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Structure of 70-23-5
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
4.5
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Single-Source Precursors for the Controlled Aqueous Synthesis of Bismuth Oxyhalides
Gordon, Matthew N. ; Liu, Yanyao ; Brown, M. Kevin ; Skrabalak, Sara E. ;
Abstract: Bismuth oxyhalides are a promising class of photocatalysts for harvesting solar energy. These materials are often synthesized in aqueous media with poor synthetic control resulting from the extremely fast nucleation and growth rates of the particles. These fast rates are caused by the rapid precipitation of bismuth salts with free halide ions. We have developed water-soluble precursors combining bismuth with either chlorine or bromine atoms in the same metal-organic complex. With the application of heat, halide ions are released, which then precipitate with bismuth ions as BiOX (X = Cl, Br). By controlling the halide ion formation rate, the nucleation and growth rates of BiOX materials can be tuned to provide synthetic control. The diverse potential of these precursors is demonstrated by synthesizing BiOX in three ways: aqueous colloidal synthesis, solid-state decomposition, and fabrication of films of BiOX via spray pyrolysis of the aqueous precursor solutions. These broadly applicable single-source precursors will enhance the ability to synthesize future BiOX materials with controlled morphologies.
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Indole C6 Functionalization of Tryprostatin B Using Prenyltransferase CdpNPT
Gardner, Eric D. ; Dimas, Dustin A. ; Finneran, Matthew C. ; Brown, Sara M. ; Burgett, Anthony W. ; Singh, Shanteri
Abstract: Tryprostatin A and B are prenylated, tryptophan-containing, diketopiperazine natural products, displaying cytotoxic activity through different mechanisms of action. The presence of the 6-methoxy substituent on the indole moiety of tryprostatin A was shown to be essential for the dual inhibition of topoisomerase II and tubulin polymerization However, the inability to perform late-stage modification of the indole ring has limited the structure-activity relationship studies of this class of natural products. Herein, we describe an efficient chemoenzymic approach for the late-stage modification of tryprostatin B using a cyclic dipeptide N-prenyltransferase (CdpNPT) from Aspergillus fumigatus, which generates novel analogs functionalized with allylic, benzylic, heterocyclic, and diene moieties. Notably, this biocatalytic functionalizational study revealed high selectivity for the indole C6 position. Seven of the 11 structurally characterized analogs were exclusively C6-alkylated, and the remaining four contained predominant C6-regioisomers. Of the 24 accepted substrates, 10 provided >50% conversion and eight provided 20-50% conversion, with the remaining six giving <20% conversion under standard conditions. This study demonstrates that prenyltransferase-based late-stage diversification enables direct access to previously inaccessible natural product analogs.
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Keywords: biocatalysts ; chemoenzymatic synthesis ; late-stage functionalization ; prenyltransferase ; tryprostatin
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CAS No. : | 70-23-5 |
Formula : | C5H7BrO3 |
M.W : | 195.01 |
SMILES Code : | O=C(OCC)C(CBr)=O |
MDL No. : | MFCD00000204 |
InChI Key : | VICYTAYPKBLQFB-UHFFFAOYSA-N |
Pubchem ID : | 66144 |
GHS Pictogram: |
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Signal Word: | Danger |
Hazard Statements: | H302+H312-H314 |
Precautionary Statements: | P260-P264-P270-P280-P301+P312+P330-P301+P330+P331-P303+P361+P353-P304+P340+P310-P305+P351+P338+P310-P362+P364-P405-P501 |
Class: | 8 |
UN#: | 3265 |
Packing Group: | Ⅲ |
Num. heavy atoms | 9 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.6 |
Num. rotatable bonds | 4 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 35.5 |
TPSA ? Topological Polar Surface Area: Calculated from |
43.37 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.48 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.16 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.51 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.46 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.01 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.93 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.52 |
Solubility | 5.95 mg/ml ; 0.0305 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.67 |
Solubility | 4.21 mg/ml ; 0.0216 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.57 |
Solubility | 5.24 mg/ml ; 0.0269 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.67 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
2.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.99 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50.6% | at 20 - 110℃; | Step A: Preparation of ethyl 6,8-dibromoimidazo[1 ,2-a]pyrazine-2-carboxylateTo a stirred solution of 2-amino-3,5-dibrompyrazine (20 g, 79mmol) in dimethylcarbonate (133 mL) at rt was added ethyl 3-bromo-2-oxopropanoate (17.14 g, 79 mmol) in one portion. After stirring at 1 10 C for 3 h, the solution was stirred at rt overnight. Water and DCM were added and the aqueous phase was extracted with DCM. After washing of the organic phase with water, drying over a2(S04) and filtration the organic phase was evaporated. Flash chromatography yielded 13.95 g (50.6 percent) ethyl 6,8-dibromoimidazo[1 ,2-a]pyrazine-2-carboxylate: 1H-NMR (300 MHz, CDCl3): δ =8.30 (s, 1 H), 8.27 (s, 1 H), 4.48 (q, 2H), 1 .43 (tr, 3H) ppm. |
50.6% | at 110℃; for 3 h; | Step A: Preparation of ethyl 6,8-dibromoimidazo[ 1 , 2-a]pyrazine-2-carboxylateTo a stirred solution of 2-amino-3, 5-dibrompyrazine (20 g, 79mmol) in dimethyicarbonate (1 33 mL) at rt was added ethyl 3-bromo-2-oxopropanoate (17.14 g, 79 mmol) in one portion. After stirring at 1 10° C for 3 h, the solution was stirred at rt overnight. Water and DCM were added and the aqueous phase was extracted with DCM. After washing of the organic phase with water, drying over Na2(S04) and filtration the organic phase was evaporated. Flash chromatography yielded 13.95 g (50.6 percent) ethyl 6,8-dibromoimidazo[1 ,2-a]pyrazine-2-carboxylate: 1H-NMR (300 MHz, CDC ): δ =8.30 (s, 1 H), 8.27 (s, 1 H), 4.48 (q, 2H), 1 .43 (tr, 3H) ppm. |
50.6% | at 20 - 110℃; for 3 h; | Intermediate Example 1 -2: Preparation of (6,8-dibromoimidazo[1 ,2-a]pyrazin-2- yl)methanolStep A: Preparation of ethyl 6,8-dibromoimidazo[1 , 2-a]pyrazi'ne-2-carboxylateTo a stirred solution of 2-amino-3,5-dibrompyrazine (20 g, 79mmol) in dimethylcarbonate (133 mL) at rt was added ethyl 3-bromo-2-oxopropanoate (17.14 g, 79 mmol) in one portion. After stirring at 1 10° C for 3 h, the solution was stirred at rt overnight. Water and DCM were added and the aqueous phase was extracted with DCM. After washing of the organic phase with water, drying over a2(S04) and filtration the organic phase was evaporated. Flash chromatography yielded 13.95 g (50.6 percent) ethyl 6,8-dibromoimidazo[1 ,2-a]pyrazine-2-carboxylate: 1H-NMR (300 MHz, CDCI3): δ =8.30 (s, 1 H), 8.27 (s, 1 H), 4.48 (q, 2H), 1 .43 (tr, 3H) ppm. |
50.6% | at 110℃; | Step A: Preparation of ethyl 6,8-dibromoimidazo[1,2-a]pyrazine-2-carboxylateTo a stirred solution of 2-amino-3,5-di brom pyrazi ne (20 g, 79m mol ) i n dimethylcarbonate (133 mL) at rt was added ethyl 3-bromo-2-oxopropanoate (17.14 g, 79 mmol) in one portion. After stirring at 1 10° C for 3 h, the solution was stirred at rt overnight. Water and DCM were added and the aqueous phase was extracted with DCM. After washing of the organic phase with water, drying over Na2(S04) and filtration the organic phase was evaporated. Flash chromatography yielded 13.95 g (50.6 3/4) ethyl 6,8-dibromoimidazo[1 ,2-a]pyrazine-2-carboxylate: 1H-NMR (300 MHz, CDCl3): δ =8.30 (s, 1 H), 8.27 (s, 1 H), 4.48 (q, 2H), 1 .43 (tr, 3H) ppm. |
50.6% | at 20 - 110℃; | To a stirred solution of 2-amino-3,5-dibrompyrazine (20 g, 79 mmol) in dimethylcarbonate (133 mL) at rt was added ethyl 3-bromo-2-oxopropanoate (17.14 g, 79 mmol) in one portion. After stirring at 110° C. for 3 h, the solution was stirred at rt overnight. Water and DCM were added and the aqueous phase was extracted with DCM. After washing of the organic phase with water, drying over Na2(SO4) and filtration the organic phase was evaporated. Flash chromatography yielded 13.95 g (50.6percent) ethyl 6,8-dibromoimidazo[1,2-a]pyrazine-2-carboxylate: 1H-NMR (300 MHz, |
50.6% | at 110℃; for 3 h; | To a stirred solution of 2-amino-3,5-dibrompyrazine (20 g, 79 mmol) in dimethylcarbonate (133 mL) at rt was added ethyl 3-bromo-2-oxopropanoate (17.14 g, 79 mmol) in one portion. After stirring at 110° C. for 3 h, the solution was stirred at rt overnight. Water and DCM were added and the aqueous phase was extracted with DCM. After washing of the organic phase with water, drying over Na2(SO4) and filtration the organic phase was evaporated. Flash chromatography yielded 13.95 g (50.6percent) ethyl 6,8-dibromoimidazo[1,2-a]pyrazine-2-carboxylate: 1H-NMR (300 MHz, CDCl3: δ=8.30 (s, 1H), 8.27 (s, 1H), 4.48 (q, 2H), 1.43 (tr, 3H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28.9% | at 0 - 30℃; for 4.5 h; Inert atmosphere | Pyrazin-2-amine 4a (1 g, 10 mmol) was dissolved in 50 mL of ethylene glycol dimethyl ether, followed by addition of 50 mL of methanol and 3-bromo-2-oxo-propionate (2.30 g, 12 mmol). After stirring for 4 hours at room temperature, the reaction mixture was cooled to 0 °C and stirred for 30 minutes until a solid precipitated. The reaction mixture was filtered, and the filter cake was washed with ether (10 mLx3). The solid was dissolved in 50 mL of anhydrous ethanol and the solution was refluxed for 4 hours. The reaction mixture was concentrated under reduced pressure, added with 100 mL of dichloromethane, washed successively with saturated sodium carbonate solution (40 mL) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain ethyl imidazo[1,2-a]pyrazine-3-carboxylate 14a (0.55 g, yield 28.9percent) as a brown solid. MS m/z (ESI): 192.1 [M+1] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.6% | Method A:; [00082] At 20-25 C., 24.6 mmol of ethyl bromopyruvate were added to 5.0 g (24.2 mmol) of thioamide in 47 ml of isopropanol, and the mixture was stirred for 5 h. 24.0 mmol of NaOH as a 20% strength aqueous solution of sodium hydroxide were then added, the product was extracted with methyl tert-butyl ether, the organic phase was washed with water and saturated sodium chloride solution and dried over sodium sulfate and the solvent was completely stripped off. This gave 6.2 g of the ethyl thiazole carboxylate, corresponding to a yield of 89.6%. [00083] 1H-NMR (DMSO-d6, in ppm): 8.41 (s, 1H, Ar-H), 7.86 (t, broad, NH), 4.41 (d, 2H, CH2), 4.30 (q, 2H, CH2), 1.40 (s, 9H, tert-butyl), 1.30 (t, 3H, CH3). | |
85% | With calcium carbonate; In ethanol; for 12h; | Compound 24 (10.53g, 55 . 4mmol) dissolved in anhydrous ethanol (100 ml), added calcium carbonate (11.08g, 111mmol), instillment bromo pyruvic acid ethyl ester (10.4 ml, 83mmol), reaction 12h through the diatomite filter, decompression turns on lathe ethanol, the residue is dissolved in ethyl acetate (300 ml) is dissolved, the organic phase is washed with saturated sodium bicarbonate solution, dried anhydrous sodium sulfate, after concentrating the residue by silica gel column chromatography, the obtained crude product with petroleum ether and ethyl acetate is recrystallized to get white solid compound 25 (13.47g, 85%). |
81.7% | Method B:; [00085] At 20-25 C., 1.07 mol of ethyl bromopyruvate were added to 200 g (1.05 mol) of thioamide in 2.0 l of ethanol and 105 g of KHCO3 powder, and the mixture was stirred overnight. 225 ml of water and 50 g of 20% strength aqueous sodium hydroxide solution were then added, about 600 ml of ethanol were distilled off, 500 ml of water were added and the mixture was cooled to 0 C. The precipitated solid was filtered off and dried. This gave 246 g of ethyl thiazole carboxylate which, according to NMR, was pure. This corresponds to a yield of 81.7%. |
67% | To compound 387 (6.00 g, 31.5 mmol) dissolved in CH2CI2 (150 mL) was added ethyl bromopyruvate (6.76 g, 4.4 mL, 34.7 mmol). Stirred at room temperature for 5 h then concentrated. Added 3 A sieves (6 g) and EtOH (150 mL) and refluxed for 16 h. Filtered and concentrated to give a dark foam. Dissolved foam in 1:1 CH2CI2:EtOH (100 mL) and added triethylamine (6.40 g, 8.8 mL, 63.1 mmol) and tBOC anhydride (7.60 g, 34.7 mmol). Stirred at room temperature for 5 h then concentrated. Added 0.25 N NaOH (100 mL), extracted with CH2CI2, dried combined organic extracts (MgS04), filtered, and concentrated. Purified by silica gel chromatography (eluant: 10% EtOAc- CH2Cl2 to 30% EtOAc-CH2Cl2) to give 6.00 g (67%) of the product 388 as a brown oil. MS m/e: 287 (M+H). For n=2: MS m/e: 301 (M+H) | |
65% | With pyridine; In ethanol; for 24h;Inert atmosphere; Reflux; | Ethyl bromopyruvate (1.75 mL, 14.0 mmol) and pyridine (1.69 mL, 21.0 mmol) were added to a solution of 8 (1.33 g, 7.0 mmol) in dry EtOH (60 mL) under N2 atmosphere. The reaction mixture was refluxed 24 hs. The volatile components were removed in vacuo. The resulting residue was dissolved in EtOAc (40 mL), washed with water (30 mL) and brine (30 mL). The organic layer was dried with MgSO4, filtered and concentrated in vacuo. Purification by column chromatography afforded 5 (1.31g, 65%) as a brown solid. Rf = 0.5 (hexane/ EtOAc, 1:1); 1H NMR (400MHz, CDCl3) delta 1.39 (t, 3H, J = 7,1 Hz), 1.46 (s, 9H), 4.14 (q, 2H, J = 7.1 Hz), 4.64 (d, 2H, J = 6.3 Hz), 5.31 (bs, 1H), 8.11 (s, 1H5). 13C NMR (100MHz, CDCl3) delta 14.3, 28.3 (3C), 42.4, 61.5, 80.5, 127.9, 146.9, 155.6, 161.3, 170.0. |
In ethanol; at 20 - 25℃; for 5h;Product distribution / selectivity; | a) Boc-2-Aminomethylthiazole-4-carboxamide [00073] At 10 C., ethyl bromopyruvate (386 g, 1.98 mol) was added dropwise to a solution of Boc-glycinethioamide (370 g, 1.94 mol) in 3.9 liters of ethanol, and the mixture was then stirred at 20-25 C. for 5 h, after which 299 ml of a 25% strength aqueous ammonia solution were added. [00074] From 940 ml of this mixture (corresponds to 19.9% of the total volume), 380 ml of ethanol were distilled off, a further 908 ml of a 25% strength aqueous ammonia solution were added and the mixture was stirred at 20-25 C. for 110 h. The mixture was cooled to 0 C. and the solid was filtered off, washed twice with water and dried. This gave 60.1 g of the BOC-protected thiazole carboxamide of an HPLC purity of 97.9 area %, which corresponded to a yield over these two steps of 60.5%. [00075] 1H-NMR (DMSO-d6, in ppm): 8.16 (s, 1H, Ar-H), 7.86 (t, broad, 1H, NH), 7.71 and 7.59 (2×s, broad, 1H each, NH2), 4.42 (d, 2H, CH2), 1.41 (s, 9H, tert-butyl). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With methyloxirane; In 1,2-dimethoxyethane; ethanol; | EXAMPLE 29 ethyl 6-chloroimidazo-[1,2-a]-quinoline-2-carboxylate 140 mg of <strong>[68050-37-3]2-amino-5-chloroquinoline</strong> were dissolved in 2.5 ml of dimethoxyethane and then a mixture of 170 mg of ethyl bromopyruvate and 30 mg of propylene oxide was added. The mixture was stirred at room temperature for 2 hours and 2 ml of ether were added. Then, the mixture was cooled in ice and the precipitated quaternary salt was filtered off, was dissolved in 5 ml of ethanol and the solution was heated at reflux for 2 hours. Then, the solvent was removed under vacuum and the residue was partitioned between sodium bicarbonate solution and chloroform. The chloroform solution was dried over magnesium sulfate and was evaporated to dryness. The residue was chromatographed over silica with chloroform as eluent and the purified product was recrystallized from ethyl acetate/petroleum ether to obtain colorless needles of ethyl 6-chloroimidazo-[1,2-a]-quinoline-2-carboxylate melting at 193-194 C. I.R. (KBr Disc): 3145 cm-1 (C--H1 stretch) 1707 cm-1 (Ester C=O) Analysis: C14 H11 N2 Cl O2. Calculated: %C 61.21; %H 4.04; %N 10.20; Found: C 61.13; H 4.05; N 10.07 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of 2-chlorocyclopentanone (11.8 g, 100 mmol) and thiourea (8.0 g 101 mmol) was refluxed in ethanol:THF (1:2) for 16 hrs. The reaction mixture was cooled to room temperature and the separated white solid was filtered (9.0 g separated). The white solid was dissolved in anhydrous ethanol (100 ml) and sodium methoxide (2.7 g, 51 mmol) was added. After 15 minutes, ethyl bromopyruvate (10.0 g) was added to the solution, stirred at room temperature for 2 hrs, and then refluxed for 48 hrs. The reaction mixture was cooled to room temperature and concentrated. The residue was extracted with chloroform and washed well with water, and concentrated. The product was purified by silica-gel column chromatography by eluding it with 50% ethyl acetate:hexane. Red semi-solid; Yield: 3.0 g; M+H 237. The ester was reduced with LiAlH4 and the resultant alcohol was oxidized with active MnO2. The aldehyde obtained was taken to the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.5% | In methanol; for 4h;Reflux; | Compound 3 (4.1 g, 16.8 mmol) and ethyl bromopyruvate (3.94 g, 20.2 mmol) were dissolved in anhydrous methanol (100 ml). The reaction system was heated under reflux and stirred for 4 h, until the reaction was detected by TLC. The reaction solution was concentrated and purified by a silica gel column to obtain 5.5 g of product 4 as a yellow powdery solid with a yield of 96.5%. Can be used directly in the next step. |
82% | 4-THIOCARBAMOYL-PIPERIDINE-L-CARBOXYLIC acid tert-butyl ester (3) (25 g, 102 mmol) was dissolved in anhydrous N, L9-DIMETHYLFORMAMIDE (DMF) (125 mL) and cooled to 0C in an ice-bath. A solution of ethyl bromopyruvate (22.2 g, 14.3 mL, 114 mmol, 1.1 equiv) in anhydrous DMF (125 mL) was added dropwise with stirring. The reaction mixture was allowed to warm slowly to room temperature and stirred overnight. Triethylamine (25 mL) was added dropwise with stirring at the rate of 1 mL/g of thioamide used. The DMF was removed in vacuo keeping the temperature below 60C. The resulting residue was partitioned between ethyl acetate (75 mL) and brine (100 mL). Sufficient water was added to ensure complete dissolution of the precipitated salts in the aqueous phase. The aqueous phase was extracted twice with ethyl acetate and the combined organic extracts washed successively with brine (x2), water (x2) and brine (x2). The organic phase was simultaneously dried with MGS04 and decolourised with finely divided charcoal. The mixture was filtered through Celite and concentrated in vacuo to give a yellow oil. Trituration with hexane yielded a yellow solid. This was diluted with an excess of hexane and cooled overnight to allow complete crystallisation of product. The product was collected by filtration, washed with hexane and dried in vacuo at room temperature. Recrystallisation from IPA/water gave the title compound (4) (28.33 g, 83 mmol, 82%). | |
74.2% | To a suspension of tert-butyl 4-carbamothioylpiperidine- 1 -carboxylate (1.50 g, 6.14 mmol) in ethanol (6 mL) at 0 C was added dropwise a solution of ethyl 3-bromo- 2-oxopropanoate (0.788 mL, 6.26 mmol) in ethanol (6 mL). The ice bath was then removed and the reaction mixture was stirred at ambient temperature overnight. Triethylamine (1.5 mL, 10.76 mmol) was then added and the mixture was concentrated to near dryness and the concentrate was diluted with ethyl acetate, washed with brine, dried (MgS04) and evaporated to dryness. The residue was purified by flash chromatography using hexanes-ethyl acetate as eluent to give ethyl 2-(l-(tert-butoxycarbonyl)piperidin-4- yl)thiazole-4-carboxylate (1.55 g, 74.2%) as a nearly colorless oil that crystallized on standing to give a white solid. LC (Method A): 2.115 min. 1H NMR (DMSO-d6, 400 MHz) δ ppm: 8.42 (s, 1H), 7.20 (br s, 2H), 4.29 (q, J= 7.0 Hz, 2H), 4.00 (m, 1H), 3.24 (m, 1H), 2.88 (br s, 1H), 2.03 (m, 2H), 1.54 (m, 2H), 1.29 (t, J= 7.2 Hz, 3H). |
71% | With triethylamine; In DMF (N,N-dimethyl-formamide); at 5℃; | tert-Butyl 4-(AMINOCARBOTHIOYL) TETRAHYDROPYRIDINE-1 (2H)-CARBOXYLATE (May- bridge) (85 mmol ; 20. 8 g) is dissolved in 250 ml of DIMETHYLFORMAMIDE and placed at 5C. Ethyl bromopyruvate (1 EQ. ; 85 MMOL ; 16. 6 g) dissolved in 50 ml of dimethylformamide is added dropwise. The reaction medium is stirred overnight and excess triethylamine is then added dropwise. The reaction medium is evapo- rated and the residual brown oil is taken up in ethyl acetate and washed with water (twice) and then with saturated sodium chloride solution (twice). The organic phase is dried over sodium sulfate and evaporated to dryness. The crude product is chromatographed on silica, eluting with DICHLOROMETHANE to DICHLOROMETHANE/3% methanol, to give 20. 5 g of the expected product in the form of oily crystals. TLC : 1/1 ethyl acetate/hexane : Rf = 0. 55 Yield = 71 %. |
71% | With triethylamine; In DMF (N,N-dimethyl-formamide); at 5℃; | Tert-butyl-4-(aminocarbothioyl)tetrahydropyridine-1(2H)-carboxylate (Maybridge) (85 mmol; 20.8 g) is dissolved in 250 ml of dimethylformamide and placed at 5 C. Ethyl bromopyruvate (1 eq.; 85 mmol; 16. 6 g) dissolved in 50 ml of dimethylformamide is added dropwise. The reaction medium is stirred overnight and excess triethylamine is then added dropwise. The reaction medium is evaporated and the residual brown oil is taken up in ethyl acetate and washed with water (twice) and then with saturated sodium chloride solution (twice). The organic phase is dried over sodium sulfate and evaporated to dryness. The crude product is chromatographed on silica, eluting with dichloromethane to dichloromethane/3% methanol, to give 20.5 g of the expected product in the form of oily crystals. TLC: 1/1 ethyl acetate/hexane: Rf = 0.55 Yield = 71 %. |
In ethanol; at 80℃; for 4h; | (2-methyl-4,5,6,7-tetrahydro-2H-indazol-3-yl)amide 2-Piperidin-4yl-thiazole-4-carboxylic acid ethyl ester dihydrobromide salts A solution of tert-butyl-4-(aminocarbothioyl)tetrahydropyridine-1(2H)-carboxylate (2.0 g, 8.2 mmol) and ethyl bromopyruvate (1.6 g, 8.2 mmol) in 30 mL of EtOH was stirred at 80 C. for 4h. Afterwards, the mixture cooled to room temperature and then charged with 48% HBr (1.0 mL, 14 mmol. The reaction mixture was allowed to stir an additional 1 h, and then concentrated to an oily solid. Trituration with diethyl ether afforded 3.0 g (91%) of a tan solid. 1H NMR (400 Liz, DMSO-d6) δ 9.02 (br s, 1 H), 8.77 (br s, 1 H), 8.46 (s, 1 H), 7.01 (br s, 1 H),4.29 (q, J=7.1 Hz,2 H), 3.44-3.33 (m, 3 H), 3.-2 (q, J=11.7 Hz 2 H), 2.19 (d, J=13.2 Hz, 2 H), 1.97-1.88 (m, 2 H), 1.29 (t, J=7.0 Hz, 3 H). MS calculated for C11H16N2O2S+H: 241, observed: 241. | |
Step A: Preparation of 1 , 1 -dimethylethyl 4-[4-(ethoxycarbonyl)-2-thiazolyl]- 1 - piperidinecarboxylate; To a suspension of 1,1 -dimethylethyl 4-(aminothioxomethyl)-l-tetrahydropyridine- carboxylate (30 g, 123 mmol) in ethanol (180 mL) cooled to 0 C in an ice bath, was added dropwise a solution of ethyl bromopyruvate (15.7 mL, 125 mmol) in ethanol (180 mL). The ice bath was removed, and the mixture was stirred at ambient temperature overnight. Triethylamine (30 mL) was added, and the mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give 31 g of a brown oil, which solidified on standing. A portion of this crude product (8.1 g) was heated with ether (200 mL), and the ether was then decanted. This was repeated a second time, and the combined ether solutions <n="53"/>were evaporated under reduced pressure to give 7.6 g of the title compound as a yellow solid.1H NMR (CDCl3) δ 1.40 (t, 3H), 1.46 (s, 9H), 1.7 (m, 2H), 2.1 (m, 2H), 2.85 (m, 2H), 3.25 (m, IH), 4.2 (m, 2H), 4.42 (q, 2H), 8.08 (s, IH). | ||
In ethanol; at 0 - 20℃; | To a suspension of 1,1-dimethylethyl 4-(aminothioxomethyl)-l-tetrahydropyridine- carboxylate (30 g, 123 mmol) in ethanol (180 mL), cooled to 0 C in an ice bath, was added dropwise a solution of ethyl bromopyruvate (15.7 mL, 125 mmol) in ethanol (180 mL). The <n="71"/>ice bath was removed, and the mixture was stirred at ambient temperature overnight. Triethylamine (30 mL) was added, and the mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give 31 g of a brown oil, which solidified on standing. A portion of this crude product (8.1 g) was heated with 200 mL of ether, and the ether was then decanted. This was repeated a second time, and the combined ether solutions were evaporated under reduced pressure to give 7.6 g of the title compound as a yellow solid. 1H NMR (CDCl3) 6 1.40 (t, 3H), 1.46 (s, 9H), 1.7 (m, 2H), 2.1 (m, 2H), 2.85 (m, 2H), 3.25 (m, IH), 4.2 (m, 2H), 4.42 (q, 2H), 8.08 (s, IH). | |
Synthesis of 4-(4-Carboxy-thiazol-2-yl)-piperidine-l-carboxylic acid tert-butyl ester (Intermediate 1-3.2)R9 m u R11 I-3.2Step 1: Synthesis of 4-(4-Ethoxycarbonyl-thiazol-2-yl)-piperidine-l-carboxylic acid tert- butyl ester (Rl l)A solution of R9 (1.0 g, 4.09 mmol) in dimethylformamide (DMF) (5 ml) is cooled to 0C under nitrogen. To this mixture is added R10 (0.63 ml, 4.50 mmol) as a DMF solution (5 ml, drop wise addition). Upon complete addition, the reaction is allowed to gradually warm to ambient temperature and stirred over night. After this time the reaction is treated with triethylamine (1 ml, drop wise) and stirred for 10 minutes. The reaction is then poured into water and the product is extracted into EtO Ac (3x). The combined organics are dried (MgS04), filtered and concentrated. The remaining residue is purified via column chromatography (25g silica gel, 5-50% EtO Ac/heptane) to afford Rl l. (1.0 g) | ||
EXAMPLE 1. Preparation of 2- [ 1 - [(2, 5-dimethylphenyl) acetyl] -4-piperidinyl] -N-methyl-N- [( 1R)- 1 - phenylpropyl]-4-thiazolecarboxamide (Compound 58). Step A: Preparation of 1,1-dimethylethyl 4-[4-(ethoxycarbonyl)-2-thiazolyl]-l- piperidinecarboxylate. To a suspension of 1,1-dimethylethyl 4-(aminothioxomethyl)-1-tetrahydropyridine- carboxylate (30 g, 123 mmol) in ethanol (180 mL), cooled to 0 C in an ice bath, was added dropwise a solution of ethyl bromopyruvate (15.7 mL, 125 mmol) in ethanol (180 mL). The ice bath was removed, and the mixture was stirred at ambient temperature overnight. Triethylamine (30 mL) was added, and the mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give 31 g of a brown oil, which solidified on standing. A portion of this crude product (8.1 g) was heated with 200 mL of ether, and the ether was then decanted. This was repeated a second time, and the combined ether solutions were evaporated under reduced pressure to give 7.6 g of the title compound as a yellow solid. 1H NMR (CDCl3): 1.40 (t, 3H), 1.46 (s, 9H), 1.7 (m, 2H), 2.1 (m, 2H), 2.85 (m, 2H), 3.25 (m, 1H), 4.2 (m, 2H), 4.42 (q, 2H), 8.08 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
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74% | A solution of 2-amino-5-chloropyridine (2.0 g, 16 mmol) [Matrix Scientific, 021118] in acetone (39 mL) was treated with ethyl bromopyruvate (2.2 mL, 16 mmol) and heated at 60 C for 45 min. The reaction mixture was cooled to 20 C and the suspension was filtered. The solid that was collected was washed with a small amount of cold acetone and dried in vacuo. The solid was diluted with ethanol (12 mL) and water (19 mL), heated at 65 C, and treated with sodium bicarbonate (1.6 g, 19 mmol) portionwise. The reaction mixture was cooled to 20 C and the suspension was filtered. The solid that was collected was washed with water (4 x 80 mL) and dried in vacuo to give the desired product (2.6 g, 74%). LCMS for Ci QHI 0CIN2O2(M+H)+: m/z = 225.1. | |
In 1,2-dimethoxyethane; | Step 1. Ethyl 6-Chloroimidazo[1,2-a]pyridine-2-carboxylate To 2-amino-5-chloropyridine (Aldrich; 2.19 g) in dimethoxyethane (Aldrich; 25 mL) is added ethyl 2-bromopyruvate (Aldrich; 2.37 mL). After stirring overnight, the solid is collected and washed with diethyl ether. The solid is dried under reduced pressure at 45 C. and then is partitioned between dichloromethane and aqueous sodium bicarbonate. The organic phases are dried over sodium sulfate and concentrated to give 3.05 g of ethyl 6-chloroimidazo[1,2-a]pyridine-2-carboxylate. 1 H NMR (CDCl3) delta1.44, 4.46, 7.23, 7.64, 8.16, 8.21. |
Yield | Reaction Conditions | Operation in experiment |
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EXAMPLE XXI Following the procedure of Example II, but substituting for the ethyl bromopyruvate and 4-methylquinazoline used therein equivalent amounts of the suitable reactants, the following respective compounds are prepared: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; | EXAMPLE I 2-Carbethoxy-1H-pyrrolo[1,2-c]quinazolin-4-ium bromide A solution of ethyl bromopyruvate (32.76 g, 0.172 m) and <strong>[700-46-9]4-methylquinazoline</strong> (15.61g, 0.109 m) in dry ethanol (400 ml) was heated at reflux for 16 hours during which time a yellow precipitate formed. The reaction mixture was cooled and the solid filtered and dried to yield crude product. Crystallization from MeOH afforded the product as a yellow solid; m.p. 274-275 C. Anal: Calcd for C14 H13 BrN2 O2: C, 52.33; H, 4.05; N, 8.72. Found: C, 52.30; H, 4.06; N, 8.75. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; In ethanol; | EXAMPLE II 2-Carbethoxypyrrolo[1,2-c]quinazoline: A solution of ethyl bromopyruvate (3.2g, 0.016 m) and <strong>[700-46-9]4-methylquinazoline</strong> (2.0g, 0.014 m) in dry ethanol (150 ml) was heated at reflux for two hours. During this time, a tan solid formed. Excess ethyl bromopyruvate was added (1.0g) and the reaction mixture was allowed to reflux overnight. After this time, the reaction was complete. The alcohol was removed in vacuo and the residue diluted with H2 O. Sodium bicarbonate was added until effervescence ceased and the aqueous mixture extracted with ether. The ether extracts were combined, dried over Na2 SO4, filtered and the solvent removed in vacuo to yield a tan solid. Crystallization from MeOH afforded the product as a white solid; m.p. 138-139 C. Anal. Calcd for C14 H12 N2 O2: C, 69.99; H, 5.03; N, 11.66. Found: C, 70.11; H, 5.17; N, 11.66. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; for 18h;Heating / reflux; | A solution of 2,2,2 -trifluoroacetamide (7.12 g, 63 mmol) and Lawesson's Reagent (15.3 g, 37.8 mmol) in THF (60 ml) was stirred at reflux for 18 h. The reaction mixture was cooled, ethyl bromopyruvate (8 ml, 63 mmol) added and the reaction refluxed for 18 h. The reaction was cooled, evaporated in vacuo, and the resulting crude material extracted into ethyl acetate and washed with water. The organic fraction was dried over MgSO4 and condensed to give a yellow/orange oil. The oil was purified by flash column chromatography on silica eluting with 15 % ethyl acetate in hexane to provide the title compound as a clear oil (3 g, 21 %). 1H NMR (400 MHz, CDCl3) delta 8.39 (1 H, s), 4.47 (2 H, q, J7.1), 1.42 (3 H, t, J7.2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | Step 1: 2-Piperidin-4-yl-thiazole-4-carboxylic acid ethyl ester A mixture of 10 g (41 mmol) 4-thiocarbamoyl-piperidine-1-carboxylic acid tert-butyl ester (commercially available) and 7.98 g (41 mmol) ethyl bromopyruvate (commercially available) in 120 ml ethanol was stirred at 70 C. for 90 min. The mixture was evaporated to dryness, Na2CO3 aq. was added and the residue was extracted with ethyl acetate. The organic phases were washed with NaCl aq., dried with MgSO4 and evaporated to dryness. The residue was purified on silica eluding with DCM/MeOH/25% NH3 in water 100/20/1 to yield after evaporation of the product fractions 7.28 g (74%) of the title compound as light brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,2-dimethoxyethane; at 20℃; for 18h;Reflux; | To a solution of <strong>[79456-30-7]2-amino-3-bromo-5-(trifluoromethyl)pyridine</strong> (10.0 g, 41.5 mmol) in 1,2 dimethoxyethane (300 rnL) at room temperature was added ethyl bromopyruvate (9.889 g, 45.64 mmol) dropwise. The reaction mixture was heated to reflux for 18 h. The 1,2- dimethoxyethane was removed under reduced pressure and the residual solid was recrystalized from 1-chlorobutane. The solid was isolated by filtration and dried to afford an off-white solid, 8-bromo-6-(trifluoromethyl)imidazo[l,2-alpha]pyridine-2-carboxylic acid, ethyl ester (11.044 g).The solid obtained above was dissolved in tetrahydrofuran (150 mL) and a solution of LiOH (2.353 g, 98.29 mmol) in water (100 mL) was added. The reaction mixture was stirred at room temperature for 4 h. The tetrahydrofuran was removed under reduced pressure to provide an aqueous solution which was cooled to 5 0C. Dilute HCl was added dropwise until a pH < 5.0 was achieved. After several minutes a solid began to precipitate from the solution. The solid was collected by filtration, washed once with water (50 mL), and dried in a vacuum oven for 18 h at 80 0C to afford 8.632 g of the title compound as a solid. 1H NMR (dmso-d6) delta 13.17 (br s, IH), 9.31 (s, IH), 8.69 (s, IH), 8.03 (s, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; at 20℃; | Synthesis of 7-cyano-imidazo[l,2-a]pyridine-2-carboxylic acid and 7-carbamoyl- imidazo[l,2-a]pyridine-2-carboxylic acid; To a solution of <strong>[42182-27-4]2-amino-4-cyanopyridine</strong> (4.00 g, 33.6 mmol) in THF (100 mL) add ethyl bromopyruvate (6.55 g, 33.6 mmol). Stir the mixture at rt overnight. A light yellow suspension forms. After filtration and washing with THF, dissolve the light yellow solid in EtOH (50 mL) and heat to reflux for 4 h. Concentrate in vacuo to afford the desired product 7-cyano-imidazo[l,2-a]pyridine-2-carboxylic acid ethyl ester as a solid (6.21 g, 28.9 mmol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50.6% | In carbonic acid dimethyl ester; at 20 - 110℃; | Step A: Preparation of ethyl 6,8-dibromoimidazo[1 ,2-a]pyrazine-2-carboxylateTo a stirred solution of 2-amino-3,5-dibrompyrazine (20 g, 79mmol) in dimethylcarbonate (133 mL) at rt was added ethyl 3-bromo-2-oxopropanoate (17.14 g, 79 mmol) in one portion. After stirring at 1 10 C for 3 h, the solution was stirred at rt overnight. Water and DCM were added and the aqueous phase was extracted with DCM. After washing of the organic phase with water, drying over a2(S04) and filtration the organic phase was evaporated. Flash chromatography yielded 13.95 g (50.6 %) ethyl 6,8-dibromoimidazo[1 ,2-a]pyrazine-2-carboxylate: 1H-NMR (300 MHz, CDCl3): delta =8.30 (s, 1 H), 8.27 (s, 1 H), 4.48 (q, 2H), 1 .43 (tr, 3H) ppm. |
50.6% | In carbonic acid dimethyl ester; at 110℃; for 3.0h; | Step A: Preparation of ethyl 6,8-dibromoimidazo[ 1 , 2-a]pyrazine-2-carboxylateTo a stirred solution of 2-amino-3, 5-dibrompyrazine (20 g, 79mmol) in dimethyicarbonate (1 33 mL) at rt was added ethyl 3-bromo-2-oxopropanoate (17.14 g, 79 mmol) in one portion. After stirring at 1 10 C for 3 h, the solution was stirred at rt overnight. Water and DCM were added and the aqueous phase was extracted with DCM. After washing of the organic phase with water, drying over Na2(S04) and filtration the organic phase was evaporated. Flash chromatography yielded 13.95 g (50.6 %) ethyl 6,8-dibromoimidazo[1 ,2-a]pyrazine-2-carboxylate: 1H-NMR (300 MHz, CDC ): delta =8.30 (s, 1 H), 8.27 (s, 1 H), 4.48 (q, 2H), 1 .43 (tr, 3H) ppm. |
50.6% | In carbonic acid dimethyl ester; at 20 - 110℃; for 3.0h; | Intermediate Example 1 -2: Preparation of (6,8-dibromoimidazo[1 ,2-a]pyrazin-2- yl)methanolStep A: Preparation of ethyl 6,8-dibromoimidazo[1 , 2-a]pyrazi'ne-2-carboxylateTo a stirred solution of 2-amino-3,5-dibrompyrazine (20 g, 79mmol) in dimethylcarbonate (133 mL) at rt was added ethyl 3-bromo-2-oxopropanoate (17.14 g, 79 mmol) in one portion. After stirring at 1 10 C for 3 h, the solution was stirred at rt overnight. Water and DCM were added and the aqueous phase was extracted with DCM. After washing of the organic phase with water, drying over a2(S04) and filtration the organic phase was evaporated. Flash chromatography yielded 13.95 g (50.6 %) ethyl 6,8-dibromoimidazo[1 ,2-a]pyrazine-2-carboxylate: 1H-NMR (300 MHz, CDCI3): delta =8.30 (s, 1 H), 8.27 (s, 1 H), 4.48 (q, 2H), 1 .43 (tr, 3H) ppm. |
50.6% | In carbonic acid dimethyl ester; at 110℃; | Step A: Preparation of ethyl 6,8-dibromoimidazo[1,2-a]pyrazine-2-carboxylateTo a stirred solution of 2-amino-3,5-di brom pyrazi ne (20 g, 79m mol ) i n dimethylcarbonate (133 mL) at rt was added ethyl 3-bromo-2-oxopropanoate (17.14 g, 79 mmol) in one portion. After stirring at 1 10 C for 3 h, the solution was stirred at rt overnight. Water and DCM were added and the aqueous phase was extracted with DCM. After washing of the organic phase with water, drying over Na2(S04) and filtration the organic phase was evaporated. Flash chromatography yielded 13.95 g (50.6 ¾) ethyl 6,8-dibromoimidazo[1 ,2-a]pyrazine-2-carboxylate: 1H-NMR (300 MHz, CDCl3): delta =8.30 (s, 1 H), 8.27 (s, 1 H), 4.48 (q, 2H), 1 .43 (tr, 3H) ppm. |
50.6% | at 20 - 110℃; | To a stirred solution of 2-amino-3,5-dibrompyrazine (20 g, 79 mmol) in dimethylcarbonate (133 mL) at rt was added ethyl 3-bromo-2-oxopropanoate (17.14 g, 79 mmol) in one portion. After stirring at 110 C. for 3 h, the solution was stirred at rt overnight. Water and DCM were added and the aqueous phase was extracted with DCM. After washing of the organic phase with water, drying over Na2(SO4) and filtration the organic phase was evaporated. Flash chromatography yielded 13.95 g (50.6%) ethyl 6,8-dibromoimidazo[1,2-a]pyrazine-2-carboxylate: 1H-NMR (300 MHz, |
50.6% | In water; at 110℃; for 3.0h; | To a stirred solution of 2-amino-3,5-dibrompyrazine (20 g, 79 mmol) in dimethylcarbonate (133 mL) at rt was added ethyl 3-bromo-2-oxopropanoate (17.14 g, 79 mmol) in one portion. After stirring at 110 C. for 3 h, the solution was stirred at rt overnight. Water and DCM were added and the aqueous phase was extracted with DCM. After washing of the organic phase with water, drying over Na2(SO4) and filtration the organic phase was evaporated. Flash chromatography yielded 13.95 g (50.6%) ethyl 6,8-dibromoimidazo[1,2-a]pyrazine-2-carboxylate: 1H-NMR (300 MHz, CDCl3: delta=8.30 (s, 1H), 8.27 (s, 1H), 4.48 (q, 2H), 1.43 (tr, 3H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | In ethanol; at 150℃; for 0.333333h;Sealed tube; | A mixture of <strong>[5319-77-7]2-amino-5-methylthio-1,3,4-thiadiazole</strong> (25 g, 0.17 mol), ethyl 3-bromopyruvate (23.7 mL, 0.189 mol) and ethanol (125 mL) in a 350 mL sealable vessel was heated at 150 C (oil bath temperature) for 20 min. The cooled mixture was concentrated to dryness and the residue was partitioned with ethyl acetate-saturated NaHCO3. The organic phase was washed (brine), dried (MgSO4), filtered and concentrated to dryness. The residue was taken up in a minimum volume of dichloromethane and the resulting slurry was filtered and the filter-cake was washed with a little dichloromethane. The solid was dried in vacuo to give recovered amino-5- methylthio-1,3,4-thiadiazole (3.72 g, 15%). The filtrate was concentrated to dryness and the residue was crystallized from a minimum volume of hot ethanol to give the title compound as a beige crystalline solid (10.8 g, 0.044 mol, 26%>). LC (Method E): 1.267 min. 1H NMR (600 MHz, DMSO-d6) delta ppm 8.76 (s, 1H), 4.27 (q, J= 7.2Hz, 2H), 2.78 (s, 3H), 1.28 (t, J= 7.2Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; at 75 - 80℃; for 1h; | Example 83 Ethyl 9-oxo-7-thia-2,5-diazatricyclo[6.4.0.02'6]dodeca-l(8),3,5-triene-4-carboxylate Ethyl 3-bromo-2-oxopropanoate (3.85 mL, 30.5 mmol) was added dropwise to a solution of 2-amino-4,5,6,7-tetrahydro-l,3-benzothiazol-7-one (4.27 g, 25.4 mmol) in anhydrous DMF (90 mL) and stirred at 75-80°C for 60 min. The solution was cooled to room temperature and about half of the solvent was removed under reduced pressure. The remaining solution was diluted with EtOAc (100 mL) and washed with water (5 x 100 mL). The organic layer was concentrated in vacuo to yield a yellow residue which was chromatographed on silica (eluent: 50 to 90percent EtOAc in heptane) to afford the title compound as a yellow solid (2.60g, 74percent purity, 29percent yield); 1H NMR (250 MHz, DMSO-d6) delta 1.31 (t, 3H), 2.23 (p, 2H), 2.57 - 2.70 (m, 2H), 3.12 (t, 2H), 4.30 (q, 2H), 8.69 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a stirred solution of potassium hydroxide (2.97 g, 53 mmol) in methanol (60 mL) under nitrogen at 0° C. was added a solution of the product from Example 1C (6 g, 53 mmol) in methanol (10 mL) dropwise. After the addition was complete, the mixture was stirred at 0° C. for 1 hour, and then a solution of ethyl bromopyruvate (7.01 mL, 55.7 mmol) in methanol (10 mL) was added dropwise. After allowing the mixture to stir at ambient temperature for 2.5 hours, the solvent was removed, and the residue was purified by silica gel column chromatography eluted with methanol/dichloromethane (0-10percent) to afford 3.4 g of crude product which was further purified via Teledyne Isco CombiFlash® Companion® XL eluted with methanol/10 mM ammonium acetate in water (0-50percent) on a 120 g RediSep® C18 column to provide the titled compound. 1H NMR (400 MHz, DMSO-d6) delta ppm 6.87 (s, 1H), 4.59 (d, J=10.0 Hz, 1H), 4.34 (d, J=10.4 Hz, 1H), 4.11 (m, 2H), 3.27-3.34 (m, 2H), 2.50-2.55 (m, 2H), 1.16 (t, J=7.2 Hz, 3H) | ||
Example 1D ethyl 3-hydroxy-4-oxo-2,3,4,5,6,7-hexahydrofuro[3,2-c]pyridine-3-carboxylate To a stirred solution of potassium hydroxide (2.97 g, 53 mmol) in methanol (60 mL) under nitrogen at 0° C. was added a solution of the product from Example 1C (6 g, 53 mmol) in methanol (10 mL) dropwise. After the addition was complete, the mixture was stirred at 0° C. for 1 hour, and then a solution of ethyl bromopyruvate (7.01 mL, 55.7 mmol) in methanol (10 mL) was added dropwise. After allowing the mixture to stir at ambient temperature for 2.5 hours, the solvent was removed, and the residue was purified by silica gel column chromatography eluted with methanol/dichloromethane (0-10percent) to afford 3.4 g of crude product which was further purified via Teledyne Isco CombiFlash® Companion® XL eluted with methanol/10 mM ammonium acetate in water (0-50percent) on a 120 g RediSep® C18 column to provide the titled compound. 1H NMR (400 MHz, DMSO-d6) delta ppm 6.87 (s, 1H), 4.59 (d, J=10.0 Hz, 1H), 4.34 (d, J=10.4 Hz, 1H), 4.11 (m, 2H), 3.27-3.34 (m, 2H), 2.50-2.55 (m, 2H), 1.16 (t, J=7.2 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; at 70℃; for 5h; | General procedure: Amide (1.0 equiv) and ethyl bromopyruvate (1.2 equiv) were dissolved in ethanol and heated to 70C for 5h. The reaction was monitored with TLC until completion. The solvent was evaporated, dried over anhydrous MgSO4. The ethyl ester (1a-1k) was purified by flash column chromatography (ethyl acetate/cyclohexane 3:7 (v/v)). |
Yield | Reaction Conditions | Operation in experiment |
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23.4 g | With sodium hydrogencarbonate; In ethanol; at 20℃; for 2h; | <strong>[552331-00-7]2-amino-4-iodopyridine</strong>19.0 g and ethanol 100 ml, at room temperature,9.4 g of sodium hydrogencarbonate,22.0 g of ethyl bromopyruvate were sequentially added.The reaction mixture was stirred under heating reflux for 2 hours.After completion of the reaction,The solvent was distilled off under reduced pressure.100 ml of water and 100 ml of diisopropyl ether were added to the obtained residue, and the precipitated solid was taken out by filtration. To the obtained solid was added 100 ml of ethanol, and the solvent was distilled off under reduced pressure. 100 ml of toluene was added to the obtained residue, and the solvent was distilled off under reduced pressure to obtain 23.4 g of the objective compound as an orange solid. |
23.4 g | With sodium hydrogencarbonate; In ethanol; for 2h;Reflux; | 9.4 g of sodium hydrogencarbonate and 22.0 g of ethyl bromopyruvate were sequentially added to a mixed solution of 19.0 g of <strong>[552331-00-7]4-iodo-2-aminopyridine</strong> and 100 ml of ethanol at room temperature. After completion of the addition, the mixture was stirred under heating reflux for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. 100 ml of water and 100 ml of diisopropyl ether were added to the obtained residue, and the precipitated solid was taken out by filtration. 100 ml of ethanol was added to the obtained solid, and the solvent was distilled off under reduced pressure. 100 ml of toluene was added to the obtained residue, and the solvent was distilled off under reduced pressure to obtain 23.4 g of the objective compound as an orange solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | A method for preparing thiazole-4-carboxylic acid,Include the following steps: Mix ethyl bromopyruvate, thiourea, and water,Raise the temperature to 40°C, incubate and stir for 5 hours, then add concentrated hydrochloric acid, and add 30 wtpercent sodium nitrite aqueous solution dropwise.The mixture was further stirred for 2 hours, and the filter cake was filtered to obtain thiazole-4-carboxylic acid. The molar ratio of ethyl bromopyruvate to thiourea was1:1.05, the molar ratio of ethyl bromopyruvate to sodium nitrite is 1:1.5, and the weight ratio of ethyl bromopyruvate to water is1.95:10, the volume ratio of water to concentrated hydrochloric acid is 1:1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | Ethyl bromopyruvate (1.51mL, 10.86mmol) was added dropwise to a solution of 32 2-amino-4-iodopyrimidine (0.80g, 3.62mmol) in dry 33 THF (40mL). The mixture was stirred at rt for 2h after which it was filtered. This solid was then dissolved in 34 ethanol (20mL) and refluxed for 1h. The reaction mixture was cooled down, concentrated in vacuo and partitioned between CH2Cl2 (20mL) and saturated aqueous NaHCO3 (20mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Purification by flash column chromatography (eluent 30-40C petrol/EtOAc, 3:1 to 1:6) afforded 35 1 as a white solid (0.59g, 52%): mp 209-211C; numax (cm-1) 1721 (C=O); 1H NMR (400MHz, CDCl3) 8.77 (d, J=2.0Hz, 1H), 8.69 (d, J=2.0Hz, 1H), 8.10 (s,1H), 4.45 (q, J=7.0Hz, 2H), 1.42 (t, J=7.0Hz, 3H); 13C NMR (100MHz, CDCl3) 162.6, 157.0, 146.1, 138.3, 114.8, 75.6, 61.7, 14.5; HRMS (ESI+) C9H9O2N3127I+ [M+H]+ requires 317.9734; found 317.9725. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 9 Synthesis of (5-methylimidazo[1,2-a]pyridin-2-yl)methanol. A solution of <strong>[36936-23-9]5-chloro-6-methylpyridin-2-amine</strong> (568 mg, 4.0 mmol), ethyl 3-bromo-2-oxopropanoate (1.2 g, 6.0 mmol) in dry EtOH (10 mL) was stirred at 80 C. for 8 h. The mixture was concentrated and purified by silica gel chromatography (DCM/MeOH=20/1) to give ethyl 6-chloro-5-methylimidazo[1,2-a]pyridine-2-carboxylate (800 mg, yield: 84.0%) as a yellow solid. ESI-MS [M+H]+: 239.1. |
Tags: 70-23-5 synthesis path| 70-23-5 SDS| 70-23-5 COA| 70-23-5 purity| 70-23-5 application| 70-23-5 NMR| 70-23-5 COA| 70-23-5 structure
A118302 [57332-84-0]
3-Bromo-2-oxo-butyric acid ethyl ester
Similarity: 0.83
A118302 [57332-84-0]
3-Bromo-2-oxo-butyric acid ethyl ester
Similarity: 0.83
A118302 [57332-84-0]
3-Bromo-2-oxo-butyric acid ethyl ester
Similarity: 0.83
A118302 [57332-84-0]
3-Bromo-2-oxo-butyric acid ethyl ester
Similarity: 0.83
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