqueous common salt (500mL), adjusts pH value to 3-4, is extracted with dichloromethane (100mL × 2) with 1N HCl/waters solution, organic to be harmonious
And, dry, be concentrated to give compound 10-3 for 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
Compound 10-3 (17g, 44mmol), compound 5-1 (9.3g, 44mmol), two are sequentially added in 500mL reaction bulbs
Chloromethanes (300mL), is then added dropwise triethylamine (8mL).1 hour is stirred at room temperature in reaction solution, has a large amount of solids to separate out.Filter
Yellow solid, is washed with dichloromethane, and it is yellow solid product (18.4g, yield that compound 11-3 is obtained after drying：91%, it is pure
Degree：96.5%), it is directly used in the next step.LC-MS (ES+) m/z=458 [M+H]+
Embodiment 14
Compound 11-3 (18.4g, 40mmol), potassium carbonate (33g, 240mmol), water are sequentially added in 250mL reaction bulbs
(100mL), isopropanol (10mL), reaction solution heated overnight at reflux.Reaction solution extracts (75mL × 2), organic phase with dichloromethane
Merge, dry, be concentrated to give crude product.Crude product is purified with column chromatography, obtains compound 12-3 for white solid (15.5g, yield：88%,
Purity：97.1%).
1H NMR (400MHz, DMSO-d6) 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
Compound 2-1 (10g, 41.1mmol) and 250mL HCl/ methyl tertiary butyl ether(MTBE)s are added in 500mL there-necked flask
Solution, is stirred overnight at room temperature, and TLC detection raw materials disappear.Reaction solution concentrated by rotary evaporation, dichloromethane is dissolved in by concentration residue
(100mL), mixed solution is added in 250mL there-necked flask, and lower addition triethylamine (12.5g, 123mmol) is stirred at room temperature,
Reaction solution is cooled to 0 DEG C, and trimethyl-aceyl chloride (5g, 41.1mmol) is added dropwise.Completion of dropping, reaction solution is slowly raised to room temperature, stirs
Mix 2 hours.Reaction solution washes (100mL), saturated aqueous common salt (100mL) with 0.5N HCl (100mL), 1M sodium bicarbonate aqueous solutions
Wash, separate organic phase, dry, filtering is concentrated to give crude product.Concentration residue is dissolved in ethanol (200mL), hydrazine hydrate is added
(41g, 822mmol).Reaction solution is heated to backflow, and is stirred overnight.Reaction solution is concentrated to give grease, adds 100mL ethanol, then
Secondary concentrated by rotary evaporation, obtained grease dchloromethane is dried, and is filtered, and concentration obtains white slurry compound 5-2
(8.7g, yield：93%, purity：97.2%), it is directly used in the next step.LC-MS (ES+) m/z=228 [M+H]+
Embodiment 16
Sequentially add compound 10-3 (14.7g, 38mmol) in 500mL reaction bulbs, compound 5-2 (26.1g,
114mmol), toluene (300mL), is then added dropwise triethylamine (16.6mL).Reaction solution is to slowly warm up to 100 DEG C, stirs 0.5h, delays
Slowly room temperature is cooled to, there are a large amount of solids to separate out.Yellow solid is filtered to obtain, is washed with toluene, it is Huang that compound 11-4 is obtained after drying
Color solid product (16.8g, yield：93%, purity：97.8%), it is directly used in the next step.LC-MS (ES+) m/z=474 [M
+H]+
Embodiment 17
Compound 9-1 (16.8g, 35.5mmol), potassium carbonate (29g, 213mmol), water are sequentially added in 250mL reaction bulbs
(150mL), isopropanol (15mL), reaction solution heated overnight at reflux.Reaction solution extracts (100mL × 2), organic phase with dichloromethane
Merge, dry, be concentrated to give crude product.Crude product is purified with column chromatography, obtains compound 12-4 for white solid (14.4g, yield：89%,
Purity：98.4%).
1H NMR(CDCl3,400MHz):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 (9)
1. a kind of synthetic method of the triadimefon compound 12 as fatty acid sythetase inhibitor, it is characterised in that comprising such as
Lower step：
C. compound 8 obtains compound 9 under catalyst action through Suzuki couplings；
D. compound 9 and SM3 reacts in the basic conditions obtains compound 10；
E. compound 10 is reacted with compound 5 in the presence of alkali obtains compound 11；
F. compound 11 is in the presence of alkali, and cyclization obtains compound 12；
Wherein R1 is substituted or non-substituted C1-6Alkyl, substituted or non-substituted C3-7Cycloalkyl ,-OC1-6Alkyl, C4-6Azacyclo-
Alkyl, oxacycloalkyl；R2For 6 yuan of aryl or heteroaryl ring, or 6 yuan of aryl or heteroaryl ring and 5 yuan or 6 yuan of rings, institute and 5
Contain 0-3 hetero atom and 0-2 double bond in member or 6 yuan of rings.
2. the synthetic method of compound 12 according to claim 1, it is characterised in that the R1For cyclopropyl or the tert-butyl group, institute
State R2Selected from benzimidazole, indoles, benzofuran, Dihydrobenzofuranes, indoline, imidazopyridine, quinoline, azepine Yin
Diindyl, isoquinolin, isoquinolone, quinazoline, naphthalene, indane, indenes and indazole.
3. the synthetic method of compound 12 according to claim 1, it is characterised in that in step c, the catalyst is four
(triphenyl phosphorus) palladium, palladium, [double (diphenylphosphino) ferrocene of 1,1'-] palladium chloride, three (dibenzalacetone) two palladium
In one or more, the molar feed ratio of the catalyst and compound 8 is 0.01~0.2:1.
4. the synthetic method of compound 12 according to claim 1, it is characterised in that in step d, the compound SM3 with
The molar feed ratio of compound 9 is 1~3:1；Alkali is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium acid carbonate, saleratus, hydrogen-oxygen
Change sodium, potassium hydroxide, lithium hydroxide, barium hydroxide, pyridine, triethylamine, diisopropyl ethyl amine, triethylene diamine, 1,8- bis-
Carbon -7- the alkene of azabicyclo [5.4.0] 11,1,5- diazabicyclo [4.3.0] nonyl- 5- alkene DMAPs, N- methyl
In morpholine, tetramethylethylenediamine any one or at least two combination；The mol ratio of the alkali and compound 9 for 1~
5:1；The solvent of the reaction is dichloromethane, acetonitrile, DMF, dioxane, ethyl acetate, methyl tertiary butyl ether(MTBE), tetrahydrochysene furan
Mutter, 2- methyltetrahydrofurans, ether, toluene, or above-mentioned solvent any mixing；The temperature of the reaction is 0~100 DEG C.
5. the synthetic method of compound 12 according to claim 4, it is characterised in that the compound SM3 and compound 9
Molar feed ratio is 1~2:1；The alkali is pyridine, and the mol ratio of itself and compound 9 is 1~2:1；The solvent of the reaction is
Dichloromethane；The temperature of the reaction is 20~40 DEG C.
6. the synthetic method of compound 12 according to claim 1, it is characterised in that in step e, alkali is sodium carbonate, carbonic acid
Potassium, cesium carbonate, sodium acid carbonate, saleratus, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, pyridine, triethylamine,
Diisopropyl ethyl amine, triethylene diamine (DABCO), the carbon -7- alkene (DBU) of 1,8- diazabicyclos [5.4.0] 11,1,5- bis-
In azabicyclo [4.3.0] nonyl- 5- alkene (DBN), DMAP (DMAP), N-methylmorpholine, tetramethylethylenediamine
Any one or at least two, the mol ratio of the alkali and compound 8 is 1~5:1；The solvent of the reaction is dichloromethane
Alkane, acetonitrile, DMF, dioxane, ethyl acetate, methyl tertiary butyl ether(MTBE), tetrahydrofuran, 2- methyltetrahydrofurans, ether, toluene,
Or any mixing of above-mentioned solvent；The time of the reaction is untill detecting that reaction is completed；The temperature of the reaction is 20~40
℃。
7. the synthetic method of compound 12 according to claim 1, it is characterised in that in step f, alkali is sodium carbonate, carbonic acid
In potassium, cesium carbonate, sodium acid carbonate, saleratus, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide any one or
Person at least two；The mol ratio of the alkali and compound 5 is 5~15:1；The solvent that ring closure reaction is used is water, isopropanol, first
Any one in alcohol, ethanol, tetrahydrofuran, DMF, dioxane, 2- methyltetrahydrofurans, ether or at least two；Reaction
Time is 1~24 hour；Reaction temperature is 0~120 DEG C.
8. the synthetic method of compound 12 according to claim 1, it is characterised in that the preparation method bag of the compound 5
Containing following steps：
A. compound 1 is reacted with halide reagent in alcohol obtains compound 2；
B. compound 2 obtains compound 5 through three-step reaction synthesis；
Wherein R3For substituted or non-substituted C1-6Alkyl.
9. the synthetic method of compound 12 according to claim 8, it is characterised in that in step a, halide reagent is selected from chlorination
Sulfoxide, phosphorus trichloride, phosphorus tribromide, POCl3, the molar feed ratio of itself and compound 1 is 1~10:1；Described alcohol is selected from
Methanol, ethanol, propyl alcohol, butanol, amylalcohol, hexanol, isopropanol, isobutanol, the tert-butyl alcohol, isoamyl alcohol, tert-pentyl alcohol, 3- amylalcohols, it is described
The volume ratio of alcohol and compound 1 be 5~20:1；The temperature of the reaction is 0~100 DEG C.
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| US5728834A (en) * | 1996-11-14 | 1998-03-17 | Wyckoff Chemical Company, Inc. | Process for preparation of 4-aryl-1,2,4-triazol-3-ones |
| CN1960979A (en) * | 2004-03-30 | 2007-05-09 | 阿斯利康(瑞典)有限公司 | Triazolone derivatives as MMP inhibitors for the treatment of asthma and copd |
| 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 |
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| US20150329524A1 (en) * | 2013-01-10 | 2015-11-19 | Glaxosmithkline Intellectual Property (No.2) Limited | Fatty acid synthase inhibitors |
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| US5728834A (en) * | 1996-11-14 | 1998-03-17 | Wyckoff Chemical Company, Inc. | Process for preparation of 4-aryl-1,2,4-triazol-3-ones |
| CN1960979A (en) * | 2004-03-30 | 2007-05-09 | 阿斯利康(瑞典)有限公司 | Triazolone derivatives as MMP inhibitors for the treatment of asthma and copd |
| 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 |
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