CARMEGLIPTIN

 

CARMEGLIPTIN

http://newdrugapprovals.org/2014/09/18/carmegliptin-a-dpp-4-inhibitor/

Org. Process Res. Dev. 2011, 15, 503–514. doi:10.1021/op2000207

http://pubs.acs.org/doi/full/10.1021/op2000207

 

A short and high-yielding synthesis of carmegliptin (1) suitable for large-scale production is reported. The tricyclic core was assembled efficiently by a decarboxylative Mannich addition−Mannich cyclization sequence. Subsequent crystallization-induced dynamic resolution of enamine 7 using (S,S)-dibenzoyltartaric acid was followed by diastereoselective enamine reduction to give the fully functionalized tricyclic core with its three stereogenic centers. The C-3 nitrogen was introduced by Hofmann rearrangement of amide 28, and the resulting amine 10was coupled with (S)-fluoromethyl lactone 31. Following cyclization to lactam 13 and amine deprotection, 1 was obtained in 27−31% overall yield with six isolated intermediates.

Preparation of (2S,3S,11βS)-1-(2-Amino-9,10-dimethoxy-1,3,4,6,7,11β-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-(4S)-fluoromethyl-pyrrolidin-2-one Dihydrochloride (1)   CARMEGLIPTIN

A suspension of carbamate 13 (136 kg, 285 mol) in a mixture of H₂O (112 kg) and acetone (122 kg) was treated at 50 °C within 60 min with 37% aq HCl (98.0 kg). After 90 min at 47−52 °C the solution was polish filtered through a 5 μm filter. The first reactor and the transfer lines were washed with a hot (47−52 °C) mixture of H₂O (13.0 kg) and acetone (116 kg). The filtrate was cooled to 25 °C and treated at this temperature within 80 min with acetone (1600 kg) whereupon the product crystallized out. The resulting suspension was stirred for 1 h at 25 °C and subsequently centrifuged. The crystals were washed in two portions with acetone (391 kg) and dried at 50 °C and <30 mbar until constant weight to afford 122.4 kg (95%) of the title compound as colorless crystals with an assay (HPLC) of 98.8% (w/w).

 

¹H NMR (400 MHz, D₂O) δ 2.11−2.22 (m, 1H); 2.45 (dd, J = 17.6 Hz, 6.7 Hz; 1H); 2.76 (dd, J = 17.6 Hz, 9.55 Hz, 1H); 2.90−3.05 (m, 1H); 3.08−3.19 (m, 2H); 3.24−3.36 (m, 1H); 3.43 (dd, J = 9.8 Hz, 5.75 Hz, 1H); 3.49−3.58 (m, 1H); 3.70−3.84 (m, 4H); 3.87 (s, 3H); 3.88 (s, 3H); 4.12 (td, J = 11.6 Hz, 4.5 Hz, 1H); 4.45−4.55 (m, 1H); 4.56−4.68 (m, 3H); 6.91 (s, 1H), 6.95 (s, 1H).

 

 

IR (cm⁻¹): 3237, 2925, 1682, 496, 478.

 

MS (ESI): m/z 378.3 ([M + H]⁺ (free amine)).

 

Anal. Calcd for C₂₀H₃₀Cl₂FN₃O₃: C, 53.34; H, 6.71; N, 9.33; Cl, 15.74; F 4.22; O, 10.66. Found: C, 53.04; H, 6.43; N, 9.45; Cl, 15.66; F, 4.29; O, 11.09.

 

REF FOR ABOVE

http://newdrugapprovals.org/2014/09/18/carmegliptin-a-dpp-4-inhibitor/

 

Mattei, P.; Böhringer, M.; Di Giorgio, P.; Fischer, H.; Hennig, M.; Huwyler, J.; Kocer, B.; Kuhn, B.; Löffler, B. M.; MacDonald, A.; Narquizian, R.; Rauber, E.; Sebokova, E.; Sprecher, U. Bioorg. Med. Chem. Lett. 2010, 20, 1109

 

Böhringer, M.; Kuhn, B.; Lübbers, T.; Mattei, P.; Narquizian, R.; Wessel,H. P. (F. Hoffmann-La Roche AG). U.S. Pat. Appl. 2004/0259902, 2004.

(1S,2S,5R,6S) -2-tert-Butoxycarbonylamino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid

Synthesis of (1S,2S,5R,6S) -2-tert-Butoxycarbonylamino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid

 A 1 L flask was charged with (1S,2S,5R,6S)-2-amino-bicyclo [3.1.0]hexane-2,6-dicarboxylic acid monohydrate (24.4 g, 0.12 mol, 1 equiv), dioxane (200 mL) and di-tert-butyl dicarbonate (52.4 g, 0.24 mol, 2.0 equiv). The suspension was vigorously stirred while sodium hydroxide 1N (420 mL, 3.5 equiv) was added. The mixture was stirred for 2 days, then 2.0 more equiv of di-tert-butyl dicarbonate were added and the reaction stirred for 3 additional days at rt. After 5 total days of reaction, water (400 mL) was added to dissolve the salts. The aqueous layer was extracted with ethyl acetate (4×100 mL) to remove the excess of reagent, and then taken to ca. pH=2 using 6 N hydrochloric acid. The acidic aqueous phase was then extracted using ethyl ether (6×200 mL). The combined organic layers were washed with water (250 mL) and brine (250 mL). After drying over sodium sulfate, solvents were evaporated in vacuum to afford a foamy white solid (26.4 g).

77% Yield. 

http://www.google.im/patents/US20040138304?cl=un

mp 100-101° C. 

[α]_D ²⁵=−41.1° (c=1.0, MeOH). 

¹H NMR (Methanol-d₄) δ: 4.98 (brs, 1H), 2.44 (dd, 1H, J=6.2, 2.6 Hz), 2.19-1.92 (m, 4H), 1.62 (t, 1H, J=2.8 Hz), 1.43 (s, 9H), 1.29 (m, 1H). 

¹³C NMR (Methanol-d₄) δ: 175.6, 175.2, 158.2, 60.1, 34.6, 31.9, 28.4, 27.2, 25.6, 20.6. MS (Neg. Electrospray): 284.2 (M⁺−H).

(1S, 2S,5R, 6S)-2-Allyloxycarbonylamino-bicyclo [3.1.0]hexane-2,6-dicarboxylic acid

Synthesis of (1S, 2S,5R, 6S)-2-Allyloxycarbonylamino-bicyclo [3.1.0]hexane-2,6-dicarboxylic acid

http://www.google.im/patents/US20040138304?cl=un

[0123] (1S,2S,5R,6S)-2-Amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (15.0 g, 73.9 mmol) was slowly dissolved in 250 mL of saturated sodium bicarbonate. After complete solution, dioxane (100 mL) and allyl chloroformate (15.7 mL, 147.8 mmol) were added at room temperature and the mixture was stirred overnight. The reaction mixture was diluted with water (100 mL) and washed with three portions of ethyl acetate. The organic layer was extracted once with saturated sodium bicarbonate. The combined aqueous layers were acidified to pH 1 with 4N hydrochloric acid and extracted with two portions of ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated to provide the title compound as an oil (13.4 g, 67% yield).

¹H-NMR (CD₃OD)

δ: 6.01-5.82 (m, 1 H); 5.35-5.13 (m, 2 H); 4.51 (d, J=5.1 Hz, 2 H); 2.48-1.78 (m, 5 H); 1.69-1.62 (m, 1 H); 1.45-1.29 (m, 1 H).

 ¹³C-NMR (CD₃OD)δ: 176.7, 176.6, 158.3, 134.2, 117.4, 67.3, 66.3, 35.8, 33.1, 29.9, 27.0, 22.0.

N-[(3R)-l-azabicyclo [2.2.2] oct-3-yl]-5-amino-l-benzofuran-2-carboxamide

N-[(3R)-l-azabicyclo [2.2.2] oct-3-yl]-5-amino-l-benzofuran-2-carboxamide

N-[(3R)-l-azabicyclo [2.2.2] oct-3-yl]-5-nitro-l-benzofuran-2-carboxamide (100 mg, 0.32 mmol) is mixed with 2.0 ml (4 mmol) of a 2 M tin added (II) chloride solution in DMF. The mixture is stirred overnight. The reaction mixture is poured into water and made basic with 1 N aqueous sodium hydroxide solution. The aqueous phase is extracted six times with ethyl acetate. The combined organic

Phases are dried over magnesium sulfate and the solvent under reduced pressure on a rotary evaporator enfemt. The crude product is taken up in methanol and with acidic ion exchange resin (Dowex WX2-200) min about 20. shaken. The loaded ion exchanger. Three times with 30 ml of methanol, then with water / methanol 8:2, again with methanol, dichloromethane, and finally washed with methanol The product is eluted with methanol / triethylamine 95:5. The solvent is removed under reduced pressure on a rotary evaporator. 52 mg can be isolated (58% of theory) of the title compound. 

1H NMR (400 MHz, methanol-d_4): δ = 7.35 (d, IH), 7.32 (s, IH), 6.97 (d, IH), 6.89

(Dd, 3H), 4:24 to 4:18 (m, IH), 3:34 to 3:29 (m, IH), 3.07-2.97 (m, IH), 2.93-2.77 (m, 4H), 2:13 to 2:05 (m, IH) , 1.98-1.86 (m, IH), 1.84-1.75 (m, 2H), 1.63-1.53 ​​(m, IH) ppm. 

MS (ESIpos): m / z = 286 (M + H) ⁺ (free base) 

LC-MS (Method D): R _t = 2.02 min, m / z = 286 (M + H) ⁺ (free base).

http://www.google.com/patents/EP1461335A1?cl=en

(2-chloro-3-nitrophenyl) methanol

(2-chloro-3-nitrophenyl) methanol

10.0 g (49.61 mmol) of 2-chloro-3-nitrobenzoic acid in 50 ml of THF. While cooling in ice mixed with 104 ml of 1 M borane-THF complex and allowed to stir overnight at room temperature. At 0 ° C is carefully hydrolyzed with water. After completion evolution of gas with 500 ml of water is diluted, and the aqueous phase extracted three times with a total of 500 ml ethyl acetate. The organic phase is washed with saturated saline solution and dried over magnesium sulfate. Finally the solvent is removed under reduced pressure on a rotary evaporator. There are obtained 9.20 g (98% of theory) of the title compound.

 Η-NMR (300 MHz, DMSO-d _6): δ = 7.89 (m, 2H), 7.62 (t, IH), (t, IH), 5.70, 4.67 (d, 2H).

HPLC: R _t = 3.53 min (Method H) MS (ESIpos): ⁺ m / z = 205 (M + NH ₄₎

http://www.google.com/patents/EP1461335A1?cl=en









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7-methoxy-1-benzothiophene-2-carboxylic acid methyl ester

7-methoxy-1-benzothiophene-2-carboxylic acid methyl ester

To a solution of 600 mg (3.31 mmol) of 3-methoxy-2-nitrobenzaldehyde in 8 ml of DMF 550 mg (3.97 mmol) of potassium carbonate and 350 mg (3.31 mmol)

Mercaptoacetate added. The reaction mixture is heated for 4 h at 70 ° C. After cooling water is added. The resulting precipitate is filtered, washed with water and dried in vacuo. Obtained 387 mg (45.7% of theory) of the title compound. 

1H NMR (200 MHz, DMSO-d _6): δ = 8.21 (s, IH), 7.63 (d, IH), 7.46 (dd, IH), 7.11 (d, IH), 

3.98 (s, 3H), 

3.89 (s, 3H) ppm. 

MS (ESIpos): m / z = 240 (M + NH ₄₎ ⁺
http://www.google.com/patents/EP1461335A1?cl=en

Methyl thieno [2,3-f] [l, 3] benzodioxole-6-carboxylate

Methyl thieno [2,3-f] [l, 3] benzodioxole-6-carboxylate

Starting from 3.0 g (13.1 mmol) 6-Brompiperonal with 0.79 g (19.7 mmol) of sodium hydride (60% strength) and 1.53 g (14.4 mmol) mercaptoacetate 732 mg (18.5% o of theory) of the title compound.

1H NMR (200 MHz, DMSO-d _6):

 δ = 8.03 (s, IH), 

7.62 (s, IH), 

7.48 (s, IH), 

6.14 (s, 2H), 

3.86 (s, 3H) ppm 

.

HPLC: R _t = 4.6 min (Method H) 

MS (ESIpos): ⁺ m / z = 237 (M + H)


http://www.google.com/patents/EP1461335A1?cl=en