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Synonyms: 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine
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Pieterse, Lianie ; Beteck, Richard M. ; Baratte, Blandine ; Jesumoroti, Omobolanle J. ; Robert, Thomas ; Ruchaud, Sandrine , et al.
Abstract: Protein kinases, including CDK9/CyclinT and Haspin, are regarded as potential drug targets in cancer therapy. Findings from a previous study suggested 7-azaindole as a privileged scaffold for producing inhibitors of CDK9/CyclinT and Haspin. Inspired by these findings, the current study synthesized and evaluated thirteen (13) C6-substituted 7-azaindole and twenty (20) C4-substituted structurally related 7H-pyrrolo[2,3-d]pyrimidine derivatives against a panel of protein kinases, including CDK9/CyclinT and Haspin. Eleven of the 7H-pyrrolo[2,3-d]pyrimidine derivatives exhibited activity toward CDK9/CyclinT, while 4 of compounds had activity against Haspin. The best CDK9/CyclinT (IC50 of 0.38 μM) and Haspin (IC50 of 0.11 μM) activities were achieved by compounds 7d and 7f, resp. Hence, these compounds may be valuable starting points for development of new anti-cancer drugs.
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Keywords: 7-Deazapurine ; Anticancer ; CDK9/CylinT ; Haspin ; Protein kinase
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Purchased from AmBeed: 98437-24-2 ; 71597-85-8 ; 3680-69-1 ; 6165-68-0 ; 51067-38-0 ; 87199-18-6
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CAS No. : | 3680-69-1 |
Formula : | C6H4ClN3 |
M.W : | 153.57 |
SMILES Code : | ClC1=C2C(NC=C2)=NC=N1 |
Synonyms : |
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine
|
MDL No. : | MFCD01686865 |
InChI Key : | BPTCCCTWWAUJRK-UHFFFAOYSA-N |
Pubchem ID : | 5356682 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P264-P271-P280-P302+P352-P304+P340-P305+P351+P338-P312-P362-P403+P233-P501 |
* 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 |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; | METHOD L 7-Benzyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidine To a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (250 mg/1.63 mmol) in 12 mL of DMF was added 676 mg (4.89 mmol) of potassium carbonate and the resulting mixture stirred at room temperature for 20 min. Benzylchloride (310 mg/2.45 mmol) was added and the new mixture stirred at room temperature for 24 h then filtered, concentrated and the residue purified by silica gel chromatography (3:1 hexanes/ethyl acetate) affording 318 mg (80%) of the title compound. LRMS: 244.1 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5% | To a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.075 g, 0.488 mmol) and <strong>[32202-61-2]4-aminoindan</strong> (0.072 g, 0.537mmol) in isopropanol (1 ml) was added concentrated HCl (2 drops). The reaction was heated at 600C for 5 h, then cooled to room temperature and concentrated to dryness. The reaction was diluted with ethyl acetate (5 ml) and washed with saturated aqueous NaHCO3 solution (3 x 5 ml). The organic extract was washed with H2O (5 ml), washed with brine (5 ml), dried (Na2SO4), and concentrated. The crude material was purified by column chromatography on silica gel (0-5 percent DCM/MeOH). The resulting material was recrystallized from ethyl acetate/hexanes to give the desired product (0.0060 g, 5percent) as a white solid.1H NMR (300 MHz, CD3OD) delta ppm: 2.06 (t, J = 7 Hz, 2 H), 2.82 (t, J = 7 Hz, 2 H), 2.99 (t, J = 7 Hz, 2 H), 6.29 (d, J = 4 Hz, 1 H), 7.09 (d, J = 4 Hz, 1 H), 7.16 - 7.23 (m, 3 H), 8.10 (s, 1 H). HPLC: 100percent at 2.100 minutes; Sunfire C18 4.6 x 50 mm; 10-90percent methanol: water with 0.1percent TFA; Gradient time = 2 min; 3.5 ml/ min; 254 nm. MS = 251 M+H+. | |
5% | To a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.075 g, 0.488 mmol) and <strong>[32202-61-2]4-aminoindan</strong> (0.072 g, 0.537mmol) in isopropanol (1 ml) was added concentrated HCl (2 drops). The reaction was heated at 600C for 5 h, then cooled to room temperature and concentrated to dryness. The reaction was diluted with ethyl acetate (5 ml) and washed with saturated aqueous NaHCO3 solution (3 x 5 ml). The organic extract was washed with H2O (5 ml), washed with brine (5 ml), dried (Na2SO4), and concentrated. The crude material was purified by column chromatography on silica gel (0-5 percent DCM/MeOH). The resulting material was recrystallized from ethyl acetate/hexanes to give the desired product (0.0060 g, 5percent) as a white solid.1H NMR (300 MHz, CD3OD) delta ppm: 2.06 (t, J = 7 Hz, 2 H), 2.82 (t, J = 7 Hz, 2 H), 2.99 (t, J = 7 Hz, 2 H), 6.29 (d, J = 4 Hz, 1 H), 7.09 (d, J = 4 Hz, 1 H), 7.16 - 7.23 (m, 3 H), 8.10 (s, 1 H). HPLC: 100percent at 2.100 minutes; Sunfire C18 4.6 x 50 mm; 10-90percent methanol: water with 0.1percent TFA; Gradient time = 2 min; 3.5 ml/ min; 254 nm. MS = 251 M+H+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.2% | Step 1: 4-methyl-7H-pyrrolo[2,3-d]pyrimidine 150 g of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine and 5.72 g of Pd(bppf)Cl2 were added to 1.5 L of tetrahydrofuran, stirred at room temperature for 0.5 hour, and then cooled down to below 0 C. To the resulting mixture was slowly added dropwise 850 mL of methylmagnesium bromide (3M dissolved in ether). After the addition was completed, the temperature was raised to 6065 C., and the resulting mixture reacted under reflux for 2 hours. Then, the temperature was lowered to below 0 C., and the reaction was quenched by slowly adding dropwise concentrated hydrochloric acid. After the addition was completed, 650 mL of purified water was added to the resulting mixture and stirred for 15 minutes, the phases were separated and the organic phase was discarded. The aqueous phase was adjusted to pH 6 with NaHCO3 and then suction-filtered, the filter cake was washed with 455 mL of purified water, and the filtrate was collected and extracted three times with 1.05 L of ethyl acetate, and then the organic phase was concentrated to obtain 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (109.5 g, 84.2%). 1H-NMR (500 MHz, DMSO-d6): delta=12.00 (bs, 1H), 8.61 (s, 1H), 7.47 (d, J=3.6 Hz, 1H), 6.62 (d, J=3.5 Hz, 1H), 2.64 (d, J=1.6 Hz, 3H); MS (ES): 134.07 (M+H+). | |
(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In diethyl ether; toluene; at 20 - 60℃;Inert atmosphere; | Into a round bottom flask the catalyst PdCl2(dppf), under an atmosphere of nitrogen, was placed with 15 mL of toluene along with a stir bar. A suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 1.47 g, 9.57 mmol) in 15 mL of toluene was added at room temperature. After stirring for 10 minutes, methylmagnesium bromide (17.00 mL, 3.00 M in ether, 51.00 mmol) was added dropwise. The solution turned from orange to yellow, and was slowly heated to 60 C. and stirred for 3 hrs at 60 C. and then overnight at room temperature. The resulting dark orange reaction mixture was quenched with 1 N hydrochloric acid and adjusted to pH~5, then extracted with ethyl acetate and water saturated with sodium chloride. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluding with ethyl acetate and hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a yellow solid (42, 202 mg). 1H-NMR(dmso-d6) was consistent with the desired compound. MS(ESI) [M+H+]+=134.3. | |
Step 1a-Preparation of 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (15)To 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (9, 5.03 g, 32.8 mmol) in 100 mL of toluene, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) 1:1 complex with dichloromethane (0.627 g, 0.328 mmol) is added under an atmosphere of nitrogen. After stirring for 10 minutes, methylmagnesium bromide (62.9 mL, 3.00 M in ether, 189 mmol) is added slowly. The reaction is heated at 55 C. overnight, then cooled to -70 to -80 C. and quenched by adding ammonium chloride dropwise. Then 1N hydrochloric acid is added and the pH is adjusted to 7-8 with the addition of saturated sodium bicarbonate. This is extracted 3× with ethyl acetate. The combined organic layer is washed with saturated ammonium chloride and brine, then dried with magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with ethyl acetate and dichloromethane, then methanol and dichloromethane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound as a tan solid (15). MS (ESI) [M+H+]+=134. This is reacted similarly to steps 2 and 3 of Scheme 4 to provide the desired compound 16. |
Step 1 - Preparation of 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (7):[0215] Into a round bottom flask the catalyst [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II), 1 : 1 complex with dichloromethane (70.0 mg, 0.09 mmol), is placed under nitrogen with 15 mL of toluene along with a stir bar. A suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 1.47 g, 9.57 mmol) in 15 mL of toluene is added at room temperature. After stirring for 10 minutes, methylmagnesium bromide (17.00 mL, 3.00 M in ether, 51.00 mmol) is added dropwise. The solution is slowly heated to 60 C and stirred for 3 hrs at 60 C, then overnight at room temperature. The resulting dark orange reaction mixture is quenched with 1 N hydrochloric acid and adjusted to pH ~5, then extracted with ethyl acetate and water saturated with sodium chloride. The organic layer is washed with water and brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography eluting with ethyl acetate and hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound as a yellow solid (8, 202 mg). 1H-NMR(dmso-d6) is consistent with the desired compound. MS(ESI)[M+H+]+ = 134.3. | ||
To 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (17, 5.03 g, 32.8 mmol) in 100 mL of toluene, [1,1?-bis(diphenylphosphino)ferrocene]dichloropalladium(II) 1:1 complex with dichloromethane (0.627 g, 0.328 mmol) was added under nitrogen. After stirring for 10 minutes, methylmagnesium bromide (62.9 mL, 3.00 M in ether, 189 mmol) was added slowly. The reaction was heated at 55 C. overnight, then cooled to -70 to -80 C. and quenched by adding ammonium chloride dropwise. Then 1N hydrochloric acid was added and the pH was adjusted to 7-8 with addition of saturated sodium bicarbonate. This was extracted 3× with ethyl acetate. The combined organic layer was washed with saturated ammonium chloride and brine, then dried with magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with ethyl acetate and dichloromethane, then methanol and dichloromethane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a tan solid (18). MS (ESI) [M+H?]?=134. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 4h; | A typical procedure for the preparation of 3a:2-bromopropane (74 mg, 0.6 mmol) was added to a solution of 1a (92 mg, 0.6 mmol) and K2CO3 (110 mg, 0.8 mmol) in 5 mL DMF at 70 C. According to TLC the reaction went to completion after 4 h. The mixture was extracted with ethyl acetate (3 * 10 mL). The combined organic layers were washed with brine(10 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product 2a, which was added to a solution of amino-phenol(66 mg, 0.6 mmol) and Cs2CO3 (585 mg, 1.8 mmol) in 10 mL DMSO without further purification. After stirring for 6 h at 80 C, the mixture was cooled to room temperature and extracted with ethyl acetate (3 * 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was further purified by column chromatography(petroleum ether/ethyl acetate 2:1) to afford compound 3a as a brown solid(121 mg, 75% over two steps). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; toluene;Reflux; | To a previously degassed solution of 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (418mg, 2.72mmol) and palladium tetrakis (157mg, 0.14mmol) in THF (27mL) was added a solution of trimethylaluminium (2.72mL, 5.44mmol, 2M in toluene). After refluxing overnight, the mixture was cooled to 0C and quenched by slow addition of saturated aqueous ammonium chloride. The medium was diluted with EtOAc. The mixture was filtered and the filtrate was decanted. The organic layer was washed with brine, filtered and concentrated under vacuum to afford impure title compound (338mg). LC/MS (ES+): (0290) 134.1 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
561 mg | With tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; toluene; at 60 - 80℃; for 40h;Inert atmosphere; | A suspension of 4-chloro-7H-pyrrolo[2,3-d]pyri- midine (1.54 g, 10 mmol) and Pd(PPh3)4(ii6 mg, 0.100 mmol) in THF (10.0 mE, iM) was vacuum purged with N2. Then a solution of dimethylzinc (3.82 g, 40.0 mmol, 20.0 mE, 2M in toluene) was added and the mixture was vacuum flushed with N2 and then heated to 60 C. for 16 h. ECMSAPC1(+) showed .-i:i mixture of starting material to product. The reaction was heated to 80 C. for another 24 h, in which ECMS showed a 2: 1 mixture of product to starting material. The reaction mixture was cooled in an ice-water bath then quenched with saturated NaHCO3 (aq) and extracted with EtOAc. The EtOAc was washed with brine, dried with Mg504, filter and concentrated to an oil. The crude material was purified by ISCO-Rf on a 24 g column eluting with 0-100% EtOAc-Heptane to give compound V-1 (561 mg, 42%). ECMS [M+i] 134; ?HNMR (400 MHz, CDC13) oe ppm8.94 (s, iH), 7.42 (d, J=3.4 Hz, iH), 6.68 (d, J=3.4 Hz, iH),2.87 (s, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 100℃; for 14h;Inert atmosphere; | To 4-chloro-7H-pyrrolo[2,3-d]pyrimidin (2.97 g), the compound (9.39 g) of Reference Example 1(2a) and tripotassiumphosphate (10.2 g), 1,4-dioxane (66 mL) and water (11 mL) were added, followed by nitrogen substitution, andPdCl2(dppf)CH2Cl2 (1.41 g) was then added to the reaction mixture. The thus obtained mixture was stirred at 100C for14 hours. Thereafter, the reaction mixture was cooled to a room temperature, and ethyl acetate and water were thenadded to the mixture. Thereafter, the thus obtained mixture was filtered through Celite. The filtrate was then extractedwith ethyl acetate, and the gathered organic layer was then washed with water and then with a saturated saline. Theresultant was dried over anhydrous sodium sulfate, and was then concentrated under a reduced pressure. The obtainedresidue was purified by silica gel chromatography (chloroform : methanol) to obtain tert-butyl (3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)cyclohex-3-en-1-yl)carbamate. The above obtained compound was used in the subsequent reaction withoutfurther purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; copper diacetate; at 50 - 60℃; | General procedure: Preparation Rla (460 mg, 3 mmol, 1 eq.), heteroaryl/aryl-boronic acid (7.5 mmol) and copper(II)-acetate (817 mg, 4.5 mmol) were stirred in pyridine (10 ml) at 50-60 C for 16-72 hours. (0176) Work-up 1 : (0177) The mixture was evaporated to Celite and purified by flash chromatography (heptane:EEO, gradient). (0178) Work-up 2: (0179) The mixture was filtered and the resulted filtrate was purified by preparative LC (on C-18 Gemini-NX 5 pm column, 5 mM aqueous NH4HC03-MeCN, gradient). |
Tags: 6-Chloro-7-deazapurine | 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine | Other Aromatic Heterocycles | Pyrroles | Pyrimidines | Chlorides | Organic Building Blocks | Heterocyclic Building Blocks | 3680-69-1
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P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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