* 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.
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 % of a brown crystalline solid with GC purity of 97.2 %.
(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.).
Example 3 Synthesis of a compound of formula (VII): (R)-methyl 3-(tert-butyldimethylsilyloxy)-5-(1H-imidazol-1-yl)-5-oxopentanoate A solution of (R)-benzyl mandelate (49.4 g, 204 mmol) in anhydrous THF (500 mL) under N2 atmosphere is cooled to -78 C. and a 2.3 M hexyllithium solution in THF (97 mL, 224 mmol, 1.1 equivalents) is added drop by drop. The mixture is kept under stirring at -78 C. for 30 minutes, then a solution of 3-[(tert-butyldimethylsilyl)oxy]pentanedioic anhydride (50.0 g, 204 mmol) in anhydrous THF (100 mL) is added at -78 C. and the resulting mixture is kept under magnetic stirring at -78 C. for 2 hours. The reaction is warmed to -15 C., acidified with 1 N HCl and extracted with AcOEt. The organic phase is washed with 1 N HCl and brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The reaction crude is dissolved in cyclohexane (250 ml) and kept under stirring at 20 C. for 16 h. The precipitated solid is filtered, washed with cyclohexane (50 ml) and the organic solution is evaporated under reduced pressure. The resulting oil is dissolved in MeOH (150 mL) and the solution is added to a 25% solution of MeONa in MeOH (370 ml) kept at 7 C. under stirring under N2 atmosphere. After completion of the addition, the mixture is reacted for 1 hour at 7 C., then poured into a 6.5% HCl solution (1000 ml). The mixture is reacted for 10 minutes, extracted with AcOEt, the organic phase is washed with brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The resulting oil is dissolved in toluene, extracted with a 5% K2CO3 solution in water and the aqueous phase is washed with toluene and treated with 37% HCl.
A solution of (R)-benzyl mandelate (49.4 g, 204 mmol) in anhydrous THF (500 mL) under N2 atmosphere is cooled to -78C and a 2.3 M hexyllithium solution in THF (97 mL, 224 mmol, 1.1 equivalents) is added drop by drop. The mixture is kept under stirring at -78C for 30 minutes, then a solution of 3-[(tert-butyldimethylsilyl)oxy]pentanedioic anhydride (50.0 g, 204 mmol) in anhydrous THF (100 mL) is added at -78C and the resulting mixture is kept under magnetic stirring at -78C for 2 hours. The reaction is warmed to -15C, acidified with 1 N HCl and extracted with AcOEt. The organic phase is washed with 1 N HCl and brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The reaction crude is dissolved in cyclohexane (250 ml) and kept under stirring at 20C for 16h. The precipitated solid is filtered, washed with cyclohexane (50 ml) and the organic solution is evaporated under reduced pressure. The resulting oil is dissolved in MeOH (150 mL) and the solution is added to a 25% solution of MeONa in MeOH (370 ml) kept at 7C under stirring under N2 atmosphere. After completion of the addition, the mixture is reacted for 1 hour at 7C, then poured into a 6.5% HCl solution (1000 ml). The mixture is reacted for 10 minutes, extracted with AcOEt, the organic phase is washed with brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The resulting oil is dissolved in toluene, extracted with a 5% K2CO3 solution in water and the aqueous phase is washed with toluene and treated with 37% HCl. The phases are separated and the aqueous phase is extracted with AcOEt, washed with brine, dried over Na2SO4 and evaporated under reduced pressure. The reaction crude is solubilized in toluene under N2 atmosphere and treated with 1,1'-carbonyldiimidazole (18.8 g, 115.6 mmol, 1.1 equivalents). The mixture is left under stirring at 20C for 2 hours and then at 5C for 1 hour. The suspended solid is filtered and the resulting toluene solution is directly used in the subsequent step as described in Example 2.
Example 1 Synthesis of a compound of formula (VII): (R)-methyl 3-(tert-butyldimethylsilyloxy)-5-(1H-imidazol-1-yl)-5-oxopentanoate A solution of (S)-benzyl mandelate (6 g, 24.79 mmol) in anhydrous THF (100 mL) under N2 atmosphere is cooled to -78 C. and a solution of BuLi 2.5 M in hexane (10.9 mL, 27.27 mmol) is added therein drop by drop. The mixture is kept under stirring at -78 C. for 20 minutes, then a solution of 3-[(tert-butyldimethylsilyl)oxy]pentanedioic anhydride (6.05 g, 24.79 mmol) in anhydrous THF (25 mL) is added and the resulting mixture is kept under magnetic stirring at -78 C. for 2 hours. The reaction is acidified with 1 N HCl and extracted with AcOEt. The organic phase is washed with 1 N HCl and brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The reaction crude is purified by flash silica gel chromatography (eluent: EtPet/AcOEt 4:1) and the resulting product is dissolved in anhydrous THF (150 ml), then treated with dimethyl dicarbonate (2.47 mL, 23.04 mmol) and DMAP (201 mg, 1.65 mmol). The mixture is kept under stirring at 25 C. for 20 minutes, then the solvent is evaporated off under reduced pressure and the residue purified by flash chromatography (eluent: EtPet/AcOEt 9:1). The colourless oil obtained is dissolved in ethyl acetate (90 mL) and the resulting solution is kept under stirring under H2 atmosphere in the presence of 20% Pd(OH)2/C (652 mg, 0.93 mmol) at 20 C. for 10 hours. The mixture is filtered through perlite and the solvent is evaporated off under reduced pressure. The reaction crude (containing phenylacetic acid as impurity) is dissolved in anhydrous THF under N2 atmosphere and treated with 1,1'-carbonyldiimidazole (3.02 g, 18.68 mmol). The mixture is left under stirring at 20 C. for 3 hours. The solvent is evaporated off under reduced pressure and the residue is purified by flash silica gel chromatography (eluent: EtPet/AcOEt 30:70). 2.85 g of a pale yellow oil are obtained (yield 41.6% over 4 steps). 1H NMR (400 MHz, CDCl3) δ: 8.06 (s, 1H); 7.37 (s, 1H), 6.92 (s, 1H); 4.54-5.52 (m, 1H); 3.53 (s, 3H); 3.04-2.96 (s, 2H); 2.50-2.40 (m, 2H); 0.62 (s, 9H); -0.1 (s, 3H), -0.21 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 170.36; 167.19; 136.06; 130.47; 115.68; 65.69; 51.11; 42.35; 41.41; 24.95; 17.17; -5.58; -5.79. MS (ES+): m/z 349 [M+Na]+.
A solution of (S)-benzyl mandelate (6 g, 24.79 mmol) in anhydrous THF (100 mL) under N2 atmosphere is cooled to -78C and a solution of BuLi 2.5 M in hexane (10.9 mL, 27.27 mmol) is added therein drop by drop. The mixture is kept under stirring at -78C for 20 minutes, then a solution of 3-[(tert-butyldimethylsilyl)oxy]pentanedioic anhydride (6.05 g, 24.79 mmol) in anhydrous THF (25 mL) is added and the resulting mixture is kept under magnetic stirring at -78C for 2 hours. The reaction is acidified with 1 N HCl and extracted with AcOEt. The organic phase is washed with 1 N HCl and brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The reaction crude is purified by flash silica gel chromatography (eluent: EtPet/AcOEt 4:1) and the resulting product is dissolved in anhydrous THF (150 ml), then treated with dimethyl dicarbonate (2.47 mL, 23.04 mmol) and DMAP (201 mg, 1.65 mmol). The mixture is kept under stirring at 25C for 20 minutes, then the solvent is evaporated off under reduced pressure and the residue purified by flash chromatography (eluent: EtPet/AcOEt 9:1). The colourless oil obtained is dissolved in ethyl acetate (90 mL) and the resulting solution is kept under stirring under H2 atmosphere in the presence of 20% Pd(OH)2/C (652 mg, 0.93 mmol) at 20C for 10 hours. The mixture is filtered through perlite and the solvent is evaporated off under reduced pressure. The reaction crude (containing phenylacetic acid as impurity) is dissolved in anhydrous THF under N2 atmosphere and treated with 1,1'-carbonyldiimidazole (3.02 g, 18.68 mmol). The mixture is left under stirring at 20C for 3 hours. The solvent is evaporated off under reduced pressure and the residue is purified by flash silica gel chromatography (eluent: EtPet/AcOEt 30:70). 2.85 g of a pale yellow oil are obtained (yield 41.6% over 4 steps). 1H NMR (400 MHz, CDCl3) δ: 8.06 (s, 1H); 7.37 (s, 1H), 6.92 (s, 1H); 4.54-5.52 (m, 1H); 3.53 (s, 3H); 3.04-2.96 (s, 2H); 2.50-2.40 (m, 2H); 0.62 (s, 9H); -0.1 (s, 3H), -0.21 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 170.36; 167.19; 136.06; 130.47; 115.68; 65.69; 51.11; 42.35; 41.41; 24.95; 17.17; -5.58; -5.79. mS(ES+): m/z 349 [M+Na]+.
Example 2: Preparation of (3R)-3-[(tert-Butyldimethylsilyl) oxy] pentanedioic acid, 1-[(R)-Mandelic acid] EsterA solution of ethyl-(R)-mandelate (25 g) in tetrahydrofuran (375 ml) was cooled to -78 C, and a solution of 1.6 M BuLi in hexane (87 ml) was added drop wise, and stirred for 1 hr .To this reaction mixture a solution of 3-[(tert-butyldimethylsilyl)oxy] pentanedioic anhydride (33.6 g) in THF (125 ml) was added, and the resulting reaction mass was stirred for 2-3 Hrs. The reaction mixture was acidified with Aq hydrochloric acid and the product was extracted with ethyl acetate. The organic layer was washed with water and sodium chloride solution. The organic layer was concentrated. The concentrated reaction mass taken into 100 ml methanol and to this 100 ml of DM water was added. To this sodium hydroxide (0.55 g) solution in DM water (50 ml) was added and the reaction mass was stirred at room temperature for 2-3 hrs. The reaction mass was concentrated. To the concentrate a mixture of DM water and dichloromethane was added and acidified with Aq hydrochloric acid solution. The Aq layer was extracted with dichloromethane and the organic layer was washed twice with DM water. The combined organic extracts were dried and concentrated. The concentrated mass was crystallized in toluene to give (3R)-3-[(tert-Butyldimethylsilyl) oxy] pentanedioic acid, 1-[(R)-Mandelic acid] Ester. The above crude product was purified in Ethyl acetate/ hexane to give (3R)-3-[(tert- Butyldimethylsilyl) oxy] pentanedioic acid, 1-[(R)-Mandelic acid] Ester (45.0 g).
(3R)-3-<(tert-Butyldimethylsilyl)oxy>pentanedioic acid 1-<benzyl (R)-mandelate> ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
380 mL of anhydrous tetrahydrofuran was added to the reaction flask.Put 20.8g, 0.09mol benzyl mandelate,The air in the reaction system was replaced with nitrogen three times. Cool the contents with liquid nitrogen to a temperature of -75 to -78C,56.9 mL of 1.6 M butyl lithium-n-hexane solution was initially added dropwise.After the addition was completed, the temperature of the feed solution was maintained at -75 to -78C. After stirring was continued for 45 to 60 minutes, the temperature of the feed solution was maintained at -75 to -78C, and the dropwise addition of XII-tetrahydrofuran solution (XII 21g+tetrahydrofuran 40 mL) was started. , control the dropping rate to keep the temperature at -75 ~ -78 C. After the addition was completed, the contents were kept at a temperature of -75 to -78C until the TLC method showed that the content of the starting material benzyl mandelate in the reaction solution was less than 5%. After the reaction was completed, the reaction solution was poured into 0.25 N 420 mL of hydrochloric acid under stirring, and 520 mL of diethyl ether was added and stirred for 10-15 minutes. The liquid was separated by standing and the aqueous layer was extracted with ether (160m x 2). mergeThe organic layer was washed with saturated aqueous sodium chloride (420 mL x 2). The mixture was left to stand for separation, the aqueous layer was discarded, and the organic layer was concentrated to obtain Compound XIII 40.0 g in 82% yield.
Example 1: Process for the preparation of (3R)-3-[(tert-Butyldimethylsilyl) oxy] pentanedioic acid, 1-[(R)-Mandelic acid] EsterA solution of N-pyrrolidinyl norephedrine in toluene and catalytic amount of triphenyl methane in tetrahydrofuran (750 ml) was cooled to -78 C, and to this a solution of 1.6 M BuLi in hexane (257 ml) was added drop wise, and the reaction mixture was stirred for 1 hr. To this reaction mixture a solution of benzyl(R)-mandelate (100 g) in THF (500 ml) was added and stirred for 1 hr. To this a solution of 3-[(tert-butyldimethylsilyl)oxy] pentanedioic anhydride (101 g) in THF (250 ml) was added and the resulting reaction mass was stirred for 2-3 Hrs. The reaction mixture was acidified with Aq hydrochloric acid and the product was extracted with ethylacetate. The organic layer was washed with water and sodium chloride solution and concentrated. The concentrated reaction mass taken into ethyl acetate and to this solution 10 % Palladium on Charcoal was added and the reaction mass was stirred at room temperature in a hydrogen atmosphere. The reaction mass was filtered and the filtrate was extracted with sodium bicarbonate solution .The resulting Aq layer was washed with ethyl acetate, dichloromethane and acidified with Aq hydrochloric acid solution. The Aq layer was extracted with dichloromerthane and the organic layer was washed twice with DM water. The combined organic extracts were dried and concentrated. The concentrated mass was crystallized in toluene to give (3R)-3-[(tert-Butyldimethylsilyl) oxy] pentanedioic acid, 1-[(R)-Mandelic acid] Ester. The above crude product was purified in Ethylacetate/ hexane to give (3R)-3-[(tert- Butyldimethylsilyl) oxy] pentanedioic acid, 1-[(R)-Mandelic acid] Ester (130 g).
(1) Into a three-necked flask, 36 g of tetrahydrofuran was added, the temperature was lowered to -25 C, 6.7 g of n-butyllithium (0.025 mol, 2.5 mol / L)Insulation for 10 minutes;Continue to cool to below -40 ,5.5 g (0.026 mol) of hexamethyldisilazane and5g tetrahydrofuran solution, plus insulation 20 minutes;(2) continue to cool to below -60 ,6.1 g (0.0252 mol) of benzyl mandelate was added dropwiseTetrahydrofuran 18g mixture,During the dropwise addition temperature control at -60 ~ -90 ,Drip finished insulation 2h, the temperature dropped below -80 ,J1 (4 g, 0.016 mol) andTetrahydrofuran 18g solution, drip finished insulation 2h;(3) plus acid and stratified, washed with water until neutral to obtain J2 reaction solution;
Example 3: Preparation of (3R)-3-[(tert-ButyldimethyIsil I) oxy] pentanedioic acid, 1-[(R)-Mandelic acid] EsterA solution of Trityl-(R)-mandelate (25 g) in tetrahydrofuran (375 ml) was cooled to -78 C, and a solution of 1.6 M BuLi in hexane (40 ml) was added drop wise, and the reaction mixture was stirred for 1 hr. To the reaction mixture a solution of 3-[(tert- butyldimethylsilyl)oxy] pentanedioic anhydride (15.5 g) in THF (125 ml) was added, and the resulting reaction mass was stirred for 2-3 Hrs. The reaction mixture was acidified with Aq hydrochloric acid and the product was extracted with ethyl acetate. The organic layer was washed with water and sodium chloride solution. The organic layer was concentrated. Concentrated reaction mass taken into 100 ml methanol and to this 100 ml DM water added. To this Aq hydrochloric acid solution (50 ml) was added and the reaction mass was stirred at room temperature for 2-3 hrs. The reaction mass was concentrated. To the concentrate a mixture of DM water and dichloromethane was added, Stirred and separated the layers. The Aq layer was extracted with dichloromethane and the organic layer was washed twice with DM water. The combined organic extracts were dried and concentrated. The concentrated mass was crystallized in toluene to give (3R)-3- [(tert-Butyldimethylsilyl) oxy] pentanedioic acid, 1-[(R)-Mandelic acid] Ester. The above crude product was purified in Ethyl acetate/ hexane to give (3R)-3-[(tert- Butyldimethylsilyl) oxy] pentanedioic acid, 1-[(R)-Mandelic acid] Ester (22.0 g).
(R)-6-(4-(2-(2-methylpyrrolidin-1-yl)ethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline dihydrochloride[ No CAS ]
[ 91424-40-7 ]
[ 76-05-1 ]
3-hydroxy-5-(6-(4-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoic acid trifluoroacetic acid salt[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In a reaction vial was placed (R)-6-(4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenyl)- 1,2,3,4- tetrahydroisoquinoline dihydrochloride (48 mg, 0.122 mmol), 4-(tert- butyldimethylsilyloxy)dihydro-2/i-pyran-2,6(3//)-dione (89 mg, 0.366 mmol), and sodium bicarbonate (51.3 mg, 0.610 mmol) in DMF (2 mL). The reaction was stirred at 60 C overnight. The mixture was filtered and purified by HPLC to give the TFA salt of the title compound. LCMS m/z = 451.4 [M+H]+.
(R)-6-(4-(2-(2-methylpyrrolidin-1-yl)ethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline dihydrochloride[ No CAS ]
[ 91424-40-7 ]
3-hydroxy-5-(6-(4-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 60℃;
Example 1.8: Preparation of 3-hydroxy-5-(6-(4-(2-((R)-2-methylpyrrolidin-1- yl)ethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentanoic acid (Compound 6).In a reaction vial was placed (R)-6-(4-(2-(2-methylpyrrolidin- 1 -yl)ethyl)phenyl)- 1,2,3,4- tetrahydroisoquinoline dihydrochloride (48 mg, 0.122 mmol), <strong>[91424-40-7]4-(tert-butyldimethylsilyloxy)dihydro-2H-pyran-2,6(3H)-dione</strong> (89 mg, 0.366 mmol), and sodium bicarbonate (51.3 mg, 0.6 10 mmol) in DMF (2 mL). The reaction was stirred at 60 C overnight. The mixture was filtered and purified by HPLC to give the TFA salt of the title compound. LCMS m/z = 451.4 [M+H]t
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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