* 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.
With triethylamine; magnesium chloride In acetonitrile at 20℃;
Experimental operation: Take malonate potassium salt 1.00g (about 5.47mmol) and anhydrous magnesium chloride was added 0.65g (about 6.84mmol) in 25mL round bottom flask, 0.55g triethylamine was dropped after 6mL dissolved in acetonitrile, stirred at room temperature for 30min. Then dropped by 2mL acetonitrile dissolved 0.48g (2.5mmol) of o-chlorobenzoyl chloride 1c, supplemented triethylamine 0.06mL, stirred at room temperature overnight. Post-treatment: 30mL of water was added to dilute the reaction solution, and then were added 30,20,20mL ethyl acetate and the ethyl acetate layer was collected. After washing with saturated brine 30mL ethyl acetate layer was dried over anhydrous sodium sulfate, and spin dry column chromatography (PE: EA = 15: 1) 2c product obtained is isolated, a yield of 91percent
91%
Stage #1: With triethylamine; magnesium chloride In acetonitrile at 20℃; for 0.5 h; Stage #2: With triethylamine In acetonitrile at 20℃;
Experimental operation: Take malonate potassium salt 1.00 g (about5.47 mmol) and anhydrous magnesium chloride 0.65 g (about 6.84mmol) in 25 mLround bottom flask, 0.55 g of triethylamine was added dropwise after 6 mL ofacetonitrile was dissolved, followed by stirring at room temperature for 30min. Then dropped by 2 mL of acetonitrile was dissolved 0.48 g (2.5 mmol) ofo-chlorobenzoyl chloride 1c, supplemented triethylamine 0.06 mL, stirred atroom temperature overnight. After treatment: 30 mL of water was added to dilutethe reaction solution, and then were added 30,20,20 mL ethyl acetate, and theethyl acetate layer was collected. After, 30 mL with saturated brine ethylacetate layer was dried over anhydrous sodium sulfate, and spin dry columnchromatography (PE: EA = 15: 1) to give the product isolated 2c, in 91percent yield.
Reference：
[1] Patent: CN105566340, 2016, A, . Location in patent: Paragraph 0010
[2] Patent: CN105663112, 2016, A, . Location in patent: Page/Page column 12
2
[ 2142-68-9 ]
[ 105-58-8 ]
[ 19112-35-7 ]
Yield
Reaction Conditions
Operation in experiment
34%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 40℃; for 2 h; Stage #2: With ethanol In tetrahydrofuran; mineral oil for 4 h; Reflux
A. Ethyl 3-(2-chlorophenyl)-3-oxopropanoate [00192] Sodium hydride (1.45 g, 36 mmol) and diethyl carbonate (2.14 g, 18 mmol) were suspended in 10 ml of THF. l-(2-Chlorophenyl)ethanone (1.4 g, 9 mmol) was gradually added into the reaction flask, maintaining the reaction mixture temperature at 40 °C for 2 h. Then 1 mL of ethanol was added thereto and heated under reflux conditions for 4 h. After cooling, 1 mL of ethanol was added and the mixture was poured onto ice water, and extracted with ether. Ether extracts are combined, washed with water, dried with anhydrous magnesium sulfate, and evaporated. The resulting oil is purified by flash column chromatography (PE/EA = 50/1) to afford the title compound (680 mg, 34percent) as a yellow oil. 1H NMR (400 MHz, CDC13): δ 1.24 (3H, t, J = 6.8 Hz), 4.03 (2H, s), 4.19 (2H, q, J = 6.8 Hz), 7.31-7.36 (2H, m), 7.42-7.45 (2H, m). [M+H] Calc'd for CnHnC103, 227; Found, 227.
Reference：
[1] Patent: WO2014/89364, 2014, A1, . Location in patent: Paragraph 00191; 00192
[2] Patent: US4711898, 1987, A,
[3] Chemistry - A European Journal, 2008, vol. 14, # 27, p. 8082 - 8085
[4] Patent: CN105636957, 2016, A, . Location in patent: Paragraph 0675; 0676; 0677; 0678
3
[ 37517-78-5 ]
[ 118-91-2 ]
[ 19112-35-7 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 16, p. 4400 - 4404
4
[ 1336-21-6 ]
[ 141-97-9 ]
[ 609-65-4 ]
[ 19112-35-7 ]
Yield
Reaction Conditions
Operation in experiment
15%
With sodium hydroxide; sodium chloride; ammonium chloride In water; benzene
EXAMPLE 5 Preparation of Ethyl 2-Amino-4-(o-Chlorophenyl)-5-Thiazolecarboxylate To a cold (5° C.) mixture of 55.0 g (0.423 mole) of ethyl acetoacetate, 70 ml. of benzene, 18.3 ml. of 33percent sodium hydroxide, and 141 ml. of water was added simultaneously with vigorous stirring 80.0 g (0.457 mole) of o-chlorobenzoyl chloride and 76 ml. of 33percent sodium hydroxide in 1 hour. The aqueous solution of the sodium salt of ethyl o-chlorobenzoylacetoacetate was stirred with 22.5 g (0.424 mole) of ammonium chloride for 18 hours. The aqueous solution was then saturated with 25.0 g of sodium chloride. At this moment, some precipitate formed which was filtered. The analysis indicated this material was mainly the sodium salt of ethyl o-chlorobenzoylacetoacetate. The sodium salt and the aqueous filtrate were combined and acidified with dilute hydrochloric acid. The oil which separated was extracted with ether. The ether solution was dried (MgSO4) and concentrated under reduced pressure. The residue was Kugelrohr distilled to give 30.0 g of oil which contained mainly ethyl o-chlorobenzoylacetoacetate. This material was stirred with a mixture of 7.2 g of ammonium chloride, 14 ml. of concentrated ammonium hydroxide and 150 ml. of water and worked up as described in Example 4 to give 16.6 g (15percent) of crude ethyl o-chlorobenzoylacetate which was about 92percent pure.
15%
With sodium hydroxide; sodium chloride; ammonium chloride In water; benzene
EXAMPLE 5 Preparation of Ethyl 2-Chloro-4-(o-Chlorophenyl)-5-Thiazolecarboxylate To a cold (5° C.) mixture at 55.0 g (0.423 mole) of ethyl acetoacetate, 70 ml. of benzene, 18.3 ml. of 33percent sodium hydroxide, and 141 ml. of water was added simultaneously with vigorous stirring 80.0 g (0.457 mole) of o-chlorobenzoyl chloride and 76 ml. of 33percent sodium hydroxide in 1 hour as described in Example 4. The aqueous solution of sodium salt of ethyl o-chlorobenzoylacetoacetate was stirred with 22.5 g (0.424 mole) of ammonium chloride for 18 hours. The aqueous solution was then saturated with 25.0 g of sodium chloride. At this moment, some precipitate formed which was filtered. The analysis indicated this material was mainly the sodium salt of ethyl o-chlorobenzoylacetoacetate. The sodium salt and the aqueous filtrate were combined and acidified with dilute hydrochloric acid. The oil which separated was extracted with ether. The ether solution was dried (MgSO4) and concentrated under reduced pressure. The residue was Kugelrohr distilled to give 30.0 g of oil which contained mainly ethyl o-chlorobenzoylacetoacetate. This material was stirred with a mixture of 7.2 g of ammonium chloride, 14 ml. of concentrated ammonium hydroxide and 150 ml. of water and worked up as described in Example 4 to give 16.6 g (15percent) of crude ethyl o-chlorobenzoylacetate which was about 92percent pure.
Reference：
[1] Patent: US4308391, 1981, A,
[2] Patent: US4336389, 1982, A,
5
[ 141-97-9 ]
[ 609-65-4 ]
[ 19112-35-7 ]
Reference：
[1] Tetrahedron Letters, 2007, vol. 48, # 42, p. 7448 - 7451
[2] Journal of Heterocyclic Chemistry, 1985, vol. 22, p. 1621 - 1630
6
[ 1071-46-1 ]
[ 609-65-4 ]
[ 19112-35-7 ]
Reference：
[1] Journal of Organic Chemistry, 1979, vol. 44, # 2, p. 310 - 311
[2] Organic Syntheses, 1983, vol. 61, p. 5 - 5
7
[ 74476-71-4 ]
[ 19112-35-7 ]
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1988, vol. 53, # 4, p. 839 - 850
A mixture of 15.0 g. (0.065 mole) of ethyl o-chlorobenzoylacetate, 9.5 (0.070 mole) of sulfuryl chloride and 20 ml. of chloroform was held at reflux for 6 hours and concentrated to give 17.3 g of crude ethyl 2-chloro-o-chlorobenzoylacetate.
(R)-3-(2-Chloro-phenyl)-3-hydroxy-propionic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
With bis(1,5-cyclooctadiene)diiridium(I) dichloride; (R)-N-(3-methylpyridine-2-methyl)-7-bis-(3,5-di-tert-butylphenyl)phosphino-7?-amino-1,1?-spirodihydroindane; potassium tert-butylate; hydrogen; In ethanol; at 20℃; under 6080.41 - 7600.51 Torr; for 4h;Inert atmosphere; Sealed tube;
Example 11: Application of chiral spiro-pyridylamidophosphine ligand (R)-Ii (prepared in Example 9) in the asymmetric catalytic hydrogenation reaction of carbonyl compounds[0059] [0060] Under the protection of nitrogen atmosphere, 0.5 mg (0.74mumol) [Ir(COD)]Cl2, 1.2 mg (1.6mumol) (R)-Ii were added to the inner hydrogenation tube. Subsequently, 1 ml absolute ethyl alcohol was added and stirred for 1 h at room temperature. The inner reaction tube was placed into the hydrogenation reactor. After substitution by hydrogen, the reaction was stirred for 1 h at a hydrogen pressure of 1 atmosphere. The reactor was opened, and 7.5-150 mmol substrate (solid substrate, added after dissolved by ethanol) was added, followed by 0.05-25 mmol potassium tert-butoxide solution in ethanol (0.5 ml (0.1 mmol/mL)-25 ml (1 mmol/mL)) added with a syringe. The reactor was sealed, and hydrogen was filled to a pressure of 8-10 atm, and the reaction was stirred under the hydrogen pressure at room temperature for a while ranging from 10 minutes to 24 hours. After the hydrogenation was finished, the reaction solution was filtered through a short silica gel column to remove the catalyst, and the conversion rate and yield of the reaction were analyzed by gas chromatography or nuclear magnetic resonance (NMR); and the optical purity of the product was analyzed by gas chromatography or high performance liquid chromatography. The results of the hydrogenation experiments were listed in Table 1.
97%
With bis(1,5-cyclooctadiene)diiridium(I) dichloride; (R)-N-(3-methylpyridine-2-methyl)-7-bis-(3,5-di-tert-butylphenyl)phosphino-7?-amino-1,1?-spirodihydroindane; potassium tert-butylate; hydrogen; In ethanol; at 20℃; under 6080.41 - 7600.51 Torr; for 4h;Autoclave;
Example 11 Application of Chiral Spiro-Pyridylamidophosphine Ligand (R)-Ii (Prepared in Example 9) in the Asymmetric Catalytic Hydrogenation Reaction of Carbonyl Compounds Under the protection of nitrogen atmosphere, 0.5 mg (0.74 gmol) [Ir(COD)]Cl2, 1.2 mg (1.6 mumol) (R)-Ii were added to the inner hydrogenation tube. Subsequently, 1 ml absolute ethyl alcohol was added and stirred for 1 h at room temperature. The inner reaction tube was placed into the hydrogenation reactor. After substitution by hydrogen, the reaction was stirred for 1 h at a hydrogen pressure of 1 atmosphere. The reactor was opened, and 7.5-150 mmol substrate (solid substrate, added after dissolved by ethanol) was added, followed by 0.05-25 mmol potassium tert-butoxide solution in ethanol (0.5 ml (0.1 mmol/mL)-25 ml (1 mmol/mL)) added with a syringe. The reactor was sealed, and hydrogen was filled to a pressure of 8-10 atm, and the reaction was stirred under the hydrogen pressure at room temperature for a while ranging from 10 minutes to 24 hours. After the hydrogenation was finished, the reaction solution was filtered through a short silica gel column to remove the catalyst, and the conversion rate and yield of the reaction were analyzed by gas chromatography or nuclear magnetic resonance (NMR); and the optical purity of the product was analyzed by gas chromatography or high performance liquid chromatography. The results of the hydrogenation experiments were listed in Table 1.
7-(1-aza-bicyclo[2.2.2]oct-3-ylamino)-5-(2-chloro-phenyl)-1-(2,6-dichloro-phenyl)-3,4-dihydro-1<i>H</i>-pyrimido[4,5-<i>d</i>]pyrimidin-2-one[ No CAS ]
5-(2-chloro-phenyl)-1-(2,6-dichloro-phenyl)-7-(2,2,6,6-tetramethyl-piperidin-4-ylamino)-3,4-dihydro-1<i>H</i>-pyrimido[4,5-<i>d</i>]pyrimidin-2-one[ No CAS ]
5-(2-chloro-phenyl)-1-(2,6-dichloro-phenyl)-7-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylamino)-3,4-dihydro-1<i>H</i>-pyrimido[4,5-<i>d</i>]pyrimidin-2-one[ No CAS ]
5-(2-chloro-phenyl)-1-(2,6-dichloro-phenyl)-7-(1,4,6,7-tetrahydro-pyrazolo[4,3-<i>c</i>]pyridin-5-yl)-3,4-dihydro-1<i>H</i>-pyrimido[4,5-<i>d</i>]pyrimidin-2-one[ No CAS ]
5-(2-chloro-phenyl)-1-(2,6-dichloro-phenyl)-7-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-3,4-dihydro-1<i>H</i>-pyrimido[4,5-<i>d</i>]pyrimidin-2-one[ No CAS ]
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