(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

IMATINIB

Imatinib

CAS No:- [152459-95-5]

IUPAC Name:- 4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]benzamide

M. P.:- 211-213 °C

MW: 493.604

4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide

-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide

N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)-4-((4-methylpiperazin-1-
yl)methyl)benzamide

IMATINIB BASE

http://www.rsc.org/suppdata/cc/c0/c001550d/c001550d.pdf

Mp 206 – 207 °C (lit.:1   207 – 210 °C);

1=  1 Y.‐F. Liu, C.‐L. Wang, Y.‐J. Bai, N. Han, J.‐P. Jiao and X.‐L. Qi, Org. Process Res. Dev., 2008, 12, 490.

 

IR νmax/cm-1 3275.0(w), 2928.5(w),
2796.5(w), 1645.9(m), 1586.0(m), 1575.1(s), 1554.0(m), 1531.5(s), 1510.3(m), 1478.1(m),
1448.9(s), 1416.7(m), 1377.7(m), 1352.2(m), 1334.8(m), 1325.6(m), 1308.8(m), 1290.3(s),
1261.1(m), 1204.3(m), 1164.1(m), 1141.7(m), 1124.6(w), 1102.6(m), 1089.2(w), 1052.0(w),
1024.4(w), 1010.0(m), 992.5(w), 968.3(w), 924.5(w), 886.2(w), 857.9(w), 850.3(w),
807.8(m), 795.7(s), 748.1(m), 703.2(m), 690.1(m), 670.7(m);

δH (d6-DMSO, 600 MHz) =
10.14 (1 H, s, NH), 9.26 (1 H, d, J = 1.5 Hz, 2H-pyridin-3-yl), 8.95 (1 H, s, NH), 8.66 (1 H, dd,
J = 4.8 and 1.2 Hz, 6H-pyridin-3-yl), 8.49 (1 H, d, J = 5.1 Hz, 6H-pyridin-2-amine), 8.46 (1 H,
ddd, J = 7.9, 1.5 and 1.2 Hz, 4H-pyridin-3-yl), 8.06 (1 H, d, J = 1.5 Hz, 3H-2-aminotoluene),
7.89 (2 H, d, J = 8.1 Hz, 2H-benzamide), 7.50 (1 H, dd, J = 7.9 and 4.8 Hz, 5H-pyridin-3-yl),
7.46 (1 H, dd, J = 8.3 and 1.5 Hz, 5H-2-aminotoluene), 7.42 – 7.40 (3 H, m, 3H-benzamide
and 5H-pyridin-2-amine), 7.18 (1 H, d, J = 8.3 Hz, 6H-2-aminotoluene), 3.51 (2 H, s, CH2),
2.50 - 2.20 (8 H, m, piperazine CH2), 2.20 (3 H, s, CCH3), 2.13 (3 H, s, NCH3);

δC (CDCl3,
150 MHz) = 165.42(C), 162.72(C), 160.57(C), 158.99(CH), 151.44(CH), 148.48(CH),
142.52(C), 137.77(C), 136.60(C), 134.92(CH), 133.88(C), 132.66(C), 130.75(CH),
129.28(CH), 127.00(CH), 124.23(C), 123.71(CH), 115.35(CH), 113.19(CH), 108.32(CH),
62.49(CH2), 55.07(CH2), 53.10(CH2), 45.98(CH3), 17.65(CH3);

Rf (MeOH) = 0.09; Rt 3.48,

M+H m/z = 494.2; HRMS calculated for C29H31N7ONa [M + Na]+, 516.2488; found 516.2491.

1H NMR

13 C NMR

REPEAT

1H NMR

13 C NMR

Encenicline (EVP-6124, MT-4666)

EVP-6124 , MT-4666, α7-nAChR agonist
Chemical Name: (R)-7-chloro-N-quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide
Therapy Type: Small Molecule
Target Type: Cholinergic System
CAS : 550999-75-2

C₁₆ H₁₇ Cl N₂ O S

Benzo[b]​thiophene-​2-​carboxamide, N-​(3R)​-​1-​azabicyclo[2.2.2]​oct-​3-​yl-​7-​chloro-

(R)​-​7-​Chloro-​N-​(quinuclidin-​3-​yl)​benzo[b]​thiophene-​2-​carboxamide; EVP 6124

Condition(s): Alzheimer’s Disease, Schizophrenia
U.S. FDA Status: Alzheimer’s Disease (Phase 3), Schizophrenia (Phase 3)
Status in Select Countries: Investigational in Japan
Company: FORUM Pharmaceuticals Inc. (was EnVivo Pharmaceuticals), Mitsubishi Tanabe Pharma
Approved for: None  AS ON SEPT 2014



CAS  550999-74-1
Benzo[b]​thiophene-​2-​carboxamide, N-​(3R)​-​1-​azabicyclo[2.2.2]​oct-​3-​yl-​7-​chloro-​, monohydrochloride
(R)​-​7-​Chloro-​N-​(quinuclidin-​3-​yl)​benzo[b]​thiophene-​2-​carboxamide hydrochloride
Mitsubishi Tanabe Pharma  ..Encenicline-hydrochloride (EVP-6124) for Alzheimer’s disease by partner EnVivo Pharmaceuticals. Mitsubishi Tanabe has licensed EVP-6124 from EnVivo and is currently developing the drug under the code MT-4666.
The drug is a new alpha-7 potentiator intended to improve cognition in patients affected with Alzheimer’s disease. T


http://www.google.com.ar/patents/WO2014051055A1?cl=pt-PT
Synthesis (hereinafter, the compound of Reference Example 25) carboxamide hydrochloride (Reference Example 25) (R) -7 – chloro-N-(quinuclidin-3 – – yl) benzo [b] thiophene-2:
[First Step]
Synthesis of carboxamide (R) -7 – chloro-N-(quinuclidin-3 – – yl) benzo [b] thiophene-2:

-N, N, N ‘, N’-tetra-7 – chloro-1 – benzothiophene -2 – – o-(yl benzotriazol-1) chloroform solution (210mg, 1.0mmol) of carboxylic acid in (10mL) was added (0.70mL, 4.0mmol) and (570mg, 1.5mmol), diisopropylethylamine methyl hexafluorophosphate, (R) – (200mg, 1.0mmol) amine hydrochloride – quinuclidine-3 was added, and the mixture was stirred at room temperature. 16 hours later, was added distilled water, 1.0N sodium hydroxide solution, and extracted with chloroform. Was washed with saturated brine and the organic layer was concentrated and then dried over anhydrous sodium sulfate. (Fuji Silysia Chemical amine silica gel DM1020, chloroform alone – chloroform / methanol = 90/10) on silica gel column chromatography of the crude product obtained was purified by the title compound; was obtained as a white solid (170mg 53%).
¹ _H-NMR (400MHz, _DMSO-d 6)
δ :1.22-1 .38 (1H, m) ,1.53-1 .62 (2H, m) ,1.75-1 .82 (2H, m) ,2.63-2 .73 (4H , m) ,2.84-2 .94 (1H, m) ,3.07-3 .18 (1H, m) ,3.90-4 .00 (1H, m), 7.49 (1H, dd , J = 7.6,8.0 Hz), 7.59 (1H, d, J = 7.6Hz), 7.96 (1H, d, J = 8.0Hz), 8.31 (1H, s) ,8.62-8 .66 (1H, m).
MS (ESI): 321 [M ^{+ H]} +
[Second Step]
Synthesis of the compound of Reference Example 25:

Ethyl acetate solution – solution of hydrogen chloride in ethyl acetate (170mg, 0.53mmol) of the (2.0mL) carboxamide – (R) -7 – chloro-N-(quinuclidin-3 – yl) benzo [b] thiophene-2 was added (4.0M, 0.20mL, 0.80mmol), and the mixture was stirred at room temperature. 10 minutes later, by which is filtered off and the resulting solid was washed with ethyl acetate and hexane, and dried, the compound of Reference Example 25; was obtained as a white solid (170mg 90%).
¹ _H-NMR (400MHz, _DMSO-d 6)
δ :1.70-1 .78 (1H, m) ,1.86-1 .94 (2H, m) ,2.10-2 .19 (2H, m) ,3.18-3 .35 (5H , m) ,3.63-3 .72 (1H, m) ,4.27-4 .36 (1H, m), 7.50 (1H, d, J = 7.6,8.0 Hz), 7 .61 (1H, d, J = 7.6Hz), 7.98 (1H, d, J = 8.0Hz), 8.38 (1H, s) ,9.07-9 .10 (1H, m) ,9.80-9 .85 (1H, m).
MS (ESI): 321 [M ^{+ H]} +

SEE
 http://newdrugapprovals.org/2014/09/16/mitsubishi-tanabe-and-envivo-in-phase-iii-trial-of-alzheimers-disease-treatment-mt-4666/