Byakangelicin

C18H20O7, 348.00

IR

(KBr) 1728, 1617, 1479, 1143

MASS

FABMS m/z 349 [M + H]+

1H NMR

(300 MHz, CDCL3) δ : 1.26 (3H, s, H-4"), 1.29 (3H, s, H-5"), 3.81 (1H, m, H-2"), 4.16 (OCH3), 4.23 (1H, dd, J = 7.9, 10.1 Hz, H-1b"), 4.57 (1H, dd, J= 2.7, 10.1 Hz, H-1a"), 6.27 (1H, d, J = 9.7 Hz, H-3), 6.99 (1H, d, J = 2.4 Hz, H-3'), 7.61 (1H, d, J = 2.4 Hz, H-4'), 8.10 (1H, d, J = 9.7 Hz, H-4)

13 C NMR

(75 MHz, CDCL3) 

δ : 24.99 (C-4"), 

26.62 (C-5"), 

60.61 (OCH3), 

71.50 (C-3"), 

75.91 (C-2"), 

76.04 (C-1"),

105.34 (C-3'), 

107.32 (C-10),

112.70 (C-3), 

114.39 (C-6), 

126.67 (C-8), 

139.58 (C-4), 

143.77 (C-9),

144.80 (C-5), 

145.21 (C-2'), 

150.09 (C-7), 

160.33 (C-2)

Tricyclo[3.3.1.13,7]decan-1-amine hydrochloride

Tricyclo[3.3.1.13,7]decan-1-amine hydrochloride


A solution of acetamide (0.97 g, 5.0 mmol) in dry THF (15 mL) was treated with
pyridine (0.485 mL, 6.00 mmol) and cooled to 0 °C. Dropwise addition of oxalyl
chloride (0.480 mL, 5.50 mmol) was accompanied by vigorous bubbling and conversion
of the clear, colorless solution to a bright yellow and then turbid orange solution. After
stirring at 0 °C for 30 min., dry propylene glycol (0.73 mL, 10.0 mmol) was added in one
portion and the reaction warmed to room temperature.
During this warming phase, the solution changed, first turning orange brown before lightening to yellow. The reaction was diluted with ethanol before being concentrated to an orange brown oil. The oil was
partitioned between 1 N HCl (10 mL) and MtBE (10 mL) and the organic layer washed
with 1 N HCl (2 x 5 mL). The combined aqueous layers were basified with 4 N NaOH to
pH 11, extracted with EtOAc (3 x 40 mL), dried over Na2SO4, filtered, and concentrated
in vacuo.
The oily residue was suspended in Et2O (8 mL) and treated with 1 M HCl in
Et2O (8 mL). This addition formed a lightly colored slurry which was filtered and
washed with Et2O. After drying under vacuum at 50oC for 16 h, 0.66 g of an off-white solid was recovered
decomp. >330 °C.

1H NMR (400 MHz, DMSO-d6)
δ 8.06 (br s, 3H),
2.06 (br s, 3H),
1.77 (m, 6H),
1.59 (m, 6H).





13C NMR (100 MHz, DMSO-d6)
δ 50.8,
40.1,
35.1,
28.2.





 Substance data agrees with previously reported information.8

PHENYLMETHANAMIE HYDROCHLORIDE

\
1H NMR

δ 8.61 (br s, 3H), 
7.51 (m, 2H), 
7.35 (m, 3H), 
3.97 (s, 2H). NH-CH2

13 C NMR

13C NMR (100 MHz, DMSO-d6) 

δ 134.1, 
128.9, 
128.4, 
128.3, 
42.0.  NH-CH2

Dasotraline, 1R,4S Transnorsertraline, SEP-225289

Dasotraline,  SEP-225289, DSP-225289  

1R,4S Transnorsertraline

Generic Name:Dasotraline
Synonym: SEP-225289
Chemical Name:(1R,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-amine

4(S)-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1(R)-ylamine hydrochloride
CAS Number:675126-05-3, Cas of THE DRUG SUBSTANCE hydrochloride is 675126-08-6
Indication:Attention deficit hyperactivity disorder (ADHD)
Drug Company:Sunovion Pharmaceuticals. Inc. in phase 2 as on sept 2014, Sunovion Pharmaceuticals Inc.

SEE

http://newdrugapprovals.org/2014/09/19/dasotraline-1r4s-transnorsertraline-sep-225289-for-treatment-of-attention-deficit-hyperactivity-disorder-adhd/

PRONUNCIATION da soe tra’ leen
THERAPEUTIC CLAIM Treatment of attention deficit hyperactivity
disorder (ADHD)
CHEMICAL NAMES
1. 1-Naphthalenamine, 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-, (1R,4S)-
2. (1R,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-amine

MOLECULAR FORMULA C16H15Cl2N
MOLECULAR WEIGHT 292.2

SPONSOR Sunovion Pharmaceuticals. Inc.
CODE DESIGNATION SEP-225289
CAS REGISTRY NUMBER 675126-05-3
UNII 4D28EY0L5T
WHO NUMBER 9885

Koenig, Stefan G.; Vandenbossche, Charles P.; Zhao, Hang; Mousaw, Patrick; Singh, Surendra P.; Bakale, Roger P.
Organic Letters, 2009 ,  vol. 11,  2  pG . 433 - 436

http://pubs.acs.org/doi/abs/10.1021/ol802482d

Imidoyl chlorides, generated from secondary acetamides and oxalyl chloride, can be harnessed for a selective and practical deprotection sequence. Treatment of these intermediates with 2 equiv of propylene glycol and warming enables the rapid release of amine hydrochloride salts in good yields. Notably, the reaction conditions are mild enough to allow for a swift deprotection with no observed epimerization of the amino center.

Supporting Information             A Facile Deprotection of Secondary Acetamides

•      PDF
  • ol802482d_si_001.pdf (913.61 kB)

http://pubs.acs.org/doi/suppl/10.1021/ol802482d/suppl_file/ol802482d_si_001.pdf

(1R,4S)-4-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-amine hydrochloride – Compound 1, Scheme 1 / Table 3, entry 1A:

decomp. > 290 °C.

1H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 3H), 7.71 (d, 1H, J = 7.7 Hz), 7.53 (d, 1H, J = 8.1 Hz), 7.34 (s, 1H), 
7.29 (m, 1H), 7.22 (m, 1H), 7.01 (d, 1H, J = 8.1 Hz), 6.81 (d, 1H, J = 7.7 Hz), 4.56 (s, 
1H), 4.26 (s, 1H), 2.26 (m, 1H), 2.15 (m, 1H), 1.83 (m, 2H).

13C NMR (100 MHz, DMSO-d6) δ 147.3, 138.8, 133.5, 130.9, 130.5, 130.4, 130.0, 128.9, 128.8, 128.3, 128.1, 
126.7, 47.8, 43.0, 27.7, 25.1.

NMR  GRAPHS GIVEN

 

13 C NMR

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.