* 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 sodium hydroxide; acetic anhydride In methanol; diethyl ether; benzene
B. 4-[[(Dimethylethyl)dimethylsilyl]oxy]dihydro-2H-pyran-2,6(3H)-dione A solution of Part A silyl-ether (theory 63.6 g, 200 mmole) in methanol (200 ml) was treated with NaOH pellets (16.0 g, 400 mmole) and stirred at room temperature under argon for 18 hours. The cloudy yellow solution was evaporated to dryness and dried in vacuo to give the diNa salt as a pale yellow solid. The diNa salt (42.1 g) was suspended in benzene (400 ml), treated with acetic anhydride (200 ml) and refluxed under argon for 1.5 hours. The brown mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and half-saturated NaHCO3 solution. The organic phase was washed with half saturated NaHCO3 and saturated NaCl solutions, dried over Na2 SO4 and evaporated to give the crude title anhydride as a brown solid. The crude product was taken up in ethyl ether, treated with Darco (3 g), filtered through Celite and evaporated. The crystalline residue was triturated with cold hexane to give pure title anhydride (33.26 g, 68percent overall from diethyl 3-hydroxy glutarate) as white plates, m.p. 77°-78° C., C13 -NMR (15 MHz, CDCl3)--5.22 ppm, 17.64, 25.31, 38.88, 61.87, 165.26.
Reference：
[1] Patent: US4804770, 1989, A,
[2] Journal of Organic Chemistry, 1984, vol. 49, # 19, p. 3657 - 3659
[3] Journal of Organic Chemistry, 1988, vol. 53, # 10, p. 2374 - 2378
[4] Journal of Medicinal Chemistry, 1987, vol. 30, # 10, p. 1858 - 1873
[5] European Journal of Organic Chemistry, 2014, vol. 2014, # 3, p. 631 - 638
[6] Patent: CN107011378, 2017, A,
2
[ 113794-48-2 ]
[ 91424-40-7 ]
Yield
Reaction Conditions
Operation in experiment
90%
at 130 - 135℃; for 2 - 3 h;
Example 1. Preparation of 3-hvdroxy protected glutaric anhydride, compound of formula 3. A four-neck round bottom flask fitted with a mechanical stirrer, condenser, and charging tube was charged with acetic anhydride (609 ml) followed by charging of 3-hydroxy protected glutaric acid at 25 to 300C. The reaction mass was refluxed for 2-3 hours at 130-1350C. The unreacted acetic anhydride, along with acetic acid, was completely distilled under vacuum at 60-950C. The product was crystallized from cyclohexane, and dried to obtain 90-95 percent of a brown crystalline solid with GC purity of 97.2 percent.
Reference：
[1] Patent: WO2008/130638, 2008, A2, . Location in patent: Page/Page column 30-31
[2] Journal of Medicinal Chemistry, 1987, vol. 30, # 10, p. 1858 - 1873
[3] European Journal of Organic Chemistry, 2014, vol. 2014, # 3, p. 631 - 638
3
[ 32328-03-3 ]
[ 91424-40-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 1987, vol. 30, # 10, p. 1858 - 1873
[2] Journal of Organic Chemistry, 1988, vol. 53, # 10, p. 2374 - 2378
[3] Journal of Organic Chemistry, 1984, vol. 49, # 19, p. 3657 - 3659
[4] European Journal of Organic Chemistry, 2014, vol. 2014, # 3, p. 631 - 638
[5] Patent: CN107011378, 2017, A,
4
[ 18162-48-6 ]
[ 91424-40-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 1987, vol. 30, # 10, p. 1858 - 1873
[2] Journal of Organic Chemistry, 1988, vol. 53, # 10, p. 2374 - 2378
[3] Journal of Organic Chemistry, 1984, vol. 49, # 19, p. 3657 - 3659
[4] European Journal of Organic Chemistry, 2014, vol. 2014, # 3, p. 631 - 638
[5] Patent: CN107011378, 2017, A,
5
[ 18162-48-6 ]
[ 152294-14-9 ]
[ 91424-40-7 ]
Reference：
[1] Asian Journal of Chemistry, 2014, vol. 26, # 22, p. 7867 - 7868
6
[ 77-92-9 ]
[ 91424-40-7 ]
Reference：
[1] Asian Journal of Chemistry, 2014, vol. 26, # 22, p. 7867 - 7868
7
[ 542-05-2 ]
[ 91424-40-7 ]
Reference：
[1] Asian Journal of Chemistry, 2014, vol. 26, # 22, p. 7867 - 7868
Dissolve 18,0 kg 3-hydroxy-TBS-ether-l,5-pentanoic diacid anhydrate (SI) in 90 1 methanol under the protection of nitrogen gas and reflux for 24 h. The reaction is observed by TLC. When the starting material has disappeared (as detected by TLC), the reaction mixture is concentrated to dryness and 20,0 kg of the title compound are obtained.
With sodium hydroxide; acetic anhydride; In methanol; diethyl ether; benzene;
B. 4-[[(Dimethylethyl)dimethylsilyl]oxy]dihydro-2H-pyran-2,6(3H)-dione A solution of Part A silyl-ether (theory 63.6 g, 200 mmole) in methanol (200 ml) was treated with NaOH pellets (16.0 g, 400 mmole) and stirred at room temperature under argon for 18 hours. The cloudy yellow solution was evaporated to dryness and dried in vacuo to give the diNa salt as a pale yellow solid. The diNa salt (42.1 g) was suspended in benzene (400 ml), treated with acetic anhydride (200 ml) and refluxed under argon for 1.5 hours. The brown mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and half-saturated NaHCO3 solution. The organic phase was washed with half saturated NaHCO3 and saturated NaCl solutions, dried over Na2 SO4 and evaporated to give the crude title anhydride as a brown solid. The crude product was taken up in ethyl ether, treated with Darco (3 g), filtered through Celite and evaporated. The crystalline residue was triturated with cold hexane to give pure title anhydride (33.26 g, 68% overall from diethyl 3-hydroxy glutarate) as white plates, m.p. 77-78 C., C13 -NMR (15 MHz, CDCl3)--5.22 ppm, 17.64, 25.31, 38.88, 61.87, 165.26.
(R)-3-(tert-Butyl-dimethyl-silanyloxy)-7-[(1S,2S,8S,8aR)-2-methyl-8-((S)-2-methyl-butyryloxy)-1,2,6,7,8,8a-hexahydro-naphthalen-1-yl]-5-oxo-heptanoic acid methyl ester[ No CAS ]
Example 2. Preparation of 3-(t-butyldimethylsiIanyloxy)-l, 5-pentane dioic acid monomethyl ester, compound of formula 4. A four neck round bottom flask fitted with a mechanical stirrer, condenser, and charging tube was charged with methylene dichloride (75 ml) and the compound of formula 3 ( 25 g, 0.1 mole) under inert atmosphere at 25 to 300C. The reaction mass was cooled to -35 to -4O0C, followed by addition of a solution of quinidine (35.68 g, 0.11 mole) in methylene dichloride (125 ml). The methanol (28.3 ml) was slowly added into the reaction mass at -35 to -400C and it was maintained for 15-20 hours. Methylene dichloride was distilled off under vacuum at 25-35C, followed by addition of sufficient amount of methyl t-butyl ether and water (25 ml). The pH of the reaction mass was adjusted to 4-5 using hydrochloric acid. The aqueous phase was separated. The organic phase was washed with acidic water to remove quinidine, followed by removal of methyl t-butyl ether under vacuum, to give the compound of formula 4 in 96 % yield, with chiral purity of 93:7 and GC purity of 99.25 %.
83.5%
Example 3. Preparation of 3-(t-butvIdimethylsiIanyloxy)-l, 5-pentane dioic acid monomethyl ester, compound of formula 4. A four neck round bottom flask fitted with a mechanical stirrer, condenser and charging tube, was charged with toluene (500 ml), followed by charging of the compound of formula 3 (50g, 0.181 mole) under inert atmosphere at 25 to 300C. The reaction mass was cooled to -30 to -550C, followed by addition of quinidine (76.33g, 0.235 mole). The methanol (55 ml) was slowly added into the reaction mass at -30 to -550C and it was maintained for 10-20 hours. Water (25 ml) was added and the pH was adjusted to 4-5 using hydrochloric acid. The aqueous phase was separated. The organic phase was washed with acidic water to remove quinidine, followed by removal of toluene under vacuum, giving the compound of formula 4a in 83.5 % yields, with chiral purity of 93.2: 6.8 and GC purity of 96.6 %.
(3S,1'S)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-5-[(1-phenylethyl)amino]-5-oxopentanoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In toluene;
C. (3S,1'S)-3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-5-[(1-phenylethyl)amino]-5-oxopentanoic acid A solution of Part B anhydride (7.32 g, 30.0 mmole) in dry toluene (120 ml) was cooled to -78 C. (dry ice-ethanol) under argon (some anhydride precipitated). To this mixture was added dropwise Et3 N (4.2 ml, 30.0 mmole) followed by S(-) α-methyl benzylamine (4.2 ml, 32.6 mmole). After stirring at -78 C. for 4.5 hours, the cooling bath was removed, the mixture allowed to warm to room temperature, and stirred for one hour. The mixture was partitioned between ethyl acetate (100 ml)-tetrahydrofuran (THF) (50 ml)/5% KHSO4 (175 ml). The organic phase was washed with 5% KHSO4 and saturated NaCl solutions, dried over Na2 SO4 and evaporated to give crude title acid compound as a white semi-solid. Esterification of a 25 mg sample of the crude product with CH2 N2 gave a 79:21 mixture of (3S,1'S): (3R,1'S) methylesters as determined by 1 H-NMR (270 MHz, CD3 CN). TLC:(ethyl ether-hexane; 2:1) Rf =0.37 (major, 3S,1'S), 0.29 (minor, 3R,1'S). 1 H-NMR (3S,1'S) δ0.08 ppm (3H,S), 0.10 (3H,S), 0.86 (9H,S). 1 H-NMR (3R,1'S) δ0.03 ppm (3H,S), 0.06 (3H,S), 0.79 (9H,S).
Dissolve 4.1 mmol of <strong>[91424-40-7]4-(tert-butyldimethylsilyloxy)dihydro-2H-pyran-2,6(3H)-dione</strong> (Nagao Y et al., Chem. Lett. 1990 9: 1503) in 10 mL of dioxane in a pressure tube. Cool in an ice/water bath, add 15 mL of saturated ammonium hydroxide and treat with gaseous ammonia via bubbler for about 10 min. Cap the pressure tube and heat in a 100 C. oil bath for 17 h. Cool the mixture and concentrate in vacuo. Purify the residue by silica gel chromatography using ethyl acetate/hexanes eluant to yield the title compound.
Example 520.5 mmol of an anhydride (1j) was dissolved in 10 mL of methyl t-butyl ether at -20 C., 10 mol % of an organocatalyst (Q-BTBSA) was added thereto, 10 equivalents of methanol was added once thereto, and the mixture was stirred at -20 C. for 28 hours. This reaction was quenched using an aqueous solution of dilute hydrochloric acid (1N, 3 mL). The aqueous layer was extracted with ethyl acetate (2×10 mL), and the combined organic layer was dried with MgSO4 and concentrated. The residue was purified by flash chromatography (25% ethyl acetate in normal-hexane) to obtain a hemiester (28 h, 98% yield). According to the known method (H. Han, Tetrahedron Lett. 2004, 45, 3301-3304), it was determined to obtain an enantiomeric excess of 93% by reacting the hemiester and R-1-(1-naphthyl)ethyl amine to be converted to an ester amide corresponding to the hemiester. The enantioselectivity was measured using high performance liquid chromatography (Hypersil, 40:1, hexane:isopropyl alcohol, 1 mL/min., t (main product)=7.6 min., t (side product)=11.9 min.).
5-((2-(((benzyloxy)carbonyl)amino)ethyl)amino)-3-((tert-butyldimethylsilyl)oxy)-5-oxopentanoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In tetrahydrofuran; at 25℃; for 16h;
A solution of 4-((tert-butyldimethylsilyl)oxy)dihydro-2H-pyran-2,6(3H)-dione 1-431 (cas: 91424-40-7, 5.0 g, 20.5 mmol), benzyl (2-aminoethyl)carbamate (cas: 72080-83-2, 3.97 g, 20.5 mmol) and TEA (6.2 g, 61.5 mmol) in anhydrous THF (150 mL) was stirred at 25 C for 16 hours. The reaction mixture was concentrated to afford the crude 5-((2- (((benzyloxy)carbonyl) amino)ethyl)amino)-3-((tert-butyldimethylsilyl)oxy)-5- oxopentanoic acid 1-432 (8.9 g), which was taken on to the next reaction without further purification. MS (ESI, positiveion) m/z: 439.2(M+l)
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