* 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 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In acetonitrile at 20℃; for 0.5 h; Inert atmosphere
[72] Malonic acid (5.0 g, 48 mmol) and /-BuOH (1.8 mL, 19 mmol) were dissolved in 150 mL of ACN at room temperature under nitrogen. EDC (9.2 g, 48 mmol) was added and the reaction conducted at room temperature under nitrogen for 30 min. ACN was removed under reduced pressure and the residue dissolved in 200 mL of ether. The product was back- extracted with two 50-mL portions of saturated NaHCCb, and the combined aqueous layer acidified to pH 2 with 1 N sodium bisulfate. Finally, the product was extracted with three 200-mL portions of DCM which were combined and washed with water, brine and dried over sodium sulfate. DCM was removed under reduced pressure and the product obtained as a white solid in 76percent yield (2.3 g). [73] NMR (CDCh, 400 MHz): δ 3.28 (s, 2H), 1.42 (s, 9H); 13C NMR (CDCh, 100 MHz): δ 168.5, 162.1, 83.5, 39.7, 27.9, 27.8, 25.6.
Reference：
[1] Journal of Organic Chemistry, 2018, vol. 83, # 3, p. 1116 - 1133
[2] Patent: WO2018/144880, 2018, A1, . Location in patent: Paragraph 72-73
[3] Journal of Medicinal Chemistry, 2006, vol. 49, # 17, p. 5273 - 5281
[4] Patent: US2006/211634, 2006, A1, . Location in patent: Page/Page column 15
[5] Organic and Biomolecular Chemistry, 2008, vol. 6, # 19, p. 3561 - 3572
[6] Chemistry - A European Journal, 2015, vol. 21, # 46, p. 16374 - 16378
2
[ 2033-24-1 ]
[ 75-65-0 ]
[ 40052-13-9 ]
Yield
Reaction Conditions
Operation in experiment
100%
for 6 h; Reflux
A 200 mL round-bottom flask equipped with a stirring bar was charged with 2,2-dimethyl-1,3-dioxane-4,6-dione 5 (Meldrum's acid, 5.0 g, 34.7 mmol) and tert-butyl alcohol (40 mL). The reaction was allowed to stir for 6 h at reflux conditions. The reaction mixture was concentrated in vacuo to afford the desired product 6 (5.56 g, 100percent) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 10.51 (br s, 1H), 3.35 (s, 2H), 1.42 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.8, 166.3, 81.9, 42.1, 27.9; HR-FAB MS calcd for C7H13O4 [M+H]+ 161.0814, found 161.0809.
Reference：
[1] Tetrahedron Asymmetry, 2015, vol. 26, # 4, p. 214 - 218
[2] Journal of Organic Chemistry, 2010, vol. 75, # 9, p. 3085 - 3096
[3] Tetrahedron Letters, 2011, vol. 52, # 46, p. 6072 - 6075
[4] Tetrahedron Letters, 1984, vol. 25, # 41, p. 4623 - 4626
[5] Tetrahedron Letters, 1997, vol. 38, # 38, p. 6689 - 6692
[6] Tetrahedron Letters, 2003, vol. 44, # 40, p. 7499 - 7502
[7] Journal of Chemical Research, 2006, # 9, p. 586 - 588
[8] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 24, p. 6553 - 6557
[9] Organic Letters, 2012, vol. 14, # 23, p. 5864 - 5867
[10] Organic Letters, 2013, vol. 15, # 10, p. 2426 - 2429
[11] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 18, p. 4367 - 4371
[12] Beilstein Journal of Organic Chemistry, 2016, vol. 12, p. 1153 - 1169
[13] Chemical Communications, 2017, vol. 53, # 13, p. 2170 - 2173
3
[ 124-63-0 ]
[ 75-65-0 ]
[ 40052-13-9 ]
Yield
Reaction Conditions
Operation in experiment
71%
With pyridine; sodium hydroxide; malonic acid In tetrahydrofuran; water; ethyl acetate
Example 2 Synthesis of mono-tert.-butyl malonate To a solution of malonic acid (5.2 g, 50 mmol) in tetrahydrofuran (40 ml), pyridine (9.1 g, 115 mmol) and tert.-butanol (10 ml, 106 mmol) were added and stirred, followed by cooling to 0° C. To the mixture, methanesulfonyl chloride (6.59 g, 57.5 mmol) was added over 20 minutes and stirred for one hour. A precipitated salt was filtered off. To a filtrate, ethyl acetate (30 ml) and water (100 ml) were added, and pH of the mixture was adjusted to 8 to 9 with a 20percent aqueous solution of sodium hydroxide. The mixture was separated and an aqueous layer was washed with methylene chloride (50 ml) three times. After adjusting pH of the aqueous layer to 2.5 with conc. hydrochloric acid, the aqueous layer was extracted with methylene chloride (50 ml) eight times. The combined organic layer was dried over sodium sulfate and concentrated to obtain the substantially pure entitled compound (5.71 g). Yield, 71 percent. The results of 1 H-NMR and IR were the same as those in Example 1.
70%
With pyridine; hydrogenchloride; sodium hydroxide; malonic acid In tetrahydrofuran; dichloromethane; water
Example 1 Synthesis of mono-tert.-butyl malonate To a solution of malonic acid (5.2 g, 50 mmol) in tetrahydrofuran (40 ml), pyridine (9.1 g, 115 mmol) and tert.-butanol (10 ml, 106 mmol) were added and stirred, followed by cooling to 0° C. To the mixture, methanesulfonyl chloride (6.59 g, 57.5 mmol) was added over 20 minutes and stirred for one hour. Then, methylene chloride (30 ml) and water (10 ml) were added, and pH of the mixture was adjusted to 10 to 11 with a 30percent aqueous solution of sodium hydroxide. The mixture was separated and an aqueous layer was washed with methylene chloride (10 ml) three times. After adjusting pH of the aqueous layer to 2.5 with 6N hydrochloric acid, the aqueous layer was extracted with methylene chloride (30 ml) four times. The combined organic layer was dried over sodium sulfate and concentrated to obtain the substantially pure entitled compound (5.64 g). Yield, 70percent. 1 H-NMR (CDCl3): δ=1.45 (s, 9H), 3.33 (s, 2H), 9.97 (brs. 1H). IR (neat): 3000, 1730, 1160 cm-1.
Reference：
[1] Patent: US5214199, 1993, A,
[2] Patent: US5214199, 1993, A,
4
[ 75-65-0 ]
[ 40052-13-9 ]
Yield
Reaction Conditions
Operation in experiment
67%
With pyridine; hydrogenchloride; sodium hydroxide; malonic acid; acetic anhydride In tetrahydrofuran; dichloromethane; water
Example 3 Synthesis of mono-tert.-butyl malonate To a solution of malonic acid (5.2 g, 50 mmol) in tetrahydrofuran (40 ml), pyridine (9.49 g, 62 mmol) and tert.-butanol (10 ml, 106 mmol) were added and stirred, followed by cooling to 0° C. To the mixture, acetic anhydride (6.13 g, 60 mmol) was added over 20 minutes and stirred for 10 minutes at 0° C. and then 5 hours at room temperature. After concentrating the reaction mixture under reduced pressure, methylene chloride (30 ml) and water (10 ml) were added, and pH of the mixture was adjusted to 10 to 11 with a 30percent aqueous solution of sodium hydroxide followed by stirring for one hour at room temperature. The mixture was separated and an aqueous layer was washed with methylene chloride (10 ml) three times. After adjusting pH of the aqueous layer to 2.5 with 6N hydrochloric acid, the aqueous layer was extracted with methylene chloride (30 ml) four times. The combined organic layer was dried over sodium sulfate and concentrated to obtain crude mono-tert.-butyl malonate, which was concentrated under reduced pressure in order to remove acetic acid to obtain the substantially pure entitled compound (5.37 g). Yield, 67percent. The results of 1 H-NMR and IR were the same as those in Example 1.
Reference：
[1] Patent: US5214199, 1993, A,
5
[ 32864-38-3 ]
[ 40052-13-9 ]
Reference：
[1] Tetrahedron, 1993, vol. 49, # 18, p. 3691 - 3734
[2] Journal of Organic Chemistry, 1994, vol. 59, # 24, p. 7259 - 7266
[3] Carbohydrate Research, 1987, vol. 169, p. 171 - 188
[4] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 16, p. 2659 - 2662
6
[ 141-82-2 ]
[ 75-65-0 ]
[ 40052-13-9 ]
[ 541-16-2 ]
Reference：
[1] Journal of Organic Chemistry, 2002, vol. 67, # 25, p. 8975 - 8982
[2] Journal of Organic Chemistry, 1993, vol. 58, # 4, p. 879 - 886
7
[ 24424-99-5 ]
[ 40052-13-9 ]
Reference：
[1] Patent: US5214199, 1993, A,
8
[ 540-88-5 ]
[ 40052-13-9 ]
Reference：
[1] Journal of the American Chemical Society, 1946, vol. 68, p. 27
Reference：
[1] Journal of the American Chemical Society, 1944, vol. 66, p. 1038
11
[ 42726-73-8 ]
[ 40052-13-9 ]
Reference：
[1] Journal of Organic Chemistry, 1993, vol. 58, # 4, p. 879 - 886
12
[ 72594-86-6 ]
[ 40052-13-9 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 2, p. 369 - 372
13
[ 67-56-1 ]
[ 40052-13-9 ]
[ 42726-73-8 ]
Yield
Reaction Conditions
Operation in experiment
91%
at 20℃; for 48 h;
A 200 mL round-bottom flask equipped with a stirring bar was charged with compound 6 (3.0 g, 18.7 mmol) and methyl alcohol (70 mL). To the solution, hafnium(IV) chloride tetrahydrofuran complex (1:2) (88 mg, 0.19 mmol) was added. The reaction was allowed to stir for 2 days at room temperature. To the reaction mixture, brine was added and extracted with CH2Cl2 (3*), dried over MgSO4, and concentrated in vacuo. The remaining residue was purified by silica gel column chromatography (hexanes/AcOEt = 50:50) to afford the desired product 7 (3.0 g, 91percent) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 3.74 (s, 3H), 3.30 (s, 2H), 1.47 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 167.5, 165.8, 82.1, 52.3, 42.7, 27.9; HR-FAB MS calcd for C8H15O4 [M+H]+ 175.0883, found 175.0875.
A 200 mL round-bottom flask equipped with a stirring bar was charged with 2,2-dimethyl-1,3-dioxane-4,6-dione 5 (Meldrum's acid, 5.0 g, 34.7 mmol) and tert-butyl alcohol (40 mL). The reaction was allowed to stir for 6 h at reflux conditions. The reaction mixture was concentrated in vacuo to afford the desired product 6 (5.56 g, 100%) as a colorless oil. 1H NMR (400 MHz, CDCl3) delta 10.51 (br s, 1H), 3.35 (s, 2H), 1.42 (s, 9H); 13C NMR (100 MHz, CDCl3) delta 171.8, 166.3, 81.9, 42.1, 27.9; HR-FAB MS calcd for C7H13O4 [M+H]+ 161.0814, found 161.0809.
In toluene; for 5h;Reflux;
General procedure: The Meldrum?s acid (3.6g, 25mmol) was added into toluene (50ml), then added alcohol or phenol (25mmol). The mixture was heated and refluxed for 5 hrs. When the mixture was cooled to room temperature, added substituted benzaldehyde (10mmol), pyridine (2.5ml) and piperidine (0.25ml). The stirring continued at room temperature, using TLC to trace the reaction until the reaction completely finished. The solvents were distilled out in vacuum; the residue was dissolved in diethyl ether (about 30ml), washed with saturated solution of sodium bicarbonate two times (20ml×2), then diluted hydrochloride acid and distilled water, respectively. The ether phase was driedby anhydrous MgSO4 overnight. After removal of the drier, the solvent was distilled out to get crude solid. (If the crude product was oil, dissolved in dichloromethane (10ml) and then was subjected to chromatograph on a silica gel column (15 g), eluted with ethyl acetate and petroleum ether 1:15. The eluted fraction was distilled outto get crude product. ) The crude solid was recrystallized from a mixture of benzene and diethyl ether (8:2) to afford pure product.
In toluene; at 110℃;
General procedure: Step 1: As described in reference [1], a flame-dried round-bottom flask was charged with Meldrum?s acid [1.0 equiv (generally in 10 g scale)] and required alcohol (10.0 equiv). The reaction mixture was heated under refluxed at 110 C for 6-12 h. Upon completion of the reaction (judged by TLC analysis), the reaction mixture was cooled to room temperature. Then most of the volatile components were evaporated under reduced pressure. The crude malonic acid monoesters were directly used for coupling reaction without purification.
In toluene; at 100℃;
Meldrum?s acid (14.4 g, 0.1 mol, 1.0 eq) was dissolved in an appropriate amount of toluene, followed by adding tert-butyl alcohol (96 mL, 1.0 mol, 10.0 eq), and the mixture was heated to reflux. The reaction was monitored by TLC. The solvent was removed by evaporation in vacuo to get the intermediate 9, to which was added a catalytic amount of piperidine and pyridine, and then vanillin (18.3 g,0.12 mol, 1.2 eq) followed by refluxing for 10 h. The reaction mixture was diluted with ethyl acetate, washed with water, and the organic layer was dried over anhydrous Na2SO4. The crude product was purified by flash column chromatography using EtOAc/hexane (1/10, v/v) as eluent giving the title compound 10 as a white solid (78%).
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 24h;Inert atmosphere;
[00352] To a solution of mono-fert-butyl malonate (Oakwood Products, Inc., Estill, SC) (1.5 g, 9.2 mmol) and 1-octanol (1.6 mL, 10.1 mmol) in 20 mL dry DCM was added l-ethyl-3- (dimethylaminopropyl)carbodiimide hydrochloride (3.1 g, 13.8 mmol) followed by 4- (dimethylamino)pyridine (0.34 g, 2.7 mmol) and finally NN-diisopropylethylamine (4.8 mL, 27.5 mmol) with stirring under dry nitrogen to give a colorless solution. This was stirred at room temp, for 24 hours, after which LC/MS showed no starting acid remaining. The yellow solution was diluted with DCM, washed twice with a saturated aqueous sodium bicarbonate solution, twice with an aqueous 10% citric acid solution, dried (MgSCU), filtered and the filtrate cone, to a yellow oil which was purified by silica gel chromatography (0-15% EtOAc in hexanes) to give fert-butyl octyl malonate (1.86 g, 6.8 mmol, 74%) as a colorless liquid. NMR (300 MHz, CDCb) delta: ppm 4.11-4.06 (m, 4H); 3.41 (t, 2H, J= 6.7 Hz); 2.62 (s, 4H); 1.87 (quint., 2H, J = 7.2 Hz); 1.69-1.57 (m, 4H); 1.50-1.30 (m, 10H); 0.89 (t, 3H, J= 6.3 Hz).
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In acetonitrile; at 20℃; for 0.5h;Inert atmosphere;
[72] Malonic acid (5.0 g, 48 mmol) and /-BuOH (1.8 mL, 19 mmol) were dissolved in 150 mL of ACN at room temperature under nitrogen. EDC (9.2 g, 48 mmol) was added and the reaction conducted at room temperature under nitrogen for 30 min. ACN was removed under reduced pressure and the residue dissolved in 200 mL of ether. The product was back- extracted with two 50-mL portions of saturated NaHCCb, and the combined aqueous layer acidified to pH 2 with 1 N sodium bisulfate. Finally, the product was extracted with three 200-mL portions of DCM which were combined and washed with water, brine and dried over sodium sulfate. DCM was removed under reduced pressure and the product obtained as a white solid in 76% yield (2.3 g). [73] NMR (CDCh, 400 MHz): delta 3.28 (s, 2H), 1.42 (s, 9H); 13C NMR (CDCh, 100 MHz): delta 168.5, 162.1, 83.5, 39.7, 27.9, 27.8, 25.6.
51.98%
With pyridine; methanesulfonyl chloride; In tetrahydrofuran; at 0 - 20℃; for 2h;Inert atmosphere;
To a stirred solution of malonic acid (0.50g) in Dry THF (3 ml), Pyridine (lml) and tert-butanol (0.64g) was added at 0C under nitrogen gas atmosphere. Mesyl chloride (0.55g) was added in to reaction mixture at room temperature. The reaction was stirred for 2h at room temperature. The reaction was monitored by TLC (mobile phase: 5.0% MeOH/DCM) and LCMS. After completion of reaction, the reaction mixture was filtered off under vacuum filtration and the filtrate ML was diluted with l5ml chilled DM Water and then basified with 4N NaOH solution up to 11 pH. The aqueous layer was washed with DCM (2x 10ml). The aqueous layer was acidified with 33% HC1 solution in water. The product was extracted in to DCM (3 x20ml). The combined organic layer was washed with brine solution (2x l5ml) and then dried over anhydrous sodium sulphate and then it was concentrated under reduced pressure below 35C to isolate the crude 3-(tert-butoxy)-3-oxopropanoic acid (Int-A) (0.40g, 51.98%)
({4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylcarbamoyl}-methyl)-carbamic acid t-butylester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃; for 2h;
(1-5) Preparation of ({4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]- quinazolin-6-ylcarbamoyl}-methyl)-carbamic acid t-butylester297 mg of 1 -hydroxy lbenzotriazole and 959 mg of l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added to 664 mg of ^-buthoxycarbonylacetic acid dissolved in 10 ml of THF, and the solution was reacted at room temperature for 2 hours after adding 1 g of the compound obtained in (1-4). The reacted solution was washed with distilled water, dried over magnesium sulfate, filtered and distilled under a reduced pressure to obtain impure residue, and the resulting residue was subjected to column chromatography (column- silica gel 60 (Merck, 107719); eluent- methylene chloride : methanol = 20 : 1) to obtain the title compound (1.35 g, 97%).1H-NMR (CDCl3, 300MHz): delta 9.40 (br s, IH), 8.67 (s, IH), 8.34 (br s, IH), 8.02 (d, IH), 7.73 (m, 3H), 7.4 8(m, 2H), 7.35 (m, 2H), 7.15 (t, IH), 7.07 (d, IH), 5.63 (t, IH), 5.26 (s, 2H), 4.16 (d, 2H), 1.59 (s, 9H).
Surprisingly it was found that a fast purification of mono tert-butyl malonate via its ammonium salt is possible. This salt can be isolated with a yield of 86.7%. Treatment of this salt with hydrochloric acid affords pure (NMR) mono tert-butyl malonate with a yield of 94.3%.
94.3%
With hydrogenchloride; In diethyl ether; water; at 0℃; for 0.5h;
10. tert.-Butyl malonate (8); A mixture of 50 g of ammonium salt 7 and 300 ml of ether was cooled in ice bath, and 100 ml of ca. 9% HCI solution was slowly added. After 30 min organic layer was separated and washed with brine (3x100 ml). Ether solution was dried over Na2SO4 and evaporated. The residue was dried in high vacuum till constant pressure. Yield 42.6 g (94.3%). 1H NMR (CDCI3), delta (ppm): 1.49 (s, 9H, Me3), 3.36 (s, 2H, CH2) 11.59 (broad s, 1 H, COOH). 13C NMR (CDCI3), delta (ppm): 28.11 (Me), 42.32 (CH2), 83.12 (Me3C), 166.43 and 172.47 (COO). Anal. Calcd for C7H12O4: C, 52.49; H, 7.55. Found: C, 51.81 ; H, 7.35.
A suspension of 2-(tert-butoxycarbonyl)acetic acid (21 mg, 0.11 mmol), PyBOP (57 mg, 0.11 mmol), DIEA (38 muL, 0.22 mmol) in anhydrous CH2Cl2 (0.5 mL) EPO <DP n="111"/>was stirred at RT for 10 minutes. This solution of activated acid was added to a suspension of tert-butyl 5-(2-(3 -aminophenyl)quinazolin-4-ylamino)- 1 H-indazole- 1 - carboxylate (100 mg, 0.22 mmol) and anhydrous CH2Cl2 (1 mL). The reaction mixture was stirred at RT for 1 h. Activated and added another 0.5 equivalent of the acid as described above and stirred for 1 h. Activated and added another 0.3 equivalents of the acid as described above. Stirred for and additional hour and diluted with CH2Cl2. Extracted with H2O (3x) and the organic layer was dried under Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica (1:1 EtOAc :Hexanes) to give the desired product tert-butyl 5-(2-(3-(2-(tert- butoxycarbonyl)acetamido)phenyl)quinazolin-4-ylamino)-lH-indazole-l-carboxylate.( 123 mg, 0.20 mmol, 90%).
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;
Step 1. To a solution of <strong>[40052-13-9]mono-tert-butyl malonate</strong> (1.6 g, 10 mmol) in DMF (20 mL) was added cesium carbonate (3.42 g, 10.5 mmol) followed by allyl bromide (1.33 g, 11 mmol). The reaction was stirred at RT for 16 hours, diluted with EA and worked up with water and brine. The organic solution was dried over NaS04 and concentrated. The residue was purified by chromatography (silica gel eluted with EA- hexanes) to give compound malonic acid, monoallyl, mono-t-butyl ester (1.873 g, 93%).
Example 3; (4-methyl-5-methylsulfanyl-4H- [ l,2,4]triazol-3-yl)acetic acid f-butyl ester steps 1 & 2 - To a solution of tert-butyl hydrogen malonate (93.7 g, 585 mmol) inMeCN (1.6 L) was added l,l '-carbonyldiimidazole (93.9 g, 579 mmol) over 20 min at RT. After 1 h 4-methylthiosemicarbazide (92.3 g, 878 mmol) was added over ca. 20 min. After stirring for 1 h, the slurry was heated at reflux for 30 h and then cooled to RT. Concentration in vacuo while replacing with water afforded a slurry. After aging at 0 C, the product was filtered off, washed with water, and dried in vacuo at 50 C to afford 98.86 g (73.7%) of 24 which was recrystallized from EtOAc.
With N-ethyl-N,N-diisopropylamine; HATU;dmap; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 16h;
3-(Dimethylamino)-3-oxopropanoic acid. To a stirred solution of 3-tert-butoxy-3-oxopropanoic acid (680 mg, 4.25 mmol) and 2M dimethylamine in THF (3.18 mL, 6.37 mmol) in DMF (10 mL) was added diisopropyl-ethylamine (2.224 mL, 12.74 mmol), 4-(dimethylamino)pyridine (DMAP) (104 mg, 0.849 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (2421 mg, 6.37 mmol) and the resulting mixture was stirred at room temperature for 16 h. Water was then added and the resulting mixture was extracted with ethyl acetate (2×50 mL), washed with 1N HCl (20 mL), dried (Na2SO4), filtered and concentrated to give crude product which was dissolved in CH2Cl2 (5.00 mL), treated with trifluoroacetic acid (4.91 mL, 63.7 mmol) and stirred at room temperature for 16 h. The solvent was then removed under reduced pressure to afford the title compound (230 mg, 41% yield) as a light-yellow solid, which was used in the next step without further purification. 1H NMR (500 MHz, DMSO-d6) delta: 12.1 (1H, br s), 3.4 (2H, s), 2.9 (3H, s), 2.8 (3H, s). LCMS (M+H)=132.33.
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide;
78C. (Sytert-butyl 3-(4-(6~(l-(tert-butoxycarbonylamino)-2- phenylethyl)pyridazin-4-yI)phenylamino)-3-oxopropanoate: To a solution of 78B(58mg, 0.149 mmol) in DMF (5.0 mL) were added 3-/ert-butoxy-3-oxopropanoic acid (28.5 mg, 0.178 mmol), PyBOP (93 mg, 0.178 mmol) and DIEA (0.052 mL, 0.297 mmol). The reaction mixture was stirred over night. The reaction mixture was diluted with EtOAc, washed with IM HCl (1 x 5 mL), saturated NaHCO3 (1 x 5 mL) and brine (1 x 5 mL). The organic phase was dried over MgSOphi filtered and concentrated.Purification by normal phase chromatography gave 78C (70mg, 0.131 mmol, 88 % yield) as a solid. LC-MS (ESI) m/z: 533.1(M+H)+.
With triethylamine; dicyclohexyl-carbodiimide; In tetrahydrofuran; at 0 - 20℃;
General procedure: Step 2: In a flame-dried round-bottom flask, crude malonic acid monoester (1.0 mmol) was taken in THF (5 mL/mmol) and cooled to 0 C on an ice-bath. To this reaction mixture was added triethylamine (3 mmol). DCC (1.2 mmol) was then added to the mixture at same temperature. After 5 minutes of stirring at same temperature, a solution of N-methylaniline derivatives (1.0 mmol) in THF was added drop wise to the reaction mixture and slowly allowed to warm to rt. Then the stirring was continued untill TLC showed complete consumption of starting materials. The reaction mixture was then diluted with dichloromethane (approx. 40 mL) and then successively washed with water (20 mL), 2 N HCl (20 mL), saturated NaHCO3 (20 mL) and finally with brine (20 mL). The organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude mixture was purified through flash chromatography (hexanes/EtOAc mixture as eluent) to afford beta-N-arylamido esters.
A suspension of 2-(tert-butoycarbonyl)acetiotac acid (21 mg, 0 1 1 mmol), PyBOP" (57 mg, U I I mmol), UIhA (38 muL, U 22 mmol ) in anhydrous CH2CI2 (0 5 mL) was stirred at RT for 10 minutes This solution of activated acid was added to a suspension of tert-buryl 5-(2-(3-amtnophenyl)quinazolin-4-ylamino)-l H-indazole-l - carboxylate ( 100 mg, 0 22 mmol) and anhydrous CH2CI2 (I mL) The reaction mixture was stirred at RT for I h Activated and added another 0 5 equivalent of the acid as described above and stirred for 1 h Activated and added another 0 3 equivalents of the acid as desc?bed above Stirred for and additional hour and diluted with CH2CI2 Extracted with H2O (3x) and the organic layer was dried under Na2SO^ and concentrated /// vacuo The residue was purified by flash chromatography on silica (1 1 EtOAc Hexanes) to give the desired product tert-butyl 5-(2-(3-(2-(tert- butoxycarbonyl)acetamido)phenyl)quinazolin-4-ylamino)- 1H-indazole-l -carboxylate ( 123 mg, 0 20 mmol, 90%)
Methyl 4-[(3-tert-butoxy-3-oxopropanoyl)amino]butyrate (4). 5 g (42.68 mmol) of methyl 4-aminobutyrate hydrochloride, 6.41 g (40.02 mmol) of mono-tert-Butyl malonate and 4.17 g (41.3 mmol) of triethylamine were dissolved in IL Of CH2Cl2 and cooled to 00C. 10.99 g (53.3 mmol) of DCC were added and the mixture was stirred overnight letting the reaction reach room temperature. A few drops of acetic acid were added to precipitate all the N9N1- dicyclohexylurea and then the solution was filtered. The solvent was evaporated in vacuo to leave an impure yellow oil. For further purification, 50 mL of cyclohexane was added and left to rest for two hours in the refrigerator. The precipitate formed was filtered off, the solvent removed in vacuo and the remaining oil was flash chromatographed on silica gel using CH2Cl2 as eluent. The solvent was removed again in vacuo to give a clear oil as product. Yield 6.72 g (88 %). FT-IR (cm"1) upsilon 3293 (s, N-H stretch), 2935 (m, C-H), 2862 (s, C-H), 1732 (s, ester C=O), 1651 (s, amide C=O), 1552 (s, N-H bend), 1437 (m, CH2 bend), 1367 (s, CH3 bend), 1253 (s, C-N stretch), 1145 (d, ester C-O)-1H NMR (CDCl3) delta 1.47 (s, 9H), 1.85 (p, 2H), 2.36 (t, 2H), 3.22 (s, 2H), 3.31 (q, 2H), 3.68 (s, 3H). MALDI-TOF MS calcd. 259. 29. Found 259.07 [M + H+].
With triethylamine; HATU; In N,N-dimethyl-formamide; at 25℃; for 24h;
Step 2 To a solution of <strong>[40052-13-9]mono-tert-butyl malonate</strong> (0.034 mL, 0.222 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniu m hexafluorophosphate hexafluorophosphate salt (91.0 mg, 0.240 mmol) in dimethylformamide (2.0 mL), Compound I-148 (50.0 mg, 0.185 mmol) and triethylamine (0.051 mL, 0.370 mmol) were added. The solution was then stirred at 25C for 24 hours. The reaction solution was poured to water, and then extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, then dried with anhydrous magnesium sulfate, and concentrated in vacuo. The residue was then purified by silica gel chromatography (hexane/ethyl acetate = 1/1). The resulting powder was further washed with ethyl acetate and hexane to yield subject compound I-160 (35.6mg, 47%) as a white powder. 1H-NMR (DMSO-d6) delta12.41 (1H, s), 10.35 (1H, s), 8.29 (1H, d, J = 2.1 Hz), 7.61-7.63 (3H, m), 7.30-7.35 (2H, m), 7.05 (1H, d, J = 7.5 Hz), 4.29 (2H, t, J = 4.5 Hz), 3.97 (2H, t, J = 4.5 Hz), 3.38 (2H, s), 1.43 (9H, s) LC/MS (Method A): 2.15 min, [M+HH]+ = 413.5.
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1h;
Preparation 59: Synthesis of ' (2-[2-tert-butylmalonyl-Arg(Pbf)J '-aminoethylj-methyl-carbamic acid benzyl ester (F).A solution of compound E (21.1 g, -30.4 mmol), mono-te/ -butyl malonate (5.9 mL, 36.7 mmol), BOP (16.2 g, 36.7 mmol) and DIEA (14.9 mL, 83.5 mmol) in DMF (100 mL) was maintained at ambient temperature for 1 h. The reaction mixture was diluted with EtOAc (1 L) and extracted with water (500 mL), 5% aq. NaHC03 (500 mL), water (3 x 500 mL) and brine (500 mL). The organic layer was dried over MgS04, filtered, and then evaporated to provide compound F (24.5 g, 97%) as a yellowish amorphous solid. LC-MS [M+H] 759.6 (C37H54N6O9S +H, calc: 759.9). Compound F was used without further purification.
97%
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1h;
Preparation 59: Synthesis of ' (2-[2-tert-butylmalonyl-Arg(Pbf)J '-aminoethylj-methyl-carbamic acid benzyl ester (F).A solution of compound E (21.1 g, -30.4 mmol), mono-te/ -butyl malonate (5.9 mL, 36.7 mmol), BOP (16.2 g, 36.7 mmol) and DIEA (14.9 mL, 83.5 mmol) in DMF (100 mL) was maintained at ambient temperature for 1 h. The reaction mixture was diluted with EtOAc (1 L) and extracted with water (500 mL), 5% aq. NaHC03 (500 mL), water (3 x 500 mL) and brine (500 mL). The organic layer was dried over MgS04, filtered, and then evaporated to provide compound F (24.5 g, 97%) as a yellowish amorphous solid. LC-MS [M+H] 759.6 (C37H54N6O9S +H, calc: 759.9). Compound F was used without further purification
97%
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1h;
Preparation 26: Synthesis of ' (2-[2-tert-butylmalonyl-Arg(Pbf)J '-aminoethylj-methyl-carbamic acid benzyl ester (FF ).A solution of compound EE (21.1 g, -30.4 mmol), mono-te/t-butyl malonate (5.9 mL, 36.7 mmol), BOP (16.2 g, 36.7 mmol) and DIEA (14.9 mL, 83.5 mmol) in DMF (100 mL) was stirred at ambient temperature for 1 h. The reaction mixture was diluted with EtOAc (1 L) and extracted with water (500 mL), 5% aq. NaHC03 (500 mL), water (3 x 500 mL) and brine (500 mL). The organic layer was dried over MgS04, filtered and then evaporated to provide compound FF (24.5 g, 97%) as a yellowish amorphous solid. LC-MS [M+H] 759.6 (C37H54N6O9S +H, calc: 759.9). Compound FF was used without further purification.
97%
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1h;
Preparation of Compound IA solution of Compound H (21.1 g, 30.4 mmol), <strong>[40052-13-9]mono-tert-butyl malonate</strong> (5.9 mL, 36.7 mmol), BOP (16.2 g, 36.7 mmol) and DIEA (14.9 mL, 83.5 mmol) in DMF (100 mL) was maintained at ambient temperature for 1 h. The reaction mixture was diluted with EtOAc (1 L) and extracted with water (500 mL), 5% aq. NaHCO3 (500 mL), water (3×500 mL) and brine (500 mL). The organic layer was dried over MgSO4, filtered, and then evaporated to provide Compound I (24.5 g, 97%) as a yellowish amorphous solid. LC-MS [M+H] 759.6 (C37H54N6O9S+H, calc: 759.9). Compound I was used without further purification.
97%
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1h;
Preparation of Compound IA solution of Compound H (21.1 g, 30.4 mmol), <strong>[40052-13-9]mono-tert-butyl malonate</strong> (5.9 mL, 36.7 mmol), BOP (16.2 g, 36.7 mmol) and DIEA (14.9 mL, 83.5 mmol) in DMF (100 mL) was maintained at ambient temperature for 1 h. The reaction mixture was diluted with EtOAc (1 L) and extracted with water (500 mL), 5% aq. NaHCO3 (500 mL), water (3×500 mL) and brine (500 mL). The organic layer was dried over MgSO4, filtered, and then evaporated to provide Compound I (24.5 g, 97%) as a yellowish amorphous solid. LC-MS [M+H] 759.6 (C37H54N6O9S+H, calc: 759.9). Compound I was used without further purification.
97%
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1h;
Compound E (21.1 g, ca. 30.4 mmol) in DMF (100 mL),Malonate mono-tert-butyl (5.9 mL, 36.7 mmol),A solution of BOP (16.2 g, 36.7 mmol) and DIEA (14.9 mL, 83.5 mmol) was maintained at ambient temperature for 1 hour. The reaction mixture was diluted with EtOAc (1 L) and extracted with water (500 mL), 5% aqueous NaHCO 3 (500 mL), water (3 × 500 mL) and brine (500 mL). The organic layer was dried over MgSO 4, filtered and then evaporated to provide compound F (24.5 g, 97%) as a yellowish amorphous solid.
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1h;
Preparation 59 Synthesis of {2-[2-tert-butylmalonyl-Arg(Pbf)]-aminoethyl}-methyl-carbamic acid benzyl ester (F) A solution of compound E (21.1 g, ~30.4 mmol), <strong>[40052-13-9]mono-tert-butyl malonate</strong> (5.9 mL, 36.7 mmol), BOP (16.2 g, 36.7 mmol) and DIEA (14.9 mL, 83.5 mmol) in DMF (100 mL) was maintained at ambient temperature for 1 h. The reaction mixture was diluted with EtOAc (1 L) and extracted with water (500 mL), 5% aq. NaHCO3 (500 mL), water (3*500 mL) and brine (500 mL). The organic layer was dried over MgSO4, filtered, and then evaporated to provide compound F (24.5 g, 97%) as a yellowish amorphous solid. LC-MS [M+H] 759.6 (C37H54N6O9S+H, calc: 759.9).
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1h;
A solution of Compound H (21.1 g, 30.4 mmol), monotert-butyl malonate (5.9 mE, 36.7 mmol), BOP (16.2 g, 36.7 mmol) and DIEA (14.9 mE, 83.5 mmol) in DMF (100 mE) was maintained at ambient temperature for 1 h. The reaction mixture was diluted with EtOAc (1 E) and extracted with water (500 mE), 5% aq. NaHCO3 (500 mE), water (3x500 mE) and brine (500 mE). The organic layer was dried over MgSO4, filtered, and then evaporated to provide Compound I (24.5 g, 97%) as a yellowish amorphous solid. EC-MS [M+H] 759.6 (C37H54N509S+H, calc: 759.9). Compound I was used without thrther purification.
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 5 - 20℃; for 1.25h;
Preparation 70 Synthesis of N-((S)-1-{2-[(Dihydrocodein-6-enyloxycarbonyl)-methylamino]-ethylcarbamoyl-4-guanidino(Pbf))-butyl}-malonamic acid tert-butyl ester (H) To a cooled solution (~5 C.) of compound G (2.7 g, 3.0 mmol) was added mono tert-Butyl malonate (474 mg, 3.0 mmol, 438 muL) in DMF (25 mL) followed by BOP (1.4 g, 3.2 mmol) over 5 min and finally by DIEA (1.6 g, 12.1 mmol, 2.1 mL) drop wise over 10 min. After an additional 15 min, the ice bath was removed and the mixture stirred at ambient temperature. After 45 min, the reaction mixture was diluted with EtOAc (300 mL) and poured into water (200 mL). The layers were separated and the aqueous layer extracted with EtOAc (2*250 mL). The combined organic layers were washed with water (500 mL), 2% aq. H2SO4 (100 mL), water (3*500 mL) and brine (2*500 mL). After drying over MgSO4, the solvent was evaporated in vacuo and the residue dried under high vacuum to give H (1.7 g, 1.8 mmol, 58%) as a yellowish solid. LC-MS [M+H] 950.8 (C48H67N7O11S+H, calc: 951.2).
58%
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 5 - 20℃; for 1.58333h;
Preparation 70: Synthesis ofN-((S)-l-(2-[(Dihydrocodein-6-enyloxycarbonyl)-methylamino]- ethylcarbamoyl-4-guanidino(Pbf))-butyl}-malonamic acid tert-butyl ester (H)To a cooled solution (~5 C) of compound G (2.7 g, 3.0 mmol) was added mono tert- Butyl malonate (474 mg, 3.0 mmol, 438 mu.) in DMF (25 mL) followed by BOP (1.4 g, 3.2 mmol) over 5 min and finally by DIEA (1.6 g, 12.1 mmol, 2.1 mL) drop wise over 10 min. After an additional 15 min, the ice bath was removed and the mixture stirred at ambient temperature. After 45 min, the reaction mixture was diluted with EtOAc (300 mL) and poured into water (200 mL). The layers were separated and the aqueous layer extracted with EtOAc (2 x 250 mL). The combined organic layers were washed with water (500 mL), 2% aq. H2SO4 (100 mL), water (3 x 500 mL) and brine (2 x 500 mL). After drying over MgS04, the solvent was evaporated in vacuo and the residue dried under high vacuum to give H (1.7 g, 1.8 mmol, 58%) as a yellowish solid. LC-MS [M+H] 950.8 (C48H67N70iiS +H, calc: 951.2). Compound H was used without further purification.
58%
Preparation 70: Synthesis ofN-((S)-l-(2-[(Dihydrocodein-6-enyloxycarbonyl)-methylamino]- ethylcarbamoyl-4-guanidino(Pbf))-butyl}-malonamic acid tert-butyl ester (H)To a cooled solution (~5 C) of compound G (2.7 g, 3.0 mmol) was added mono tert- Butyl malonate (474 mg, 3.0 mmol, 438 mu.) in DMF (25 mL) followed by BOP (1.4 g, 3.2 mmol) over 5 min and finally by DIEA (1.6 g, 12.1 mmol, 2.1 mL) drop wise over 10 min. After an additional 15 min, the ice bath was removed and the mixture stirred at ambient temperature. After 45 min, the reaction mixture was diluted with EtOAc (300 mL) and poured into water (200 mL). The layers were separated and the aqueous layer extracted with EtOAc (2 x 250 mL). The combined organic layers were washed with water (500 mL), 2% aq. H2SO4 (100 mL), water (3 x 500 mL) and brine (2 x 500 mL). After drying over MgS04, the solvent was evaporated in vacuo and the residue dried under high vacuum to give H (1.7 g, 1.8 mmol, 58%) as a yellowish solid. LC-MS [M+H] 950.8 (C48H67N70iiS +H, calc: 951.2). Compound H was used without further purification
58%
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1.25h;Cooling with ice;
Compound G (2.7 g, 3.0 mmol)(474 mg, 3.0 mmol, 438 muL) malonate mono-tert-butyl in DMF (25 mL) was added followed by BOP (1.4 g, 3.2 mmol) for 5 min , And finally DIEA (1.6 g, 12.1 mmol, 2.1 mL) was added dropwise over 10 minutes. After an additional 15 minutes the ice bath was removed and the mixture was stirred at ambient temperature. After 45 minutes, the reaction mixture was added toDiluted with EtOAc (300 mL) and poured into water (200 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2 × 250 mL). The combined organic layers were washed with water (500 mL), 2% aqueous H 2 SO 4 (100 mL), water (3 × 500 mL) and brine (2 × 500 mL). After drying over MgSO 4, the solvent was evaporated under reduced pressure and the residue was dried under high vacuum to give H (1.7 g, 1.8 mmol, 58%) as a yellowish solid
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 5 - 20℃; for 1.25h;
Preparation of Compound CTo a cooled solution (5 C) of compound B (11.9 g, 19.0 mmol) and mono tert-butyl malonate (3.2 g, 20.0 mmol) in DMF (70 mL) was added portion wise, BOP (9.0 g, 20.3 mmol) over 5 min. This step was then followed by drop wise addition of DIEA (13.3 mL, 76.0 mmol) over 15 min. Stirring was continued for an additional 15 min, after which the ice bath was removed and the mixture warmed to ambient temperature. After 30 min at ambient temperature, the reaction mixture was diluted with EtOAc (600 mL) and poured into water (600 mL). The layers were separated and the aqueous layer extracted with EtOAc (2 x 300 mL). The combined organic layers were washed with 2% aq. HiS04 (150 mL), water (2 x 450 mL) and brine (400 mL), followed by drying over MgS04, filtration, and finally the solvent was evaporated in vacuo. The resulting residue was dried in vacuo to give compound C in 93% yield (12.1 g, 17.6 mmol) Atty Dkt: PFOR-0801WO as a yellowish foamy solid. LC-MS [M+H] 686.5 (C35H51N5O7S +H, calc: 685.9). Compound C was used without further purification.
93%
With benzotriazole-1-yl-oxy-tris-(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 5 - 20℃; for 1.08333h;
of Compound CTo a cooled solution (5 C) of compound B (11.9 g, 19.0 mmol) and mono tert-butyl malonate (3.2 g, 20.0 mmol) in DMF (70 mL) was added portion wise, BOP (9.0 g, 20.3 mmol) over 5 min. This step was then followed by drop wise addition of DIEA (13.3 mL, 76.0 mmol) over 15 min. Stirring was continued for an additional 15 min, after which the ice bath was removed and the mixture warmed to ambient temperature. After 30 min at ambient temperature, the reaction mixture was diluted with EtOAc (600 mL) and poured into water (600 mL). The layers were separated and the aqueous layer extracted with EtOAc (2 x 300 mL). The combined organic layers were washed with 2% aq. H2S04 (150 mL), water (2 x 450 mL) and brine (400 mL), followed by drying over MgS04, filtration, and finally the solvent was evaporated in vacuo. The resulting residue was dried in vacuo to give compound C in 93% yield (12.1 g, 17.6 mmol) as a yellowish foamy solid. LC-MS [M+H] 686.5 (C35H51N5O7S +H, calc: 685.9). Compound C was used without further purification.
In flask No.1, a solution of 12.23 g (67.22 mmol) of 3-(methoxycarbonyl)pyrazine-2-carboxylic acid (Compound 6) in 88 mL of DMF was treated slowly with 12.53 g (77.28 mmol) of CDI. The reaction mixture was stirred at ambient temperature for 2 hours.[00145] In a separate flask, flask No.2, to 147 mL of DMF cooled to 0 C was added portionwise 8.32 g (87.39 mmol) of MgCl2. After stirring at 0 C for 5 minutes, 13.5 mL (87.39 mmol) of <strong>[40052-13-9]mono-tert-butyl malonate</strong> and 37.4 mL (269 mmol) of triethylamine was added and the resulting reaction mixture stirred at ambient temperature for 2 hours. After 2 hours, the content of flask No.1 was added to flask No.2 and the combined reaction mixture stirred at ambient temperature overnight. Subsequently, the reaction mixture was poured into aqueous 1.0 M HC1 cooled to 0 C and stirred for 15 minutes. To the mixture was added Et20, the layers separated, and the ethereal layer washed sequentially with water (lx), saturated aqueous NaHC03 (lx), water (lx) and brine (lx). The organic organic layer was dried over Na2S04, filtered and concentrated in vacuo to yield crude methyl 3-(3-(tert- butoxy)-3-oxopropanoyl)pyrazine-2-carboxylate (Compound 7) that was used without further purification.
Example 292-Hydroxy-N,N,N-trimethylethanaminium 3-(2-{4-[2-amino-6-([2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}thio)-3,5-dicyanopyridin-4-yl]phenoxy}ethoxy) 3-oxopropanoate Step a):1 g (1.92 mmol) of 2-amino-6-([2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}thio)-4-[4-(2-hydroxy-ethoxy)phenyl]pyridine-3,5-dicarbonitrile, 0.389 g (2.12 mmol) of <strong>[40052-13-9]mono-tert-butyl malonate</strong>, 0.442 g (2.31 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.023 g (0.19 mmol) of 4-dimethylaminopyridine are combined in 40 ml of dichloromethane and 10 ml of DMF and stirred at room temperature overnight. The reaction mixture is then poured into a mixture of semisaturated ammonium chloride solution and dichloromethane. The organic phase is separated off, washed successively with water, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue is dissolved in dichloromethane, reprecipitated with petroleum ether, filtered off with suction and then purified by flash chromatography on silica gel using the mobile phase dichloromethane/ethyl acetate (gradient 10:1?7:1?5:1). The appropriate fractions are combined, and the solvent is removed under reduced pressure. After the residue has been dried under high vacuum, 0.916 g (72% of theory) of the protected intermediate remain.LC-MS (Method 10): Rt=3.24 min; MS (ESIpos): m/z=662 (M+H)+.
2-Amino-5-({amino-[(E)-2,2,4,6,7-pentamethyl-2,3-dihydro-benzofuran-5-sulfonylimino]-methyl}-amino)-pentanoic acid ((R)-1-methyl-2-phenyl-ethyl)-amide[ No CAS ]
[ 19023-94-0 ]
N-[4-({Amino-[(E)-2,2,4,6,7-pentamethyl-2,3-dihydro-benzofuran-4-sulfonylimino]-methyl}-amino-1-((R)-1-methyl-2-phenyl-ethylcarbamoyl)-butyl]-malonamic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With DIEA; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; In N,N-dimethyl-formamide;
Preparation 3 Synthesis of N-[4-({Amino-[(E)-2,2,4,6,7-pentamethyl-2,3-dihydro-benzofuran-4-sulfonylimino]-methyl}-amino-1-((R)-1-methyl-2-phenyl-ethylcarbamoyl)-butyl]-malonamic acid tert-butyl ester (C) To a cooled solution (~5 C.) of compound B (11.9 g, 19 mmol) and mono tert-butyl malonate (3.2 g, 20.0 mmol) in DMF (70 mL) was added portion wise, BOP (9.0 g, 20.3 mmol) over 5 min, followed by DIEA (13.3 mL, 76 mmol) drop wise over 15 min. After an additional 15 min, the ice bath was removed and the mixture warmed to ambient temperature. After 30 min, the reaction mixture was diluted with EtOAc (600 mL) and poured into water (600 mL). The layers were separated and the aqueous layer extracted with EtOAc (2*300 mL). The combined organic layers were washed with 2% aq. H2SO4 (150 mL), water (2*450 mL) and brine (400 mL). After drying (over MgSO4) the solvent was evaporated in vacuo and the residue dried under high vacuum to give compound C (12.1 g, 17.6 mmol, 93%) as a yellowish foamy solid. LC-MS [M+H] 686.5 (C35H51N5O7S+H, calc: 685.9).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 14h;Inert atmosphere;
To a solution of Compound 4 (4.5 g, 16 mmol) in anhydrous dimethylformamide (45 ml) were successively added 3-tert-butoxy-3-oxopropanoic acid (3.34 g, 20.83 mmol), WSCD-HCl (6.14 g, 32.0 mmol) and HOBt (2.81 g, 20.83 mmol) under nitrogen atmosphere at room temperature, then the reaction mixture was stirred for 14 hours. To the reaction solution were added 0.1M hydrochloric acid and ethyl acetate, then the reaction solution was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. To the residue was added ethyl acetate/hexane, then the insoluble residue was collected by filtration to give Compound 5 (3.2 g, 47%).Compound 5; 1H-NMR (DMSO-d6) delta: 1.41 (s, 9H), 3.21 (s, 2H), 4.15 (s, 2H), 7.39 (t, J=6.9 Hz, 1H), 7.50 (t, J=7.5 Hz, 2H), 7.74-7.82 (m, 3H), 8.02 (d, J=8.4 Hz, 1H), 8.39 (s, 1H), 10.41 (br s, 1H).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 14h;Inert atmosphere;
To a solution of Compound 12 (1.1 g, 3.93 mmol) in anhydrous dimethylformamide (12 ml) were successively added 3-tert-butoxy-3-oxopropanoic acid (0.76 g, 4.71 mmol), WSCD HCl (0.90 g, 4.71 mmol), HOBt (0.11 g, 0.79 mmol) and triethylamine (1.36 ml, 9.82 mmol) under nitrogen atmosphere at room temperature, then the reaction mixture was stirred for 14 hours. To the reaction solution was added 1N hydrochloric acid, then the reaction solution was extracted with ethyl acetate. The extraction was washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure. The residue was crystallized with diethylether, then the obtained crystal was collected by filtration to give Compound 13 (1.2 g, 72%).Compound 13; 1H-NMR (DMSO-d6) delta: 1.40 (s, 9H), 3.17 (s, 2H), 3.88 (s, 2H), 7.60 (d, J=8.4 Hz, 1H), 7.85-7.90 (m, 2H), 8.26 (s, 1H), 8.31 (d, J=8.4 Hz, 1H), 10.26 (br-s, 1H)
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 3h;Inert atmosphere;
To a solution of Compound (G-6) (60.6 g, 199 mmol) in anhydrous dimethylformamide (500 ml) were successively added 3-tert-butoxy-3-oxopropanoic acid (46.1 ml, 299 mmol), WSCD HCl (57.3 g, 299 mmol), HOBt (13.5 g, 100 mmol) and triethylamine (55.3 ml, 399 mmol) under nitrogen atmosphere at room temperature, then the reaction mixture was stirred for 3 hours. To the reaction solution was added water, then the reaction solution was extracted with ethyl acetate. The extraction was washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure. The obtained residue was crystallized with diisopropyl ether, then the obtained crystal was collected by filtration to give Compound (G-7) (80.6 g, 91%).Compound (G-7);1H-NMR (DMSO-d6) delta: 1.40 (s, 9H), 3.21 (s, 2H), 4.22 (s, 2H), 7.80-7.82 (m, 2H), 10.42 (br-s, 2H).
With ammonium acetate; acetic acid; In methanol; at 60℃; for 64h;
4.1.2 (+-)-Benzyl-(1'-amino)-tert-butyl-4-propanoyl-benzoate 9 Acetic acid (25 mL) was added to a mixture of methyl 4-formylbenzoate 7 (9.57 g, 58.3 mmol), ammonium acetate (89.9 g, 1170 mmol), <strong>[40052-13-9]mono-tert-butyl malonate</strong> 8 21 (18.7 g, 117 mmol), and methanol (120 mL) and the mixture heated to 60 C for 64 h. The methanol was evaporated and the residue partitioned between EtOAc and satd NaHCO3. The organic phase was extracted with 1 M aq citric acid (*3). The aqueous phase was made basic to approximately pH 9 with NaHCO3 and extracted with EtOAc (*3). The combined extracts were washed with brine, dried (MgSO4), and evaporated to give 9 (10.4 g, 64%) as a pale-yellow syrup, which crystallized on standing, mp 63-5 C; numax 2978, 1716, 1611, 1436 cm-1; deltaH 8.02 (d, J=8.3 Hz, 2H), 7.46 (d, J=8.3 Hz, 2H), 4.45 (t, J=6.8 Hz, 1H), 3.93 (s, 3H), 2.61 (d, J=6.8 Hz, 2H), 1.43 (s, 9H); deltaC 170.9, 166.8, 149.8, 129.8, 129.1, 126.3, 80.9, 52.5, 52.0, 45.0, 28.0; m/z (ES) 581 (8%, [2M]Na+), 302 (100); HRMS (ES): [2M]Na+, found 581.2834. C30H42N2NaO8 requires 581.2839.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 3h;Inert atmosphere;
To a solution of Compound (G-12) (4.5 g, 14.2 mmol) in anhydrous dimethylformamide (10 ml) were successively added 3-tert-butoxy-3-oxopropanoic acid (2.96 g, 18.5 mmol), WSCD-HCl (3.55 g, 18.5 mmol), HOBt (580 mg, 4.27 mmol) and triethylamine (2.96 ml, 21.4 mmol) under nitrogen atmosphere at room temperature, then the reaction mixture was stirred for 3 hours. To the reaction solution was added water, then the reaction solution was extracted with ethyl acetate. The extraction was washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure. The obtained crystal was collected by filtration to give Compound (G-13) (6.0 g, 92%).Compound (G-13);Method C: Rt=1.81 min, 459.85 (ES+)
tert-butyl 2-[(10R,14S)-14-[1-(3-chloro-2-fiuorophenyl)-5-methyl-1H-1,2,3-triazole-4-amido]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamoyl}acetate trifluoroacetic acid salt[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 55℃;
[00605] Example 146. tert-Butyl 2-[(10R,14S)-14-[l-(3-chloro-2-fiuorophenyl)-5- methyl- 1 H- 1 ,2,3-triazole-4-amido]- 10-methyl-9-oxo-8, 16- diazatricyclo[13.3.1.02'7]nonadeca-l(19),2(7),3,5,15,17-hexaen-5-yl]carbamoyl}acetate, TFA salt: To a solution of Example 89 (0.02 g, 0.026 mmol) in DMF (1 mL) was added 3-(tert-butoxy)-3-oxopropanoic acid (0.012 g, 0.077 mmol), EDC (9.88 mg, 0.052 mmol), HOBT (7.89 mg, 0.052 mmol), and DIPEA (0.023 mL, 0.129 mmol). The reaction was stirred at rt overnight and at 55 C for 2 h. The mixture was cooled to rt and concentrated. The residue was purified by reverse phase to yield the desired product (12 mg, 57%) as a white solid. 1H NMR (500 MHz, MeOD) delta 8.76 (d, J = 6.1 Hz, 1H), 8.25 (d, J = 1.7 Hz, 1H), 7.93 (dd, J = 6.1, 1.9 Hz, 1H), 7.81 (ddd, J = 8.3, 6.8, 1.7 Hz, 1H), 7.76 (d, J = 1.9 Hz, 1H), 7.69 (d, J = 8.3 Hz, 1H), 7.62 (dd, J = 8.4, 2.1 Hz, 1H), 7.56 (ddd, J = 8.1, 6.5, 1.7 Hz, 1H), 7.46 (td, J = 8.1, 1.4 Hz, 1H), 5.37 (dd, J = 11.3, 6.1 Hz, 1H), 3.43 (s, 2H), 2.82 - 2.74 (m, 1H), 2.43 (d, J = 0.8 Hz, 3H), 2.30 - 2.20 (m, 1H), 2.08 - 1.90 (m, 2H), 1.68 - 1.43 (m, 11H), 0.97 (d, J = 6.9 Hz, 3H), 0.56 - 0.45 (m, 1H) ppm. MS(ESI) m/z: 690.3 (M+H)+. Analytical HPLC RT = 7.03 min (Method A).
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide[ No CAS ]
[ 1428847-06-6 ]
Yield
Reaction Conditions
Operation in experiment
84%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;
A mixture of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (1 g, 2.380 mmol), 3-tert-butoxy-3-oxopropanoic acid (0.457 g, 2.86 mmol), EDC (1.369 g, 7.14 mmol), and DMAP (0.291 g, 2.380 mmol) in DCM (50 ml) was stirred at RT overnight. The reaction mixture was washed with HCl 1N, NaHCO3 5% and brine. The organic layer was dried over Na2SO4 and evaporated to dryness. The crude was purified by flash chromatography on silica gel column (DCM:EtOAc=40:60) affording (S)-4-(2-(3-tert-butoxy-3-oxopropanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (1.1303 g, 2.010 mmol, 84% yield, MS/ESI+ 562.0 [MH]+)
84%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;
A mixture of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4- (difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (1 g, 2.380 mmol), 3-tert-butoxy-3-oxopropanoic acid (0.457 g, 2.86 mmol), EDC (1.369 g, 7.14 mmol) and DMAP (0.291 g, 2.380 mmol) in DCM (50 ml) was stirred at RT overnight. The reaction mixture was washed with HC1 IN, NaHC03 5% and brine. The organic layer was dried over Na2S04 and evaporated to dryness. The crude was purified by flash chromatography on silica gel column (DCM : EtOAc = 40 : 60) affording (S)-4-(2-(3-tert-butoxy-3-oxopropanoyloxy)-2-(3-(cyclopropylmethoxy)-4- (difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (1.1303 g, 2.010 mmol, 84% yield, MS/ESI+ 562.0 [MH] +).
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In N,N-dimethyl-formamide; acetonitrile; at 0℃; for 24h;
To tert-butyl 4-aminophenylcarbamate (2.60 g, 12.49 mmol) and 3-tert- butoxy-3-oxopropanoic acid (2 g, 12.49 mmol) in EtOAc (100 mL), cooled to 0 C, was added TEA (5.22 mL, 37.5 mmol) and a 50 % solution of T3P in DMF (6.00 mL, 21.23 mmol). After 24 h, the reaction was partitioned with dilute HC1 (15 mL) and EtOAc (75 mL). The organic layer was washed with brine (15 mL) and dried (MgS04). Purified by silica gel chromatography to afford 3.3 g (75%). MS (ESI) m/z: 351 (M+H)+.
Decanoic acid 1 (700 mg, 4.06 mrnol) was added to a round- bottom flask and dissolved in THF (5.0 mL) under nitrogen atmosphere at 25 C. CDI (725 mg, 4.47 mmol) was then added and the resulting mixture was stirred at 25 C for 4 h. In a second round-bottom flask, t-butyl malonate (716 mg, 4.47 mmol) was dissolved in THF (4.0 mL) under nitrogen atmosphere at 25 C. The flask was cooled to 0 C and isopropyl magnesium chloride (4.5 mL, 2.0 M in THF, 8.93 mmol) was then added dropwi.se. The resulting mixture was stirred at 0 C for 30 min and then warmed to 50 C for 30 min. After cooling to 0 C, the decanoic acid solution was added via cannula and stirred from 0 C-25 C overnight. The reaction was then quenched with 1 M HC1 (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phases were washed with brine, dried with Na2S04 and concentrated in vacuo. The resulting residue was purified by flash column chromatography (98:2 hexanes in EtOAc) to obtain 3 (950 mg, 86% yield). The characterization data for 3 matched that previously reported.1'4 1H NMR (400 MHz, CDC13, 25 C): delta = 3.31 (s, 2H), 2.48 (t, 2H, J= 7.2 Hz), 1.56-1.53 (m, 2H), 1.44 (s, 9H), 1.21-1.18 (m, 12H), 0.85 (t, 3H, J = 6.8 Hz).
N-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)malonamide tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In tetrahydrofuran; N,N-dimethyl-formamide; at 0 - 20℃; for 16h;pH 8.0;Molecular sieve;
General procedure: The peracetylated glycosylamin 10a-d (1 eq) was dissolved in dry THF. The solutionwas cooled to 0C and molecular sieve 3 A was added. Afterwards a solution ofmono-tert-butyl-malonate (1.1 eq) and HBTU (1.1 eq) in dry DMF was added.Immediately the pH was adjusted to pH 8 by adding NEt3 and the resulting mixturewas stirred at 0C for 1 h. Thereafter the solution was stirred at r.t. for 15 h. Theslurry was filtered and the solvent was removed under reduced pressure. The residuewas dissolved in ethyl acetate and transferred into a separatory funnel. The organiclayer was acidified with 10 % citric acid-soln., washed with sat. NaHCO3-soln., sat.NaCl-soln., dried over Na2SO4 and the solvent was evaporated. Purification of theresidue via column chromatography afforded pure title compound 11a-d as whitesolid.
N-(2,3,4,6-tetra-O-acetyl-β-D-galctopyranosyl)malonamide tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In tetrahydrofuran; N,N-dimethyl-formamide; at 0 - 20℃; for 16h;pH 8.0;Molecular sieve;
General procedure: The peracetylated glycosylamin 10a-d (1 eq) was dissolved in dry THF. The solutionwas cooled to 0C and molecular sieve 3 A was added. Afterwards a solution ofmono-tert-butyl-malonate (1.1 eq) and HBTU (1.1 eq) in dry DMF was added.Immediately the pH was adjusted to pH 8 by adding NEt3 and the resulting mixturewas stirred at 0C for 1 h. Thereafter the solution was stirred at r.t. for 15 h. Theslurry was filtered and the solvent was removed under reduced pressure. The residuewas dissolved in ethyl acetate and transferred into a separatory funnel. The organiclayer was acidified with 10 % citric acid-soln., washed with sat. NaHCO3-soln., sat.NaCl-soln., dried over Na2SO4 and the solvent was evaporated. Purification of theresidue via column chromatography afforded pure title compound 11a-d as whitesolid.
N-(2-acetamido-2-deoxy-3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)malonamide tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In tetrahydrofuran; N,N-dimethyl-formamide; at 0 - 20℃; for 16h;pH 8.0;Molecular sieve;
General procedure: The peracetylated glycosylamin 10a-d (1 eq) was dissolved in dry THF. The solutionwas cooled to 0C and molecular sieve 3 A was added. Afterwards a solution ofmono-tert-butyl-malonate (1.1 eq) and HBTU (1.1 eq) in dry DMF was added.Immediately the pH was adjusted to pH 8 by adding NEt3 and the resulting mixturewas stirred at 0C for 1 h. Thereafter the solution was stirred at r.t. for 15 h. Theslurry was filtered and the solvent was removed under reduced pressure. The residuewas dissolved in ethyl acetate and transferred into a separatory funnel. The organiclayer was acidified with 10 % citric acid-soln., washed with sat. NaHCO3-soln., sat.NaCl-soln., dried over Na2SO4 and the solvent was evaporated. Purification of theresidue via column chromatography afforded pure title compound 11a-d as whitesolid.
N-(2-acetamido-2-deoxy-3,4,6-tetra-O-acetyl-β-D-galactopyranosyl)malonamide tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In tetrahydrofuran; N,N-dimethyl-formamide; at 0 - 20℃; for 16h;pH 8.0;Molecular sieve;
General procedure: The peracetylated glycosylamin 10a-d (1 eq) was dissolved in dry THF. The solutionwas cooled to 0C and molecular sieve 3 A was added. Afterwards a solution ofmono-tert-butyl-malonate (1.1 eq) and HBTU (1.1 eq) in dry DMF was added.Immediately the pH was adjusted to pH 8 by adding NEt3 and the resulting mixturewas stirred at 0C for 1 h. Thereafter the solution was stirred at r.t. for 15 h. Theslurry was filtered and the solvent was removed under reduced pressure. The residuewas dissolved in ethyl acetate and transferred into a separatory funnel. The organiclayer was acidified with 10 % citric acid-soln., washed with sat. NaHCO3-soln., sat.NaCl-soln., dried over Na2SO4 and the solvent was evaporated. Purification of theresidue via column chromatography afforded pure title compound 11a-d as whitesolid.
Stage #1: mono-tert-butyl malonate; N-(2-fluoro-4-cyanophenyl)methanesulfonamide With dimethyl sulfide borane In tetrahydrofuran for 3h; Reflux;
Stage #2: With hydrogenchloride In tetrahydrofuran; water for 15h; Reflux;
With hafnium(IV) chloride tetrahydrofuran complex; at 20℃; for 48h;
A 200 mL round-bottom flask equipped with a stirring bar was charged with compound 6 (3.0 g, 18.7 mmol) and methyl alcohol (70 mL). To the solution, hafnium(IV) chloride tetrahydrofuran complex (1:2) (88 mg, 0.19 mmol) was added. The reaction was allowed to stir for 2 days at room temperature. To the reaction mixture, brine was added and extracted with CH2Cl2 (3*), dried over MgSO4, and concentrated in vacuo. The remaining residue was purified by silica gel column chromatography (hexanes/AcOEt = 50:50) to afford the desired product 7 (3.0 g, 91percent) as a colorless oil. 1H NMR (400 MHz, CDCl3) delta 3.74 (s, 3H), 3.30 (s, 2H), 1.47 (s, 9H); 13C NMR (100 MHz, CDCl3) delta 167.5, 165.8, 82.1, 52.3, 42.7, 27.9; HR-FAB MS calcd for C8H15O4 [M+H]+ 175.0883, found 175.0875.
Stage #1: 4-(4-isopropylphenyl)-4-oxobutanoic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 1h;
Stage #2: mono-tert-butyl malonate With isopropylmagnesium bromide In tetrahydrofuran at 0 - 20℃; for 4h;
Stage #1: 4-(2,5-dimethylphenyl)-4-oxobutanoic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 1h;
Stage #2: mono-tert-butyl malonate With isopropylmagnesium bromide In tetrahydrofuran at 0 - 20℃; for 4h;
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 5 - 20℃; for 1h;
Preparation of Compound ZTo a solution of CompoundY (0.75 g, 0.89 mmol), monotert-Butyl Malonate (0.13 mE, 1.08 mmol), and DIEA (0.46 mE, 2.7 mmol) in DMF (15 mE) at 5 C. was added BOP (0.39 g, 1.08 mmol) in portions. The reaction mixture was stirred at ambient temperature for 1 h. DMF was removed under vacuum, and the residue was diluted with EtOAc (100 mE), and washed with water (2x50 mE) and brine (25 mE). The organic layer was dried over Na2SO4 and filtered; theremoval of the solvents afforded Compound Z in quantitative yield (1.2 g, 0.89 mmol) as an oil. EC-MS [M+H] 912.8 (C47H73N709S+H, calc: 912.5). Compound Z was used directly in the next reaction without further purification.
tert-butyl (4S)-4-methoxy-3-oxo-pentanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
tert-Butyl (4S)-4-methoxy-3-oxo-pentanoate (15): CDI (4.39 g, 27.1 mmol) was added to a solution of (2S)-2-methoxypropanoic acid (2.56 g, 24.6 mmol) in THF (100 mL) at 0 C and the reaction mixture was stirred at room temperature for 3 hours. In a separate flask, isopropylmagnesium chloride (2 M in THF, 37 mL, 74 mmol) was added dropwise to a solution of 3-(ie/t-butoxy)-3-oxopropanoic acid (5.91 g, 37 mmol) in THF (100 mL) at 0 C, the reaction mixture was stirred at room temperature for 3 hours and this solution was added dropwise to the acyl imidazole solution at 0 C with stirring The resulting mixture was allowed to warm to room temperature and stirred overnight, then quenched with 10% aqueous citric acid (100 mL). The aqueous layer was extracted with EtOAc (3 x 100 mL) and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica chromatography (hexane: EtOAc= 30: 1) to give the title compound (3.90 g, 78%). 1H NMR (400 MHz, CDC13): delta 3.83 (q, 1H), 3.54 (2d, 2H), 3.46 (s, 3H), 1.47 (s, 9H), 1.31 (d, 3H).
60%
N,N'-carbonyldiimidazole (17.0 g, 105 mmol) was added 0 'C to a solution of (S)-2- methoxypropanoic acid (10.0 g, 96.1 mmol) in THF (200 mL) and the mixture was stirred at rt for 3 h. In a separate flask, 2M isopropyl magnesium chloride in THF (140 mL, 280 mmol) was added dropwise at 0 C to a solution of 3-(tert-butoxy)-3-oxopropanoic acid (23.0 g, 143 mmol) in THF (200 mL) and the reaction mixture was stirred for 3h rt. This second solution was added drop wise to the first solution at 0 C and the resulting mixture was stirred at rt for 1 h. The reaction was monitored by TLC and when deemed completed it was quenched with 10% aqueous citric acid solution (100 mL). The mixture was diluted with water (250 mL) and the aqueous layer was extracted with EtOAc (2 x 500 ml). The combined organic layers were washed with saturated sodium bicarbonate solution (200 mL), dried over sodium sulphate filtered and concentrated under reduced pressure. The obtained crude material was purified by column (100-200 silica gel) eluted with 0 - 10%EtOAc in p.ether. Fractions containing the pure compound was concentrated which gave the title compound as a liquid (13.2 g, 60%). MS (ES+) 201 .1 1 [M+H]+.
50%
Solution 1 : N,N'-carbonyldiimidazole (17.0 g, 104.84 mmol) was added at 0 C to a stirred solution of (S)-2-methoxypropanoic acid (10 g, 96.1 mmol) in THF (200 mL) and the mixture was stirred at rt for 3 h. Solution 2: 2M isopropyl magnesium chloride in THF (140 mL, 280 mmol) was added dropwise at 0 C to a solution of 3-tert-butoxy-3-oxopropanoic acid (15 g, 93.6 mmol) in THF (200 mL) and the reaction mixture was stirred for 3 h at rt. Solution 2 was then added drop wise at 0 C to solution 1 and the resulting mixture was stirred at rt for 1 h. The reaction was quenched by addition of 10% aqueous citric acid solution (50 mL) and the mixture was diluted with water (100 mL). The aqueous layer was extracted with EtOAc (2 x 200 ml). The organic layer was washed with saturated sodium bicarbonate solution (100 mL), dried (Na2S04), filtered and concentrated under reduced pressure which gave the title compound (25 g, 57%). LCMS (ES+) m/z 203.3 [M+H]+.
To a soution of (S)-2-methoxypropanoic acid (10.0 g, 96 mmo) in THF (200 m) at 0 C was added CD (17.13 g, 106 mmo) and the reaction mixture was stirred at RT for 3h. n a separate flask, to a so?ution of 3-(tert-butoxy)-3-oxopropanoic acid (22.2 m, 144 mmo) in THF (200 m) at 0 C was added dropwise 2M isopropymagnesium choride in THF (139 m, 279 mmo) and the reaction mixture was stirred for 3h at 20 C. Then, this so?ution was added dropwise to the acy imidazoe so?ution at 0 C and the resuting mixture was stirred for lh at RT. The reaction mixture was quenched with 10% aqueouscitric acid (25 rn), extracted wth AcOEt, washed with aqueous saturated NaHCO3, dried over Na2SO4, fHtered and concentrated. The residue was pufied by flash coumn chromatography on sihca ge (cycohexane/AcOEt: 100/0 to 70/30) to afford (S)-tert-buty 4-methoxy-3-oxopentanoate. M/z = 203 [M+H]+, Rt = 0.91 mn (UPLC Method BI), 1H NMR (400 MHz, DM80-cl6) O ppm: 3.85 (q, IH), 354-3.46 (m, 2H), 3.27 (s, 3H), 1.40 (s, 9H), 119 (d, 3H).
General procedure: A solution of 1H-benzo[d]imidazol-5-amine (1 eq.) and the respective aldehyde (1 eq.) in dry methanol (1-3 ml per mmol) was stirred at room temperature for 3 hours. After addition of mono-tert-Butyl malonate (1 eq.) and 1-isocyano-2-methylpropan-2-yl methyl carbonate (1 eq.) stirring was continued for 48 hours. The solvent was evaporated and the residue was purified by flash chromatography on silica gel using a CHCl3/MeOH gradient.
tert-butyl 5-(((benzyloxy)carbonyl)amino)-3-oxopentanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
Compound (f): tert-butyl 5-(((benzyloxy)carbonyl)amino)-3-oxopentanoate.To a solution of commercially available Cbz-P-Ala-OH , Compound (d), (15.0 g, 67.24 mmol, 1 equiv) in 180 mL of THF was added CDI (13.08 g, 80.69 mmol, 1.2 equiv) and the resulting solution was stirred for 18h at 25 "C. In a separate flask, 3-(tert-butoxy)-3-oxopropanoic acid, Compound (e), (1.61 g, 100.86 mmol, 1.5 equiv) was treated with isopropylmagnesium chloride (2 M in THF, 202 mL, 3 equiv) at 0 C for 30 min, then 30 min at rt and 30 min at 40 C to generate the dianion. The activated acid of Compound (d) (the first solution) was then added dropwise to a 0 C solution of the dianion. A precipitated start to form, and after warming to 25 C, the mixture was stirred for 4 h. The resulting mixture was quenched with an ice cooled aqueous 1 M H3PO4 solution and then extracted three times with EtOAc. The combined organics were washed with saturated NaHC03, brine, dried (Na2S04) and concentrated to afford a colorless oil (20.62 g, 64.20 mmol, 95% yield) which was used without further purification in the next step. 1H NMR (400MHz ,CDC13) delta = 7.34 - 7.23 (m, 5 H), 5.21 (br. s., 1 H), 5.00 (s, 2 H), 3.40 - 3.35 (m, 2 H), 3.27 (s, 2 H), 2.71 (t, J= 5.6 Hz, 2 H), 1.38 (s, 9 H); 13C NMR (101MHz , CDC13) delta = 202.7, 166.0, 156.3, 136.4, 128.5, 128.5, 128.1, 128.0, 82.2, 66.6, 50.6, 42.7, 35.4, 27.9 IR: 3350, 2979, 1706, 1515, 1248, 1144; HRMS (ESI) m/z [M + Na+] calcd for Ci7H23NNa05, 344.1474; found, 344.1470.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 10 - 35℃; for 24h;
[COMPARATIVE EXAMPLE 19] (Synthesis Process R): Preparation of des(1-7)-Dibenzylaminocarbamoylacetyl-[Arg(Me)9,Trp10]MS10 (Compound No. 434) Dibenzylaminocarbamoylacetyl-Leu-Arg(Me)-Trp-NH2 After 1.54 mL of <strong>[40052-13-9]mono-tert-butyl malonate</strong>, 1.08 g of fluorenylmethanol and 61 mg of DMAP were dissolved in 20 mL of DCM 20, 1.15 g of WSCD HCl was added to the solution, followed by stirring at room temperature for 24 hours. The solvent was distilled off in vacuum, the residue was dissolved in AcOEt. The solution was then washed with 1N HCl aq. solution, satd. NaHCO aq. solution and then satd. NaCl aq. solution. After drying over NaSO, the solvent was concentrated and the concentrate was purified by flush column chromatography to give 1.62 g (yield 96%) of tert-butyl fluorenylmethyl malonate. In 20 mL of TFA, 61 mg of tert-butyl fluorenylmethyl malonate was dissolved and the solution was stirred at room temperature for 2 hours. After the solvent was distilled off in vacuum, the residue was dissolved in AcOEt, followed by washing with satd. NaCl aq. solution. After drying over NaSO, the solvent was concentrated and purified by flush column chromatography to give 850 mg (yield 67%) of mono-fluorenylmethyl malonate. After 5 mL of 20% piperidine/DMF was added to 46 mg (15 mumol) of Fmoc-LeuArg(Me,Boc)Trp(Boc)-Rink amide MBHA resin prepared in a manner similar to COMPARATIVE EXAMPLE 15, the solution was shaken at room temperature for 30 minutes. After the resin washed, 42 mg of mono-fluorenylmethyl malonate, 70 mg of PyBrop, 300 muL of 0.5M HOAt/DMF, 52 muL of DIEA and 1 mL of DMF were added to the resin, and the mixture was shaken for 15 hours. After this procedure was repeated twice, 8 muL of AcO, 5 muL of DIEA and 2 mL of DCM were added, followed by stirring at room temperature for 30 minutes. After the resin washed and then dried, 5 mL of 20% piperidine/DMF was added to a half of the resin, followed by stirring at room temperature for 30 minutes. After the resin washed, 13 mg of dibenzylhydrazine, 28 mg of PyBrop, 120 muL of 0.5M HOAt/DMF, 21 muL of DIEA and 1 mL of DMF were added to the resin, followed by shaking for 15 hours. After the resin washed and then dried, 200 muL of TFA/PhSMe/m-cresol/TIS/EDT (85/5/5/2.5/2.5) was added to the resin, followed by stirring for 2 hours. Ether was added to the reaction solution, the resulting precipitate was centrifuged and the supernatant was removed. This procedure was repeated for washing. The residue was extracted with an aqueous acetic acid solution and the extract was filtered to remove the resin. Then, linear density gradient elution (120 minutes) was performed with eluants A/B: 83/17-63/37 using: 0.1% TFA in water and eluant B: 0.1% TFA-containing acetonitrile on preparative HPLC using YMC D-ODS-5-ST S-5 120A column (20 x 150 mm). The fractions containing the product were collected and lyophilized to give 21.6 mg of white powders. Mass spectrum (M+H)+ 767.6 (Calcd. 767.4) Elution time on HPLC: 14.5 min Elution conditions: Column: Wakosil-II 5C18 HG (4.6 x 100 mm) Eluant: linear density gradient elution with eluants A/B = 100/0-30/70, using 0.1% TFA in water as eluant A and acetonitrile containing 0.1% TFA (25 mins.) Flow rate: 1.0 ml/min.
tert-butyl 3-oxo-3-(((S)-1,1,1-trifluoro-4-oxo-4-(p-tolyl)-2-(4-((6,6,6-trifluorohexyl)oxy)phenyl)butan-2-yl)amino)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
2,2,2-Trichloroacetonitrile (0.228 mL, 2.275 mmol) was added dropwise to a solution of 3-(tert-butoxy)-3-oxopropanoic acid (0.304 g, 1.896 mmol) and triphenylphosphine (0.995 g, 3.79 mmol) in DCM (3 mL) and stirred at rt for 1 h. Then, a solution of 1B (0.35 g, 0.758 mmol) in DCM (1 mL) followed by pyridine (0.184 mL, 2.275 mmol) were added and stirred at rt for 1.5 h. The mixture was concentrated and the crude was purified using ISCO flash chromatography to give 1C (0.39 g, 0.646 mmol, 85% yield) as a yellow oil
85%
to 2, 2, 2-trichloro acetonitrile (0.228 ml, 2 . 275mmol) dropwise added to the 3 - (tert-butoxy) - 3-oxo-(0.304g, 1 . 896mmol) and triphenylphosphine (0.995g, 3 . 79mmol) in DCM (3 ml) in and stirring at room temperature to a solution of 1h. Furthermore, sequentially adding 1B (0.35g, 0 . 758mmol) in DCM (1 ml) the solution, pyridine (0.184 ml, 2 . 275mmol) and at the room temperature stirring 1.5h. ISCO concentrated mixture and rapid chromatographic purification the crude material, to obtain a yellow oily 1C (0.39g, 0 . 646mmol, yield 85%).
tert-butyl 3-(2-aminophenylamino)-3-oxopropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With dicyclohexyl-carbodiimide; In acetonitrile; at 20℃; for 0.333333h;
To a solution of 3-tert-butoxy-3-oxopropanoic acid (200 mg,1.25 mmol) and 1,2-phenylenediamine (135 mg, 1.25 mmol) in acetonitrile (5 mL) was added a solution of DCC (283 mg,1.37 mmol) in acetonitrile (2 mL) and the reaction stirred for 20 min. The white suspension was filtered and the filtrate evaporated to leave a dark yellow oil which was purified by column chromatography (1:1 ethyl acetate:40-60 C petroleum ether) followed by recrystallisation from a mixture of ethyl acetate and 40-60 C petroleum ether to give amide 16 (155 mg, 50%) as a white crystalline solid, mp 122-123 C; Rf (1:1 ethyl acetate:hexane) 0.48; IR nmax 3428, 3318, 1718, 1655 cm1; 1H NMR (CDCl3, 300 MHz) d 8.89 (1H, s, NH), 7.29e7.25 (1H, m, 3-aryl), 7.09e7.02 (1H, m, 5-aryl), 6.84e6.77 (2H, m, 4,6-aryl), 3.59 (2H, br s, NH2), 3.40 (2H, s, CH2), 1.50 (9H, s, (CH3)3); 13C NMR (CDCl3, 75 MHz) d 169.1 (COOBut), 164.2 (CONH), 140.6 (2-aryl), 127.2 (4-aryl), 125.3 (6-aryl), 123.8 (1-aryl), 119.3 (5-aryl), 117.7 (3-aryl), 83.1 (C(CH3)3),42.0 (CH2), 28.0 ((CH3)3). Anal. Calcd for C13H18N2O3 C, 62.38; H,7.25; N, 11.19. Found C, 62.29; H, 7.28; N, 11.13.
methyl 2-amino-2-(3',4',5'-trifluoro-[1,1'-biphenyl]-4-yl)acetate[ No CAS ]
tert-butyl 3-((2-methoxy-2-oxo-1-(3',4',5'-trifluoro-[1,1'-biphenyl]-4-yl)ethyl)amino)-3-oxopropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
38%
General procedure: 01 13] The carboxylic acid (1.1 eq.) and HCTU (1.2-2.4 eq.) were dissolved in DMF (2 mL/mmol) and stirred for 30 min in a nitrogen flushed microwave vial. DIPEA (2.1 -4.2 eq.) was added dropwise followed by methyl 2-amino-2-(3',4',5'-trifluoro-[1 ,1 '-biphenyl]-4- yl)acetate (1.0 eq.) in DCM (2 mL/mmol). The reaction mixture was stirred at room temperature for 1 -2 days. After completion, the reaction mixture was diluted with sat. NaHC03 (10 mL) and extracted with DCM (3 x 15 mL). The combined organic layers were washed with water (2 x 10 mL) and brine (15 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by column chromatography using either DCM/MeOH or PE/EtOAc as the eluent.
(Z)-N-(3-(isopentyldithio)-5-hydroxypent-2-en-2-yl)-N-methylformamide[ No CAS ]
tert-butyl Z-(3-(isopentyldithio)-4-(N-methylformamido)pent-3-en-1-yl) malonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In acetonitrile; at 25℃; for 12h;
The compound (Z) -N- (5-hydroxy-3- (isopentyldithio) pent-2-en-2-yl) -N-methyl formamide 277 mg(1 mmol) was dissolved in 8 ml of acetonitrile followed by <strong>[40052-13-9]malonic acid mono-tert-butyl ester</strong>192 mg (1.2 mmol),1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (250 mg (1.3 mmol), 4-N, N-dimethylaminopyridine in 25 mg (0.2 mmol) was stirred at room temperature 25 deg.C for 12 hours, tlc monitoring of chromatography. After completion of the reaction, the mixture was extracted twice with 150 ml of dichloromethane (75 ml each). The extracts were combined, concentrated on a rotary evaporator and dried over anhydrous sodium sulfate for 6 hours. The residue was purified by column chromatography (silica gel GF254, elution conditions:Petroleum ether / ethyl acetate = 18/1) to give 385 mg of a pale yellow oil in 92% yield.
t-butyl 3-((2-methoxypyrimidin-5-yl)amino)-3-oxopropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.12 g
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; for 2h;Reflux;
A solution of 3-(t-butoxy)-3-oxopropionic acid (CAS No. 40052-13-9) (1.41 g, 8.79 mmol, 1.1 equivalents), <strong>[56621-89-7]2-methoxypyrimidin-5-amine</strong> (CAS No. 56621-89-7) (1.00 g, 7.99 mmol, 1.0 equivalents), triethylamine (1.34 mL, 9.59 mmol, 1.2 equivalents) and EDC (1.84 g, 9.59 mmol, 1.2 equivalents) in DCM (20 mL) was heated to reflux for 2 hours. The reaction mixture was cooled down to room temperature. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with DCM. The organic layer was concentrated under reduced pressure. The residue was purified with silica gel column chromatography (silica gel, 50%-100% ethyl acetate/n-heptane) to afford the title compound (2.12 g). 1H-NMR (400 MHz, CDCl3) delta (ppm): 1.52 (s, 9H), 3.42 (s, 2H), 4.01 (s, 3H), 8.76 (s, 2H), 9.52 (br. s, 1H).
t-butyl 3-((5-fluoropyridin-3-yl)amino)-3-oxopropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.1 g
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 60℃; for 24h;
3-(t-Butoxy)-3-oxopropionic acid (CAS No. 40052-13-9) (2.75 mL, 17.8 mmol, 2 equivalents) and <strong>[210169-05-4]3-amino-5-fluoropyridine</strong> (CAS No. 210169-05-4) (1.00 g, 8.92 mmol, 1 equivalent) were dissolved in DMF (15 mL), and triethylamine (6.22 mL, 44.6 mmol, 5 equivalents) and EDC (5.13 g, 26.8 mmol, 3 equivalents) were added, and the mixture was stirred at 60 C. for 24 hours. The reaction mixture was cooled down to room temperature. To the reaction mixture were added water and ethyl acetate, and the organic and aqueous layers were separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (silica gel, 60%-90% ethyl acetate/n-heptane) to afford the title compound (2.1 g). 1H-NMR (400 MHz, CDCl3) delta (ppm): 1.52 (s, 9H), 3.42 (s, 2H), 8.16 (dt, J=10.5, 2.7 Hz, 1H), 8.23 (d, J=2.7 Hz, 1H), 8.31-8.49 (m, 1H), 9.83 (br. s., 1H).
t-butyl 3-oxo-3-(pyrimidin-5-ylamino)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
4.73 g
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 72h;
To a mixture of <strong>[591-55-9]5-aminopyrimidine</strong> (CAS No. 591-55-9) (2.00 g, 21.0 mmol, 1 equivalent), triethylamine (14.7 mL, 105 mmol, 5 equivalents), EDC (7.26 g, 37.9 mmol, 1.8 equivalents), N,N-dimethyl-4-aminopyridine (0.257 g, 2.10 mmol, 0.1 equivalents) and DCM (60.0 mL) was added dropwise 3-(t-butoxy)-3-oxopropionic acid (CAS No. 40052-13-9) (4.86 mL, 31.5 mmol, 1.5 equivalents), and the mixture was stirred at room temperature for 3 days. To the reaction mixture were added water and ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (silica gel, 25%-71% ethyl acetate/n-heptane) to afford the title compound (4.73 g). 1H-NMR (400 MHz, CDCl3) delta (ppm): 1.52 (s, 9H), 3.44 (s, 2H), 8.98 (s, 1H), 9.03 (s, 2H), 9.77 (br. s, 1H).
t-butyl 3-((2-methylpyrimidin-5-yl)amino)-3-oxopropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.21 g
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; for 1h;Reflux;
A mixture of 3-(t-butoxy)-3-oxopropionic acid (CAS No, 40052-13-9) (1.61 g, 10.1 mmol, 1.1 equivalents), <strong>[39889-94-6]2-methyl-5-pyrimidinamine</strong> (CAS No. 39889-94-6) (1.00 g, 9.16 mmol, 1.0 equivalent), triethylamine (1.53 mL, 11.0 mmol, 1.2 equivalents), EDC (2.11 g, 11.0 mmol, 1.2 equivalents) and DCM (20 mL) was heated to reflux for 1 hour. The reaction mixture was cooled down to room temperature, then a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with DCM. The organic layer was concentrated under reduced pressure. The residue was purified with silica gel column chromatography (silica gel, 50%-100% ethyl acetate/n-heptane) to afford the title compound (2.21 g). 1H-NMR (400 MHz, CDCl3) delta (ppm): 1.53 (s, 9H), 2.72 (s, 3H), 3.43 (s, 2H), 8.91 (s, 2H), 9.64 (br. s, 1H).
2-{4-ethyl-3-[4-(morpholin-4-yl) piperidine-yl] phenyl}-2-methylpropanoic acid[ No CAS ]
tert-butyl 4-{4-ethyl-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-4-methyl-3-oxopentanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With N-ethyl-N,N-diisopropylamine; dicyclohexyl-carbodiimide; magnesium chloride; In N,N-dimethyl-formamide; at 80℃; for 2h;Green chemistry;
2- (4-ethyl-3- [4- (morpholin-4-yl) piperidin-1-yl] phenyl} -2-methylpropionic acid (14.0 g, 38.8 mmol)And <strong>[40052-13-9]malonic acid mono-tert-butyl ester</strong> (11.2 g, 69.9 mmol) were dissolvedN, N-dimethylformamide (300 mL),Magnesium chloride (4.4 g, 46.2 mmol) was added,N, N-diisopropylethylamine (28.0 g, 216.6 mmol)N, N'-dicyclohexylcarbodiimide (9.6 g, 46.5 mmol)Heated to 80 C for 2 hours, reduced to room temperature, followed by 1N hydrochloric acid, water, saturated sodium bicarbonate solution, anhydrous magnesium sulfate drying, steaming under reduced pressure to dry, isopropyl alcohol recrystallization, 4- {4 -ethyl-3- [4- (morpholin-4-yl) piperidin-1-yl] phenyl} -4-methyl-3-oxopentanoate,White solid (15.4 g) in 87% yield.
85%
With triethylamine; 1,1'-carbonyldiimidazole; magnesium chloride; In tert-butyl methyl ether; at 70℃; for 3h;
2-(4-ethyl-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl} -2-methylpropionic acid (9.0 g, 25 Ommol) and <strong>[40052-13-9]mono-tert-butyl malonate</strong> (6.4 g, 40 mmol) were dissolved in methyl tert-butyl ether (200 mL) magnesium chloride (2.6 g, 27.3 mmol) was added, triethylamine (12.1 g, 119.6 mmol), N, N '-carbonyldiimidazole (4.7 g, 29.0 mmol) was added and heated to 70 C for 3 hours. The mixture was washed with 1N hydrochloric acid, water, saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, evaporated to dryness under reduced pressure, and recrystallized from isopropanol to give tert-butyl 4-{4-ethyl-3-[4-(morpholin-4-yl)piperidine-yl]phenyl}-4-methyl-3-oxopentanoat eas a white solid (9.7 g) in 85% yield.
2-{4-bromo-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-2-methylpropionic acid[ No CAS ]
tert-butyl 4-{4-bromo-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-4-methyl-3-oxopentanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With N-ethyl-N,N-diisopropylamine; dicyclohexyl-carbodiimide; magnesium chloride; In N,N-dimethyl-formamide; at 60℃; for 4h;
4-Bromo-2- {3- [4- (morpholin-4-yl) piperidin-1-yl] phenyl} -2-methylpropanoic acid (2. Og, 4.9mmol) and propan- acid mono-tert-butyl ester (I. Ig, 6.9mmol) was dissolved in N, N- dimethylformamide (35mL), was added magnesium chloride (0.5g, 5.3mmol), N, N_ diisopropylethylamine ( . 2.6g, 20 lmmol), N, N '- dicyclohexyl carbodiimide (I .2g, 5.8mmol), was heated to 60 C for 4 hours, cooled to room temperature, washed successively with IN hydrochloric acid, water, saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and rotary evaporated to dryness under reduced pressure, recrystallized from isopropanol, to give 4- {4-bromo-3- [4- (morpholin-4-yl) piperidine -1 - yl] phenyl} -4-oxo-pentanoic acid tert-butyl-methyl-3, an off-white solid (2. Og), yield 81%.
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 0.5h;
A mixture of compound 13 ( 190 mg, 0.33 mmol), 2-(tert- butoxycarbonyl)acetic acid (79 mg, 0.43 mmol), benzotriazol-l -yloxytris(dimethylamino)-phosphonium hexafluorophosphate (229 mg, 0.5 mmol), and /Pr2NEt (0.3 mL, 1.65 mmol) in CH2C12 ( 10 mL) was stirred at room temperature for 30 min. Water was added and the resulting mixture was extracted with CH2C12. The organic layer was concentrated and the residue was purified by silica gel column (0482) (CH2Cl2/MeOH = 20: 1) to give 33-1 (210 mg, yield: 87%) as a solid. ESI-MS m/z: 737 (M+H).
methyl 4-(3-(tert-butoxy)-3-oxopropanoyl)thiophene-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In a first flask, a solution of 5.27 g (28.31 mmol) of Compound VIII in 35 mL of MP was treated slowly with 5.28 g (32.55 mmol) of CDI. The reaction mixture was stirred at ambient temperature for 2 hours. In a separate second flask, to a solution of 5.67g (35.39 mmol) of mono-fert-butyl malonate in 50 mL of NMP cooled to 0 C was added 3.37g (35.39 mmol) of MgCk. After stirring at 0 C for 5 minutes, 14.8 mL (84.93 mmol) of N,N- diisopropylethylamine was added and the resulting reaction mixture stirred at ambient temperature for 2 hours. After 2 hours, the content of flask 1 was added to flask 2 and the combined reaction mixture stirred at ambient temperature overnight. Subsequently, the reaction mixture was cooled to 0 C and treated with aqueous 1.0 M HC1 and stirred for 20 minutes. The mixture was extracted with ether (3x) and washed sequentially with water (2x) and brine (lx). The organic layer was dried over Na2S04, filtered and concentrated in vacuo. The residue was dissolved in lOmL of ethyl acetate and 1 lOmL of hexanes was added.Stirred for 10 minutes and the solid precipitate was filtered off. Concentrated the filtrate in vacuo and the crude methyl 4-(3-(tert-butoxy)-3-oxopropanoyl)thiophene-3-carboxylate (Compound IX) was carried on without further purification
Solution A (0552) N,N'-carbonyldiimidazole (1.3 g, 8.46 mmol) was added at 0 C to a stirred solution of thiazole- 5-carboxylic acid (1.0 g, 7.74 mmol) in THF (20 mL). The reaction mixture was stirred at rt for 3 h. (0553) Solution B (0554) 2M Isopropyl magnesium chloride in THF (1 1 mL, 22.6 mmol) was added dropwise at 0 C to a solution of 3-tert-butoxy-3-oxopropanoic acid (1.24 g, 7.74 mmol) in THF (20 mL). The reaction mixture was stirred at rt for 3 h. (0555) Solution B was then added dropwise at 0 C to solution A and the resulting mixture was stirred at rt for 1 h. 10% aqueous citric acid (aq, 50 mL) and water (100 mL) was added. The aqueous layer was extracted with EtOAc (2 x 200 mL) and the combined organic layers were washed with saturated sodium bicarbonate solution, dried (Na2S04), filtered and concentrated under reduced pressure. The obtained crude was purified by column chromatography on silica gel eluted with 20% EtOAc in p.ether which gave the title compound (600 mg, 29%). LC-MS (ES+) m/z 228 [M+H]+.
tert-butyl 3-((1R,2R)-2-fluorocyclopropyl)-3-oxopropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%
N,N'-carbonyldiimidazole (2.05 g, 12.6 mmol) was added at 0 C to a stirred solution of 2- fluorocyclopropanecarboxylic acid (1.2 g, 11.5 mmol) in THF (20 mL). The reaction mixture was stirred at rt for 3 h. (0565) Solution B (0566) 2M Isopropyl magnesium chloride in THF (1 1 mL, 22.6 mmol) was added dropwise at 0 C to a solution of 3-tert-butoxy-3-oxopropanoic acid (2.77 g, 17.3 mmol) in THF (17 mL). The reaction mixture was stirred at rt for 3 h. (0567) Solution B was then added dropwise at 0 C to solution A and the resulting mixture was stirred at rt for 1 h. 10% Aqueous citric acid (aq., 25 mL) was added and the mixture was extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with saturated sodium bicarbonate solution, dried (Na2S04), filtered and concentrated under reduced pressure, which gave the title compound (1.2 g, 51 %).
Solution 1 : CDI (3.92 g, 24.2 mmol) was added at 0 C to a solution of <strong>[50681-25-9]pyridazine-4-carboxylic acid</strong> (3.0 g, 24.2 mmol) in DMF (50.0 mL). The reaction mixture was stirred at rt for 3 h. Solution 2: In a separate flask, 2M isopropyl magnesium chloride in THF (37.5 mL) was added dropwise at 0 C to a solution of mono-tert-butyl malonate (3.87 g,24.2 mmol) in THF (50.0 mL). The reaction was stirred for 3 h at rt. Solution 2 was then added to Solution 1 at 0 C and the resulting solution was stirred at rt for 1 h, then concentrated. The crude was diluted with EtOAc (200 mL), washed with water (500 mL) and brine (500 mL). The organic layer was dried (Na2S04), filtered and concentrated. The crude compound was purified by combi flash chromatography on silica gel using 30 % EtOAc in p. ether as eluent, which gave the title compound (2.5 g, 45%) as a solid. LC-MS (ES+) m/z 223.14 [M+H]+.
tert-butyl 3-(1-(((benzyloxy)carbonyl)(methyl)amino)cyclopropyl)-3-oxopropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30%
Solution 1 : CDI (10.0 g, 61.6 mmol) was added at 0 C to l-6a (10.0 g, 40.1 mmol) in dry THF (60 ml_) and stirred at rt for 3 h. Solution 2: iPrMgCI (60.0 ml_) was added to (3-tert-butoxy-3-oxopropanoic acid (10.0 g, 62.43 mmol) in dry THF (60 ml_) at 0 C and the solution was stirred at 20 C for 3 h. Solution 2 was added to Solution 1 at 0 C and whereafter the reaction mixture was stirred at rt for 1 h. 10% citric acid (aq.) was added and the mixture was extracted with EtOAc and washed with sat. NaHCC>3. The organic layer was dried (Na2S04), filtered and concentrated. The obtained residue was purified by column chromatography on silica gel using 15% EtOAc in p. ether as eluent, which gave the title compound (10.5 g, 64%). LC-MS (ES+) m/z 348.38 [M+H]+.
tert-butyl 3-(1-(dimethylamino)cyclopropyl)-3-oxopropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
49%
Solution 1 : CDI (7.0 g, 43.2 mmol) was added at 0 C to l-7a (4.0 g, 31.0 mmol) in dry DMF (20 ml_) and stirred at rt for 3 h. Solution 2: iPrMgCI (60.0 ml_) was added to (3-tert-butoxy-3-oxopropanoic acid (10.0 g, 62.4 mmol) in dry THF (60 ml_) at 0 C and the solution was stirred at 20 C for 3 h. Solution 2 was added to Solution 1 at 0 C and whereafter the reaction mixture was stirred at rt for 1 h. 10% citric acid (aq.) was added and the mixture was extracted with EtOAc and washed with sat. NaHCC>3. The organic layer was dried (Na2S04), filtered and concentrated. The obtained residue was purified by column chromatography on silica gel using 15% EtOAc in p. ether as eluent, which gave the title compound (5.4 g, 49%). LC-MS (ES+) m/z 228.25 [M+H]+
1-(difluoromethoxy)cyclopropanecarboxylic acid[ No CAS ]
tert-butyl 3-(1-(difluoromethoxy)cyclopropyl)-3-oxopropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
Solution A N,N'-carbonyldiimidazole (1.2 g, 7.1 mmol) was added at 0 C to a stirred solution of compound l-23b (800 mg, 5.30 mmol) in THF (25 ml_). The reaction mixture was stirred at rt for 3 h. Solution B 2M Isopropyl magnesium chloride in THF (8 ml_, 16 mmol) was added drop wise to a solution of 3-tert-butoxy-3-oxopropanoic acid (1.0 g, 6.24 mmol) in THF (25 ml_) at 0 C. The reaction mixture was stirred at rt for 3 h. Solution B was then added dropwise at 0 C to solution A and the resulting mixture was stirred at rt until TLC indicated completion of the reaction (2 h). 10% aqueous citric acid (aq) was added and the mixture was diluted with water. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with saturated sodium bicarbonate solution, dried (Na2S04), filtered and concentrated under reduced pressure at 30 C bath temperature, which gave the title compound (600 mg. 43%) as liquid. MS (ES+) m/z 251.16 [M+H
Stage #1: mono-tert-butyl malonate With triethylamine; magnesium chloride In tetrahydrofuran at 10 - 30℃; for 2h; Inert atmosphere;
Stage #2: 2-(4-ethyl-3-iodophenyl)-2-methylpropionic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran at 10 - 65℃; for 7h; Inert atmosphere;
5 EXAMPLE-05:PREPARATION OF tert-BUTYL 4-(4-ETHYL-3-IODO- PHENYL)-4-METHYL-3-OXO-PENTANOATE .
Mono-ie/ -butyl malonic acid (226.3 g; 1.41 moles) was dissolved in THF under nitrogen atmosphere at RT. The reaction mixture was cooled to 10-15°C triethylamine (318.1 g; 3.14 moles) was added slowly followed by magnesium chloride (157.11 g; 1.65 moles) was added and stirred for ~2h at 25-30°C. In a separate vessel, Compound (I) obtained in example-04 (250 g; 0.7858 moles) was dissolved in THF under N2 atmosphere at RT and cooled to 10-15°C. N,N- carbonyldiimidazole (CDI; 153 g; 0.94 moles) was added lots wise and stirred for ~lh at 25-30°C. This solution was then added dropwise to the above magnesium chloride complex and stirred for ~6h at 60-65°C. After completion of the reaction by HPLC, cooled to RT, diluted with Ethyl acetate and dil. aqueous HC1. Layers were separated and organic layer was washed with dil. Aq. NaOH and -15% w/v brine solution. Finally organic layer was concentrated to dryness at < 60°C under vacuum to obtain the product as a light brown colour liquid. HPLC Purity: 88.26%.
100 g
Stage #1: mono-tert-butyl malonate With triethylamine; magnesium chloride In 1,2-dimethoxyethane; isopropyl alcohol; toluene at 25 - 30℃; for 5h;
Stage #2: 2-(4-ethyl-3-iodophenyl)-2-methylpropionic acid With 1,1'-carbonyldiimidazole In 1,2-dimethoxyethane at 25 - 70℃; for 10h;
5; 20 Example-5: Preparation of tert-butyl 4-(4-ethyl-3-iodophenyl)-4-methyl-3-oxo pentanoate:
Magnesium chloride (32.9 gms) was added to the mixture of toluene (1000 ml) and isopropanol (1000 ml) at 25-30°C. Heated the reaction mixture to 80-85°C and distilled off the solvent azeotropically. Further, raised the temperature to l05-H0°C and distilled off the solvent completely azeotropically. Cooled the reaction mixture to 60-65 °C and co-distilled with toluene. Further cooled the reaction mixture to 25-30°C. 1 ,2-dimethoxyethane (400 ml) was added to the reaction mixture. 3-(tert-butoxy)-3-oxopropanoic acid (80 gms) was added to the reaction mixture. Triethyl amine (219 ml) was slowly added to the reaction mixture and stirred the reaction mixture 5 hours at 25-30°C (reaction mixture 1). 1 ,2-dimethoxyethane (300 ml) was added to 2-(4-ethyl-3-iodophenyl)-2-methylpropanoic acid (100 gms) at 25- 30°C and stirred for 15 minutes at the same temperature. Carbonyldiimidazole (56.03 gms) was added in three lots to the reaction mixture at 25-30°C and stirred for 4 hours at the same temperature (reaction mixture 2). Reaction mixture 2 was added to reaction mixture 1 at 25- 30°C. Heated the reaction mixture to 65-70°C and stirred for 6 hours at the same temperature. Cooled the reaction mixture to 20-25°C. Isopropyl acetate (300 ml) and n-Heptane (300 ml) were added to the reaction mixture. 20% aqueous hydrochloric acid solution and stirred for 45 minutes at 25-30°C. Both the organic and aqueous layers were separated. Organic layer was washed with 4% sodium hydroxide solution and then with 15% sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 100 gms.
87.8 %
Stage #1: mono-tert-butyl malonate With triethylamine; magnesium chloride In N,N-dimethyl acetamide at 20℃;
Stage #2: 2-(4-ethyl-3-iodophenyl)-2-methylpropionic acid With 1,1'-carbonyldiimidazole In dichloromethane at 70℃;
1 4-(4-Ethyl-3-iodophenyl)-4-methyl-3-oxopentanoic acid tert-butyl ester
To a solution of 3-(tert-butoxy)-3-oxopropionic acid (20.0 g, 124.8 mmol) in N,N-dimethylacetamide (100 mL) was added triethylamine (52.6 mL, 378.4 mmol) and Magnesium chloride (8.24 g, 86.6 mmol). The reaction was stirred at room temperature for 2 hours. Carbonyldiimidazole (14.7 g, 90.6 mmol) was added to a solution of 2-(4-ethyl-3-iodophenyl)-2-methylpropionic acid (25.0 g, 78.6 mmol) in dichloroethane (100 mL) and stirred at room temperature for 1 hour. The prepared solution was added dropwise to the above solution, heated to 70°C and stirred for 5 hours. The reaction was complete as monitored by LCMS. The reaction solution was diluted with ethyl acetate (500 mL) and water (500 mL), and the organic phase was separated. Washed with saturated brine and dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=40:1) to obtain 4-(4-ethyl-3-iodophenyl)-4-methyl- tert-Butyl 3-oxopentanoate (28.7 g, 87.8% yield).
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 23℃; for 16h;
A solution of amine 1-206 (315 mg, 1.81 mmol), carboxylic acid 1-207 (263 mg, 1.0 equiv.), HATU (688 mg, 1.1 equiv.), and DIPEA (851 mg, 4.0 equiv.) in anhydrous DMF (3 mL) was stirred at ambient temperature for 16 hours. The reaction was monitored by TLC. The reaction mixture was quenched with H20 (5 mL) and extracted with EtOAc (3 x 5 mL). The combined organic extracts were dried over Na2S04, and concentrated to a residue that was purified by preparative TLC (Petroleum Ether/EtOAc = 1 : 1) to afford amide 1-208 (250 mg, 48%) as a light yellow solid. TLC: Petroleum Ether/EtOAc = 1 : 1, UV 254 nm Rf (amine 1-206) = 0.1 Rf (amide 1-208) = 0.6
2-(4-ethyl-3-iodophenyl)-2-methylpropanoic acid[ No CAS ]
tert-butyl 2-(4-cyano-2-nitro-phenyl)-4-(4-ethyl-3-iodo-phenyl)-4-methyl-3-oxo-pentanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58.49 kg
A mixture of toluene (450 lts), isopropanol (450 lts) and magnesium chloride (14.85 kgs) were heated to 85-90C and stirred for 45 minutes at the same temperature under nitrogen atmosphere. Distilled off the solvent from the reaction mixture. Further raised the temperature of the reaction mixture to H0-ll5C and distilled off the solvent from the reaction mixture and then co-distilled with toluene. Cooled the reaction mixture to 25-30C. l,2-Dimethoxy ethane (180 lts) and 3-(tert-butoxy)-3-oxopropanoic acid (36.0 kgs) was added to the reaction mixture at 25-30C and stirred for 15 minutes at the same temperature. Triethyl amine (98.6 lts) was slowly added to the reaction mixture at 25-30C and stirred for 5 hours at the same temperature (reaction mixture 1). l,2-Dimethoxyethane (135 lts) was added to 2-(4- ethyl-3-iodophenyl)-2-methylpropanoic acid (45.0 kgs) at 25-30C and stirred for 15 minutes at the same temperature. Carbonyldiimidazole (25.26 kgs) was added in three lots to the reaction mixture at 25-30C and stirred for 4 hours at the same temperature (reaction mixture 2). Reaction mixture 2 was slowly added to the reaction mixture 1 at 25-30C. Heated the reaction mixture to 65-70C and stirred for 6 hours at the same temperature. Cooled the reaction mixture to 20-25C. n-Heptane (135 lts) and isopropyl acetate (135 lts) to the reaction mixture at 20-25C. Aqueous hydrochloric acid was slowly added to the reaction mixture at 20-25 C and stirred for 45 minutes at the same temperature. Both the organic and aqueous layers were separated and extracted the organic layer using water. Aqueous sodium hydroxide solution was added to the organic layer at 20-25C and stirred for 15 minutes at the same temperature. Both the organic and aqueous layers were separated. Aqueous sodium chloride was added to the organic layer at 20-25C and stirred for 15 minutes at the same temperature. Both the organic and aqueous layers were separated. Distilled off the solvent completely from the organic layer under reduced pressure. Dimethylformamide (180 lts) and caesium carbonate (105.75 kgs) was added to the obtained compound at 25-30C. Dimethylformamide (67.5 lts) and <strong>[939-80-0]4-chloro-3-nitrobenzonitrile</strong> (24.30 kgs) was added to the reaction mixture at 25-30C. Raised the temperature of the reaction mixture to 40-45C and stirred for 8 hours at the same temperature. Cooled the reaction mixture to 25-30C. A mixture of tetrahydrofuran and ethyl acetate was added to the reaction mixture at 25-30C and stirred for 15 minutes at the same temperature. Aqueous acetic acid solution was added to the reaction mixture at 25-30C and stirred for 30 minutes at the same temperature. Both the organic and aqueous layers were separated. Aqueous sodium chloride was added to the organic layer at 25-30C and stirred for 20 minutes at the same temperature. Both the organic and aqueous layers were separated. Distilled off the solvent completely from the organic layer under reduced pressure and then co-distilled with isopropanol. To the obtained compound, isopropanol (67.5 lts) was added at 25-30C and stirred for 2 hours at the same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure to get the title compound. Yield: 58.49 kgs.
tert-butyl 3-(4-bromo-3-chloro-2-fluoroanilino)-3-oxopropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
3.35 g
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl acetamide; at 50℃; for 1h;
To a solution of 4-bromo-3-chloro-2-fluoro-aniline (3 g, 13.4 mmol) and HATU (10.2 g, 26.7 mmol) in DMA (30 mL) was added TEA (5.58 mL, 40.1 mmol) and 3-tert-butoxy-3-oxopropanoic acid (3.09 mL, 20.0 mmol) at RT. The mixture was stirred at 50 C for 1 h, diluted with water, and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na 2SO 4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution, 30 - 70% EtOAc/hexane) to give tert-butyl 3-(4-bromo-3-chloro-2-fluoro-anilino)-3-oxo-propanoate (3.35 g).
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