Structure of 106004-10-8
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| CAS No. : | 106004-10-8 |
| Formula : | C12H19ClO4 |
| M.W : | 262.73 |
| SMILES Code : | O=C(C1(CCCl)CC(C(OC)=O)CCC1)OC |
* 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 |
|---|---|---|
| 97% | EXAMPLE 25; l,3-Dicarbomethoxybicyclo[3.2.1]octane; A cooled (-67C) solution of dry diisopropylamine (ll.OmL, 78 mmol) in anhydrous THF (60mL) in a 3-neck 500mL round bottom flask equipped with magnetic stirring, addition funnel, and gas inlet/thermometer was treated via syringe with 2.4N n-butyllithium/hexane (30mL, 72 mmol) at a rate to keep the pot temperature <-50C, warmed to 0C for 5 minutes, then recooled (-67 C). l,3-Dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone (DMPU, 36.3mL, 300 mmole, dried over molecular seives) was added dropwise so as to keep pot temp < -60 C, then a solution of dimethyl cyclohexane-l,3-dicarboxylate (12.01g, 60 mmol) in anhydrous THF (20mL) was likewise added dropwise. After lh at -67 C, a solution of l-bromo-2-chloroethane (12.05g, 84 mmol) in anhydrous THF (15mL) was added dropwise so as to keep pot temp <-50 C, and the mixture was warmed to room temperature over 1.5h and stirred at room temperature for 18h, then cooled on an ice bath and quenched with saturated aqueous ammonium chloride (50mL). The organic solvent was removed in vacuo and the aqueous residue was extracted with 9:1 hexane/ethyl acetate (150mL, lOOmL, 2X50mL). The combined organic extracts were washed with water (lOOmL), dried (MgS04), and concentrated in vacuo. The residue was dissolved in methylene chloride and passed through a pad of alumina in a 60mL fritted glass funnel (eluted with methylene chloride) to afford 15.36g (97% of theoretical) of a pale yellow oil which was essentially the desired intermediate with minor impurities.A solution of l-(2-chloroethyl)-l,3-dicarbomethoxycyclohexane (all of semi-purified from 60 mmol dimethyl cyclohexane-l,3-dicarboxylate) and DMPU (36.3mL, 300 mmol) in anhydrous THF (150mL) under nitrogen in a 500mL 3-neck flask equipped with magnetic stirring, addition funnel, and gas inlet/thermometer was cooled to -67C. Meanwhile, a cooled (-67C) solution of dry diisopropylamine (ll.OmL, 78 mmol) in anhydrous THF (75mL) under nitrogen was treated via syringe with 2.4N n-butyllithium/hexane (30mL, 72 mmol), the mixture was warmed to 0C for 5 min, then recooled (-67C). The LDA solution was cannulated in portions (~6) into the other solution at a rate to keep pot temperature <-60 C, then the mixture was stirred at -67 C for 30 min, warmed to room temperature over 1.5h, then stirred at room temperature for 18h,. cooled on an ice bath and quenched with saturated aqueous ammonium chloride (50mL). The organic solvent was removed in vacuo and the aqueous residue was extracted with 9:1 hexane/ethyl acetate (150mL, lOOmL, 2X50mL). The combined organic extracts were washed with water (lOOmL), dried (MgS04), and concentrated in vacuo. The residue was dissolved in methylene chloride and passed through a pad of alumina in a 60mL fritted glass funnel (eluted with methylene chloride) to afford crude subject material (9.52g) as a pale yellow oil. Chromatography on silica gel (~400cc) eluted with 40%, then 50% methylene chloride/hexane, then methylene chloride alone, then 10% ethyl acetate/methylene chloride afforded 8.32g (61% for two steps from dimethyl cyclohexane-l,3-dicarboxylate) purified subject material as a very pale yellow oil. [M+H]+=226.9. *H NMR (CDC13) 8 3.66 (s,6H), 2.20-2.30 (m,lH), 2.00-2.10 (m,2H), 1.70-1.80 (m,5H), 1.55-1.65 (m,4H). | |
| 97% | A cooled (-67C) solution of dry diisopropylamine (1 l.OmL, 78 mmol) in anhydrous THF (60mL) in a 3-neck SOOmL round bottom flask equipped with magnetic stirring, addition funnel, and gas inlet/thermometer was treated via syringe with 2.4N n-butyllithium/hexane (30mL, 72mmol) at a rate to keep the pot temperature <-50C, warmed to 0C for 5 minutes, then recooled (-67 C). l,3-Dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone (DMPU, 36.3mL, 300 mmole, dried over molecular seives) was added dropwise so as to keep pot temp < -60 C, then a solution of dimethyl cyclohexane-l,3-dicarboxylate (12.01g, 60 mmol) in anhydrous THF (20mL) was likewise added dropwise. After Ih at -67 C, a solution of l-bromo-2-chloroethane (12.05g, 84 mmol) in anhydrous THF (15mL) was added dropwise so as to keep pot temp <-50 C, and the mixture was warmed to room temperature over 1.5h and stirred at room temperature for 18h, then cooled on an ice bath and quenched with saturated aqueous ammonium chloride (50mL). The organic solvent was removed in vacua and the aqueous residue was extracted with 9:1 hexane/ethyl acetate (150mL, lOOmL, 2X50mL). The combined organic extracts were washed with water (lOOmL), dried (MgSC>4), and concentrated in vacua. The residue was dissolved in methylene chloride and passed through a pad of alumina in a 60mL fritted glass runnel (eluted with methylene chloride) to afford 15.36g (97% of theoretical) of a pale yellow oil which was essentially the desired intermediate with minor impurities.A solution of l-(2-chloroethyl)-l,3-dicarbomethoxycyclohexane (all of semi-purified from 60 mmol dimethyl cyclohexane-l,3-dicarboxylate) and DMPU (36.3mL, 300 mmol) in anhydrous THF (150mL) under nitrogen in a 500mL 3-neck flask equipped with magnetic stirring, addition funnel, and gas inlet/thermometer was cooled to -67C. Meanwhile, a cooled (-67C) solution of dry diisopropylamine (ll.OmL, 78 mmol) in anhydrous THF (75mL) under nitrogen was treated via syringe with 2.4N n-butyllithium/hexane (30mL, 72 mmol), the mixture was warmed to 0C for 5 min, then recooled (-67C). The LDA solution was cannulated in portions (~6) into the other solution at a rate to keep pot temperature <-60 C, then the mixture was stirred at -67 C for 30 min, warmed to room temperature over 1.5h, then stirred at room temperature for 18h, cooled on an ice bath and quenched with saturated aqueous ammonium chloride (50mL). The organic solvent was removed in vacua and the aqueous residue was extracted with 9:1 hexane/ethyl acetate (150mL, lOOmL, 2X50mL). The combined organic extracts were washed with water (lOOmL), dried (MgSO4), and concentrated in vacua. The residue was dissolved in methylene chloride and passed through a pad of alumina in a 60mL fritted glass funnel (eluted with methylene chloride) to afford crude subject material (9.52g) as a pale yellow oil. Chromatography on silica gel (~400cc) eluted with 40%, then 50% methylenechloride/hexane, then methylene chloride alone, then 10% ethyl acetate/methylene chloride afforded 8.32g (61% for two steps from dimethyl cyclohexane-l,3-dicarboxylate) purified subject material as a very pale yellow oil. [M+H]+=226.9. 'H.NMR (CDC13) 6 3.66 (s,6H), 2.20-2.30 (m,lH), 2.00-2.10 (m,2H), 1.70-1.80 (m,5H), 1.55-1.65 (m,4H). | |
| 70% | Step 2: Dimeth l l-{3-chIon>propyl)eycl hexane-l,3-dkarbox kteTo a pre-cooled (-78C) solution of lithium diisopropylam de (94 nil.,, 188 mmol) in anhydrous THF (250 mL) was added DMPU (76 g, 600 mmol) dropwi.se, not allowing the temperature to exceed ~65"C, followed by an addition of a solution of dimethyl cycloiiexane-1 -dicarbox late (25 g, 125 mmol) in anhydrous THF (50 mL) at -78C over 20 min. After stirring at ~78C for one hour, 1 -bramo-2-c-hloroetliane (25 g, 175 mmol) was added and the reaction was slowly warmed up to room temperature overnight After quenched with saturaied NH4CI (100 mL), the reaction mixture was concentrated under reduced pressure and then diluted with water (200 mL). The resulting aqueous mixture was extracted with DCM (4 x 100 mL) and the combined organic phase was washed with wate (100 mL) and brine (100 mL-), dried over ?S04 mid concentrated under reduced pressure. The resulting .residue was purified by column chromatography (silica gel, petroleum ether/ethyl aeetate:"20/i) to afford 23 g (70%) of the title compound, dimethyl i- (3^:hloropror¾1)cyclohexar^l Hlic-arbox?iate as a yellow oil. E- SI-MS m z: 263 (M-f-H)*. |
| Step 2: Bicyclo[3.2.1)octane-l,5-dicarboxylic acid dimethyl esterA solution of N.N-diisopropylamine (4.5 mL, 32 mmol) in tetrahydrofuran (25 mL) was cooled at -78 C and treated with 1 .6 M of n-buiyllithium in hexane ( 19 mL). The reaction was warmed to 0 C, stirred for 5 minutes, then cooled back to -78 C. 1 ,3-Dimethyl-3,4,5,6- tetrahydro-2( l H)-pyrimidinone ( 15 mL, 120 mmol) was added dropwise over 20 minutes, then a solution of cyclohexane- l ,3-dicarboxylic acid dimethyl ester (5.0 g, 25 mmol) in tetrahydrofuran (10 mL) was added dropwise and the mixture stirred for 1 hour at the same temperature. Then a solution of 1 -bromo-2-chloroethane (2.9 mL, 35 mmol) in tetrahydrofuran (8 mL) was added dropwise. The reaction was allowed to return slowly to room temperature and stirred overnight. The reaction mixture was cooled to 0 C and quenched with saturated ammonium chloride solution. The reaction mixture was concentrated under reduced pressure and the resulting residue was diluted with a small amount of water and extracted with dichloromethane (4 x 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified with chromatography to give the intermediate 1 - (2-chloro-ethyl)-cyclohexanc- l ,3-dicarboxylic acid dimethyl ester (1.22 g). A solution of NN-diisopropylamine (0.91 mL, 6.50 mmol) in tetrahydrofuran (10 mL) was cooled at -78 C and treated with 1.6 M of n-butyllithium in hexane (4.06 mL). The reaction was warmed to 0 C, stirred for 5 minutes, and then cooled back to -78 C. l ,3-Dimethyl-3,4,5,6- tetrahydro-2( l H)-pyrimidinone (2.24 mL, 18.6 mmol) was added dropwise over 20 minutes, then a solution of l -(2-chloro-ethyl)-cyclohexane- l ,3-dicarboxylic acid dimethyl ester ( 1.22 g, 4.64 mmol) in tetrahydrofuran (10 mL) was added dropwise and the mixture was stirred for 1 hour at the same temperature. The reaction was allowed to return slowly at room temperature and stirred overnight. The reaction was quenched with saturated ammonium chloride solution and concentrated under reduced pressure. The resulting residue was diluted with a small amount of water and extracted with dichloromethane (4 x 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to give crude product (3.05 g) containing DMPU. The product was used in the next step without further purification. |

Tags: 106004-10-8 synthesis path| 106004-10-8 SDS| 106004-10-8 COA| 106004-10-8 purity| 106004-10-8 application| 106004-10-8 NMR| 106004-10-8 COA| 106004-10-8 structure
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